pseudo dementia case study

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• Volume 36, Issue 4
• What do we know about pseudodementia?
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• http://orcid.org/0000-0002-0480-0262 Salomé Mouta 1 ,
• Isabel Fonseca Vaz 1 ,
• Miguel Pires 1 ,
• Sara Ramos 2 and
• Diana Figueiredo 1
• 1 Departamento de Psiquiatria e Saúde Mental , Unidade Local de Saude da Guarda EPE , Guarda , Portugal
• 2 Departamento de Saúde Mental , Unidade Local de Saúde de Matosinhos EPE , Matosinhos , Portugal
• Correspondence to Dr Salomé Mouta; salomemouta{at}gmail.com

Depression and dementia can lead to generalised cognitive and memory dysfunction. Thus, differentiating these disorders is important and challenging. Pseudodementia is a term used clinically to describe symptoms that resemble dementia but are caused by other conditions (most frequently depression), rather than being recognised as an official diagnosis. Pseudodementia is characterised by a cognitive impairment that mimics dementia but which does not have its origin in neurological degeneration, deriving instead from functional psychiatric conditions. This condition is more commonly observed in older adults (particularly those over the age of 50 or 60 years), and its risk factors overlap with those for depression. Pseudodementia is essentially characterised by deficits in memory, executive function and speech and, therefore, can easily be confused with dementia, although there are aspects that allow its differentiation. Diagnosing pseudodementia can be difficult, especially as there is significant overlap between its symptoms and those of other conditions. However, it is important to recognise characteristic aspects of this disorder, as its correct identification is essential for proper treatment.

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https://doi.org/10.1136/gpsych-2022-100939

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Introduction

The connection between depression and dementia arises from two key factors: first, cognitive impairments can be observed in depression, and second, dementia may also present with depressive symptoms.

When assessing a patient displaying signs of cognitive decline, various reversible factors must be ruled out before confirming a neurodegenerative condition. Among the well-recognised factors to consider, depression holds significant importance as it can substantially harm cognition, particularly among older individuals. In severe cases, depression may even be mistaken for neurodegenerative conditions. Historically, this phenomenon is known as ‘pseudodementia’. 1 2

Depression is a mental disorder that includes a depressed mood that lasts for at least 2 weeks, accompanied by loss of interest or pleasure in nearly all activities, feelings of guilt or suicide, social isolation and sleep and appetite disturbances. 1 3

Depressive symptoms are estimated to occur in many older individuals, with 1%–5% of older people living in the community meeting criteria for major depression. 4 Thus, geriatric depression is a common problem, with some epidemiological studies suggesting that a significant part of the older population exhibits prominent affective symptoms. 5

Certain symptoms of depressive disorders tend to be more pronounced among older adults. Post 6 had already reported in 1962 that one-third of older patients with depression had severe psychomotor retardation or agitation, and a recent meta-analysis confirmed these findings. 7 8 It also reported that hypochondria and somatic symptoms were more common in older adults, whereas guilt and loss of libido were less common than in younger adults. 7 8

The development of depressive disorders in geriatric individuals shares a broad aetiology with similar disorders occurring at younger ages, where biological, psychological and social factors all play significant roles. Studies have shown a genetic contribution comparable to that of depression occurring at a younger age. 9 10

Loneliness and the difficulties of old age can be expected to be important contributing factors. However, the main difference in the aetiology of depression in the elderly is related to vascular factors. There is evidence for a multifaceted and bidirectional relationship between geriatric depression and vascular diseases. Studies show that diabetes, stroke and an elevated vascular risk score are all significant risk factors for depression in older adults, but curiously, hypertension, smoking and dyslipidaemia are not. 11 Proposed biological mechanisms include the frequently seen white matter changes in the magnetic resonance imaging (MRI) of geriatric patients with depression, which reflect focal areas of ischaemia and infarction, with effects on brain connectivity. 11 In addition, inflammation is also considered a contributory factor. 11

Furthermore, depression often co-occurs with a wide range of medical conditions, including Alzheimer’s disease (AD), stroke and Parkinson’s disease, making the diagnosis of these diseases difficult and exacerbating the functional decline associated with each one. 12–14

Since this work represents a narrative review, the authors carried out a non-systematic review of the existing literature. We conducted a search in the PubMed database using the following Medical Subject Headings words as search terms: “pseudodementia”, “cognition”, “memory” and “depression”. Simultaneously, the authors conducted a manual search in other relevant and reliable sources (books and scientific websites).

Non-standardised inclusion and exclusion criteria were used. Search criteria were limited to articles published in English or Portuguese until May 2023. Relevant bibliographical sources were selected only if they focused on information relevant to the review, and which covered the topics the authors intended to address (definition, history, epidemiology, characteristics, causes and risks factors, diagnosis and differential diagnosis, treatment and prognosis).

The included articles (n=35) were online articles, book chapters, meta-analysis, reviews, retrospective studies, prospective cohort studies, cross-sectional studies and original research. These articles were reviewed, and relevant data were extracted to report the key findings.

Pseudodementia

The term “pseudodementia” is a popular clinical concept, although unaccepted as an independent nosological category in any classification system. 7 15–17 Pseudodementia describes various functional psychiatric conditions, with depression being the most prevalent. These conditions can simulate organic dementia but typically show the potential for reversal with appropriate treatment. 1 2 7 18

Individuals with moderate-to-severe depressive disorders frequently develop a broad decline in cognitive functioning in association with attention deficit and psychomotor retardation. These patients may also struggle with clear thinking, concentration difficulties, decision-making challenges, notable forgetfulness and problems with reasoning. 19–21

Both depression and dementia can lead to reduced motivation, impaired concentration and retardation, and, consequently, both can lead to generalised cognitive and memory dysfunctions.

Therefore, differentiating this diagnosis from dementia is important but challenging. The distinction is further complicated by the evidence that depressive pseudodementia is a strong predictor of subsequent dementia. 22

The term “pseudodementia” was initially introduced in 1961 by psychiatrist Leslie Kiloh. Kiloh observed that patients exhibiting cognitive symptoms resembling those found in individuals with dementia showed a potential for the reversal of deficits. The cognitive decline in these cases was actually due to mental health conditions rather than central nervous system disorders, and Kiloh pointed out the potential reversibility of cognitive impairment in many of these cases, making his article significant at a time when dementia was considered a condition that could not be reversed. 7 8 18 23 24

Uncertainties surrounding the classification and attributes of pseudodementia, as well as concerns regarding its misleading name, have prompted suggestions to discontinue its usage. Certain professionals and experts in the field advocate against continuing to employ this term due to the absence of distinct and objective diagnostic criteria, as well as the potential for the prefix ‘pseudo’ to inaccurately imply the cognitive deficits are not real. However, others defend its practicality and usefulness as it has held up well in clinical practice and highlights those patients who may have a treatable condition. 8

Epidemiology

There are few studies on the prevalence of pseudodementia. Ferran et al 25 found that pseudodementia accounted for 18% of referrals to a presenile dementia service, but it was not diagnosed by the majority of referrers. 15

Rabins 26 studied rates of reversible dementia in a group of patients admitted to a psychiatric hospital and found that the annual incidence among patients with dementia referred to psychiatric services was approximately 41%.

Estimates suggest that between 2% and 32% of older adults with cognitive problems actually have pseudodementia. 1

Presentation/Characteristics

Depression in old age is clinically heterogeneous, and the severity of depressive symptoms does not directly relate to the level of cognitive impairment. Despite the heterogeneity, there are some distinctive neurocognitive and behavioural changes that appear to be attributable to geriatric depression and that are characteristic of a large group of patients who do not have neurological disease. 27

Pseudodementia typically encompasses memory issues, impairments in executive functioning and speech deficits. Notable cognitive symptoms may include difficulties in remembering words or remembering things in general, reduced attention and concentration, challenges in task completion or decision-making, decreased speech fluency and speed and impaired processing speed. Individuals with pseudodementia commonly experience significant distress due to the cognitive impairments they encounter. 1 7 28

Key symptoms of pseudodementia comprise speech impairments, memory lapses or deficits, attention difficulties, emotional regulation challenges and problems with organisation or task planning. Remarkably, these symptoms are also highly prevalent among individuals with dementia. Consequently, doctors may often lean towards diagnosing and treating individuals exhibiting these symptoms as if they have dementia. 1 7 16

In addition, cognitive tasks that require sustained effort and elaborate cognitive processing may be more affected in depression than tasks that can be accomplished more automatically.

As pseudodementia is often linked to depression, the person may also experience symptoms that include depressed mood, fatigue or anergy, insomnia or hypersomnia, anhedonia, anorexia or hyperphagia and suicidal thoughts or behaviours. 3

Memory deficits

It is now generally accepted that depression presents with a series of deficits in the domains of episodic memory and learning.

Both explicit verbal and visual memory functions exhibit deficits in individuals with both melancholic (endogenous) and non-melancholic (non-endogenous) depression. Nevertheless, these patients demonstrate intact performance on implicit memory tasks, and certain other memory functions appear to remain unaffected. 28 29

The neurobiological underpinnings of these memory deficits remain uncertain. Temporal lobe lesions are known to result in episodic memory deficits. Furthermore, reductions in hippocampal volume are found in patients with major depression. These findings may point to a temporal lobe deficit as the reason for cognitive decline. 28 30

However, most researchers suggest that such deficits may be primarily due to attention problems and not due to structural problems. 29

Executive function deficits

Depressive disorders commonly exhibit executive function deficits with clinically significant impact, potentially serving as a mediator of the functional impairment experienced by patients. Among the executive functions, task switching skills and attentional focus were found to be particularly affected in patients with depression. 28 29 31

Older individuals with depression experience executive function deficits, although to a lesser extent compared with patients with AD. 29

Another significant deficit is impaired processing speed, which presents clinically as psychomotor retardation. 29

On remission of the depressive episode, improvements were observed in the domains of visual learning ability, spatial recognition memory, psychomotor speed and executive function. 29

Speech and language function deficits

In measures of naming, repetition, general reading ability, syntax and auditory verbal comprehension, patients with depression exhibited superior performance compared with patients with AD. At the same time, healthy individuals tended to perform better than patients with depression in general, although these differences were considerably less obvious than those observed between patients with depression and patients with AD. 29

It is also important to highlight other points mentioned in the studies, namely 29 :

The assessment of neuropsychological functions in older individuals with depression has revealed evidence of a subtle decline in ‘right hemisphere skills’ (eg, performance intelligence quotient, visual construction ability, non-verbal visual memory).

In formal neuropsychological tests, these patients show deficits in tests sensitive to frontal lobe function.

Hence, the cognitive score pattern indicating dysfunction in the right hemisphere and anterior cerebral regions align with findings from certain studies demonstrating reduced regional cerebral blood flow in the right hemisphere and bilateral frontal lobe in individuals with depression.

Causes and risk factors

Mood-related disorders, including depression, are among the possible causes of pseudodementia. However, they are not the sole contributors. Other mental health conditions such as schizophrenia, other psychoses, dissociative disorder, conversion disorder and mania can also lead to cognitive impairment and manifest in a similar clinical condition. These disorders may cause additional typical symptoms, concomitant with apparent symptoms of dementia. 1 2 7 18

The risk factors for pseudodementia are very similar to those for depression. Among them is gender—with women being statistically more likely to develop depression—family history, divorce and lower socioeconomic status. 16

Certain researchers propose that pseudodementia may arise when a mood-related disorder develops in a brain that is already somewhat compromised due to the effects of ageing. 16

Diagnosis and differential diagnosis

Diagnosing pseudodementia in older adults poses challenges due to several factors.

First, the ageing process itself brings about cognitive and brain function changes, making it challenging to distinguish between age-related changes and initial indications of depression or dementia. Second, diagnosing pseudodementia becomes more complex as symptoms of depression and various progressive neurological conditions frequently overlap in older individuals. Lastly, it is entirely possible for an individual to concurrently experience both genuine dementia and depression, further adding to the complexity of diagnosis. 12–14 16 18 28 32

Due to the complexities involved, diagnosing pseudodementia often requires a thorough and comprehensive evaluation. Medical professionals prioritise ruling out dementia and other cognitive issues before exploring alternative potential causes. This meticulous approach may take some time to ensure an accurate diagnosis.

Distinguishing between depression and other conditions in older adults is supported by careful screening of both depressive symptoms and cognitive status, which may be complemented by a neuropsychological assessment that provides information regarding the nature of cognitive impairments and current patient status for future comparisons (baseline). The information is useful in diagnosis and management. 1 17

A diagnosis of depression rather than dementia is first considered when there are symptoms such as delirium of ruin, high levels of anxiety, significant hypochondriacal worries and a previous depressive episode. However, individuals with depression may express concerns regarding memory problems and experience distress related to this. When assessed using neuropsychological tests, they typically demonstrate satisfactory performance in memory-related tasks. On the other hand, individuals with dementia often deny having memory problems or minimise their importance, and show impairment in neuropsychological tests. 1 18 23 28

Obtaining an accurate diagnosis is crucial for individuals experiencing cognitive problems as certain causes are reversible. Cardoso et al 28 warn that several situations can lead to cognitive deficits, making it essential to collect a complete clinical history and to assess the baseline functional status of the patient. This review also emphasises that a neurological examination should always be performed, as well as excluding the main organic causes of cognitive impairment. 28

For instance, comorbidities such as vascular, infectious, traumatic, autoimmune, idiopathic and even malnutrition-related conditions can present symptoms that resemble dementia. Prime examples are individuals with chronic vitamin B 12 deficiency or hypothyroidism that may exhibit dementia-like symptoms. Thus, underlying conditions or deficiencies should be routinely excluded through an analytical study. 2 28

Imaging tests also aid the diagnosis of pseudodementia, as they provide clues to the underlying causes or show the effects of degeneration on the brain in the case of dementia. 2 28 32 MRI shows changes such as atrophy of the medial temporal lobe in people with AD, whereas positron emission tomography and single-photon emission computed tomography (CT) images of the brain show reduced blood flow in some areas. 23 32 33

Lastly, certain forms of dementia, such as AD and Parkinson’s disease, share mood-related symptoms that resemble those seen in depression. 29

The Geriatric Depression Scale (GDS) is frequently employed as a tool to assist in distinguishing between pseudodementia and other types of dementia. The results from the GDS are combined with additional patient information regarding their history and current functioning, aiding in the diagnostic process. People with pseudodementia are likely to score high on the GDS—this reflects that the patient is depressed. 1 16 18 32 34

The short version of this scale ( box 1 ) when applied in a consultation context can be useful, more practical and less exhaustive.

Short version of the Geriatric Depression Scale 38

The patient must choose the answer that best applies to the last week.

Are you satisfied with your life? YES/ NO

Have you abandoned many of your activities and interests? YES /NO

Do you feel that your life is empty? YES /NO

Do you often get bored? YES /NO

Are you in a good mood most of the time? YES/ NO

Are you afraid that something bad will happen to you? YES /NO

Do you feel happy most of the time? YES/ NO

Do you often feel hopeless? YES /NO

Do you prefer to stay at home instead of going out and doing new things? YES /NO

Do you feel that you have more memory problems than most? YES /NO

Do you think it is wonderful to be alive now? YES/ NO

Do you feel very useless the way you are now? YES /NO

Do you feel full of energy? YES/ NO

Do you feel that your situation is hopeless/insoluble? YES /NO

Do you think most people are better than you? YES /NO

Answers in bold indicate signs of depression. One point is given for each answer in bold.

A score >5 points is suggestive of depression.

A score ≥10 points is almost always indicative of depression.

A score >5 points should justify a follow-up assessment.

The factors that can help us to differentiate between pseudodementia and dementia are presented in table 1 .

• View inline

Features that help distinguish between dementia and pseudodementia 2 18 23 28 32 33 39

Pseudo-pseudodementia

With regard to the differential diagnosis, it is important to be aware of another entity: pseudo-pseudodementia.

A notable limitation in much of the existing research on pseudodementia is the lack of thorough screening for organic dementia, making it challenging to exclude individuals with pre-existing neurodegenerative diseases. This brings attention to another potential scenario where neurodegenerative diseases are misdiagnosed as psychiatric disorders, a possibility acknowledged by Kiloh. 8 This scenario can be seen as the reverse of pseudodementia, where organic dementia disguises itself as a purely psychiatric condition. Due to the resemblance to pseudodementia, this condition has occasionally been referred to as ‘pseudo-pseudodementia’. 7

While it is important to note that the term does not aim to supplant existing diagnoses, its purpose is to draw attention to a clinical scenario in which psychiatric symptoms appear consistent with a primary psychiatric disorder, potentially leading to misinterpretation and obscuring the true underlying diagnosis of a neurodegenerative disease.

This phenomenon appears to be relatively common, as evidenced by a study that reported approximately 28% of patients with neurodegenerative diseases receiving an initial psychiatric diagnosis during the period between symptom onset and the ultimate diagnosis. Individuals with the behavioural variant of frontotemporal dementia seem to be particularly susceptible, with 51% of them receiving a preceding psychiatric diagnosis, in contrast to 23% of those diagnosed with Alzheimer’s dementia. For both groups, the most common psychiatric diagnosis given was depression, followed, in the case of frontotemporal dementia, by bipolar disorder and schizophrenia. 7

The frequency of these errors highlights the challenges involved in recognising the correct diagnosis.

An article published in 2020 proposes that pseudo-pseudodementia serves as a valuable concept that acknowledges the intricacies beyond the conventional dementia-pseudodementia dichotomy. It highlights the difficulties in distinguishing between pseudodementia and pseudo-pseudodementia and determining whether psychiatric symptoms mimic or result from neurodegeneration. 7

Comorbid dementia and depression

The incidence of depression may be 30% in vascular dementia and in AD, and over 40% in Parkinson’s disease dementia and Huntington’s disease dementia. 27 A study published in 2023 shows that depression is a comorbidity often associated with dementia and also that depression increases the risk of dementia. 13 People with any type of dementia have a high incidence of major depression, particularly if they have vascular dementia or Parkinson’s disease dementia—these patients often have more insight and awareness of their condition than people with AD. 11 13 27–29 However, there is some disagreement on this point. For example, the conclusions of a study from 2022 cast doubt on the frequency of depressive pseudodementia disorder in older populations with documented depression and memory impairments. 24

Due to the similarities in symptoms between dementia and depression, it can be challenging to ascertain whether an individual living with dementia is also experiencing depression. Some revealing signs include loss of interest and pleasure in activities the person usually enjoys, social isolation, lack of energy, negativity, hopelessness or even nihilistic feelings of worthlessness or sadness, ideas of guilt and self-harm and increased confusion. 34 35

Furthermore, when people with dementia develop depression, their overall cognitive ability may decline significantly, with worsening of memory and concentration symptoms. 12 34 35

The treatment of pseudodementia can be a time-consuming and individualised process, as various individuals may respond differently to various treatment options.

Once other potential diagnoses have been ruled out and pseudodementia is suspected, the recommended treatment will primarily concentrate on addressing the underlying cause. This often entails treating the underlying depression that triggered the symptoms. Treatment for depression can vary by individual, but typically should involve a combination of psychotherapy and antidepressant medication. 1 2

Providing appropriate medical treatment for depression can potentially aid in differentiating between pseudodementia and dementia. Effective treatment with antidepressants may help alleviate the cognitive dysfunction associated with depression, leading to an improvement in cognitive symptoms. In contrast, the cognitive dysfunction associated with dementia typically persists and progresses over time. By observing the response to antidepressant treatment, a distinction can be made between the reversible cognitive impairment of pseudodementia and the progressive cognitive decline of dementia. 7

Pharmacological intervention

When it comes to antidepressants, vortioxetine is a drug approved by the Food and Drug Administration in 2013 for major depressive disorder that is similar to a selective serotonin reuptake inhibitor, and it has emerged as a promising potential treatment for the cognitive symptoms of depression. Preclinical animal studies and extensive randomised controlled trials have demonstrated that vortioxetine can notably enhance cognition in patients with depression who have achieved remission, independent of its antidepressant properties. Clinical trials have revealed significant enhancements in working memory, processing speed, executive function and attention among individuals treated with this medication. 35 MRI studies have shown that vortioxetine modulates a brain circuit involved in the working memory. They have also shown that it stimulates the growth of dendritic spines and synaptic connections in vitro and stimulates gene expression of factors involved in neuroplasticity. These findings suggest a possible biological mechanism underlying vortioxetine’s procognitive effect in patients with depression and healthy controls. 21 23 36

Non-pharmacological interventions

It should be noted that, in cases where antidepressant therapy is not well tolerated or is ineffective, electroconvulsive therapy can be considered. 23

In addition to medical treatments, other mental health therapies play a vital role in depression treatment. Psychotherapeutic approaches, such as cognitive-behavioural therapy or interpersonal therapy, are valuable in addressing the symptoms and some aetiological causes of depression. These therapies can be conducted on an individual basis or in group settings and offer strategies for managing and reducing depressive symptoms. 1

While depression can be effectively treated, symptoms, including cognitive impairment, typically do not subside immediately. Both medication and psychotherapy techniques may take several weeks before a noticeable reduction in symptoms occurs. Additionally, individuals with depression may experience relapses, highlighting the importance of ongoing treatment and support. 1

Lastly, even with adequate treatment, not all cognitive deficits associated with depression necessarily resolve, especially in the geriatric population. In older patients, it may even be due to the co-occurrence of another pathological process such as AD or cerebrovascular disease.

Outcomes/Prognosis

Reversible cognitive impairment in moderate-to-severe depression in older adults is considered a strong predictor of dementia according to most authors, although some consider that depression with reversible cognitive impairment may be a prodromal phase of dementia rather than a risk factor. 13 14 19 20 31 In these cases, the type of depression appears to be qualitatively different: more resistant to treatment and with a more chronic course. 15

Evidence indicates that the most likely types of dementia to develop are AD and vascular dementia. 15

In one study, 44 older patients with depressive pseudodementia were followed for up to 18 years at 6-month intervals. Eighty-nine per cent of the patients originally recruited into the study developed dementia. The main limitation of this study was the lack of a control group. 15

In another study of 5-year to 7-year follow-up conducted by Saez Fonseca et al , the conversion rate to dementia over follow-up in a group of older adults with depression with impaired cognitive function was found to be 71.4%, compared with only 18.2% conversion in the cognitively intact group. The group of older patients with depression with impaired cognitive function had a higher risk of dementia and institutionalisation than the group of older patients with depression without impaired cognitive function. Impaired cognitive function was one of the strongest predictors of dementia, with an absolute risk increase of 53.2%.

In another study conducted by Xu et al , the incidence rate of dementia in people with depression was far more than those who were free of depression, and high-risk lifestyle factors (like physical inactivity) were associated with higher risk of transition from depression to dementia, highlighting the great significance of integrating comprehensive behavioural interventions, particularly for regular physical activity, for prevention of both depression and postdepression dementia. 37

A review carried out by Brodaty and Connors shows that although pseudodementia presenting later in life is associated with an increased likelihood of subsequently developing organic dementia, pseudodementia presenting earlier in life does not show this effect. 7

Processing speed abnormalities and memory function impairments are cognitive characteristics primarily observed during acute depressive episodes. However, executive deficits may persist in certain individuals with a history of depression and can serve as predictors of treatment response. Recent research indicates that more severe executive deficits at the onset of depression correlate with a poorer prognosis for recovery. In contrast, deficits in visual memory, visual spatial ability and nonverbal intelligence may be depressive cognitive features that remain after recovery from depression and possibly signal an underlying chronic abnormality in the right hemisphere. 15

Pseudodementia describes a collection of symptoms commonly observed in older adults that resemble dementia but do not involve neurodegeneration. Pseudodementia is not an official diagnosis but rather a descriptive term for a specific group of patients. In the older population, pseudodementia can have a detrimental impact on cognition and functionality, and it may also serve as a predictor for the subsequent development of dementia.

Pseudodementia shares similar risk factors with depression, including female gender, family history, divorce and low socioeconomic status. While depression is the primary cause of pseudodementia, other mental health conditions such as schizophrenia, psychoses, dissociative disorder, conversion disorder and mania can also lead to cognitive impairment and produce similar clinical symptoms.

Dementia and depression can coexist, and pseudodementia and dementia can be difficult to distinguish. The main characteristics that allow the differentiation of these conditions must be addressed in the interview (onset and course of symptoms, family history, personal history, etc). Treating pseudodementia involves treating the underlying condition.

To the best of our knowledge, there is no other review on pseudodementia as complete as ours, nor as up-to-date.

The lack of combined information regarding the different dimensions of pseudodementia may itself add to the challenge of managing this condition. Our review compiles a wide range of features of pseudodementia—epidemiology, history, presentation/characteristics, causes, risk factors, diagnostic approach, differential diagnosis, treatment and prognosis. Our work stands out for addressing novel findings and for being extensive Thus, it will provide valuable help in clinical practice, given the significant prevalence of pseudodementia and the associated challenges of diagnosis and management.

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Salomé Mouta holds a master’s degree in Medicine from the University of Minho School of Medicine in Portugal. Since 2019, she has been a registered medical doctor in Portugal. She also has a graduate degree in Cognitive Behavioral Therapy and a graduate degree in Chemical and Behavioral Addictions. Currently Dr Mouta works as a Psychiatric Trainee at the Department of Psychiatry and Mental Health of Guarda’s Local Health Unit in Portugal. She is the author of book chapters, as well as several pamphlets and oral communications presented at national and international congresses and training meetings. Presently, she is a member of the Portuguese Society of Psychiatry and Mental Health, the Portuguese Association of Psychiatric Trainees and the Portuguese Society for the Clinical Application of Entheogens.

Contributors SM: conceptualisation, investigation, writing—original draft, writing—review and editing. IFV: conceptualisation, methodology, supervision. MP: investigation, writing—review and editing. SR: investigation, writing—review and editing. DF: writing—review and editing, supervision.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

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• Winter 2024 | VOL. 22, NO. 1 Reproductive Psychiatry: Postpartum Depression is Only the Tip of the Iceberg CURRENT ISSUE pp.1-142

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Dementia Syndrome of Depression: Diagnostic Challenges and Clinical Relevance

• Anusuiya Nagar , M.D .,
• Mina Boazak M.D. ,
• Adriana P. Hermida M.D.

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Late-life depression is frequently associated with cognitive impairment. Because of the overlap of symptoms, however, it can be challenging to discern a neurocognitive disorder (NCD) from a late-life depressive disorder. Although neuropsychological testing provides evidence, there are limited neurochemical or neuroimaging biomarkers for the etiological classification of NCD versus late-life depression. Without formal DSM-5 criteria for a dementia syndrome of depression (DSD), patients may be incorrectly diagnosed as having an NCD. Without recognition and appropriate aggressive treatment, patients may develop severe depression with cognitive impairment leading to significant morbidity. It is crucial that clinicians become aware of and assess for elements that differentiate DSD from neurocognitive disorders. In so doing, this syndrome can be identified and treated early in its course, allowing for the best patient outcomes. In this article, the authors demonstrate, through a case presentation, the diagnostic challenges and clinical value of accurately identifying and treating DSD.

In recent years, there has been a reemergence in the effort to recognize and identify the complex diagnosis of dementia syndrome of depression (DSD). The diagnosis does not have proposed criteria and is not mentioned in DSM-5 , even though neuropsychological changes mimicking dementia in older patients with depression have been long recognized. In the 1880s, melancholic dementia was identified by Mairet, and in 1961, Kiloh coined the term, “pseudo-dementia,” in an article that outlined cases of patients with affective disorders and apparent dementia ( 1 ). Yet, more than 50 years later, this syndrome is frequently misdiagnosed and inappropriately treated. The field might reconsider its attempts to cast aside the notion of pseudodementia, because not all patients with cognitive impairment and depression have an unrelenting course of further cognitive decline. DSD is certainly a complicated entity, because depressive symptoms are sometimes associated with or precede a dementia syndrome ( 2 ). Therefore, considerable clinical overlap can exist between the two diagnoses. The objective of this article is to discuss the difficulties in accurately diagnosing and treating this syndrome, as illustrated below in our reported case.

Mr. A is a 60-year-old Caucasian man, with a remote psychiatric history of depression, who presented originally to the emergency department (ED) for confusion, decreased functionality, psychomotor retardation, and difficulty with activities of daily living (ADLs) for the previous 6 month​s. Three years prior, his wife had noted a gradual decompensation in his functional ability. She described inappropriate behaviors, such as lying down in the middle of a golf course, becoming acutely agitated, making inappropriate comments in a public speech, and isolating himself from the family—all of which were highly uncharacteristic of him. One year prior, the patient had taken on a new executive position out of state, after which he quickly decompensated. He lost 40 pounds, was living in unhygienic conditions, and was not attending to his ADLs. His wife also witnessed changes in his personality, describing him as more passive and amotivated. In the few months prior to the ED visit, Mr. A’s wife had noted that he appeared more confused, was unable to participate in conversation, was clumsier in his actions, and had difficulties with his balance. She also noticed that he had become apathetic and needed to be instructed to keep up with his ADLs.

At the original interview, Mr. A described difficulty with concentration, short-term memory, formulating thoughts, and writing sentences. He endorsed feeling “overwhelmed” with his job, describing it as “doom and gloom.” He reported neurovegetative symptoms of anhedonia, poor sleep, poor energy, guilty thoughts, poor concentration, poor appetite, apathy, and psychomotor retardation. He denied suicidal or homicidal ideation. Mr. A also endorsed symptoms of anxiety and paranoia: he believed the police were going to arrest him for insignificant actions and was worried about his computer being hacked and his wife being abducted. He denied auditory or visual hallucinations, as well as history of manic or hypomanic symptoms or recent substance use. His psychiatric history included being prescribed paroxetine by his primary care provider in 2000 for “anxiety.” He had taken paroxetine for a year and reported that it had been helpful. Mr. A’s family history included a maternal grandfather with Alzheimer’s disease; a mother with alcohol dependence, depression, anxiety, and some cognitive issues; and a father with substance dependence.

The patient underwent neurologic and psychiatric evaluation, and a differential diagnosis of frontotemporal dementia (FTD) versus major depressive disorder was made. There was a decision for further neurological work up. Mr. A was simultaneously started on sertraline, which was titrated to 200 mg per day. Laboratory testing included vitamins D, B12, a complete blood count, comprehensive metabolic panel, rapid plasma reagin (RPR), thyroid stimulating hormone (TSH), urine toxicology screen, and urinalysis—all were within normal limits. Computed tomography and magnetic resonance imaging (MRI) of the head, an electroencephalogram, and cerebrospinal fluid studies were also normal. On the Montreal Cognitive Assessment (MOCA), Mr. A’s score was 26 of 30, and neuropsychological testing identified impairments in executive function, attention, and memory. He was particularly slow in Trails A and B and demonstrated an increased score on global deficit. Over the next few months, Mr. A’s symptoms worsened. His family began to consider options, such as nursing home placement, because of the possibility of FTD and its poor prognostic course. Mr. A became significantly more abulic and eventually was admitted to the psychiatric inpatient unit due to the risk of self-harm. Pharmacological intervention was recognized as insufficient, because of the severity of the patient’s symptoms. Electroconvulsive therapy (ECT) was recommended. After educating Mr. A and his family, a course of ultrabrief right unilateral ECT was initiated. After two treatments, Mr. A was found to be more sociable, participating in group therapy, and more organized in his thoughts. Over the next few weeks, he received a total of seven ultrabrief right unilateral treatment with minimal cognitive side effects. The patient’s family and providers noted dramatic improvement in his mood as well as organization of thoughts. On follow up, Mr. A’s cognitive function was back to baseline, and his mood was much improved. He remained in remission with no deterioration in his cognition, normal neuropsychological test results, and a MOCA score of 30 out of 30. Two years after his full remission with the acute course of ECT and continued pharmacotherapy, he took on a new executive position and gave an inspiring speech in front of 350 individuals in which he gave a testimony of his effective treatment.

In 1978, Drs. McHugh and Folstein attempted to rename pseudodementia as dementia syndrome of depression, which they felt was more descriptive of the syndrome ( 3 ). This attempt was followed in 1981 by Dr. Caine’s proposed diagnostic criteria for pseudodementia, which included intellectual impairment with a primary psychiatric disorder, features of impairment similar to those seen in central nervous system disorders, cognitive deficits that are reversible, and lack of a known neurological condition to account for the presentation ( 4 ). Yet, none of the versions of the DSM have ever included DSD as a singular disorder. This exclusion from the DSM may be due to the lack of consistent evidence demonstrating that DSD and NCD are two clearly separate disorders, but instead that DSD is “forme fruste” of NCD. Meta-analyses of the literature have suggested that history of depression is a risk factor for dementia ( 5 ) and for Alzheimer’s disease in particular ( 6 ). However, if DSD and NCD are treated as if on a continuum, those suffering from DSD are not appropriately diagnosed or treated, resulting in a greater morbidity.

It is well documented that depressive disorders frequently cause mild cognitive deficits, which show up in psychometric testing ( 7 ). In late life, however, the relationship between depression and dementia becomes increasingly complicated, given the significant symptomatic overlap, including loss of interest, apathy, difficulty making decisions, agitation, irritability, and changes in sleep and appetite ( 2 ). This symptom overlap results in a diagnostic and treatment dilemma that may manifest in delayed treatment of profound depression resulting in persistent major functional impairment ( 8 ). The difficulties specific to the geriatric population with DSD have been identified as memory loss, attention deficits, initiation problems, and word-finding difficulties.

Fortunately, variations exist between DSD and NCD that clinicians can use to guide their diagnostic assessments. Specific studies have demonstrated that late-life depression can present with deficits of episodic memory and learning ( 9 ). However, performances on implicit memory tasks and other memory functions may be spared ( 10 – 12 ). It has been proposed that difficulties with motivation, effort, and arousal are linked to the performance of effort-demanding cognitive operations among depressed patients ( 13 ). Furthermore, when engaged in effort-demanding exercises, patients with depression fared worse than those with a primary diagnosis of NCD ( 13 ). It has also been suggested that these deficits represent attention problems rather than a lack of ability caused by structural deficits ( 2 ). Finally, executive function impairment, specifically task switching or set-shifting ability, is distinctly more impaired among patients with depression versus those with Alzheimer’s dementia ( 14 ). These features can be used by clinicians to guide diagnoses. Therefore, in terms of psychometric testing, this syndrome can objectively be separated from a pure NCD with memory impairment that would result in gradual decline regardless of intervention in affective symptoms. This differentiation is often missed in primary care settings or in settings where late-life depression is treated as a prelude to impending Alzheimer’s disease, because there is evidence suggesting that depression may occur as a prodrome for Alzheimer’s dementia ( 7 ). However, there is evidence to support that treatment of late-life depression with a combined antidepressant and memantine treatment for patients with depression and cognitive impairment is associated with improved cognition and a low rate of conversion to dementia ( 15 ). Therefore, it is essential to validate DSD and to search for depressive syndromes even when cognitive symptoms have presented first.

Late-life depression is frequently associated with cognitive impairment, and the frequent overlap of symptoms makes it quite challenging to discern one from the other. Although there is evidence in neuropsychological testing, there are limited neurochemical or neuroimaging biomarkers for the etiological classification of dementia versus DSD. There is a plethora of evidence suggesting that late-life depression is a prodrome to impending dementia. Some proposed mechanisms supporting the development of depression into dementia include depression being an emotional response to the awareness of cognitive deficits, expressions of the same underlying process that causes the dementia, cholinergic system disruptions, prolonged hypercortisolemia, as well as depletion of cognitive reserve ( 16 ). Studies ( 17 , 18 ) have demonstrated that patients with Alzheimer’s disease are more likely to have a history of major depression. Hippocampal atrophy has also been identified on MRI of older adults with depression ( 19 ). An interesting autopsy study ( 20 ) has shown increased plaques and tangles of patients who had Alzheimer’s disease and lifelong depression. One theory is that prolonged depression resulting in persistent hypercortisolemia may cause hippocampal damage, which does not necessarily cause dementia, but increases susceptibility to its development ( 16 ).

Further studies are needed to determine whether adequate treatment of depression associated with cognitive symptoms in mid or late life may help to maintain cognitive function and delay onset of a major NCD. This topic is quite relevant given the anticipated increase in dementia prevalence during the next few decades.

Conclusions

Clinically, the diagnosis and treatment of DSD remain a challenge. Without formal DSM-5 criteria, patients can be pigeonholed into a diagnosis of major depression or NCD. Without recognition and aggressive treatment, these patients may develop severe depression with cognitive impairment, leading to significant morbidity. It is critical for clinicians to be aware of and to assess for elements that differentiate DSD from NCD and to aggressively treat severe major depression, regardless of the extent of cognitive impairment. In doing so, clinicians would be better able to identify and treat this syndrome early in its course.

The authors have confirmed that details of the case have been disguised to protect patient privacy and that the patient consented to publication.

The authors report no financial relationships with commercial interests.

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Volume 5 Supplement 1

International Society on Brain and Behaviour: 2nd International Congress on Brain and Behaviour

• Poster presentation
• Open access
• Published: 28 February 2006

Conversion pseudodementia in an elderly subject

• Vaios Peritogiannis 1 ,
• Argiro-Irene Pappas 1 ,
• Spyros Zafiris 1 ,
• Dimitrios Pappas 1 &
• Venetsanos Mavreas 1  

Annals of General Psychiatry volume  5 , Article number:  S285 ( 2006 ) Cite this article

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Few cases of conversion pseudodementia in older people have been reported. The term is used to describe a syndrome of cognitive impairment, regression and physical dependency without evidence for an organic dementia. Conversion pseudodementia raises important diagnostic and therapeutic issues.

Materials and methods

We present a case of a 73-year old male with symptomatology compatible with conversion pseudodementia. Differential diagnosis and therapeutic interventions are discussed.

The patient was admitted to our hospital presenting cognitive decline of a rapid onset and progress in 20 days time. Agitation and bursts of anger against his wife characterized his behavior. During the past six years he had been receiving antidepressant medication. Recent CT scan of the brain was normal and the score in MMSE (Mini Mental State Examination), six months ago was 27/30. During his hospitalization no apparent depressive symptoms were detected, but the performance of MMSE revealed a score of 0/30 and poor cooperation. The patient received mirtazapine, at a dose of 60 mg/day. He kept being aggressive towards his wife, on whom he was dependent and sometimes he was wandering in the hospital, being unable to find his way to the ward. The information about his premorbid personality suggested a stubborn person characterized by perfectionistic traits and somatising behavior. The rapid onset of the symptoms of dementia and the clinical observation of this patient suggested the diagnosis of conversion pseudodementia. He was discharged after 35 days. No improvement of his mental state was observed.

The incidence of conversion pseudodementia is not known. It is possible that many cases go unrecognized and get a diagnosis of pseudodementia due to depression. This entity has also been reported in younger patients. When present in older subjects it requires careful assessment and may be diagnosed only in the absence of organic dementia or depression. In some cases the diagnosis is confirmed only by long-term follow up.

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Vaios Peritogiannis, Argiro-Irene Pappas, Spyros Zafiris, Dimitrios Pappas & Venetsanos Mavreas

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Peritogiannis, V., Pappas, AI., Zafiris, S. et al. Conversion pseudodementia in an elderly subject. Ann Gen Psychiatry 5 (Suppl 1), S285 (2006). https://doi.org/10.1186/1744-859X-5-S1-S285

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An Overview of Pseudodementia

Symptoms, Diagnosis, Treatment

• Differences
• Dementia and Depression
• Screening/Diagnosis

Pseudodementia is a term—not an official diagnosis—that is sometimes used to describe symptoms that resemble dementia  but are actually due to other conditions, most commonly depression. Thus, depressive pseudodementia has symptoms of dementia but, unlike true dementia, these symptoms may be reversible with treatment for depression.

In other cases, pseudodementia has been identified as a possibility in schizophrenia , other psychoses, dissociative disorder, conversion disorder, and mania .

This article describes the history of this term and lists the characteristics and symptoms of pseudodementia. You'll learn the difference between dementia and pseudodementia and the role that depression plays. You'll also find out how healthcare providers screen for, diagnose, and treat this condition.

Though the term was being used prior, it wasn’t until psychiatrist Leslie Kiloh published the paper “Pseudo-dementia” in 1961 that others were given the impetus to try reversing cognitive impairments that may have been due to other psychiatric disorders, such as depression.

It's hard to classify exactly what pseudodementia is. Plus, it's name is misleading. That's why some professionals advocate to stop using this term altogether. Others argue that pseudodementia is still a useful term because it can help identify patients who may have a treatable condition.

Pseudodementia can be thought of as cognitive impairment that looks like dementia but is actually due to depression.   Common symptoms of pseudodementia sound a lot like dementia symptoms and include memory loss and impaired executive functioning . Executive functioning impacts the ability to make decisions, as well as plan and organize ideas.

Pseudodementia vs. Dementia

While pseudodementia is not included in the Diagnostic and Statistical Manual-5, there may still be value in trying to differentiate it from dementia. One study noted that people who were experiencing the cognitive deficits of pseudodementia had the following characteristics:

• They displayed equal memory loss for recent and past events where typically, short-term memory loss would be the more common early-stage dementia symptom.
• Their memory loss was described as "patchy" and specific.
• They frequently answered that they “didn’t know” when asked questions.
• Their cognitive ability varied significantly when given different neuropsychological tasks that were of about the same level of difficulty.

Though others have made this list more clinically specific, the above has been a good benchmark to start.

Experiencing Both Dementia and Depression

Older adults are at an increased risk of experiencing dementia and depression. To complicate things, they can also experience a combination of dementia and depression. This challenge may be one reason why there have been reports of high rates of both false-positive and false-negative errors in the diagnosis of dementia.

So, how do you tell the difference between depression and dementia? One important factor is that people with depression might complain about their memory, but they often do reasonably well on  mental status exams  and other tests that evaluate cognitive function.

On the other hand, those with dementia often deny any memory problems but don't do as well on cognitive tests. Also, a depressed person is less likely to show severe mood swings, whereas someone with dementia shows a wider range of emotions and sometimes makes inappropriate emotional responses (e.g., laughing while others are sad).

Screening and Diagnosis

There are many different opinions out there about the idea of pseudodementia. Some clinicians use this term regularly and describe seeing multiple patients who were incorrectly diagnosed with dementia and whose cognitive functioning later improved with treatment for their depression.

However, other physicians question this idea of pseudodementia and refer to cases where memory loss that might have been initially blamed on depression progressed to true dementia. Their perspective is that cognitive impairment, along with the signs of depression , were merely early signs of the individual's dementia.

The Geriatric Depression Scale (GDS) is a screening instrument used to detect depression among older adults. The GDS should be one of several methods used in an evaluation. Older adults might have depression that looks like  Alzheimer's or they might have both depression and Alzheimer's or other dementia.

If depression is detected, it can be treated alongside other disorders, such as Alzheimer's disease. The Cornell Scale for Depression in Dementia is another helpful screening test to use since it helps identify if both depression and dementia are present.

The idea of pseudodementia is that the cause of the memory loss, for example, is untreated depression. Treatment of pseudodementia, therefore, would essentially be the same as treatment for depression, such as antidepressant medication .

Whether you agree or disagree with the use of the term pseudodementia, it has become an important idea to consider in the care and treatment of older adults. While not an official diagnosis, pseudodementia appears to have the same loss of memory and executive functioning seen in dementia, but it's true cause is depression.

See a healthcare provider when symptoms of dementia or depression become apparent. The timely recognition of depression, dementia, and depression in dementia, can help improve quality of life and life functioning for older adults.

Kang H, Zhao F, You L, Giorgetta C, D V, Sarkhel S, Prakash R. Pseudo-dementia: a neuropsychological review . Ann Indian Acad Neuro l. 2014;17(2):147-54. doi:10.4103/0972-2327.132613

Mouta S, Fonseca Vaz I, Pires M, Ramos S, Figueiredo D. What do we know about pseudodementia? Gen Psychiatry . 2023;36e:100939. doi:10.1136/gpsych-2022-100939

Sahin S, Okluoglu Önal T, Cinar N, Bozdemir M, Çubuk R, Karsidag S. Distinguishing depressive pseudodementia from Alzheimer disease: A comparative study of hippocampal volumetry and cognitive tests .  Dement Geriatr Cogn Dis Extra . 2017;7(2):230–239. Published 2017 Jul 4. doi:10.1159/000477759

Leyhe T, Reynolds C, Melcher T, et al. A common challenge in older adults: Classification, overlap, and therapy of depression and dementia .  Alzheimer's & Dementia. 2017;13(1):59-71. doi:10.1016/j.jalz.2016.08.007

By Carrie Hill, PhD  Carrie L. Hill, PhD has over 10 years of experience working for agencies in the health, human service, and senior sectors, including The Alzheimer's Association in St. George, Utah.

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Pseudo-dementia: A neuropsychological review.

Author information, affiliations.

• Giorgetta C 3
• Prakash R 4
• Sarkhel S 5

Annals of Indian Academy of Neurology , 01 Apr 2014 , 17(2): 147-154 https://doi.org/10.4103/0972-2327.132613   PMID: 25024563  PMCID: PMC4090838

Abstract 

Free full text , pseudo-dementia: a neuropsychological review.

Department of Emergency, Yantai Yuhuangding Hospital, Yantai, Shandong Province, China

Fengqing Zhao

1 Operating Room, Yantai Yuhuangding Hospital, Yantai, Shandong Province, China

Cinzia Giorgetta

2 Department of Cognitive Science and Education, University of Trento, Rovereto, Trentino, Italy

Venkatesh D

3 Department of Physiology, M.S. Ramaiah Medical College, Mathikere, Bangalore, Karnataka, India

Sujit Sarkhel

4 Institute of Psychiatry, Kolkata, West Bengal, India

Ravi Prakash

Ever since Kiloh (1961)[ 2 ] coined the term pseudo-dementia, it has been used a little loosely for describing the cognitive deficits in depression, especially, which is found in old age. However, several diagnostic dilemmas persist regarding the nosological status of this condition. Teasing out these individual diagnostic problems is important not only for administering appropriate therapy, but also for preventing them from the unnecessary diagnostic assessments towards the other diagnoses. Thus, it is important to have a detailed knowledge of the cognitive or neuropsychological deficits in this condition. In this review, we start by addressing the important issue of diagnostic confusion between dementia and pseudo-dementia. Subsequently, we proceed by reviewing the present scientific literature on the cognitive deficits found in this clinical condition. For the sake of convenience, we will divide the cognitive deficits into:

Memory deficits

Executive function deficits and

Deficits in speech and language domains.

Finally, we will look at the progression of this condition to see the components of this condition, which can be actually called “Pseudo”.

Introduction

The term pseudo-dementia (PDEM) was coined by Kiloh (1961)[ 2 ] to describe the cases, which closely mimicked the picture of dementia. Since then, the term has been used to describe the cognitive profile of various psychiatric disorders, especially depression in old age, which present with cognitive deterioration in dementia. After the term came into the academic use, there have been several arguments against its usage[ 3 , 4 ] as well as in favor of it.[ 5 ] Inspite of these arguments, PDEM remains an important descriptive denotation for describing cognitive deficits in psychiatric disorders, especially depression. Clinically, PDEM has become synonymous with the cognitive deficits seen in patients with major depressive disorder. As the term signifies, it is the clinical condition, which presents with the picture of a full-blown dementia but actually is a different entity. This means that actually this condition has two components, which is also reflected in its name:

“The dementia component” which is the combination of various cognitive deficits found in these psychiatric disorders and

“The pseudo component” which denotes the actual lack of the neurodegenerative dementia.

Both these components are important and will be dealt with separately in this review. The relationship between depression and dementia is complex and has been the topic of many debates recently. This complexity arises from the two facts that cognitive impairments can be found in depression[ 50 ] and that dementia can manifest with depressive symptoms as well. This issue of the diagnostic dilemma will be addressed in the subsequent sections.

There are multiple reasons why there has to be a clearer understanding of this condition. Most importantly, it needs to be properly understood because of the role it plays in the functional impairment of depressive disorders. In the recent review by McIntyre et al .,[ 51 ] it was found that cognitive deficits accounted for the largest percentage of variance with respect to the link between psychosocial dysfunction and major depressive disorder (MDD). Thus, cognitive deficits are clearly important functional predictors of MDD. In this review, we will try to bring forth a better and clearer picture of cognitive deficits in depression. First, we will focus on the issue of diagnostic dilemmas between dementia and pseudo-dementia. Subsequently, we will focus on the individual cognitive deficits and the progression of this condition.

Pseudodementia vs. Dementia — Understanding the Diagnostic Dilemma

The importance of distinguishing primary dementing processes from functional disorders has been highlighted time and again since Kiloh coined this term in 1961. In his own words, such patients “may be in danger of therapeutic neglect and perhaps of unnecessary neurosurgical investigations” . However, the author also mentioned that this term does not have any nosological significance and only describes a condition. Now, we know that this condition is far more important to understand for establishing a diagnosis of either dementia or depression. The timely recognition and treatment of depression in the elderly is thus important not only to prevent the patient from the consequences of progressing depression but also to prevent them from unnecessary investigative evaluations for dementia. The difficulty in diagnostic assessments of PDEM and pervasive developmental disorder (PDD) is particularly evident in elderly patients as compared to young adults because of the additional confusion created by age-related cognitive deficits. No wonder that there have been reports of high rates of both false-positive and false-negative errors in the diagnosis of dementia.[ 52 , 53 , 54 , 55 ] This points the necessity of improved clinical diagnostic techniques. Along with this normal age-related cognitive decline, multiple health problems, and the common use of several different medications are often the additional factors obscuring appropriate diagnosis of depression in the aged people.

One of the earliest and still most cited descriptions of cognitive deficits of PDEM was provided by Small et al .[ 56 ] In their classical descriptions, depressive PDEM patients had equal loss for recent and remote events, were especially characterized by patchy or specific memory loss, their attention and concentration were intact and gave frequent “Don’t know” answers. More specifically, their performance on similarly difficult neuro-psychological tasks were much variable.

A clearer picture of this diagnostic dilemma was provided by Kaszniak[ 58 ] who delineated four clinically important reasons that make the differentiation between these two clinical states difficult:

Cognitive changes in the elderly blur the distinction between normal aging and early signs of PDD

Cognitive impairment frequently accompanies depression and can be severe enough to cause confusion between dementia and depression

Signs of some neurologic diseases associated with progressive decline (e.g., Alzheimer's disease [AD] and Parkinson's disease [PD]) have symptoms that overlap with depression

Dementia and depression can co-exist.

Cognitive Deficits in Depression: Detailing the “Dementia” Component

One of the earliest descriptions of overall cognitive deficits in depressive disorders was given by Caine[ 59 ] who characterized patients with such “neuropsychiatric disorders” as having deficits in the following areas:

Arousal, attention, and concentration;

Mood and affect;

Perception (both ideational and physical, internal and external);

Specific intellectual functions (e.g., memory, language); and

Personality.

This classification summarizes the cognitive deficits in depressive disorders. However, it lacked specificity for the cognitive deficits. Further, along this review, we will focus more on specific cognitive domains, and will do it as a comparison with the cognitive deficits in dementing disorders. We will limit present discussion to memory, executive functions and speech and language deficits among the other cognitive deficits.

Memory function deficits

Memory has been the most assessed function for evaluation of cognitive differences between depression and dementia. It is now commonly accepted that depression presents with a number of deficits in the domains of episodic memory and learning.[ 23 ] Considerable body of evidence shows that there are multiple cognitive impairments in depression as compared to normal subjects. This finding has been consistent across most studies and appears to involve both explicit verbal and visual memory functions and is similarly affected in patients suffering from both melancholic (endogenous) and non-melancholic (non-endogenous) depression types.[ 7 ] However, these patients have intact performances on implicit memory tasks, and some other memory functions appear to be spared.[ 24 , 25 , 26 , 27 ] Although the neurobiological underpinnings of these memory deficits are not clear, they can be traced to the temporal lobe related abnormalities. It is well known that temporal lobe lesions result in impairments in episodic memory. This fact along with the finding that reductions in hippocampal volume are demonstrated in patients with major depression[ 28 ] may point towards temporal lobe deficit as the culprit for these deficits.

Hart and Kwentus[ 35 ] examined memory scanning and incidental memory performance in depressed elderly ( n = 15) and normal control patients ( n = 16). They employed the Stemberg task[ 60 ] and the digit symbol (DS) subtest of the WAIS-R, Wechsler[ 82 ] both of which are measures of basic psychomotor speed, as well as incidental memory (DS) and information processing efficiency (ST). They found depressed patients’ reaction time to be significantly slowed down. However, incidental memory for symbols (on DS) and information processing capacity (slope function of the ST) were not affected by the depressive status. Authors raised the possibility that the psychomotor slowing in depressed patients was more due to “motivational” factors that are mediated by catecholaminergic systems.

Till now, we have focused on memory deficits in depression patients in comparison to normal individuals. However, there have been many other studies, which show that memory deficits in depression are considerably mild when seen in comparison to dementia.

Early work by Whitehead addressed the issue of verbal learning and memory deficits in depression by comparing elderly depressed and patients with mild dementia. They posited that variation in response strategies was the core reason for the memory-related differences observed in these groups of patients.[ 29 ] Authors had observed that depressed patients tended to take a conservative approach in making responses, thereby showing less random variation in their responses, whereas patients with mild dementia committed more random and false positive errors.[ 29 ] However, their findings were based on relatively small samples of patients ( n = 12) with weakly defined clinical diagnoses. Miller & Lewis[ 44 ] took a step ahead for evaluating this finding and verified depressed patient's conservative response strategies with well-matched and more clearly defined samples. They found that the accuracy of depressed patients on a recognition memory task was significantly better than that in dementia of Parkinson's disease patients. La Rue[ 36 ] compared depressed patients ( n = 41), AD patients ( n = 19), and patients with other organic impairments (e.g., PD, multi-infarct dementia; n = 20) on the Object Memory Evaluation (OME). A general finding was that depressed patients performed better than AD patients on “all initial learning and recall as well as delayed recall measures.” Dannenbaum et al [ 38 ] used the Brown-Peterson task in discriminating between these delayed recall performances of normal, elderly depressed and Alzheimers dementia patients. They found superior delayed recall performance of depressed elderly relative to patients with DAT.

In addition to AD, other subcortical neurodegenerative disorders also have been reported with impairments in cognitive processing including Friedreichs Ataxia[ 39 ] and Parkinson's disease[ 41 ]. Niederehe[ 41 ] conducted a series of studies aimed at distinguishing between depressed, PDD patients, and normal individuals on measures of “episodic”, “semantic”,[ 42 ] and constructive memory tests. His studies were based on small sample size ( n = 24) and consisted of well-matched groups. A consistent outcome of his studies was a qualitatively worse performance of PDD patients as compared to depressed patients.

Hart et al .[ 43 ] with their study results suggested that depressed and AD patients might be distinguished on the basis of the rapidity with which they forget initially encoded information. In their study, the depressed patients, AD patients, and normal subjects were differentially exposed to the to-be-remembered information. Patients were presented line drawings for 2, 4, and 8 s (for normal, depressed, and Alzheimer's patients, respectively), in view of the fact that the levels of learning impairments groups were suffering was different. Their results indicated that AD patients showed a much more rapid rate of forgetting as compared to depressed and normal individuals who forgot information at the same rate. However, there was relatively equivalent general intellect, verbal fluency, and concentration ability.

Some early studies have assessed recall-memory functions using several different standardized neuropsychological tools. In a study using the incidental memory manipulation with the DS subtest of the WAX-R (mentioned above), Hart et al .[ 40 ] found that depressed ( n = 15) and mildly demented patients ( n = 15) were similar in performance with respect to psychomotor speed, but the recall of symbols demonstrated by depressed patients was significantly more than mild AD patients. Another study examining memory-recall performance using the selective reminding procedure Buschke[ 81 ] produced similar results showing that depressed patients ( n = 14) were impaired on total recall and proportion of items retained from trial to trial relative to normals ( n = 16), but were superior to mild AD patients ( n = 15) across all memory indices.[ 40 ]

Work by La Rue and collaborators have examined elderly depressed patients’ performance on a variety of clinical memory tasks.[ 36 , 37 ] Normal elderly ( n = 10), depressed patients ( n = 10), and patients with PDD ( n = 10) were compared with respect to their performance on the Benton Visual Retention Test (BVRT), Inglis Paired Associate Learning Test (IPA), and Fuld Object Memory Evaluation (OME).[ 37 ] Depressed patients performed at or below the level of normal controls on most BVRT and IPA indices, and were generally superior to dementia patients. However, the OME was far better at distinguishing between groups.

In view of these findings of memory impairments in depression, the question of etiopathogenesis becomes all the more important. Till now, there is no ‘unified theory’ for these cognitive deficits but most theories point towards an encoding problem in such patients. This encoding deficit can be seen in the context of different information processing stages of memory.[ 30 ] From the perspective of a “levels of processing” approach of depression,[ 31 ] such patients might not be able to encode information to the same “depth” as normal subjects. In a small sample study, Weingartner et al .[ 4 ] examined normal and depressed subjects’ ability to employ elaborative encoding strategies when learning new information. Their findings suggested that depressed patients failed to engage in encoding strategies that would maximize the likelihood of subsequent recall which however, improved in performance when material was presented in a predecided organized fashion. Weingartner[ 32 ] on the other hand looked at depressed patients’ encoding abilities as a function of the relative amount of effort expended in initial learning.[ 33 ] He found that depressed patients were less successful than normals when engaging in “effort demanding” encoding exercises. This led, Weingartner[ 32 ] to propose that, “biological systems associated with motivation, effort, and arousal appear to be linked to the performance of effort demanding cognitive operations in depressed patients.”

To summarize, depression presents with several memory-function deficits most common being those related to tasks of recall or remembering. However, the sample sizes of these studies have been relatively small (generally 10-30 subjects per group), and the methodologies vary widely, which have been the main limitations of these studies. Additionally, these memory deficits inspite of being significantly worse than normal individuals, are comparably better than those associated with dementia Regarding the basic neurobiology of these deficits, most researchers have suggest that such differences represent general cognitive inefficiency and attention problems rather than a fundamental lack of ability due to structural deficits. This can be seen in the differences between depression and dementia patients as well as in the temporariness of these deficits in the clinical picture of depression, which will be dealt in next sections.

Executive function deficits

Executive function deficits are prevalent in depressive disorders and recently they have been found to produce clinically significant effects, which may in fact be a significant mediator of the functional impairments found in such patients. Task switching or the set-shifting abilities have been the most commonly found impairments among executive functions in depressed patients. In a recently well-reviewed article by McIntyre,[ 51 ] authors found that executive function deficits occur at a rate of 20-30% of patients suffering from MDD. Studies in past decade examining impairment in executive tasks have produced somewhat consistent findings of impairments in set shifting tasks in depressed patients.[ 6 , 7 , 8 , 9 , 57 ] In general, significant impairments have been observed in subjects with more severe depression.[ 10 , 11 , 12 ] For example, Beats et al .[ 8 ] found a severely depressed elderly sample to be most prominently impaired on verbal fluency and attentional set-shifting. Same finding has been reflected even in younger patients suffering from moderate depression by Purcell et al .[ 9 ] so that no impairment on working memory was found but impairments on measures of motor speed and attentional set-shifting were observed, with half of the depression group even failing to complete all stages of this task. Same study also revealed that these ‘impaired’ subjects had higher rates of admissions for treatment of depression, suggesting that those with overall greater illness severity were more impaired on set-shifting tasks. Similar to these findings, the studies by Channon[ 61 ] and Channon & Green[ 62 ] showed that even patients suffering from mild to moderate depression (mean Beck Depression Inventory[ 63 ] scores of 17-21) suffered from impairment in executive functions of matching, task completion and task switching based on their performance in Wisconsin Card Sorting Test even though they belonged to younger age group (mean 20-40 years). Similar findings of set shifting ability deficits have been observed in several other studies.[ 6 , 7 , 57 ] An interesting comparison of executive function of depressed patients with manic patients was conducted by Murphy et al .[ 57 ] In a study comparing the performance of subjects with depression and mania on a novel affective set-shifting task, they found that subjects with depression were impaired in their ability to shift the focus of attention (corresponding to the set-shifting component of the WCST), while patients with mania were impaired in their ability to inhibit behavioural responses. This impairment corresponds to the inability to prevent the corresponding to the interference effect of the Stroop test as described by Golden[ 18 ]. There have also been attempts to evaluate the executive functions on various subgroups of depression. Some particularly interesting studies were conducted by Austin et al ..[ 6 , 7 ] They divided depression patients into endogenous and non-endogenous subsets using standardized definitions of endogenous depression by the Newcastle system.[ 19 ] Further, they subdivided the samples into melancholic and non-melancholic according to the CORE instrument.[ 17 ] In the Austin et al .)[ 7 ] study, subjects with endogenous/melancholic depression were impaired (as in the Austin et al . 1992a study)[ 6 ] on working memory (digits backwards) as well as on tasks heavily reliant on set-shifting (Trails B, and digit symbol substitution) as well as an increased perseverative response on the Wisconsin Card Sorting Task.[ 34 ]

Other than these set-shifting problems, several other executive function deficits have been observed. Bomstein, et al .,[ 64 ] studied a sample of elderly depressed patients ( n = 62) for the presence of the “Fuld profile”[ 65 ] on the Wechsler Adult Intelligence Scale-Revised (WAIS-R; Wechsler)[ 82 ] which was thought to be relatively specific (though not necessarily sensitive) to disorders in which there is prominent temporal lobe pathology, most notably AD. Results from this study indicated that the Fuld profile was present although less frequently in depressed elderly patients (16%) than in the AD samples (44%) as reported in 1984 by Fuld, but similar to that observed in a normal subject group (12.8%).[ 66 ] These findings suggest that the elderly patients with depression do present with executive function deficits but less than AD patients. Recently, the trend of such assessment studies has been to employ comprehensive batteries and/or intelligence tests for examining neuropsychological function in depressed patients. Gray, et al .,[ 67 ] looked at the performances of depressed ( n = 30) PDD ( n = 26) and general neurological patients ( n = 24) on subtests of the Halstead-Reitan Neuropsychological Battery (HRB). They found that depressed patients were generally less impaired, as measured by the Halstead impairment index, than PDD and neurological groups. In fact, depressed individuals were superior to the other groups on all HRB measures except, Tactual Performance Test location, Speech Sounds Perception Test, and Trail-Making Test A.[ 67 ] In a similar vein, McCue, Goldstein, and Shelly[ 68 ] compared the performances of depressed ( n = 45) and PDD patients ( n = 34) on a short form of the Luria Nebraska Neuropsychological Battery (LNNB). They were able to differentiate between the groups on all the 10 clinical scales of the form employed. Patients with depression who were misclassified as having PDD tended to have more extreme degrees of depressive symptomatology and lower educational levels.[ 68 ] These studies, with larger sample sizes and a broader range of cognitive domains assessments, further strengthen the general finding of substantial differences between depressed and demented individuals. In a most recent study, Egerhazi et al .[ 14 ] used Cambridge Automated Neuropsychological Battery in patients suffering from MDD during their acute stage. They found that during the acute episode, delayed matching to sample, paired associate learning, spatial recognition memory, rapid visual processing and visuospatial planning were impaired. In remission, improvements in the domains of visual learning ability, spatial recognition memory, psychomotor speed, and executive function were observed. The authors concluded that MDD is associated with neurocognitive dysfunctions in different domains, the most prominent deficit being found in the paired associate learning test, which requires both the elaboration of “frontal strategies” and the “mnemonic processes”.

Processing speed impairment is another important executive function deficit observed in depression. In a recent study by Brown et al .,[ 13 ] it was found that impairments in processing speed partially mediated the effect of depression on functioning in patients suffering from minimal cognitive deficits. A more clinical outcome of this processing speed impairment is psychomotor slowing, which is almost universally found in the depressed patients, irrespective of the number of episodes. However, there also have been exceptions to these near-universal findings. Elliott et al .[ 16 ] conducted a study on middle-aged subjects with moderate, predominantly chronic depression, and demonstrated impaired abilities of these patients on the tasks of Tower of London, verbal fluency and spatial working memory but intact performance on a modified and easier version of the Cambridge Neuropsychological Battery (CANTAB) set-shifting task.[ 15 ] Works by Bieliauskas and colleagues (Bieliauskas et al .; Bieliauskas & Lamberty; Bieliauskas, et al .)[ 20 , 21 , 22 ] have repeatedly presented the findings showing the lack of significant differences between normal and depressed patients on EF and other cognitive measures. In a series of studies using screening measures such as the MMSE and the Neurobehavioral Cognitive Status Exam[ 58 ] no differences were found between depressed ( n = 15) and non-depressed patients ( n = 33) across a wide array of cognitive and motor tasks (with the exception of the NCSE Attention subtest). On the basis of these findings, they put forth the notion that differences between normal and depressed patients are sufficiently subtle to not significantly influence scores on standard cognitive screening instruments.

Speech and language function deficits

Small number of studies has specifically examined speech-language function in elderly depressed patients. While most of the tasks used to measure cognitive abilities in above-mentioned studies have obvious receptive and expressive language components, it is important to highlight some studies which have looked at specific language skills. For instance, in the study by Emery and Breslau[ 67 ] it was observed that depressed patients performed better than AD patients on measures of naming, repetition, general reading skill, syntax, and auditory verbal comprehension. At the same time, normal individuals tended to show better language performance than depressed patients overall, though these differences were considerably less obvious than those noted between depressed and AD patients.[ 67 ] It is to be noted that “verbal fluency” tasks are recognized as sensitive indicators of general cognitive impairment; so this finding has to be seen as a measure of general impairment rather than specific language related impairment.[ 48 ] However, Hart et al .[ 46 ] found no statistically significant difference between depressed and AD patients on the familiar controlled oral word association test (a.k.a., F-A-S test; Benton & Hamsher)[ 70 ] between depressed and AD patients so that both of them showed reduced verbal fluency, However, depressed patients outperformed AD patients on a categorical fluency task (i.e., “animals”). Thus, finally a reduction in psychomotor speed was considered as the main reason to explain depressed patients’ weakness on this task rather than true deficits in the domain of language and speech.[ 46 ]

Another commonly used measure of language function has been the Boston Naming Test.[ 45 ] Using a 30-item version of the BNT, Speedie et al .[ 49 ] reported that depressed patients were impaired to the same extent as patients with irreversible dementias whereas prominent language deficits (including confrontation naming) are not thought to be common in depression.[ 59 ] Most of the findings of language related impairments have only been incidental while examining for other cognitive domains.

Progression of Pseudo-Dementia: Perspectives for the “Pseudo” Component

As we highlighted in the previous sections, it is difficult to tease out true cases of pseudo-dementia given the overlaps between the clinical findings in dementia and depression with regards to both depressive symptoms and cognitive impairments. Saez-fonseca[ 71 ] found in their 5-7 year follow up study that 71.4% of those suffering from PDEM had converted into dementia at follow-up compared to only 18.2% of the conversion in the cognitively intact group. Kral & Emery[ 1 ] conducted a similar study of progression of pseudo-dementia. Forty-four elderly patients of both sexes (mean age 76.5 years) suffering from depressive PDEM were intensively treated for the depression. When the depression subsided, cognitive function also reverted to premorbid level. Patients were regularly interviewed and retested at six months intervals for four to 18 years (average 8). Some patients experienced, during the follow-up period, a recurrence of the depression for which they were again successfully treated. For testing the progression of these cognitive deficits with time, several different study designs have been used. Some studies have used the more direct method of comparing cross-sectionally the performance of subjects who have recovered from depression with that of matched controls. Paradiso et al .[ 72 ] found significant cognitive impairments on the set-shifting tasks in subjects who had recovered from unipolar depression as compared to normal controls. Additionally, these cognitive deficits were not related to medication status which suggested the independence of these deficits from treatment related variables. In the same line, Marcos et al .[ 73 ] found persistent deficits in both immediate memory and delayed recall of visual and verbal material, and block design in patients of melancholia after 3 months of their recovery.

Although these studies provide a cross-sectional perspective regarding poor neuropsychological performance of depressed patients in comparison to normal controls, definitive findings can only be provided by testing the cognitive status before and after recovery so that any baseline cognitive deficits are eliminated. Abas et al .[ 74 ] tested elderly patients with endogenous depression on several memory measures and reported that nearly half of those performing poorly at baseline were poor performers inspite of absence of clinically evident dementia or minimal cognitive deficits. In a similar sample of elderly patients, Beats et al .[ 8 ] also found that many, but not all deficits had remitted upon recovery: Specifically, measures of simple and choice reaction times, perseveration on the set shifting task and verbal fluency did not fully recover.

There have also been studies showing that cognitive impairments improve with treatment. In one of the earliest studies, Sternberg & Jarvik[ 75 ] reported that in endogenous depression subjects responding to a tricyclic antidepressant treatment, although performance on learning and short-term memory tasks remained impaired after treatment, there was improvement in immediate memory and this was related to degree of depressive recovery. Similar findings were reported by Calev et al .[ 76 ] and Bazin et al .[ 27 ] neither of which found residual impairments in either explicit (verbal and visual) or implicit memory tasks upon recovery. Similarly, Trichard et al .[ 78 ] in a controlled study of executive task performance in middle-aged subjects with severe depression, reported improved performance on the verbal fluency task but not the Stroop test upon recovery. A very significant finding was reported by Peselow et al .[ 79 ] who in a study of patients with unipolar depression treated with imipramine for 4 weeks, found significant improvement in all mnemonic measures only those responding to treatment. They concluded that in memory tasks performance, recovery of mood was associated with significant cognitive improvement. These findings have been reminded in a recent study by Egerhazi et al .,[ 14 ] where cognitive impairment was found to improve partly in remission, suggesting that an individual's current mood interacts with the ability to perform a cognitive task.

To summarize, results suggest that several cognitive domains especially those related to memory functions are improved with treatment of depressive disorders; however, several of them do persist. Thus a residual deficit in mnemonic and executive function appears to remain in some patients with a history of depression and specifically need to be investigate further because reversible cognitive impairment in late-life moderate to severe depression appears to be a strong predictor of dementia. More studies are needed to exactly understand the relationship of cognitive deficits in depression to crucial epidemiological variables such as age, treatment, duration and chronicity of illness and number of episodes.[ 80 ] Thus, it is recommended to have a full dementia screening for patients suspected to have PDEM.

Present review suggests that over past few decades, enough study results point to the fact that depressive states adversely affect cognitive functions, especially in old-age or geriatric depression. In spite of the methodological and sampling problems encountered when working with these complex populations, the differentiation between depression and early stages of dementia seems to be plausible. Although, earlier researchers have pointed out the inabilities of neuropsychological tests in the context of making these differentiations[ 2 , 59 ] most of the recent data support this practice and should be able to differentiate between true cases of dementia, depression and the ill-defined intermediate stage of pseudo-dementia. Subsequent endeavors in this area with more well-defined populations and properly designed studies are needed to generalize these conclusions.

Source of Support: Nil

Conflict of Interest: None declared

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Mental Illness Dementia What is pseudodementia?

What is pseudodementia?

Pseudodementia is a term that refers to psychiatric symptoms that mirror the cognitive decline seen in cases of dementia. The difference between pseudodementia versus dementia is that symptoms of pseudodementia are the result of a mental health condition, such as depression, rather than resulting from an organic neurocognitive disorder [1] .

Pseudodementia vs Dementia

Understanding pseudodementia.

Pseudodementia is a condition that develops alongside psychiatric conditions like depression. It does not represent neurocognitive dementia , such as in cases of Alzheimer’s . Rather, it is secondary to other psychiatric conditions.

The reason the condition is called pseudodementia is that it involves symptoms that look similar to dementia, but it is a separate condition from organic dementia. Much like dementia, pseudodementia includes symptoms of cognitive decline, such as difficulty with memory or executive functioning.

What causes it?

Pseudodementia is often caused by depression , and in some cases, the condition is called depressive cognitive disorder. According to researchers, long-term inflammation from depression can lead to deficits in cognitive functioning [2] .

Other factors that contribute to pseudodementia include the effects of depression on specific brain regions involved in learning and memory. Impairment in these brain regions can lead to cognitive deficits that appear similar to symptoms of dementia [2] .

Finally, psychological and environmental factors, such as abuse, loss of a job, lack of social support, and other stressors can take a negative toll on physiological functioning and lead to cognitive decline. Some people may also have genetic risk factors for pseudodementia [2] .

How is it diagnosed?

Pseudodementia is not an official diagnosis in the Diagnostic and Statistical Manual of Mental Disorders  (DSM-5). Instead, it is an unofficial term used to refer to cognitive impairment that occurs with psychiatric disorders, typically depression. There are no official diagnostic criteria for the condition, but a doctor or clinician may use the term pseudodementia to refer to cognitive impairment that occurs with depression [2] .

A physician or mental health professional diagnosing pseudodementia will take a full history, which involves asking questions about a patient’s medical history, mental health history, and history of symptoms. The clinician making a diagnosis will ask about the onset and duration of symptoms, and they may complete assessments of memory and learning, as well as laboratory testing and brain scans, to rule out neurodegenerative causes of cognitive decline.

To determine if a person has major depressive disorder, a clinician will utilize diagnostic criteria in the DSM-5. Major depression is diagnosed when a person has a depressed mood or a loss of interest in activities, accompanied by at least four other depression symptoms, such as low energy, sleep changes, feelings of worthlessness, and suicidal ideation [3] .

A person may be said to have pseudodementia if they have depressive symptoms, accompanied by signs of cognitive impairment, which can include difficulty with concentration, memory, and information processing [1] .

What are the symptoms of pseudodementia?

Since pseudodementia is most often associated with cognitive impairments that occur alongside depression, the signs of pseudodementia include depression symptoms accompanied by evidence of cognitive deficits.

Some common symptoms of depression that occur in pseudodementia include [3] :

• Sad or depressed mood
• Lack of interest in usual activities or hobbies
• Difficulty with concentration or decision-making
• Change in weight (either weight loss or weight gain) without attempting to change weight
• Change in sleep habits, which can involve sleeping either too much or too little
• Feeling an inappropriate amount of guilt, or struggling with feelings of worthlessness
• Changes in motor activity, which can manifest in the form of either restlessness or noticeably slowed movements
• Feeling extremely fatigued and/or having a hard time completing daily activities due to low energy and lack of productivity
• Thoughts of suicide or suicide attempts

In addition to the depression symptoms above, someone with pseudodementia will show signs of cognitive impairment, which can include [1] :

• Difficulty with speech
• Impairments in learning
• Memory loss
• Having a hard time paying attention or shifting attention between tasks
• Problems with planning and organizing
• Trouble regulating emotions

While pseudodementia that occurs with depression can look similar to dementia, the two are distinct conditions. Firstly, dementia is a neurocognitive condition associated with pathology and abnormalities within the brain. In organic dementia, these abnormalities are not reversible. On the other hand, cognitive decline in pseudodementia is often reversible with successful treatment. 

That being said, there is some evidence that pseudodementia can increase the risk that a person will develop irreversible dementia in the future. Early treatment and intervention can reverse cognitive decline in depression and lower the risk of future neurodegenerative diseases, including dementia [4] . 

Finally, cognitive impairment in dementia is often more severe than what is seen with pseudodementia. Patients who have cognitive impairments alongside depression may have only mild difficulties with memory and concentration, whereas these impairments are more severe in dementia and can interfere with daily functioning. In fact, a recent study found that patients with dementia performed worse on all cognitive tests when compared to patients with pseudodementia from depression [5] .  

What treatment options are available?

Since pseudodementia involves cognitive decline that occurs secondary to symptoms of depression, treating the depression often results in an improvement in cognitive functioning. One study with 284 patients found that over the long-term, 53% of patients no longer showed symptoms of dementia or cognitive impairment [4] .

Common treatment options that can reverse cognitive dysfunction in pseudodementia include [6] :

• Therapy : Specific therapeutic modalities, including cognitive remediation therapy and cognitive behavioral therapy (CBT) can improve cognitive functioning inpseudodementia patients. In fact, studies have shown that therapy can actually produce changes in brain functioning and connectivity in patients with depression, therapy reversing cognitive impairments. Therapies used in the treatment of pseudodementia can help patients to change distorted thinking patterns and learn new skills.
• Medication : Prescription drugs used in the treatment of depression have been found to improve cognitive functioning, which suggests these medications can be beneficial for treating pseudodementia. Two types of antidepressant medications called selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been found to be particularly effective for alleviating cognitive impairment in depression. Specific medications within these classes include sertraline and duloxetine , and studies suggest that both are effective for treating cognitive impairment. Another type of antidepressant drug , called vortioxetine, has been proven effective for treating cognitive dysfunction.
• Brain Stimulation: Various brain stimulation methods are used in the treatment of depression, and they may be beneficial for treating pseudodementia. Electroconvulsive therapy (ECT) is one method of brain stimulation, but its use is controversial, because it can cause short-term cognitive impairment after treatment. After the cognitive side effects of ECT pass, it is associated with small to medium improvements in memory, information processing, and executive functions. Transcranial magnetic stimulation (TMS) is a less invasive alternative to ECT, and this brain stimulation method has been found to be beneficial for reducing cognitive impairment in depression. 

Pseudodementia is a psychiatric condition that mirrors the symptoms of organic dementia, but it differs from the latter, because it is not a legitimate neurocognitive disorder. It is important to remember that pseudodementia is a descriptive term that refers to cognitive decline that occurs with depression or another psychiatric condition, but it is not an official diagnosis. Furthermore, it is worth noting that if left untreated, pseudodementia does increase the risk that a person will develop organic dementia. Treatment can reverse cognitive decline and reduce the risk of complications or worsening of pseudodementia.

• Kang, H., Zhao, F., You, L., Giorgetta, C., D, V., Sarkhel, S., & Prakash, R. (2014). Pseudo-dementia: A neuropsychological review. Annals of Indian Academy of Neurology, 17(2), 146-154. doi: 10.4103/0972-2327.132613
• Sekhon, S., & Marwaha, R. (2022). Depressive cognitive disorders. National Library of Medicine. Retrieved November 26, 2022, from https://www.ncbi.nlm.nih.gov/books/NBK559256/#:~:text=Depressive%20cognitive%20disorders%2C%20also%20called,less%20significance%20in%20the%20past .
• Substance Abuse and Mental Health Services Administration. (2016). DSM-5 changes: Implications for child serious emotional disturbance. National Library of Medicine. Retrieved November 26, 2022, from https://www.ncbi.nlm.nih.gov/books/NBK519712/table/ch3.t5/
• Connors, M.H., Quinto, L., & Brodaty, H. (2019). Longitudinal outcomes of patients with pseudodementia: A systematic review. Psychological Medicine,49(5), 727-737. doi:10.1017/S0033291718002829
• Sahin, S., Onal, T.O., Cinar, N., Bozdemir, M., Cubuk, R., & Karsidag, S. (2017). Distinguishing depressive pseudodementia from Alzheimer disease: A comparative study of hippocampal volumetry and cognitive tests.Dementia and Geriatric Cognitive Disorders Extra, 7(2), 230-239. doi: 10.1159/000477759
• Zuckerman, H., Pan, Z., Park, C., Brietzke, E., Musial, N., Shariq, A.S., Iacobucci, M., Yim, S.J., Lui, L.M., Rong, C., & McIntyre, R.S. (2018). Recognition and treatment of cognitive dysfunction in major depressive disorder. Frontiers in Psychiatry, 9(655). https://doi.org/10.3389/fpsyt.2018.00655

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• v.14(4); 2017 Jul

A Case Report of a 37-Year-Old Alzheimer's Disease Patient with Prominent Striatum Amyloid Retention

Yoo hyun um.

1 Department of Psychiatry, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Woo Hee Choi

2 Department of Radiology, Division of Nuclear Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea.

Won Sang Jung

3 Department of Radiology, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea.

Young Ha Park

Chang-uk lee.

4 Department of Psychiatry, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Hyun Kook Lim

With recent advancement in amyloid imaging, diagnostic application of this new modality has become a great interest among researchers. New ligands, such as 18F- florbetaben, florbetapir and flutemetamol, have been discovered to overcome limitations of preexisting ligand Pittsburgh compound B. We report here a case of a 37-year-old male patient whose initial complaints comprised of gradual cognitive decline, apraxia, disorientation and sleep disturbances. 18F-Florbetaben amyloid imaging of the patient showed diffuse amyloid retention with prominent striatal uptake. This finding supports the clinical utility of amyloid imaging in diagnostic process of early-onset AD. Moreover, striatal dominant uptake pattern demonstrated in this patient include some meaningful clinical implications that warrant special attention among clinicians.

INTRODUCTION

Amyloid deposition has long been considered one of the pathognomonic markers of Alzheimer's disease (AD). Moreover, disruption in amyloid hypothesis has been frequently discussed as important targets of intervention for many years. 1 To date, most validated research results have been narrowed down to yield a model for biological trajectory of AD, where amyloid deposition far precedes clinical symptoms. 2 Thus, early detection of amyloid deposition has emerged a major target of intervention in AD patients. In this regard, amyloid imaging has emerged as an effective diagnostic tool that could enable early intervention in patients in AD trajectory, and the clinical utility of amyloid imaging has become a main topic of interest among researchers over the recent years. 3 If validated further, clinical usage of amyloid imaging is expected to extend beyond confirming AD pathology in patients with high risk factors, helping to differentiate AD from various types of dementia in those who present with atypical course or symptoms. 4

Pittsburgh compound B has been the first ligand used to detect amyloid deposition in AD patients. 5 However, its short half-life and resultant limitations in applying it to clinical setting have resulted in the development of new ligands for detecting amyloid deposition, such as 18F-florbetaben, florbetapir and flutemetamol. 6 Amyloid deposition usually initiates from temporal and orbitofrontal cortices, which later extends to frontal, parietal, precuneus, anterior and posterior cingulate cortices. 7 However, differential uptake patterns in autosomal dominant gene carriers have been noted that warrant special clinical attention. While typical amyloid deposition occurs from cortical structures, those with autosomal dominant gene carriers demonstrated initial amyloid deposition in striatum. 8 , 9

We report here a case where a case of early-onset AD patient who received a confirmatory diagnosis of AD by beta-amyloid imaging. There is relatively few evidence on the clinical application of beta-amyloid imaging in early-onset AD patients, and therefore, we expect our case can contribute to this line of inquiry. Moreover, validity of utilizing beta-amyloid imaging in differential diagnosis of dementias will be discussed.

A 37-year old male patient visited outpatient clinic, with complaints of gradual cognitive decline which had started 3 years earlier. Working as an industrial researcher, he started to make serious calculation mistakes that made him quit the job and began working as a manager in a company. However, his frequent forgetfulness, along with aggravation in recent memory impairments hampered him from fulfilling his duties, making him change jobs frequently. Apraxia and apathy had started 2 years before his visit to our clinic, and disorientation to time and person was worsened to a degree which it became impossible to commute daily between his workplace and home. At time of his visit to our clinic, not only he was fired from his recent job, but also he needed frequent reminder from his family to maintain hygiene. His sleep disturbance became prominent, frequently waking up middle of the night self-talking.

Before his visit to our clinic, he had visited two hospitals for evaluation and management of his symptoms, but to no avail. For a thorough examination of his symptoms, he was immediately admitted to our psychiatric ward. His laboratory findings did not reveal any abnormalities, and his tests for human immunodeficiency virus, syphilis all turned out to be negative. Upon his psychiatric admission, a neuropsychological test battery was implemented to evaluate the patient's cognitive status. He scored 22 in Mini-mental status examination, 1 in Clinical dementia rating scale (CDR), 10 and 4.5 in Clinical Dementia Rating-Sum of Box score(CDR-SB). 11 In his cognitive tests, in contrast to his relatively preserved language function, he displayed serious impairments in free recall, 20-minute delayed recall and recognition.

Brain magnetic resonance imaging demonstrated global cerebral atrophy of grade 1 by cortical atrophy scale 12 and notable medial temporal lobe atrophy of grade 2 by medial temporal lobe atrophy visual rating scale ( Figure 1A and B ). 13 Atypically early onset of dementia symptoms made the patient an eligible candidate for amyloid positron emission tomography (PET) imaging. 14 18-Florbetaben PET images revealed diffuse amyloid deposition with score 3 in brain beta-amyloid plaque load (BAPL), 15 with predominant amyloid deposition in the striatum ( Figure 1C and D ).

The patient's history, along with neuroimaging results and cognitive test results all satisfied the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association Alzheimer's (NINCDS-ADRDA) criteria16 for probable Alzheimer's disease with high level of evidence. 5 mg of donepezil was prescribed, and the patient was discharged on the 10th day of his admission. To control his persistent cognitive decline even after the discharge, donepezil was increased up to 23 mg with combination of memantine, which was also increased up to 20 mg. His cognitive decline has been relatively plateaued, but we advised the patient and his caregiver to regularly visit the clinic for monitoring of his symptoms.

This is one of the few case reports that demonstrated diagnosis of early-onset AD by 18F-florbetaben PET imaging. The patient demonstrated early onset of cognitive decline with accelerated deterioration. The fact that he meandered along various departments at different hospitals for confirmatory diagnosis reflect major role amyloid imaging played in the diagnostic process of the patient.

Amyloid imaging is usually indicated in patients with progressive MCI with dubious etiology, patients with atypical presentations and clinical course, and patients with early-onset progressive dementias. 14 Considering the patient in the case exhibited dementia symptoms at atypically early age, amyloid imaging was appropriately prescribed to diagnose the etiology of his cognitive decline. Integration of information attained from his history, clinical data indicated his diagnosis to be early-onset AD.

There have been relatively few reports utilizing 18F-labelled amyloid beta PET tracers that include clinical implications related to autosomal dominant AD. One study adopted 18F-florbetaben PET imaging in Down syndrome patients, suggesting potential role of amyloid imaging in identifying population at risk of dementia. 17 Similar study was conducted on patients with Down syndrome, but with 18F-florbetapir tracer. 18 An attempt to differentiate Down Syndrome pathology from AD has also been made with 18F-florbetapir tracer. 19 Future studies on autosomal dominant AD with 18F-labelled amyloid beta PET tracers could increase validity of adopting these new ligands in the diagnostic process.

Most notable test results in the case report arise from uptake patterns of 18F-florbetaben PET imaging. Unlike typical uptake patterns demonstrated by late-onset AD patients, where striatum is usually involved in the later course of illness, there was a dominant striatal uptake pattern in the patient. A previous study conducted on nondemented young adults with Down syndrome compared their results with that of studies conducted on autosomal dominant early-onset AD patients, where two groups of subjects concordantly showed predominant striatal uptake. 8 Indeed, previous studies on autosomal early-onset AD patients consistently showed high striatal amyloid deposition. 20 , 21 The aforementioned finding could explain 18F-florbetaben uptake patterns in the case.

The underlying mechanisms have been discussed in prior studies on the relatively early involvement of the striatum in autosomal dominant early-onset AD patients. Axonal mistrafficking induced by presenillin-1 gene mutation has been suggested as a potential culprit for striatal amyloid deposition in one animal study. 22 Such axonal mistrafficking is considered to stem from disruption in APP processing. 22 Indeed, APP processing patterns differed between autosomal dominant AD patients and sporadic AD patients. 23 Striatal vulnerability to early stages of tau protein accumulation in autosomal dominant AD has also been elucidated, and such phenomenon is considered more toxic to induce significant striatal neuronal injury. 24

The most prominent limitation of our case report is lack of genotype testing in the patient. If the genetic testing had been done, one missing puzzle in the diagnosis of patient would have been complete. Nevertheless, we believe our case report affirms diagnostic usefulness and clinical application of amyloid imaging in the differential diagnosis of early-onset dementia. We expect more prevalent use of amyloid imaging with accumulation of evidences and validation studies over time.

Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2015R1C1A1A02036578).