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 Table of Contents  
CLINICAL PEARLS
Year : 2021  |  Volume : 8  |  Issue : 2  |  Page : 93-106

The complex conundrum of geriatric depression and dementias: Revisiting the clinical ambiguity


1 Consultant Psychiatrist, Kolkata, Bangalore, India
2 Consultant Geriatric Psychiatrist, Kolkata, Member, International Psychogeriatric Association, Bengaluru, Karnataka, India

Date of Submission23-Mar-2021
Date of Decision05-May-2021
Date of Acceptance04-Jun-2021
Date of Web Publication31-Jan-2022

Correspondence Address:
Dr. Debanjan Banerjee
Consultant Geriatric Psychiatrist, Kolkata; Member, International Psychogeriatric Association, Bengaluru
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jgmh.jgmh_21_21

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  Abstract 


Late-life depression (LLD), mild cognitive impairment (MCI), and dementia are clinically distinct yet interrelated disease constructs, wherein LLD can be a prodrome, risk factor, comorbidity, or consequence of MCI and dementia. There is considerable prevalence of depression in those with MCI or dementia, and vice versa, with maximum evidence in Alzheimer's disease. These intersections often form one of the most confusing aspects of psychogeriatric practice, leading to under-detection and mismanagement of depression, thus leading to incomplete recovery in most cases. This article focuses on this clinical ambiguity in daily practice, reviews the clinico-investigative pointers for the LLD–dementia intersection, and puts forward clinical and research recommendations in view of the available evidence. Although there is conflicting evidence regarding the cause–effect relationship between LLD, MCI, and dementia, it is likely that these constructs share some common pathological processes and are often associated with each other within a longitudinal clinical continuum. This is a linear yet complex bidirectional association: either the comorbid depression exaggerates preexisting cognitive deficits or chronic persistent depression eventually leads to major neurocognitive disorders, not to mention depression as a part of behavioral and psychological symptoms of dementia, which often impairs quality of life and psychosocial morbidity. Thus, a comprehensive approach, including tailored history, neuropsychiatric examination, and relevant investigations, is necessary for assessing the differentials, with a sound clinical understanding being vital to the process. Depression, if suspected, must be treated adequately with longitudinal neuropsychological reviews. Future research warrants elucidating precision biomarkers unique to these clinicopathological entities.

Keywords: Alzheimer's disease, cognitive deficits, dementia, geriatric depression, late-life depression, late-onset depression, mild cognitive impairment


How to cite this article:
Mukhopadhyay S, Banerjee D. The complex conundrum of geriatric depression and dementias: Revisiting the clinical ambiguity. J Geriatr Ment Health 2021;8:93-106

How to cite this URL:
Mukhopadhyay S, Banerjee D. The complex conundrum of geriatric depression and dementias: Revisiting the clinical ambiguity. J Geriatr Ment Health [serial online] 2021 [cited 2022 May 23];8:93-106. Available from: https://www.jgmh.org/text.asp?2021/8/2/93/336905




  Late-Life Depression and Dementia: Inter-Relationships Top


Late-life depression (LLD) is a clinical construct describing depressive symptoms in persons aged 65 years and above.[1] It consists of both early-onset depression (EOD), continuing into or recurring in old age, and late-onset depression (LOD) manifesting in the geriatric population for the first time.[2] LOD constitutes almost 50% of all cases with LLD.[3] The lifetime prevalence of major depression, as per the National Comorbidity Survey-Replication, in people aged 60 years and above was found to be 10.6%, and the projected lifetime risk of the same in those aged 75 years and above was 23.2%.[4] Recent data from the first wave of Longitudinal Aging Study in India showed 8.3% prevalence of depression in those above 60 years of age, which is nearly ten times more than self-reported depressive complaints.[5] Considering both depressive symptoms and minor depression, the prevalence went up to 30%. These statistics are suggestive of significant disease burden caused by LLD. Medical morbidities are high in the old age, including cardiovascular, respiratory, endocrine, and neurological conditions, increasing the risk of depression.[2],[6] Dementias are a group of neurodegenerative disorders with global cognitive decline over the course of illness.[6],[7] The major types of neurodegenerative dementias are Alzheimer's dementia (AD), vascular dementia (VaD), frontotemporal dementia (FTD), Parkinson's disease (PD) dementia, and  Lewy body dementia More Details.[8] Depression and dementia are shown to be inter-related across the literature in bidirectional and complex ways. Depression may act as a risk factor, prodrome, comorbidity, or consequence of dementia.[9],[10] It is seen to double the risk of dementia in older persons.[6] On the other hand, depression is known to be more common in all-cause dementias than in general population. Overall prevalence of depression in neurodegenerative disorders may range from 15% to 50%, depending on the type of dementia. Almost 17% of patients with AD and an even higher percentage of those with subcortical dementias have major depression.[1]

There are several possible hypotheses to explain the mutual relationship between these two illnesses. Sharing of the same genetic or pathophysiological changes predisposing to both the illnesses, reduction in hippocampal neurogenesis in depression, high-risk behaviors in depression increasing vascular risk factors and leading to later cognitive decline (e.g., smoking, alcohol use, less engagement in cognitively and socially stimulating activities), medication use (e.g., those with anticholinergic effect) are just some of them.[2] Although AD, constituting about 50%–60% of the late-onset dementias, is most studied in the context of LOD, depression is present as considerable comorbidity in other dementias as well. Up to 50% with VaD, 40%–50% with PD, 40% with FTD, and 60% with dementia with hippocampal sclerosis may have depression.[9],[11],[12],[13] Depending on the diagnostic criteria and instrument use, the prevalence of comorbid LOD in dementias and depressive symptoms as a part of BPSD is seen to vary considerably across studies.[2],[6],[14] Almost 60% of patients with MCI were found to have depressive symptoms, both major and minor, as per the Italian Longitudinal Study of Aging.[15] The cumulative prevalence of depression in MCI across studies is seen to be around 30%.[1],[14],[16] Subthreshold but clinically significant depressive symptoms are nearly twice more prevalent than major depression in the community, primary care, nursing home population, as well as patients with mild cognitive impairment or dementia,[6],[14] further adding to the disease burden. Butters et al. had proposed a multiple model nonmutually exclusive pathway to explain the links in the depression–cognitive impairment–dementia continuum [Figure 1].[17] The authors proposed that depression increased the risk of neurocognitive disorders through activation of the hypothalamo–pituitary–adrenal (HPA) axis and cerebrovascular disease, which eventually led to hippocampal atrophy and generalized ischemia. This, in turn, influenced the cognitive reserve which led to AD-like presentation based on the accumulation of AD pathological changes in the brain. The clinical presentation and progression of cognitive deficits over time depend upon a critical interaction between vascular pathology, inflammation, frontolimbic damage (implicated in depression) and beta-amyloid, tau pathology, as well as hippocampal atrophy (implicated in AD). Frontostriatal abnormalities were considered to be a hallmark of this pathway. Although there has been more than a decade of further research in this field, this hypothesis still holds good to understand this clinical overlap between depression and neurocognitive disorders.
Figure 1: Pathways linking depression to predominant cognitive outcomes (Butters et al., 2008). Copyright information: This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

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In routine clinical care, the psychiatrist faces several ambiguities while dealing with this dementia–depression overlap, leading to under-detection of depression and mismanagement. Approximately 5%–15% of patients with LLD are mistaken to have dementia.[6] Discussion in this paper reviews evidence to address some of these clinical conundrums to facilitate better psychogeriatric care. The authors would like to state that this is by no means a detailed review of LLD as a clinical entity, as the focus is more on clinical distinction within the dementia–depression continuum based on the available evidence. For the purpose of this review, dementia (International Classification of Diseases [ICD-10]) and major neurocognitive disorder (Diagnostic and Statistical Manual [DSM]-5) will be considered synonymous. Besides, though LOD forms a subpart of the LLD spectrum and there exist clinical differences, for the purpose of simplification, LLD will be used to denote all forms of late-life depression throughout the manuscript.


  Pathological Subtypes of Late-Life Depression and Overlap with Dementias Top


LOD differs from EOD in having more structural brain changes (changes in white matter, brain ventricles), vascular changes, neurosensory and neuropsychological impairments, prevalence and incidence of dementia, and less frequent family history of mood disorders and lesser prevalence of psychiatric comorbidity other than dementia.[1],[3] There are several clinicopathological models or subtypes of LLD. They can be enumerated as: [6],[18]

  1. Depression executive dysfunction (DED)
  2. Vascular depression
  3. Depression with reversible dementia
  4. LOD (as mentioned above).


DED model is based on the hypothesis that frontolimbic disruption, manifested by executive dysfunction, predisposes to the development of LLD. The clinical features resemble those of medial frontal lobe syndrome, including executive dysfunction, apathy, psychomotor retardation, severe behavioral disability, reduced interest, and poor insight. DED presents with less of depressive cognition and vegetative symptoms. It shows poor and unfavorable response to antidepressant treatment with early relapse. Neurobiologically, there are white matter integrity disruption, white matter hyperintensities (WMHs) in executive function-related networks, reduced functional connectivity (FC) in cognitive control network (CCN), increased FC in default mode network (DMN), and lowered dorsolateral prefrontal cortex (DLPFC) activation on task challenging CCN.[3],[6],[18]

Vascular depression refers to the depressive syndrome developing in relation to some vascular event. This model originates from the finding that cerebrovascular events may precede, precipitate, or worsen LLD or maybe comorbid with it. Evidence of a preceding cerebrovascular disease, a temporal relation between the incident depression and vascular event, and the presence of vascular risk factors are required for this construct. The clinical features of depression include apathy, retardation, higher disability, and poor insight. Guilt is less commonly seen. Executive dysfunction is also common. This, too, responds poorly to antidepressant treatment. Neurobiologically, there are WMHs in subcortex, periventricular areas, and deep white matter, evidence of limbic hyperactivation, low FC in subgenual anterior cingulate cortex (ACC), high FC in dorsomedial PFC (DMPFC), reduced task-related DLPFC activation, perfusion deficits in the PFC, subcortex, and frontostriatocingulate areas, evidence of endothelial dysfunction, increased arterial thickness and endothelial stiffening, and persistently increased HPA axis activity.[1],[6],[18]

“Pseudodementia” or reversible dementia is commonly encountered in LLD, wherein the symptoms of cognitive impairment often reduce with improvement in depression. However, approximately 40% of patients having depression with reversible dementia are seen to develop irreversible dementias in 3 years. Thus, this construct calls for a detailed diagnostic workup, including neurological evaluation.[1],[6] This has however been debated as the cognitive deficits associated with LLD may not really be “pseudo” in all cases and tend to be persistent, often evolving into a neurocognitive disorder.[18]

Some dubious entities of geriatric depression proposed are masked depression, depletion syndrome, and subsyndromal symptomatic depression with and without mood disturbances. They lack sufficient evidence to justify individual diagnostic categories. Due to clinical heterogeneity in older persons, these entities are often on the “gray border” of depression–dementia overlap. Masked depression refers to the prominent presentation of somatic symptoms without active reporting of low mood by older adults. However, it has been attributed to cohort effect rather than actual diagnostic value.[19] Depletion syndrome is the group of symptoms of hopelessness, thoughts of death, lack of interest, and reduced appetite. Feelings of exhaustion, dysphoria, and sleep disturbances are also seen in the older cohort more than the younger adults.[14],[20],[21] Subsyndromal symptomatic depression with and without mood disturbances was suggested by Judd et al. in a study of samples taken from National Institute of Mental Health (NIMH) Epidemiological Catchment Area study. They proposed this entity to be characterized by any two or more symptoms of depression, simultaneously present for the majority of time, for at least 2 weeks, associated with the evidence of social dysfunction, in individuals not meeting the criteria for major or minor depression or dysthymia, leading to significant disability.[22]

Other pathophysiological models of LLD include inflammatory and genetic hypotheses. The inflammatory hypothesis states that there are increases in proinflammatory cytokines and chemokines with aging (e.g. interleukin-6 [IL-6], IL-1β, IL-1Ra, tumor necrosis factor [TNF]-α), with microglial activation, oxidative stress, and metabolic changes, enhancing vulnerability to develop LLD. There is evidence of differential response to antidepressants with inflammation status.[6],[18] Inflammation is often considered to be the “missing link” deciding the outcome of the LLD–MCI–AD continuum.[23] Genetic models of LLD are not definitive. Some roles of C677T mutation of methyl tetrahydrofolate reductase gene (related to risk of cerebrovascular lesions), serotonin 5HT2A receptor-A/A genotype (LLD in females), C1166 allele of type-I angiotensin receptor gene (white matter lesions), and ApoE4 allele (association with more severe depression) have been found.[1],[3],[6],[24] In addition, psychosocial factors such as personality attributes (neuroticism, hopelessness), cognitive distortions, low mastery, poor self-efficacy, low socioeconomic status, low education, cumulative stressful life events, bereavement, and perceived poor social support contribute to the development of LLD.[3],[8],[25]

The main diagnostic challenge encountered in the geriatric population is the differentiation between LLD and dementia because of symptomatic overlap.[2] As discussed before, cognitive impairment, particularly executive dysfunction as well as apathy, retardation, sleep disturbances, and bradyphrenia, are common findings in the LLD models of DED and vascular depression. Subjective memory impairment or reversible dementia often accompanies depression. Moreover, depression may be comorbid with dementia and depressive symptoms can be a part of behavioral and psychiatric symptoms in dementia (BPSD). LLD may not present with all the classical depressive symptoms of adult diagnostic criteria, thereby making the diagnosis difficult.[25] In this article for the purpose of clinical differentials, dementia will mainly encompass AD and VaD as these have the maximum evidence base in this regard.


  Depression as a Part of Behavioral and Psychological Symptoms of Dementia: How is it Different? Top


Depression in dementia may be a component of BPSD or a prodrome preceding cognitive decline for many years. It has been studied the most in AD, and hence, our discussion here will be majorly in the context of AD.[1],[2],[8],[14] Risk factors for developing depression in AD include vascular changes such as history of cerebrovascular disease, leukoaraiosis, leukoencephalopathy in frontostriatal and frontolimbic circuits, female sex, past history of depression, family history of depression, ApoE4 carrier status, and contributory medication use.[14] BPSD can also develop due, in addition to biological risk factors, to psychosocial and environmental issues such as sensory overstimulation or understimulation, unfavorable housing conditions, and poor caregiver support, including abuse and neglect and insight into cognitive decline.[26],[27],[28],[29] Depression in patients with dementia poses a difficulty in diagnosis due to the cognitive decline present in the patients, as well as atypical presentation of mood symptoms.[2] There may be acute deterioration in the cognitive status or physical condition with onset of depression in patients having dementia.[30] Apathy, decreased energy, decreased interest in activities, psychomotor abnormality, reduced attention, and concentration may be present in dementia, independent of depression. However, persistent sadness of mood with morning worsening, sense of worthlessness, guilt, recurrent thought of death, or suicidal ideation (as compared to vegetative symptoms) are more seen in dementia with depression than dementia alone.[6] Differentiating features of depression in dementia from depression alone are gradual and progressive course of symptoms, presence of cognitive decline, lack of concern for or denial of cognitive decline, situational mood changes including lability (in VaD), psychomotor agitation, less frequent guilt, suicidality, sleep disturbances, vegetative symptoms, and greater prevalence of anhedonia, rejection sensitivity, as well as self-pity.[2],[3],[14],[31] The neurobiological changes in AD with depression include more severe tau, amyloid pathology, vascular burden, and loss of serotonin receptors and transporter binding, as compared to only dementia. The reduction in regional cerebral blood flow in the amygdala and hippocampus is also higher in those with depression and dementia than either alone.[14] White matter lesions and temporal lobe atrophy are found to predict future development of both depression and dementia.[14] The NIMH developed a set of diagnostic criteria for depression in AD, wherein the DSM-4 depression criteria had been modified [Table 1]. Number of symptoms required for diagnosis was made to three instead of five (out of ten), with decreased positive affect and decreased pleasure merged into one, and addition of social withdrawal, irritability, and social isolation as symptoms.[32] Coming to depression in VaD, the neuropathology is often the same for both. Depression is more prevalent in VaD than AD and has a longer duration and higher severity. However, the symptomatic similarities in psychomotor retardation, decreased attention and concentration, as well as vegetative symptoms pose difficulty in differentiating vascular depression from VaD. These clinical and neurobiological overlaps are attributed by some researchers to a unified entity of vascular depression and VaD which involve arterial stiffness, vascular remodeling, intimal thickening, endothelial dysfunction, and inflammation.[33]
Table 1: National Institute of Mental Health Provisional Diagnostic Criteria for Depression in Alzheimer's Disease (adapted from Olin et al., 2002)[32]

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  Clinical Differentials: Decoding the Ambiguity Top


There is a lack of consensus regarding the differentiating features of LLD and depression in young adults. Some researchers have proposed that there is no unique symptom characteristic of old-age depression, though some depressive symptoms occur more frequently in the elderly than in the younger adults.[8] However, considering the unique biopsychosocial underpinnings of LLD, it has often been proposed as a separate clinical entity altogether. The challenge while differentiating LLD from dementia is mostly due to the notable presence of cognitive impairment and apathy. This distinction is vital as it can have several important management implications.

In an elderly presenting with cognitive complaints, based on the onset and course, three “D”s need to be evaluated for delirium, dementia, and depression. A basic evaluation framework to exclude these conditions is depicted in [Figure 2].
Figure 2: Schematic depiction of diagnostic differentials in an elderly presenting with cognitive complaints (prime considerations: 3 “D”s, Delirium, Dementia, Depression). AD: Alzheimer's disease

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In general, it is worthwhile to keep in mind certain considerations while assessing any individual with LLD [Table 2]. In many cases, a preexisting major or minor neurocognitive disorder may present when the comorbid depression leads to an exacerbation of the cognitive deficits and added disability. Subjective memory complaints may be more marked in LLD and early stage of dementia as well as MCI. Depressive ideations and vegetative symptoms are less common in LLD than young-onset depression but more prevalent compared to depression in dementia. Deficits in attention, processing speed, and verbal and visual memory are associated with LLD, while an individual with dementia can have all the preexisting cognitive deficits increased due to comorbid depression. The temporality of onset of mood and cognitive complaints provides an important clue as to whether the depressive diathesis has led to or is a part of the dementia syndrome, though such distinction is often not possible. In general, apathy, irritability, fatigue, and anhedonia with increased dependence are seen in depression/anxiety in dementia. Suicidality can be more, and insight is often impaired compared to either LLD or dementia alone.[14],[18],[34],[35]
Table 2: Considerations in history and physical examination while evaluating late-life depression

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The classic concept of depressive pseudodementia may manifest in LLD, especially with comorbid chronic medical illness and frailty. This is often confused with the clinical phenotype of “depression with reversible dementia.” Ideally, such pseudodementia is characterized by: [34]

  • More subjective cognitive complaints
  • Higher difficulties with attention, concentration, and recent memory
  • Discordance of memory and activity reports between patients and caregivers
  • Poor efforts during cognitive testing
  • “I do not know” or “I cannot remember” answers
  • Sequential assessments show inconsistent performances in cognitive tests.


Important to understand, that it is always necessary to grasp a holistic clinical picture and supplement it with tailored investigations rather than prelabeling an individual with cognitive deficits as “dementia,” as that brings in distress to the patient and his/her family, a guarded prognosis, and therapeutic nihilism. There is no substitute for a systematic history from multiple sources and detailed physical as well as neurocognitive examination.

We attempt to lay down some pointers to clinically differentiate between LLD, dementia, and depression (BPSD) in AD [Table 3]. In some cases, however, these symptoms occur on a continuum, and there are no water-tight categories.[1],[2],[3],[8],[14],[31]
Table 3: Clinical differentials between late-life depression, dementia, and depression in Alzheimer's dementia

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Let us look at a couple of case vignettes to have a practical idea of the possible clinical conundrums [Table 4].
Table 4: Case vignettes

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While Case Vignette 1 depicts how a possible MCI appeared clinically as mild dementia due to the overshadowing LLD, Case Vignette 2 highlights how a chronic and recurrent depressive syndrome can eventually lead to AD over the longitudinal course. These examples are common in the practice of geriatric psychiatry and are only few of the numerous similar confusing scenarios that can arise in the depression–dementia overlap.


  Assessments to Clinically Differentiate Top


In geriatric patients presenting with symptoms of depression with or without cognitive impairment, a detailed evaluation needs to be carried out, including psychiatric, medical, surgical, cognitive, social, environmental, and treatment history, thorough physical, especially neurological, examination, cognitive status evaluation, and laboratory investigations and neuroimaging to rule out contributory factors and other investigations as indicated (The readers are encouraged to go through the clinical psychiatry guidelines of comprehensive geriatric assessment by the Indian Psychiatric Society [IPS]).[36] In this article, we shall specifically focus on the intersections of LLD, dementia, and depression in dementia.

Although the most commonly used assessment tools for depression (Hamilton depression rating scale [HAM-D], Montgomery Asberg Depression Rating Scale (MADRS), and Beck Depression Inventory [BDI]) were developed in the context of adults and not the geriatric age group, several screening and diagnostic instruments have become available to assess depression in the older population with or without cognitive impairment [Table 5]. These are the most studied and well validated in the geriatric age group.[37],[38],[39],[40],[41],[42],[43] In addition, scales such as HAM-D, BDI-II, MADRS, and Patient Health Questionnaire-9 can be used for assessment.[31] Validated inventories are there to assess depression as a part of BPSD, such as neuropsychiatric inventory, behavioral pathology in AD rating scale, Manchester and Oxford Universities Scale for the psychopathological assessment of dementia, and Columbia University Scale to assess psychopathology in AD.[3],[8] Geriatric depression scale is commonly used as a screener for depression in the elderly and has been validated in the Indian setting. However, it is not sensitive to pain, somatic complaints, and health-related preoccupations which are common in LLD and is also not used for assessing depression in dementia.[1],[14]
Table 5: Commonly used screening and diagnostic assessment tools for geriatric depression and depression in dementia

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In the neuropsychological assessment, the classical finding reported in depression is the reduction of processing speed, thinking capacity, attention, and concentration, termed debatably as “pseudodementia.” More answers such as “I do not know” or “I cannot do” are observed on structured cognitive assessment, suggestive of poor motivation. However, persistent dysfunctions of other domains of cognition, including memory and executive function, are also seen in depression.[45] LLD, especially LOD, may present with more cognitive deficits than young-age depression. The deficits usually, however, do not amount to the extent observable in dementia. In depression with AD, the cognitive impairment may be higher than in either alone, and often, the pattern of cognitive deficit in LLD with or without MCI (say, episodic memory impairment) predicts future development of dementia. In addition, there may be cognitive deficits as noted in the pathological LLD models, such as executive dysfunction and profound impairments in attention and concentration.[18],[46],[47]

Research in LLD and dementias in the recent past has focused on laboratory and neuroimaging biomarkers. Some useful investigations needed in assessment of LLD (also in dementia) are: [3]

  • Complete blood count– to rule out anemia
  • Thyroid function test – T3, T4, thyroid-stimulating hormone, radioactive iodine uptake
  • Vitamin B12 and folate levels
  • Routine blood biochemistry
  • Electrocardiograph (for antidepressant use)
  • Computerized tomography (CT) scan or magnetic resonance imaging (MRI) of the brain for excluding structural/vascular/infective lesions (MRI is preferred over CT for better resolution and gray-white matter differentiation)
  • Polysomnography (PSG) (for persistent unexplained sleep disturbance and rapid eye movement-sleep behavior disorder)
  • Electromyography (EMG) and nerve conduction study (NCV) (if peroneal nerve palsy is suspected, which may occur in the depressed elderly due to weight loss and psychomotor retardation).


PSG, EMG, and NCV are used rarely only in certain selected cases.

However, it is difficult to point out any one diagnostic investigation to differentiate LLD from dementia. The composite clinical understanding is dependent on the holistic picture rather than a single investigation in vacuum. It is proposed that certain brain changes in LLD may be predictive of later development of dementia, particularly AD. Overall, neuroimaging and cerebrospinal fluid (CSF) biomarkers findings relevant to LLD–dementia discrimination are mentioned below. Neuroimaging modalities may be useful in day-to-day clinical practice, with structural MRI being a preferred baseline evaluative tool for a diagnostic confusion.

Structural neuroimaging[3],[8],[14]

  • Volumetric reduction and cortical thinning of several brain structures such as PFC, orbitofrontal cortex, anterior cingulate cortex (ACC), amygdala, thalamus, basal ganglia, hippocampus, and parahippocampal gyrus are seen in LLD (hippocampal atrophy and ventricular enlargement are shared by LLD and AD)
  • WMH, microinfarcts, and microhemorrhages may be present in frontal subcortical circuits in LLD (vascular changes may be shared by vascular depression and VaD, but not as obvious in AD), compared to more of periventricular WMH in normal aging
  • Ischemic deep white matter lesions are found more in DLPFC in LLD (compared to nondepressed elderly). These can be visualized best with T2 sequences and FLAIR
  • Structural connectivity: Diffusion tensor imaging (DTI) has shown disruption of microstructural integrity in the superior longitudinal fasciculus, uncinate fasciculus, cingulum, and corpus callosum as important markers of vascular depression, which in turn predicts progression to vascular dementia.[48] Processing speed, verbal fluency, and working memory are the main neuropsychological correlates of the same. Further, DTI findings are also correlated with WMH in genu, hippocampus, dorsal ACC, precuneus, hypothalamus, amygdala, and other paralimbic regions. The white matter lesion burden and lesion severity are the two most important parameters deciding executive function deficits and response to treatment.[49] AD Neuroimaging Initiative findings show that early DMN involvement in LLD can be a predictor of progression of dementia. On the other hand, vascular pathology so common in LLD can affect progression of preexisting AD pathology both through amyloid-beta (Aβ) dependent and independent mechanisms.[50]


Functional neuroimaging[6],[14]

  • LLD is usually conceptualized as a disorder affecting reward, cognitive, and salience networks[1]
  • Higher regional cerebral blood flow is noted in amygdala and hippocampus in LLD (versus dementia) on single-photon emission computed tomography (SPECT) (diagnostic accuracy of SPECT in distinguishing between LLD and dementia is 86%)
  • There is an absence or a relative lack of identifiable Aβ pathology on [18F]-flutemetamol amyloid positron-emission tomography (PET) in LLD (versus AD)
  • Significantly reduced uptake is seen in temporoparietal regions on [18F]-fluorodeoxyglucose PET in AD (versus LLD); glucose uptake patterns in LLD are more non-specific and heterogenous across cortex and subcortex
  • Functional MRI (fMRI) shows DMN overactivity (associated with negative self-referential ruminations) and increased FC between DMN and subgenual PFC in LLD (versus moderate decrease of DMN-FC between posterior cingulate cortex and right hippocampus and global reduction of DMN-multiscale entropy in AD).[14],[51] Some typical fMRI findings in depression are DMN dominance over the Central Executive Network (CEN), dysfunction of salience network-mediated switching between the DMN and CEN, and reduced CEN modulation of the DMN.[52] Insular hypometabolism, task-based deactivation of the DMN, decreased FC between limbic and dorsal cortical structures, and DMN–CEN disconnection have been posited as possible functional biomarkers of the “network dysfunction” in LLD.[53] Cerebellar FC differences (at vermis) with DMN, CEN, and Salience Network (SN) are seen more often in LLD than dementia.[54] Functional disconnection between anterior and posterior DMN regions and reduced global connectivity has been studied to be markers of persistent cognitive deficits in LLD, hence increasing the risk of dementias[53]
  • Increased left hippocampal and decreased right hippocampal FC with other brain regions involved in mood regulation is present in LLD (as compared to a globally reduced connectivity in amnestic MCI)[55]
  • Nondemented depressed older persons have reduced bilateral activation of dorsal ACC and hippocampus on word-activation task.


Cerebrospinal fluid markers[6],[14]

  • CSF Aβ-42 is significantly higher in LLD versus AD
  • CSF phosphorylated tau and total tau levels are significantly higher in AD versus LLD
  • CSF Aβ-42 and tau levels in LLD are comparable to controls.


From the above discussion, it is apparent that we still have a long way to go in determining an unequivocal biomarker for LLD differentiating it from dementias, and as of now, the differentiation depends on a sound clinical understanding. Moreover, other dementias are not as much studied as AD in this light. The presence of certain unique investigative pointers however encourages future research in this direction.


  Differences in the Management Strategies Top


Treatment of LLD follows the line of treatment in young adults, with certain restrictions regarding the choice of medication, dose, and duration. The clinical course of LLD is much like that in young adults, though relapse and recurrence are said to be higher.[3],[18],[56] Poorer outcome, including mortality, is noted with comorbid chronic medical diseases and functional impairment. Further, low-grade depression and incomplete remission may be chronic in older persons even after treatment that leads to subsyndromal depressive symptoms, common in the community. Depression in AD may often resolve spontaneously or with less intensive treatment, whereas that in VaD is more chronic and often refractory to treatment.[3] Severity of depression, nonmelancholic features, history of long duration of episode (past or current episode), presence of delusion, poor self-rated health, and poor social support are predictors of chronicity in LLD. Relapse and recurrence are predicted by history of frequent episodes, late age of onset, history of dysthymia, intercurrent medical illness, and high severity and chronicity of the index episode.[6]

The consensus on treatment is that a combination of psychotherapy and pharmacotherapy is often better than either alone in LLD. It is suggested that LLD responds less well to antidepressants and has a high relapse risk as compared to young adult depression.[18] The details of LLD treatment guidelines are beyond the scope of this chapter. The readers are suggested to go through the IPS Clinical Practice Guidelines for treatment of depression in the elderly, which provides a detailed discussion on treatment algorithms and antidepressant considerations in LLD.[31] However, a brief overview is provided below.

The pharmacological treatment options include selective serotonin reuptake inhibitors (SSRIs) (citalopram, escitalopram, sertraline, and fluoxetine), serotonin noradrenaline reuptake inhibitors (venlafaxine, duloxetine, and levomilnacipran), mirtazapine, bupropion, and tricyclic antidepressants (desipramine and nortriptyline). SSRIs are usually the first-line unless contraindicated. Monoamine oxidase inhibitors (phenelzine, tranylcypromine) are sometimes used in a very restricted number of cases where other treatments are ineffective or not tolerated.[3],[6],[31] The psychotherapeutic options are problem-solving therapy (PST; more rational in the context of executive dysfunction), cognitive behavioral therapy (CBT; for cognitively intact depressed elderly), behavioral activation (BA), interpersonal therapy (useful due to high prevalence of bereavement in this age group), problem adaptation therapy (PATH; in depression and moderate cognitive impairment), brief dynamic psychotherapy, and ecosystem-focused therapy (EFT; developed in poststroke depression).[6] CBT, BA, and brief dynamic psychotherapy are found equally efficacious in LLD.[3] Research domain criteria group, NIMH, has proposed “Engage” psychotherapy based on the neurobiological domains affected in LLD. It focuses on assessing and targeting negativity bias, apathy, or emotional dysregulation in response to reward exposure in depressed individuals via psychotherapy.[57]

In treatment-resistant depression (TRD), catatonia, comorbid PD, inability to tolerate antidepressants, or acute suicidality, electroconvulsive stimulation treatment (ECT) can be administered. Right unilateral, ultra-brief pulse, high-dose ECT is a common and safe choice in the elderly. Other neurostimulation methods such as vagal nerve stimulation and transcranial magnetic stimulation are not mainly studied in LLD, and the efficacy results are usually extrapolations of findings of adult study.[6] Maintenance ECT with continued pharmacotherapy has been found more efficacious in preventing relapse.[58] Treatment is suggested to be continued in LLD for at least 6 months after symptom remission and usually 2 years due to higher risk of relapse.[6],[59] Essential to note, retrograde amnesia caused by ECT can be more pronounced in older adults and persistent cognitive deficits may be seen in some cases, especially in someone with preexisting mild or major neurocognitive disorder.

Treatments targeting the models of LLD have insufficient evidence as of now (dopamine D2/D3 agonists and computerized cognitive remediation in DED, modification of risk factors in vascular depression with possible role of angiotensin receptor blockers and calcium channel inhibitors, and anti-inflammatory agents and cytokine inhibitors, such as celecoxib and infliximab, in LLD with increased inflammatory markers).[18]

Role of antidepressants in treating depression in AD is doubtful. Some studies have found mild-to-moderate short-term efficacy though not sustained in the long run. Depression in AD trial (DIADS)-1 found significantly more benefit with sertraline than placebo, given for 12 weeks, in depression in AD, whereas DIADS-2, continued on the remitted individuals for 12 more weeks, found no superior efficacy for sertraline.[60],[61] Similarly, Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia found no more benefit with sertraline or mirtazapine than placebo in treating depression in AD.[62] The National Institute of Health and Care Excellence 2018 guidelines recommend psychological treatments for mild-to-moderate depression/anxiety in people living with mild–moderate dementias.[63] Routine use of antidepressants is specifically discouraged unless indicated for a preexisting severe mental illness. Further, personalized multicomponent interventions are recommended for sleep problems with or without depression, which includes routine exercises and exposure to sunlight.

In view of the evidence, the suggested first-line treatment for depression in AD is usually psychological, such as PATH, caregiver-focused treatment, PST, and brief supportive therapy. Lifetime reminiscence and validation therapy have also shown to help depression in AD.[14] Neuroplasticity-based computerized cognitive remediation therapy targeting specific neurobiological deficits has modest evidence in treatment-resistant LLD (more in DDS phenotype) and subcortical dementias. This again is an evidence for the underlying common network abnormalities in executive dysfunction and late-life depressive syndromes.[64] Depending on response to psychotherapy, severity of depression, imminent risk of harm, functional impairment and disability due to depression, and patient and/or caregiver preference, judicial use of antidepressant can be permitted. There is some evidence of reduction in brain amyloid load with antidepressants in AD. However, the duration of use of antidepressant in context of AD is not very well formulated, and it is usually recommended to use the drugs for a short term.[6],[18] Certain specific management considerations while dealing with depression in dementia are highlighted in [Table 6].
Table 7: Suggested reads on depression-dementia conundrum for further study

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Finally, the primary preventive strategies of both all-cause dementia and LLD overlap significantly due to the common risk factors. Recently, the 2020 Lancet Commission Report on “Dementia Prevention, Intervention, and Care” mentioned about 12 modifiable risk factors based on a life-course approach which accounts for 40% theoretical risk of worldwide dementias.[65] Most of the mid-life (hypertension, alcohol consumption >21 units/week) and late-life risk factors (smoking, diabetes, obesity, and physical inactivity) are related to lifestyle modification and vascular vulnerabilities, which if modified are also hypothesized to help depression.[18] Primary care screening for depression, early detection, infection control, collaborative care, and adequate management are known to reduce cognitive decline in older adults.[66] Especially in low-resource countries, novel and large depression prevention trials such as “Depression in late life” conducted in Goa, India, involving nonspecialist lay health workers have been shown to improve quality of life and disability in the community geriatric population.[67] Whether such interventions have a long-term effect in reducing the progression to dementia stays as a question of further longitudinal research.

The bottom-line remains: In diagnostic doubt of whether comorbid depression exists with a neurocognitive disorder, it is always recommended to adequately treat the depression and then assess the cognitive status at least 6 months after remission of depressive symptoms.[59] Overtreatment of depression in this regard is often suggested as the underlying cognitive deficits may be reversible and may have been exaggerated by the coexisting LLD. Appreciation of this bidirectional relationship is vital.


  A Complex-Continuous Conundrum Top


Depression is frequently comorbid with both MCI and dementias, as already mentioned earlier. These three constructs of LLD, MCI, and dementia (especially AD) are often argued as not being categorically distinct. EOD and LOD, according to some authors, are known to increase the risk of incident dementia.[2],[14],[16] There is disagreement among researchers regarding LLD being a predictor of conversion of MCI into dementia.[68],[69] In one study, patients with MCI, who developed AD, were found to have more apathy and anxiety over 2 years.[70] MCI and LLD are considered to share the pathogenic pathway in two possible ways. The first is the accumulation of AD neuropathology with concurrent cerebrovascular disease burden over years, leading to manifestation of MCI, on being coupled with depressed mood and reduced brain reserve. The other is the role of cerebrovascular diseases in causing LLD and MCI, more in the domains of vascular cognitive impairment (e.g. executive dysfunction). Vascular depression is in fact often comorbid with recurrent strokes which in turn can lead to vascular dementia. Other mechanisms include depression being an early sign of MCI, sometimes unmasking and sometimes overlapping it.[16] Similarly, high but varying incidence of depression, from 11.7 to 26.6/100 person-years, is found in several studies in patients with MCI.[15],[16] The variation is mostly attributed to different diagnostic tool use. The depression–MCI–dementia continuum is not linear. Often, someone who presents with a first episode of LLD (Case Vignette 2) undergoes incomplete remissions, psychosocial stressors, polypharmacy, side effects of medications, chronic subsyndromal depressive symptoms, fluctuating cognitive deficits, and impaired independent functioning and then eventually slides into the spectrum of a major neurocognitive disorder.

It has been shown that hippocampal atrophy and episodic memory impairment, when observed in LLD (with or without MCI), predict long-term risk of development of AD. Depression may lead to dysfunctional glucocorticoid cascade, leading to serotonin and noradrenaline dysfunction, hippocampal atrophy, and further, cognitive impairment.[16] Persistent sleep disturbance in LLD has a deleterious effect on neuronal activity, leading to a chronic increase in soluble Aβ further increasing the risk of amyloid plaque formation, a pathological process noted in AD. Depression with sleep disturbance is seen to increase the risk of AD by about threefold. This interconnection among LLD, sleep disturbance, and dementia is stronger in those with ApoE4 carrier status.[14] DMN hyperactivity, as noted in depression, is also found to increase neuronal activity and Aβ release (link with tau release is doubtful) on amyloid-PET imaging with Pittsburgh compound-B. On the other hand, Aβ deposition is seen to be associated with significantly reduced FC between precuneus and hippocampus. These findings point at a bidirectional relationship between DMN activity and the risk of AD.[14],[71] LLD and dementia are thought to share another possible pathogenetic mechanism. White matter changes and temporal lobe atrophy are predictive of development of both depression and dementia, as mentioned earlier in the text. Worsening WMH is prognosticative of nonremission in LLD over 2 years and of cognitive decline over 5 years.[6] It is also noticed that older depressed adults with moderate-to-severe treatment resistance have higher amyloid burden, than milder and treatment-responsive depression, in parietal, temporal, occipital cortices, and precuneus. The amyloid-PET studies have shown amyloid pathology in TRD to be typically similar to AD pathology.[14] This argues for treatment-resistant LLD to be a prodrome or pointer of AD. Despite the presence of some distinguishing features between LLD and AD on SPECT, the changes often overlap. Clinically, two kinds of trajectories are seen. Some patients with LLD develop MCI or AD over the course of time, as discussed earlier. However, there are up to 30% of those diagnosed with LLD who continue to have chronic major depression over 1–6 years and almost 40% stay in partial remission.[6] All these findings suggest that LLD, MCI, and dementia possibly persist on a clinicopathological continuum though further research is warranted to elucidate more definitive biomarkers unique to each pathological state.


  Conclusion Top


This paper essentially tries to simplify the depression–dementia conundrum for facilitating clinical management and monitoring. Few related reviews/discussions related to the subject are included in [Table 7] to guide the readers for additional information. To summarize, LLD, MCI, and AD are interdependent entities, one often begetting the other throughout the course. LLD can be conceptualized as a prodrome or risk factor of MCI and dementia or may be comorbid with the same. Although there is conflicting evidence regarding the precise cause–effect relationship between these three, it is likely that these constructs share some common pathological processes and are more often associated with each other than not. A recent systematic review by Brzezinska et al. highlights that genetic polymorphisms are likely to explain the “variances in shared phenomenology” between these three conditions.[75] The authors also hypothesize that when these clinical entities occur together, the order in which they present clinically or are detected depending on individual physical condition, neurocognitive reserves, medical history, inflammatory diathesis, and frailty. Thus, it is preferable to direct the clinical management and research in this arena in a comprehensive way rather than pigeonholing the diagnoses. Patients presenting with LLD must undergo a comprehensive cognitive and mental status examination cross-sectionally and longitudinally with special emphasis on social functioning, family support, instrumental activities, and temporal evolution of symptoms. Similarly, those with MCI should be evaluated for neuropsychiatric symptoms, especially, depression, anxiety, and apathy, for a better management and prognostication. Comorbid depression often exaggerates the cognitive deficits making MCI appear as mild AD or mild dementias appearing as moderate (Case Vignette 1). Hence, in clinical ambiguity, it is always better to treat the depression adequately and then monitor for the cognitive status, change in functioning, and quality of life. Research needs to be aimed at identifying an accurate clinical and pathological relationship among LLD, MCI, and all-cause dementias, thereby paving the path toward better clinical distinction, prevention, and treatment.{Table 7}

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