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Depression versus dementia: is this construct still relevant? Zahinoor Ismail*,1,2, Arfeen Malick3, Eric E Smith1, Tom Schweizer2,4 & Corinne Fischer2,4
Practice points ●●
S creening for cognitive impairment in late-life depression is an important clinical step in determining risk of dementia.
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ognitive screening should involve a robust screening instrument that assesses multiple cognitive domains, C including executive function.
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Vascular illness can be an important predictor of dementia.
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Depression in mid- and late life may increase the risk of incident dementia.
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Late-life depression may be a prodrome to Alzheimer’s dementia.
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SUMMARY Cognitive impairment has long been identified as a component of late-life depression (LLD), and depressive symptoms are common in neurodegeneration. Depression may confer a greater risk of cognitive decline in a cognitively intact population and further cognitive decline in a mild cognitive impairment population compared with those without depression. Exploration of the link between cognitive impairment in LLD and the depressive features of neurodegeneration is an essential part of a diagnostic algorithm. In this article, we will discuss these links; we will address depressive symptoms as a risk factor for dementia and as a prodrome to dementia. We will review clinical subtypes and imaging markers as predictors of development of dementia in depressed patients and explore vascular etiologies. We will also explore LLD and dementia as a spectrum, rather than mutually exclusive diagnostic entities. Depression and cognition are intimately connected. Cognitive impairment has long been identified as a component of late-life depression (LLD), with a prevalence of mild cognitive impairment (MCI) in LLD as high as 54% [1] . Depressive symptoms are common in
neurodegenerative illness, with prevalence rates in MCI of 20% for major depression (MD) and 27% for minor depression [2] . In Alzheimer’s disease (AD), up to 30% of patients have a diagnosis of major depressive disorder (MDD) [3] and up to 40% of patients with dementia
Hotchkiss Brain Institute, University of Calgary, Calgary, Canada University of Toronto, Toronto, Canada 3 Faculty of Medicine, University of Calgary, Calgary, Canada 4 Keenan Research Centre of the Li Ka Shing Knowledge Institute, Toronto, Canada *Author for correspondence: [email protected] 1
ure UK
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Special Report Ismail, Malick, Smith, Schweizer & Fischer are treated with antidepressants [4] . Depression may confer a greater risk of cognitive decline in a cognitively intact population [5] and further cognitive decline in an MCI population [6] compared with those without depression. Confounding the understanding of LLD is the fact that depressive symptoms in late life may not be stable or persistent, and have variable trajectories [7] . A common clinical dilemma is how to approach cognitive impairment in the context of LLD – understanding subtypes of LLD with respect to cognitive impairment may have treatment implications. It may be a challenge to diagnose depression among patients who present with recent development of cognitive complaints and symptoms rather than with depressed mood. Successful treatment with antidepressants resulting in remission of cognitive symptoms may confirm the diagnosis of depression in such patients. Not addressing reversible or treatable cognitive impairment in depression can lead to an inappropriate diagnosis of dementia or poorer outcomes. Conversely, missing underlying neurodegenerative conditions manifesting as depression can delay dementia diagnosis and treatment, and result in prolonged suffering and diagnostic uncertainty. Thus, exploration of the link between cognitive impairment in LLD and the depressive features of neurodegeneration is an essential part of a diagnostic algorithm. In this article, we will discuss these associations. We will address depressive symptoms as a risk factor for and prodrome to dementia, as well as the role of vascular pathology in connecting depression and dementia. Finally, we will review clinical subtypes and imaging markers as predictors of development of dementia, to help guide the clinician in the diagnosis. Depression as a risk factor for dementia A number of studies have assessed the link between a history of depression and the onset of MCI and dementia [8–12] . A systematic review and meta-analysis by Ownby and colleagues assessed the link between depression and AD. They found an odds ratio (OR) of 2.03 in case–control studies and 1.90 in cohort studies for an increased risk of developing AD in subjects with a history of MDD. Furthermore, a longer interval between diagnoses of depression and AD conferred a greater risk of developing AD, suggesting that depression may be a remote risk factor for AD [13] . More recently
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in a meta-analysis of 12 longitudinal studies, Gao and colleagues assessed the association between depressive symptoms at baseline and the incidence of MCI and depression. In comparison with nondepressed older adults, those with depression had a higher relative risk (RR) of MCI (RR: 1.97), AD (RR: 1.66), vascular dementia (VD; RR: 1.89) and any dementia (RR: 1.55) [14] . Studies also suggest that the risk of developing dementia increases with the number of inpatient depressive episodes [15] or episodes that are self-reported [16] . These findings are supported in a systematic review and metaanalysis by da Silva and colleagues, concluding that greater frequency and severity of depressive episodes seem to increase the risk of dementia [17] . Furthermore, a prospective cohort study of 126 cognitively normal older adults with 20-year follow-up demonstrated that the degree of depressive symptoms at baseline predicted the time to development of MCI. An increase in Geriatric Depression Scale 30 scores of 1 standard deviation (3.85 points) was associated with shortening of the median time to conversion to MCI by 25.4% in APOE ε4 noncarriers, but not in APOE ε4 carriers [18] . However, even minor depression has been shown to increase risk of dementia. Using data from a populationbased cohort study of prevalence and incidence of dementia in subjects aged 70 years and over, Vilalta-Franch and colleagues demonstrated late-onset depressive episodes with depression and executive dysfunction are risk factors for dementia and AD development, regardless of the severity of the depression [19] . Studies have also demonstrated a link between depression and hippocampal volume loss [20,21] . A recent meta-analysis demonstrated that individuals with a history of MDD had significantly smaller left and right hippocampal volumes, while their total cerebral volume remained the same [22] . In post-mortem studies of AD patients, those with a history of depression demonstrated greater hippocampal amyloid plaque and neurofibrillary tangle burden and more rapid cognitive decline compared with controls without depression [23] . In another autopsy study of AD patients, more pronounced cortical neuro fibrillary tangle pathology was found in patients who suffered from AD with comorbid depression compared with those AD patients without depression [24] , further strengthening the link between depression and AD neuropathology.
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Depression versus dementia: is this construct still relevant? Understanding the neurobiology of depression may help provide insight into the possible links between depression history and risk of MCI and dementia. A major feature of MDD is the hyperactivity of the HPA axis leading to dysfunctional secretion of glucocorticoids from the adrenal cortex. In MDD patients, high levels of cortisol lead to impaired negative feedback control of the HPA axis, resulting in hippocampal damage [25] . In addition, the degree of hippocampal volume reduction correlates with the duration of MDD, with some evidence suggesting that antidepressants may reverse this atrophy [26] , highlighting the potential importance of early clinical intervention in MDD. Similarly, pathology is seen in AD where hypercortisolemia due to abnormalities at multiple levels of the HPA axis results in glucocorticoid-dependent neurodegeneration [27] . Moreover, AD patients with higher plasma cortisol levels demonstrate a more rapid disease progression [28] . One of the proposed mechanisms that links HPA axis dysfunction and AD is the ‘glucocorticoid cascade hypothesis’. This hypothesis proposes that a hyperactive HPA axis in AD creates hippocampal damage, leading to dysfunctional glucocorticoid negative feedback and eventually increased glucocorticoid levels [29,30] . Continuously elevated cortisol levels have been shown in AD transgenic mice models to be associated with amyloid-β (Aβ) and tau toxicity, the hallmark neuropathological features associated with AD [31] . Stress and sustained elevations in glucocorticoid levels have also been shown to drive amyloid precursor protein misprocessing, generating increased Aβ metabolism in the hippocampus and prefrontal cortex, as well as aberrant tau hyperphosphorylation [32,33] . Serotonergic transmission may also be linked to the association between depression and dementia. Activation of the 5-HT4 receptor increases the secretion of the nonamyloidogenic soluble Aβ protein precursor that exerts a protective effect against Aβ42-induced neuronal death. Recent studies have shown an association between decreased levels of this receptor and depression vulnerability. According to these observations, low levels of 5-HT4 receptor would both predispose to depression and to increased secretion of the Aβ1–42 peptide [34] . Thus, one can speculate that a history of MDD may either initiate or accelerate hippocampal atrophy as well as production of Aβ and phosphorylated tau, increasing the risk of dementia in the future. The potential
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protective role of antidepressants has also been assessed in Danish linked database analyses of depression treatment and dementia outcomes. Kessing and colleagues demonstrated that longterm antidepressant use may decrease the incidence of some types of dementia in a general population prescribed antidepressants [35] and patients discharged from inpatient psychiatric care [36] . AD pathogenesis has also been associated with neurovascular dysfunction, highlighting the role of vascular risk factors such as cigarette smoking, diabetes, hypertension and cardiovascular disease in AD progression. These risk factors are often present in older adults with depression. The ‘vascular depression hypothesis’ [37,38] , posits that cerebrovascular disease predisposes, precipitates, or perpetuates some geriatric depressive syndromes. This vascular burden affects fronto-striatal circuitry resulting in depression and associated cognitive impairment, especially executive dysfunction. LLD exhibits a more vascular neuropsychological profile than chronic and recurrent depression [39,40] . Examining the implications of vascular disease in both AD and depression, a recent study demonstrated that higher vascular risk scores predicted lower cognitive functioning in individuals treated for depression [41] . Depression as a prodrome to dementia Interestingly, LLD has also been hypothesized to be a prodrome to neurodegenerative diseases. This has been a topic of ongoing debate as the two may be difficult to differentiate. Examining current research, a number of studies have found a higher risk of dementia in those with a history of depressive episodes closer in proximity to dementia onset [12,42–45] . Additionally, in a recent Swedish study, it has been shown that LLD increases the risk of dementia up to three times [46] . Moreover, this study demonstrated that each 1-year increase in difference between depression onset and dementia onset decreased the likelihood of dementia by 8.4%. Additional support for the prodromal hypothesis can be seen in the analysis of the 2005–2011 National Alzheimer’s Coordinating Center – Uniform Data Set (NACC–UDS), which demonstrated that AD patients had a significant increase in depressive symptoms and functional impairment prior to AD diagnosis independent of dementia-related cognitive impairment [47] . The findings from this data suggest that depression
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Special Report Ismail, Malick, Smith, Schweizer & Fischer and functional decline could serve as markers for earlier AD detection. With respect to differentiating between dementia subtypes, Barnes and colleagues demonstrated that patients with LLD had a twofold increased risk for AD, while subjects with both midlife and late-life symptoms had more than a 3.5-fold higher risk in vascular dementia [8] . This implies that depressive symptoms in midlife or in late life are associated with higher risk of progression to dementia. While chronic depression (both midlife and late life) seems to be a risk factor for vascular depression, depression that occurs for the first time in late life could be implicated as a prodrome to AD. Neuroimaging biomarkers Neuroimaging studies tend to identify associations between depression and: regions that are also vulnerable to neurodegeneration in AD (e.g., hippocampus); and brain regions subserving executive functions, which might impair executive function and predispose to further cognitive impairment. Further consistent themes in neuroimaging studies are the impact of persisting cognitive impairment, the role of vascular burden and the involvement of fronto-striatal circuitry in identifying features of LLD associated with increased risk of cognitive decline. A number of structural studies have attempted to identify neuroimaging correlates of LLD and cognitive impairment. A case–control study of 139 depressed elderly subjects found that 54% met neuroimaging criteria for subcortical ischemic vascular depression (SID), which may be seen as specific type of LLD. In this cohort, age was associated with SID, in which case there was less likelihood of having a family history of depression [48] . A citalopram treatment study compared 22 older adults who achieved remission for MD versus 19 subjects who had persistent symptoms. MRI demonstrated decreased dorsal and rostral cingulate volumes in the nonremitters, potentially providing a marker for treatment resistance to serotonergic medications and defining a different subtype of LLD [49] . A longitudinal study of 90 depressed and 72 nondepressed healthy older adults demonstrated greater left hippocampal atrophy at 2 years in the depressed subjects. This hippocampal change was associated with subsequent cognitive decline in the depressed group, despite comparable Mini-Mental State Examination (MMSE) scores at baseline [20] . The interactions between LLD and aMCI were assessed in an MRI study.
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Older adults with clinically significant depression were compared with those with aMCI, LLD and coexisting aMCI and normal controls. The interaction between LLD and aMCI was associated with volume loss in the right inferior frontal gyrus (IFG)/anterior insula and left medial frontal gyrus. The authors suggested that the coexistence of these clinical phenotypes is a potential marker for higher risk of AD [50] . Tensor-based morphometry was used to assess the neuroanatomical changes associated with depressive symptoms in MCI. Using the Alzheimer’s Disease Neuroimaging Initiative database, patients with MCI and depression (n = 44), nondepressed with other neuropsychiatric symptoms (n = 3) and no symptoms (n = 106) were compared at baseline and 2-year follow-up. Depressive symptoms were associated with greater white matter atrophy in frontal, parietal and temporal regions, increased cognitive decline and higher rates of conversion to AD, even more so if depressive symptoms were persistent at 2 years [51] . It was suggested that the white matter changes elucidated by the presence of depressive symptoms may be interpreted as a shared early pathological process of AD rather than representative of neuroanatomical changes associated with depression alone. Functional neuroimaging has also been instructive in linking LLD and cognitive decline. A 2-year longitudinal study of LLD used fMRI with an executive function task. For patients who had persisting cognitive impairment from baseline to end point, there was decreased activation at baseline in the dorsal ACC, hippocampus, inferior frontal cortex IFC and insula compared with patients without persisting cognitive impairment, and this group was felt to be at risk for further cognitive decline [52] . Using FDG-PET, a Korean study compared 18 subjects with MCI and depression to 18 with MCI and no depression. Depressed MCI subjects showed lower glucose metabolism in the right superior frontal gyrus (SFG) than nondepressed subjects [53] . Similarly, the same researchers studied an AD population and FDG-PET was used to compare 12 depressed patients to 12 nondepressed patients. The depressed AD group showed lower glucose metabolism in the right SFG [54] . A confound in the assessment of depression is the presence of apathy. A SPECT study of 81 AD patients compared depressed, nonapathetic subjects (D+) to apathetic, nondepressed subjects (A+). D+ subjects had significantly lower perfusion in the right orbitofrontal cortex (OFC) and
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Depression versus dementia: is this construct still relevant? IFG than nondepressed (D-) subjects, whereas A+ subjects had lower perfusion in the right amygdala, temporal, posterior cingulate, superior frontal, postcentral and left superior temporal gyrus compared with nonapathetic (A-) subjects [55] . Cognitive predictors Clinically, being able to differentiate between depression and dementia has been an important step to ensure effective management. Given the fluidity between the two diagnoses, this can prove challenging. Evidence supports the use of cognitive predictors in identifying patients with depression who are at higher risk for further cognitive decline. Screening elderly patients for cognitive changes is frequently carried out using the MMSE despite the fact that is biased by language, education and culture, and is insensitive to frontal-executive changes [56] . For detecting cognitive changes in LLD, Rajji and colleagues assessed the sensitivity and specificity of the MMSE in comparison to the Mattis Dementia Rating Scale (DRS). The results of this study demonstrated 99.4% specificity but only 8.0% sensitivity, implying that the MMSE alone may not be an adequate tool for screening cognitively impaired LLD patients [57] . When measured with neuropsychological testing, studies have demonstrated significant cognitive impairment in LLD, especially in the domains of processing speed and executive function [58,59] . The term ‘depressive pseudodementia’ refers to depressed elderly patients with reversible cognitive impairment and this has been identified as a strong predictor of dementia. Neuropsychological predictors have been studied in terms of identifying depressive patients who are at higher risk of progressing to dementia. In one early study, patients who experienced comorbid cognitive impairment and depression were shown to have a 4.69-fold greater risk of progressing to dementia than those patients with depression and no cognitive difficulties at a mean of 34-month follow-up [60] . In a 1-year longitudinal study of 56 nondemented subjects aged 60 years or older who initially presented with an episode of nonpsychotic unipolar major depression and 40 nondemented, age- and education-equated comparison subjects with no history of depression, 45% of the LLD subjects remained cognitively impaired despite remission of depression. Furthermore, 23% of the patients who were
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cognitively normal while depressed developed impairment 1 year later [61] . A 5–7-year longitudinal study published in 2007 followed a group of depressive elderly patients with reversible cognitive impairment as well as a group of cognitively intact depressed elderly patients for conversion to dementia. In total, 71.4% of those suffering from pseudodementia had converted into dementia at follow-up compared with only 18.2% in the cognitively intact group (RR: 3.93) [62] . Thus, the presence of pseudodementia can be used as a cognitive predictor and should trigger dementia screening in patients who present with it. Evidence also suggests that specific cognitive domains in LLD may be predictive of conversion to dementia. Ganguli and colleagues demonstrated that individuals with lower baseline scores across cognitive domains of recall, memory, visuospatial ability and executive functioning had a higher risk of dementia [63] . Another study suggested that depressed patients with lower verbal prose recall performance and lower performance on visual organization tasks had a higher risk of cognitive decline over 15 months [64] . A longitudinal study of MDD with a mean follow-up of 5.45 years compared neuropsychological functioning in those depressed patients who converted to dementia compared with those who did not. Nondemented, acutely depressed older adults who converted to dementia during the study period exhibited broadly lower cognitive performances at baseline than acutely depressed individuals who remained cognitively normal. Discriminant function analysis indicated that two neuropsychological tests, Recognition Memory (from the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery) and Trail Making Test B, best predicted dementia conversion. The authors felt that this pattern of cognitive impairment defined a subset of LLD patients whose symptoms were prodromal for AD [65] . These studies illustrate that depressed patients who exhibit a decline in recall and recognition memory, verbal prose recall, visuospatial skills and executive functioning could be identified at being at higher risk for conversion to AD than other patients. Conclusion & future perspective Historically, clinicians have attempted to distinguish depression and dementia and great effort has been put into differentiating between
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Special Report Ismail, Malick, Smith, Schweizer & Fischer salient features of the syndromes [66,67] . However, on the basis of the current research, there is increasing evidence that AD and MDD share a similar pathophysiological pathway and that depression may be a risk factor for, and a prodrome of dementia [68] . In early life depression, hippocampal atrophy and glucocorticoid dysregulation has been linked to AD neuropathology, while in late life depression, vascular pathology has been linked to AD vascular risk. While some research indicates that treating depression may mitigate dementia burden, more studies are required. Furthermore, a high index of suspicion is required for LLD as an early manifestation of neurodegenerative illness, especially when cognitive impairment exists along with the depression. Rather than depression and dementia as mutually exclusive phenomena, understanding and pursuing the link between the two is paramount. Thus, in LLD, there should be a high index 8
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nature and determinants of neuropsychological functioning in late-life depression. Arch. Gen. Psychiatry 61(6), 587–595 (2004). 59 Sheline YI, Barch DM, Garcia K et al.
Cognitive function in late life depression:
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Mattis S, Kakuma T. The course of geriatric depression with ‘reversible dementia’: a controlled study. Am. J. Psychiatry 150(11), 1693–1699 (1993). 61 Bhalla RK, Butters MA, Mulsant BH et al.
Persistence of neuropsychologic deficits in the remitted state of late-life depression. Am. J. Geriatr. Psychiatry14(5), 419–427 (2006). •• Demonstrates that cognitive symptoms can persist despite remission of depressive symptoms in late-life depression. 62 Saez-Fonseca JA, Lee L, Walker Z. Long-term
outcome of depressive pseudodementia in the elderly. J. Affect. Disord. 101(1-3), 123–129 (2007). 63 Ganguli M, Du Y, Dodge HH, Ratcliff GG,
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epidemiological study. Arch. Gen. Psychiatry 63(2), 153–160 (2006). 64 Von Gunten A, Giannakopoulos P, Duc R.
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depression, delirium, and dementia in elderly patients. Virtual Mentor 10(6), 383–388 (2008). 67 Thorpe L. Depression versus dementia: how
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dementia. Curr. Opin. Psychiatry 25(6), 457–461 (2012).
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Depression versus dementia: is this construct still relevant? Zahinoor Ismail*,1,2, Arfeen Malick3, Eric E Smith1, Tom Schweizer2,4 & Corinne Fischer2,4
Practice points ●●
S creening for cognitive impairment in late-life depression is an important clinical step in determining risk of dementia.
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ognitive screening should involve a robust screening instrument that assesses multiple cognitive domains, C including executive function.
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Vascular illness can be an important predictor of dementia.
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Depression in mid- and late life may increase the risk of incident dementia.
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Late-life depression may be a prodrome to Alzheimer’s dementia.
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SUMMARY Cognitive impairment has long been identified as a component of late-life depression (LLD), and depressive symptoms are common in neurodegeneration. Depression may confer a greater risk of cognitive decline in a cognitively intact population and further cognitive decline in a mild cognitive impairment population compared with those without depression. Exploration of the link between cognitive impairment in LLD and the depressive features of neurodegeneration is an essential part of a diagnostic algorithm. In this article, we will discuss these links; we will address depressive symptoms as a risk factor for dementia and as a prodrome to dementia. We will review clinical subtypes and imaging markers as predictors of development of dementia in depressed patients and explore vascular etiologies. We will also explore LLD and dementia as a spectrum, rather than mutually exclusive diagnostic entities. Depression and cognition are intimately connected. Cognitive impairment has long been identified as a component of late-life depression (LLD), with a prevalence of mild cognitive impairment (MCI) in LLD as high as 54% [1] . Depressive symptoms are common in
neurodegenerative illness, with prevalence rates in MCI of 20% for major depression (MD) and 27% for minor depression [2] . In Alzheimer’s disease (AD), up to 30% of patients have a diagnosis of major depressive disorder (MDD) [3] and up to 40% of patients with dementia
Hotchkiss Brain Institute, University of Calgary, Calgary, Canada University of Toronto, Toronto, Canada 3 Faculty of Medicine, University of Calgary, Calgary, Canada 4 Keenan Research Centre of the Li Ka Shing Knowledge Institute, Toronto, Canada *Author for correspondence: [email protected] 1
ure UK
2
10.2217/NMT.14.5 © 2014 Future Medicine Ltd
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Special Report Ismail, Malick, Smith, Schweizer & Fischer are treated with antidepressants [4] . Depression may confer a greater risk of cognitive decline in a cognitively intact population [5] and further cognitive decline in an MCI population [6] compared with those without depression. Confounding the understanding of LLD is the fact that depressive symptoms in late life may not be stable or persistent, and have variable trajectories [7] . A common clinical dilemma is how to approach cognitive impairment in the context of LLD – understanding subtypes of LLD with respect to cognitive impairment may have treatment implications. It may be a challenge to diagnose depression among patients who present with recent development of cognitive complaints and symptoms rather than with depressed mood. Successful treatment with antidepressants resulting in remission of cognitive symptoms may confirm the diagnosis of depression in such patients. Not addressing reversible or treatable cognitive impairment in depression can lead to an inappropriate diagnosis of dementia or poorer outcomes. Conversely, missing underlying neurodegenerative conditions manifesting as depression can delay dementia diagnosis and treatment, and result in prolonged suffering and diagnostic uncertainty. Thus, exploration of the link between cognitive impairment in LLD and the depressive features of neurodegeneration is an essential part of a diagnostic algorithm. In this article, we will discuss these associations. We will address depressive symptoms as a risk factor for and prodrome to dementia, as well as the role of vascular pathology in connecting depression and dementia. Finally, we will review clinical subtypes and imaging markers as predictors of development of dementia, to help guide the clinician in the diagnosis. Depression as a risk factor for dementia A number of studies have assessed the link between a history of depression and the onset of MCI and dementia [8–12] . A systematic review and meta-analysis by Ownby and colleagues assessed the link between depression and AD. They found an odds ratio (OR) of 2.03 in case–control studies and 1.90 in cohort studies for an increased risk of developing AD in subjects with a history of MDD. Furthermore, a longer interval between diagnoses of depression and AD conferred a greater risk of developing AD, suggesting that depression may be a remote risk factor for AD [13] . More recently
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in a meta-analysis of 12 longitudinal studies, Gao and colleagues assessed the association between depressive symptoms at baseline and the incidence of MCI and depression. In comparison with nondepressed older adults, those with depression had a higher relative risk (RR) of MCI (RR: 1.97), AD (RR: 1.66), vascular dementia (VD; RR: 1.89) and any dementia (RR: 1.55) [14] . Studies also suggest that the risk of developing dementia increases with the number of inpatient depressive episodes [15] or episodes that are self-reported [16] . These findings are supported in a systematic review and metaanalysis by da Silva and colleagues, concluding that greater frequency and severity of depressive episodes seem to increase the risk of dementia [17] . Furthermore, a prospective cohort study of 126 cognitively normal older adults with 20-year follow-up demonstrated that the degree of depressive symptoms at baseline predicted the time to development of MCI. An increase in Geriatric Depression Scale 30 scores of 1 standard deviation (3.85 points) was associated with shortening of the median time to conversion to MCI by 25.4% in APOE ε4 noncarriers, but not in APOE ε4 carriers [18] . However, even minor depression has been shown to increase risk of dementia. Using data from a populationbased cohort study of prevalence and incidence of dementia in subjects aged 70 years and over, Vilalta-Franch and colleagues demonstrated late-onset depressive episodes with depression and executive dysfunction are risk factors for dementia and AD development, regardless of the severity of the depression [19] . Studies have also demonstrated a link between depression and hippocampal volume loss [20,21] . A recent meta-analysis demonstrated that individuals with a history of MDD had significantly smaller left and right hippocampal volumes, while their total cerebral volume remained the same [22] . In post-mortem studies of AD patients, those with a history of depression demonstrated greater hippocampal amyloid plaque and neurofibrillary tangle burden and more rapid cognitive decline compared with controls without depression [23] . In another autopsy study of AD patients, more pronounced cortical neuro fibrillary tangle pathology was found in patients who suffered from AD with comorbid depression compared with those AD patients without depression [24] , further strengthening the link between depression and AD neuropathology.
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Depression versus dementia: is this construct still relevant? Understanding the neurobiology of depression may help provide insight into the possible links between depression history and risk of MCI and dementia. A major feature of MDD is the hyperactivity of the HPA axis leading to dysfunctional secretion of glucocorticoids from the adrenal cortex. In MDD patients, high levels of cortisol lead to impaired negative feedback control of the HPA axis, resulting in hippocampal damage [25] . In addition, the degree of hippocampal volume reduction correlates with the duration of MDD, with some evidence suggesting that antidepressants may reverse this atrophy [26] , highlighting the potential importance of early clinical intervention in MDD. Similarly, pathology is seen in AD where hypercortisolemia due to abnormalities at multiple levels of the HPA axis results in glucocorticoid-dependent neurodegeneration [27] . Moreover, AD patients with higher plasma cortisol levels demonstrate a more rapid disease progression [28] . One of the proposed mechanisms that links HPA axis dysfunction and AD is the ‘glucocorticoid cascade hypothesis’. This hypothesis proposes that a hyperactive HPA axis in AD creates hippocampal damage, leading to dysfunctional glucocorticoid negative feedback and eventually increased glucocorticoid levels [29,30] . Continuously elevated cortisol levels have been shown in AD transgenic mice models to be associated with amyloid-β (Aβ) and tau toxicity, the hallmark neuropathological features associated with AD [31] . Stress and sustained elevations in glucocorticoid levels have also been shown to drive amyloid precursor protein misprocessing, generating increased Aβ metabolism in the hippocampus and prefrontal cortex, as well as aberrant tau hyperphosphorylation [32,33] . Serotonergic transmission may also be linked to the association between depression and dementia. Activation of the 5-HT4 receptor increases the secretion of the nonamyloidogenic soluble Aβ protein precursor that exerts a protective effect against Aβ42-induced neuronal death. Recent studies have shown an association between decreased levels of this receptor and depression vulnerability. According to these observations, low levels of 5-HT4 receptor would both predispose to depression and to increased secretion of the Aβ1–42 peptide [34] . Thus, one can speculate that a history of MDD may either initiate or accelerate hippocampal atrophy as well as production of Aβ and phosphorylated tau, increasing the risk of dementia in the future. The potential
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protective role of antidepressants has also been assessed in Danish linked database analyses of depression treatment and dementia outcomes. Kessing and colleagues demonstrated that longterm antidepressant use may decrease the incidence of some types of dementia in a general population prescribed antidepressants [35] and patients discharged from inpatient psychiatric care [36] . AD pathogenesis has also been associated with neurovascular dysfunction, highlighting the role of vascular risk factors such as cigarette smoking, diabetes, hypertension and cardiovascular disease in AD progression. These risk factors are often present in older adults with depression. The ‘vascular depression hypothesis’ [37,38] , posits that cerebrovascular disease predisposes, precipitates, or perpetuates some geriatric depressive syndromes. This vascular burden affects fronto-striatal circuitry resulting in depression and associated cognitive impairment, especially executive dysfunction. LLD exhibits a more vascular neuropsychological profile than chronic and recurrent depression [39,40] . Examining the implications of vascular disease in both AD and depression, a recent study demonstrated that higher vascular risk scores predicted lower cognitive functioning in individuals treated for depression [41] . Depression as a prodrome to dementia Interestingly, LLD has also been hypothesized to be a prodrome to neurodegenerative diseases. This has been a topic of ongoing debate as the two may be difficult to differentiate. Examining current research, a number of studies have found a higher risk of dementia in those with a history of depressive episodes closer in proximity to dementia onset [12,42–45] . Additionally, in a recent Swedish study, it has been shown that LLD increases the risk of dementia up to three times [46] . Moreover, this study demonstrated that each 1-year increase in difference between depression onset and dementia onset decreased the likelihood of dementia by 8.4%. Additional support for the prodromal hypothesis can be seen in the analysis of the 2005–2011 National Alzheimer’s Coordinating Center – Uniform Data Set (NACC–UDS), which demonstrated that AD patients had a significant increase in depressive symptoms and functional impairment prior to AD diagnosis independent of dementia-related cognitive impairment [47] . The findings from this data suggest that depression
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Special Report Ismail, Malick, Smith, Schweizer & Fischer and functional decline could serve as markers for earlier AD detection. With respect to differentiating between dementia subtypes, Barnes and colleagues demonstrated that patients with LLD had a twofold increased risk for AD, while subjects with both midlife and late-life symptoms had more than a 3.5-fold higher risk in vascular dementia [8] . This implies that depressive symptoms in midlife or in late life are associated with higher risk of progression to dementia. While chronic depression (both midlife and late life) seems to be a risk factor for vascular depression, depression that occurs for the first time in late life could be implicated as a prodrome to AD. Neuroimaging biomarkers Neuroimaging studies tend to identify associations between depression and: regions that are also vulnerable to neurodegeneration in AD (e.g., hippocampus); and brain regions subserving executive functions, which might impair executive function and predispose to further cognitive impairment. Further consistent themes in neuroimaging studies are the impact of persisting cognitive impairment, the role of vascular burden and the involvement of fronto-striatal circuitry in identifying features of LLD associated with increased risk of cognitive decline. A number of structural studies have attempted to identify neuroimaging correlates of LLD and cognitive impairment. A case–control study of 139 depressed elderly subjects found that 54% met neuroimaging criteria for subcortical ischemic vascular depression (SID), which may be seen as specific type of LLD. In this cohort, age was associated with SID, in which case there was less likelihood of having a family history of depression [48] . A citalopram treatment study compared 22 older adults who achieved remission for MD versus 19 subjects who had persistent symptoms. MRI demonstrated decreased dorsal and rostral cingulate volumes in the nonremitters, potentially providing a marker for treatment resistance to serotonergic medications and defining a different subtype of LLD [49] . A longitudinal study of 90 depressed and 72 nondepressed healthy older adults demonstrated greater left hippocampal atrophy at 2 years in the depressed subjects. This hippocampal change was associated with subsequent cognitive decline in the depressed group, despite comparable Mini-Mental State Examination (MMSE) scores at baseline [20] . The interactions between LLD and aMCI were assessed in an MRI study.
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Older adults with clinically significant depression were compared with those with aMCI, LLD and coexisting aMCI and normal controls. The interaction between LLD and aMCI was associated with volume loss in the right inferior frontal gyrus (IFG)/anterior insula and left medial frontal gyrus. The authors suggested that the coexistence of these clinical phenotypes is a potential marker for higher risk of AD [50] . Tensor-based morphometry was used to assess the neuroanatomical changes associated with depressive symptoms in MCI. Using the Alzheimer’s Disease Neuroimaging Initiative database, patients with MCI and depression (n = 44), nondepressed with other neuropsychiatric symptoms (n = 3) and no symptoms (n = 106) were compared at baseline and 2-year follow-up. Depressive symptoms were associated with greater white matter atrophy in frontal, parietal and temporal regions, increased cognitive decline and higher rates of conversion to AD, even more so if depressive symptoms were persistent at 2 years [51] . It was suggested that the white matter changes elucidated by the presence of depressive symptoms may be interpreted as a shared early pathological process of AD rather than representative of neuroanatomical changes associated with depression alone. Functional neuroimaging has also been instructive in linking LLD and cognitive decline. A 2-year longitudinal study of LLD used fMRI with an executive function task. For patients who had persisting cognitive impairment from baseline to end point, there was decreased activation at baseline in the dorsal ACC, hippocampus, inferior frontal cortex IFC and insula compared with patients without persisting cognitive impairment, and this group was felt to be at risk for further cognitive decline [52] . Using FDG-PET, a Korean study compared 18 subjects with MCI and depression to 18 with MCI and no depression. Depressed MCI subjects showed lower glucose metabolism in the right superior frontal gyrus (SFG) than nondepressed subjects [53] . Similarly, the same researchers studied an AD population and FDG-PET was used to compare 12 depressed patients to 12 nondepressed patients. The depressed AD group showed lower glucose metabolism in the right SFG [54] . A confound in the assessment of depression is the presence of apathy. A SPECT study of 81 AD patients compared depressed, nonapathetic subjects (D+) to apathetic, nondepressed subjects (A+). D+ subjects had significantly lower perfusion in the right orbitofrontal cortex (OFC) and
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Depression versus dementia: is this construct still relevant? IFG than nondepressed (D-) subjects, whereas A+ subjects had lower perfusion in the right amygdala, temporal, posterior cingulate, superior frontal, postcentral and left superior temporal gyrus compared with nonapathetic (A-) subjects [55] . Cognitive predictors Clinically, being able to differentiate between depression and dementia has been an important step to ensure effective management. Given the fluidity between the two diagnoses, this can prove challenging. Evidence supports the use of cognitive predictors in identifying patients with depression who are at higher risk for further cognitive decline. Screening elderly patients for cognitive changes is frequently carried out using the MMSE despite the fact that is biased by language, education and culture, and is insensitive to frontal-executive changes [56] . For detecting cognitive changes in LLD, Rajji and colleagues assessed the sensitivity and specificity of the MMSE in comparison to the Mattis Dementia Rating Scale (DRS). The results of this study demonstrated 99.4% specificity but only 8.0% sensitivity, implying that the MMSE alone may not be an adequate tool for screening cognitively impaired LLD patients [57] . When measured with neuropsychological testing, studies have demonstrated significant cognitive impairment in LLD, especially in the domains of processing speed and executive function [58,59] . The term ‘depressive pseudodementia’ refers to depressed elderly patients with reversible cognitive impairment and this has been identified as a strong predictor of dementia. Neuropsychological predictors have been studied in terms of identifying depressive patients who are at higher risk of progressing to dementia. In one early study, patients who experienced comorbid cognitive impairment and depression were shown to have a 4.69-fold greater risk of progressing to dementia than those patients with depression and no cognitive difficulties at a mean of 34-month follow-up [60] . In a 1-year longitudinal study of 56 nondemented subjects aged 60 years or older who initially presented with an episode of nonpsychotic unipolar major depression and 40 nondemented, age- and education-equated comparison subjects with no history of depression, 45% of the LLD subjects remained cognitively impaired despite remission of depression. Furthermore, 23% of the patients who were
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cognitively normal while depressed developed impairment 1 year later [61] . A 5–7-year longitudinal study published in 2007 followed a group of depressive elderly patients with reversible cognitive impairment as well as a group of cognitively intact depressed elderly patients for conversion to dementia. In total, 71.4% of those suffering from pseudodementia had converted into dementia at follow-up compared with only 18.2% in the cognitively intact group (RR: 3.93) [62] . Thus, the presence of pseudodementia can be used as a cognitive predictor and should trigger dementia screening in patients who present with it. Evidence also suggests that specific cognitive domains in LLD may be predictive of conversion to dementia. Ganguli and colleagues demonstrated that individuals with lower baseline scores across cognitive domains of recall, memory, visuospatial ability and executive functioning had a higher risk of dementia [63] . Another study suggested that depressed patients with lower verbal prose recall performance and lower performance on visual organization tasks had a higher risk of cognitive decline over 15 months [64] . A longitudinal study of MDD with a mean follow-up of 5.45 years compared neuropsychological functioning in those depressed patients who converted to dementia compared with those who did not. Nondemented, acutely depressed older adults who converted to dementia during the study period exhibited broadly lower cognitive performances at baseline than acutely depressed individuals who remained cognitively normal. Discriminant function analysis indicated that two neuropsychological tests, Recognition Memory (from the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery) and Trail Making Test B, best predicted dementia conversion. The authors felt that this pattern of cognitive impairment defined a subset of LLD patients whose symptoms were prodromal for AD [65] . These studies illustrate that depressed patients who exhibit a decline in recall and recognition memory, verbal prose recall, visuospatial skills and executive functioning could be identified at being at higher risk for conversion to AD than other patients. Conclusion & future perspective Historically, clinicians have attempted to distinguish depression and dementia and great effort has been put into differentiating between
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Special Report Ismail, Malick, Smith, Schweizer & Fischer salient features of the syndromes [66,67] . However, on the basis of the current research, there is increasing evidence that AD and MDD share a similar pathophysiological pathway and that depression may be a risk factor for, and a prodrome of dementia [68] . In early life depression, hippocampal atrophy and glucocorticoid dysregulation has been linked to AD neuropathology, while in late life depression, vascular pathology has been linked to AD vascular risk. While some research indicates that treating depression may mitigate dementia burden, more studies are required. Furthermore, a high index of suspicion is required for LLD as an early manifestation of neurodegenerative illness, especially when cognitive impairment exists along with the depression. Rather than depression and dementia as mutually exclusive phenomena, understanding and pursuing the link between the two is paramount. Thus, in LLD, there should be a high index 8
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