Ebook: Handbook of Depression in Alzheimer's Disease
Advances in healthcare have led to an extended life expectancy throughout the developed world, but cognitive impairment in later life, and Alzheimer's disease (AD) in particular, remains one of the intractable problems which can blight quality of life as we age. Depression in Alzheimer's disease is an additional factor which has a significant impact on disability, disease progression, and caregiver burden.
This book, volume 4 of the Advances in Alzheimer’s Disease book series which is published in coordination with the Journal of Alzheimer’s Disease, presents papers which reflect the progress in recent years of research into depression in AD. This research has focused on several areas, including the improvement of diagnostic criteria and outcome measures for depression and depressive symptoms in AD, genetic and imaging studies to elucidate the neurobiological mechanisms, and clinical trials of antidepressants. The book is divided into sections on phenomenology, epidemiology, neuropsychology, neurobiology and neuropathology, neuroimaging, genetics, and treatment.
Providing a stimulus to further research in this challenging area by engaging both basic and clinical researchers, this book will be of interest to all those whose work involves understanding and dealing with depression in those suffering from Alzheimer's disease.
Depression in Alzheimer's disease (AD) has a substantial impact on disability, disease progression, and caregiver burden. Furthermore, depressive symptoms in normal aging, as well as in mild cognitive impairment (MCI), are associated with cognitive and functional decline. The association of behavioral symptoms with cognitive decline in normal aging has led to the construct of mild behavioral Impairment (MBI) that is defined as a persistent behavioral change with mild psychiatric symptoms but without significant cognitive or functional impairment . MBI is associated with increased risk of AD and frontotemporal dementia. The approved medications developed to treat depression in younger individuals are of limited efficacy in older individuals, especially when the symptoms are co-morbid with cognitive impairment. Over the past decade, research in the area of depression in AD has focused in several areas including the improvement of diagnostic criteria and outcome measures for depression and depressive symptoms in AD, genetic and imaging studies to elucidate the neurobiological mechanisms, and clinical trials of antidepressants. The papers in this Volume reflect progress in these areas. The Volume is divided into sections on phenomenology/epidemiology; neurobiology; neuropsychology; neuroimaging; genetics; and treatment. The papers are a combination of original research articles and reviewers of the literature. The underlying premise of the Volume is that an understanding of the phenomenology and neurobiology of depressive symptoms across the spectrum from normal aging to MCI to AD is urgently needed to develop more effective treatments and prevention strategies in the prodromal stages of AD. Thus, the Volume includes reviews of the literature and original data papers that focus on depressive symptoms in normal aging, major depressive disorder in late life, as well as depressive symptoms in MCI and AD.
The section on Phenomenology provides a critical review of the diagnostic and assessment issues related to depression in AD and includes original research papers that demonstrated the impact of depression and apathy on cognitive decline. As presented in this section, there are fundamental questions about whether the construct of depression is the same over the spectrum of normal aging to MCI to AD? Can the same diagnostic criteria and symptom assessments be used across this spectrum? Is the depressive syndrome observed the same as major depression defined by the Diagnostic and Statistical Manual is it a milder form of depression or is it a broader affective syndrome, including such symptoms as apathy, anxiety and irritability? In this context, it is important to consider that depression, in combination with these other neuropsychiatric symptoms, are associated with cognitive decline. Further, with respect to measuring changes in depressive symptoms in treatment trials, there is discussion about which are the most appropriate symptoms assessments to use, the assessment instruments developed for major depression or the instruments developed for use in AD? Are the same assessment tools that are appropriate for AD also sensitive to detecting an improvement in depressive symptoms in normal aging and MCI? The papers in the Epidemiology and Neuropsychology sections consistently observe the substantial impact of depressive symptoms alone or in combination with other neuropsychiatric symptoms on cognitive decline across the spectrum of normal aging, MCI, and AD. The results of these studies are consistent even though the studies employ different diagnostic criteria and depression assessment measures.
The papers included in the sections on Neurobiology and Neuropathology, Neuroimaging, and Genetics have implications for addressing many fundamental questions regarding whether depressive symptoms in AD are associated with similar or different genetic polymorphisms, neural circuits, and molecular mechanisms as observed in either AD or major depression or both. While there is some overlap in neural networks affected in depression in AD, structural and functional neuroimaging studies suggest greater changes in brain structure (including white matter hyperintensities and function in frontal cortical regions in AD patients with compared to those without depression . A review of postmortem data concluded that greater AD pathology and monoamine degeneration is not associated with depression in AD and that other neurobiological mechanisms should be investigated . The impact of depression in normal aging and MCI may be different than in AD, as suggested by several genetic and neuroimaging papers in the Volume [4,5]. The overlap between the neurobiological mechanisms implicated in depression and depression in AD was demonstrated in a genome-wide gene- and pathway-based analyses study  that showed an association between several genetic pathways associated with depression and depression in AD. Thus, a critical question that may be best addressed with in vivo methods systematically applied across groups is whether the same neurobiological mechanisms underlie depressive symptoms in normal aging, MCI, and AD. An understanding of alterations in affective neural circuitry, neurotransmitter modulation, and synaptic plasticity and relationship to AD pathology is critical to inform the development of more effective treatments. As discussed further below, the papers in this volume provided converging evidence for several molecular mechanisms associated with both mood symptoms and AD such as glutamatergic dysfunction, inflammation or cerebrovascular disease, or altered synaptic plasticity (e.g., [3, 6-8]). Even if depression in AD and major depression have a common origin, the co-occurring neurochemical and molecular pathology in AD may explain why treatments effective in major depression may be less effective in treating depression in AD. These observations underscore the importance of: 1) earlier intervention targeting depressive symptoms in normal aging and MCI that may prevent further neurodegeneration and progression to AD and 2) identifications of new antidepressant targets as informed by neurobiological data, including genetics and neuroimaging approaches.
The further behavioral evaluation of transgenic animal models of AD pathology and the evaluation of the impact of inducing depressive and stress responses may elucidate the relationships between AD pathology, other neurobiological mechanisms and depressive symptoms and would inform the development of human mechanistic and intervention studies . For example, there are several examples in the literature suggesting a potential role of monoamine pathology in depressive symptoms in transgenic mouse models [10, 11] that may suggest that monoaminergic deficits may be associated with AD pathology and perhaps, neuropsychiatric symptoms.
The section on Treatment provides a critical review of the clinical trials in AD of antidepressant agents that measured depression as a primary outcome, in addition to trials of other treatment targets in which depression was measured as a secondary outcome . While the studies of antidepressants (mainly selective serotonin re-uptake inhibitors) yielded mixed results, there is a suggestion that other treatment targets should be investigated further, such as inflammation or the glycogen synthase kinase-3 (GSK-3) pathway. There are recent advances in the development of novel treatments for depression that are promising and may have implications for the treatment of depression in AD as well as in aging and MCI. It is important to reiterate that the neurobiology of depression in normal aging, MCI, and AD may be different and thus, the same intervention may not be effective across conditions. For example, the “multi-modality” antidepressants that have both pre and post-synaptic monoaminergic effects may enhance neurotransmitter modulation and there is some evidence that such ix agents may treat cognitive deficits, as well . The development of agents targeting mechanisms including glutamatergic dysfunction, inflammation, and enhancing synaptic plasticity may also be effective at treating depression and preventing further decline [e.g., ). Behavioral interventions and/or combined pharmacologic and behavioral interventions targeting mood symptoms or cognitive deficits represent another important opportunity for intervention development . Brain stimulation approaches targeting brain circuits are a major focus of treatment development in the mood disorders field and may be effective in treating depression in AD, as well especially given the evidence that brain stimulation may improve cognition . Both pharmacologic and behavioral intervention studies in MCI are critically needed. Perhaps the most important question and the most challenging to investigate, as mentioned above, is whether the early and intensive treatment of depressive symptoms in MBI and MCI prevent the development of further pathology and delay the dementia transition?
Over the next decade, there will be significant advances in animal models, genetics, and neuroimaging in mood disorders and AD, as well as an increasing focus on the study of normal aging and individuals at risk for AD. This research will have a great impact on the development of more effective approaches for the clinical management of depression in the context of normal aging and AD, as well as understanding of the potential importance of the role of depression treatment in the prevention of dementia. We sincerely hope that the material in the Volume will inspire basic and clinical researchers to undertake research on the impact of depressive symptoms across the spectrum of normal aging to MCI to AD, as well as investigate the role of depressive symptoms as a prodrome or co-morbidity in other neurodegenerative diseases including Parkinson's and Huntington's diseases.
Funding Support: GSS receives research funding from the National Institute of Health (MH 086881, AG038893, AG041633) and the National Association for Research in Schizophrenia and Depression.
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Depression is among the most frequent psychiatric comorbid conditions in dementia. There is no strong consensus as to what criteria should be used to diagnose depression in AD. This is at least partially explained by the overlap between symptoms of depression and symptoms of AD. Recent studies using latent class analysis provided clarification to this diagnostic dilemma. All nine DSM-IV symptoms of major depression were found to characterize a class with a high chance (96%) of having a clinical diagnosis of major depression, and symptoms of anxiety were also frequent. Other psychiatric symptoms may also be included under the construct of depression in AD, since both apathy and anxiety are among the most frequent comorbid conditions for major depression in AD. Subtypes of depression should also be validated in this condition. For instance, increased awareness of cognitive and functional deficits is significantly associated with dysthymia but not with major depression, suggesting that different depressive syndromes in AD may have different etiology.
Apathy and depression are the most frequent neuropsychiatric symptoms symptoms in Alzheimer's disease (AD). In a cross-sectional observational study of 734 subjects with probable mild AD, we evaluated the prevalence of apathy and depression. After the use of specific diagnostic criteria, we tested the interaction between the two syndromes and their relation with specific comorbidities, and different functional outcomes. Depression was diagnosed using the diagnostic criteria for depression in AD, and apathy with the diagnostic criteria for apathy in neuropsychiatric disorders.
According to the specific diagnostic criteria, depression has a 47.9% prevalence, as apathy prevalence is 41.6%. Apathy and depression are associated in 32.4% of patients (n=225). 9.4% (n=65) have only apathy, 15.4% (n=107) have only depression, and 42.9% have no apathy and no depression (n=298).
The three most frequent depressive symptoms are fatigue or loss of energy (59.4%), decreased positive affect or pleasure in response to social contacts and activities (46.2%) and psychomotor agitation or retardation (36.9%). Concerning apathy, loss of goal-directed cognition is the most frequently altered (63.6%), followed by loss of goal-directed action (60.6%) and loss of goal-directed emotion (43.8%). Patients with both apathy and depression more frequently require a resource allowance for dependency. Neurological comorbidities were more frequent in the “apathy and depression” and “depression alone” groups (p<0.001).
Apathy and depression overlap considerably, and this might be explained by the presence of some non-specific symptoms in both diagnostic criteria. The need for social support is higher when a patient fulfills the two diagnostic criteria.
Neuropsychiatric symptoms (NPSs) have a large impact on the quality of life of patients with dementia. A few studies have compared neuropsychiatric disturbances between dementia subtypes, but the results were conflicting. In the present study, we investigated whether the prevalence of NPSs differs between Alzheimer's disease (AD) and vascular dementia (VaD). The merit of our study is that we used clinical as well as histopathological information to differentiate between dementia subtypes. This retrospective descriptive study comprised 80 brains obtained from donors to the Netherlands Brain Bank between 1984 and 2010. These donors were diagnosed postmortem with AD (n =40) or VaD (n=40). We assessed the presence of NPSs by reviewing the information found in the patients' medical files. The most prevalent symptom in the sample as a whole was agitation (45 cases, 57.0%), followed by depression (33, 41.2%) and anxiety (28, 35.4%). Our study tried to contribute to the discussion by including, for the first time in the literature, a sample of AD and VaD patients with neuropathologically confirmed diagnoses. Since no significant differences were found between AD and VaD patients, we suggest that the prevalence of NPSs cannot be predicted from the diagnosis of AD or VaD.
Depression occurs with a high prevalence of up to 50% in patients with Alzheimer's disease (AD) and increases the caregivers' burden. Depression symptoms can precede clinical diagnosis of AD for years or occurs around the onset of AD, although the etiology and pathologic mechanism of depression in AD pathogenesis remain unclear. Here, we provide an overview on recent studies, indicating that genetic factors, neuroanatomic changes, vascular risk factors, and the imbalance of neurotransmitters might contribute to depressive symptoms in AD. Tau pathology and amyloid-β accumulation also correlate with depression in AD. In addition, the alteration of hypothalamic-pituitary-adrenal axis, inflammatory pathway, and neurotrophin deficiency are the possible biological mechanisms linking depression and AD, and might become the potential targets for AD treatment. Current data support that antidepressants are promising to alleviate the symptom, though the efficacy is controversial. Moreover, antidementia medication and non-pharmacological interventions can be potential choices. In this review, we describe the prevalence and clinical course of depression in AD, analyze the underlying mechanisms, and discuss the possible management strategies for depression in patients with AD.
Background: The literature suggests an association between depression and mild cognitive impairment (MCI) and dementia, but not all studies have examined this association with regard to MCI subtypes reflecting different dementia etiologies.
Objective: To examine if there is a cross-sectional relationship of depression and MCI and to examine if the relationship differs depending on the type of depression (currently elevated depressive symptoms or a positive history of lifetime depression or both) and on the MCI subtype (amnestic versus non-amnestic MCI (aMCI/naMCI)).
Methods: From the second examination of the population-based Heinz Nixdorf Recall study (50% men, 50–80 years), 583 participants with MCI (aMCI n=304; naMCI n=279) and 1,446 cognitively normal participants were included in the analyses. Currently elevated depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D; score ≥18). Furthermore, participants were asked if they have ever received a previous diagnosis of depression. Log-Poisson regression models (adjusted for sociodemographic/cardiovascular risk factors) were calculated to determine the association of MCI and its subtypes with all depression variables.
Results: The fully adjusted prevalence rate ratios for MCI, aMCI, and naMCI in depressed versus non-depressed participants were 2.06 (95% confidence interval, 1.60–2.64), 3.06 (2.21–4.23), and 1.93 (1.46–2.57). A positive history of lifetime depression without current depressive symptoms was solely associated with naMCI (1.31 (0.99–1.73)).
Conclusion: These results suggest that the relationship of depression/depressive symptoms and MCI might differ depending on the timing of depression and on the MCI subtype. Our longitudinal follow-up will allow us to further elucidate this relationship.
Identification of potentially modifiable risk factors for cognitive deterioration is important. We conducted a prospective study of 5,607 subjects with normal cognition and 2,500 subjects with mild cognitive impairment (MCI) at 30 Alzheimer's Disease Centers in the Unites States between 2005 and 2011. Cox regression was used to determine whether depression predicted transition from normal to MCI, or MCI to Alzheimer's disease (AD). Over an average of 3.3 visits, 15% of normal subjects transitioned to MCI (62/1000 per year), while 38% of MCI subjects transitioned to AD (146/1000 per year). At baseline, 22% of participants had recent (within the last two years) depression defined by clinician judgment; 9% and 17% were depressed using the Geriatric Depression Scale (GDS score ≥5) and the Neuropsychiatric Inventory Questionnaire (NPI-Q), respectively. At baseline, depressed subjects performed significantly worse on cognitive tests. Those always depressed throughout follow-up had an increased risk for progression from normal to MCI (RR=2.35; 95% CI 1.93–3.08) versus never depressed. Normal subjects, identified as depressed at first visit but subsequently improved, were found to have an increased but lower risk of progression (RR=1.40 (1.01–1.95)). The ‘always depressed’ had only a modest increased risk of progression from MCI to AD (RR=1.21 (1.00–1.46). Results were similar using time-dependent variables for depression or when defining depression via the GDS or NPI-Q. We found no effect of earlier depression (>2 years past). The effect of recent depression did not differ by antidepressant treatment, APOE4 allele status, or type of MCI. In conclusion, late-life depression is a strong risk factor for normal subjects progressing to MCI.
Background: A number of studies have linked neuropsychiatric symptoms to increase risk of dementia.
Objective: To determine if risk of conversion to mild cognitive impairment or dementia among healthy controls varied as a function of their pattern of neuropsychiatric symptoms.
Method: We studied individuals in the National Alzheimer Coordinating Center dataset collected from 34 Alzheimer Disease Centers between 2005 and 2013. The analysis included 4,517 volunteers who were ≥60 years old, cognitively normal, and had complete Neuropsychiatric Inventory data at their baseline visit, and had at least one follow-up. We used latent class analysis to identify four classes based on patterns of NPI symptoms. We used a Cox proportional hazards model to determine if time to MCI or dementia varied by baseline latent class membership.
Results: We identified four latent classes of neuropsychiatric symptoms: irritable, depressed, complex (depression, apathy, irritability, and nighttime behaviors) and asymptomatic. 873 participants converted to MCI or dementia. Hazard ratios for conversion by class were 1.76 (95% CI: 1.34, 2.33) for the irritable class, 3.20 (95% CI: 2.24, 4.58) for the complex class, and 1.90 (95% CI: 1.49, 2.43) for the depressed class, with the asymptomatic class as the reference.
Conclusions: Membership in all three symptomatic classes was associated with greater risk of conversion to MCI or dementia; the complex class had the greatest risk. Different patterns of neuropsychiatric symptoms may represent different underlying neuropathological pathways to dementia. Further work imaging and pathology research is necessary to determine if this is the case.
Late-life depression (LLD, major depression occurring in an adult 60 years or older) is a common condition that frequently presents with cognitive impairment. Up to half of individuals with LLD are estimated to have cognitive impairment greater than that of age- and education-matched comparators, with impairments of episodic memory, speed of information processing, executive functioning, and visuospatial ability being most common. To inform our understanding of the state- versus trait-effects of depression on neuropsychological functioning, and to overcome limitations of previous studies, we utilized baseline data from the longitudinal Pathways study to compare differences in single time point performance on a broad-based neuropsychological battery across three diagnostic groups of older adults, each comprised of unique participants (n=438): currently depressed (n=120), previously depressed but currently euthymic (n=190), and never-depressed (n=128). Consistent with our hypotheses, we found that participants with a history of depression (currently or previously depressed) performed significantly worse than never-depressed participants on most tests of global cognition, as well as on tests of episodic memory, attention and processing speed, verbal ability, and visuospatial ability; in general, differences were most pronounced within the domain of attention and processing speed. Contrary to our hypothesis, we did not observe differences in executive performance between the two depression groups, suggesting that certain aspects of executive functioning are “trait deficits” associated with LLD. These findings are in general agreement with the existing literature, and represent an enhancement in methodological rigor over previous studies given the cross-sectional approach that avoids practice effects on test performance.
The ability to predict cognitive deterioration in patients with dementia holds valuable potential for clinical trials and early intervention. This study identified cognitive domains deteriorating differentially over time as well as baseline predictors of subsequent cognitive decline in patients referred to a memory clinic. Twenty-six subjects with Alzheimer's disease (AD) and 43 subjects with Subjective Memory Impairment (SMI) were entered into a longitudinal study in which cognitive function was assessed at baseline and at 8-monthly intervals for 2 years, using a range of well-validated measures. Thirty-seven patients with depression and 39 healthy controls were also longitudinally assessed. AD was associated with disproportionate deterioration over time on general measures of cognitive function, multiple measures of mnemonic processing, mental fluency (letter and category), and aspects of motor speed. SMI showed restricted relative cognitive deterioration on general measures of cognitive function, on a subset of memory measures, and on letter but not category fluency. Secondary analysis showed that earliest detectable ADAS-cog and MMSE decline in AD was at 16 months, while several specific neuropsychological indices were sensitive as early as 8 months (graded naming test, semantic naming, and the category/letter fluency tests). In combination, baseline/early changes in cognitive performance, alongside clinical measures, predicted 48% of disease progression over two years in memory impaired patients as a whole. These findings have implications for identifying patients likely to benefit from disease modifying agents, and for designing, powering, enriching, and implementing future clinical trials. Follow-up studies in independent populations are needed to validate predictive algorithms identified.
In Alzheimer's disease (AD), cognition and function are only moderately correlated in cross-sectional studies, and studies of their longitudinal association are less common. One potential non-cognitive contributor to function is depression, which has been associated with poorer clinical outcomes. The current study investigated longitudinal associations between functional abilities, cognitive status, and depressive symptoms in AD. 517 patients diagnosed with probable AD and enrolled in The Multicenter Study of Predictors of Disease Course in Alzheimer's Disease were included. Patients were followed at 6-month intervals over 5.5 years. Longitudinal changes in the Blessed Dementia Rating Scale, modified Mini-Mental State Exam, and the depression subscale of the Columbia University Scale for Psychopathology in AD were examined in a multivariate latent growth curve model that controlled for gender, age, education, and recruitment site. Results showed that cognition and function worsened over the study period, whereas depressive symptoms were largely stable. Rates of change in cognition and function were correlated across participants and coupled within participants, indicating that they travel together over time. Worse initial cognitive status was associated with faster subsequent functional decline, and vice versa. Higher level of depressive symptoms was associated with worse initial functioning and faster subsequent cognitive and functional decline. These findings highlight the importance of both cognitive and psychiatric assessment for functional prognosis. Targeting both cognitive and depressive symptoms in the clinical treatment of AD may have incremental benefit on functional abilities.
Background: Few studies have investigated in detail which factors influence activities of daily (ADL) in Alzheimer's disease (AD).
Objective: To assess the influence of cognitive, gender, and other factors on ADL in patients with mild to moderate AD.
Methods: This study is part of the Prospective Registry on Dementia in Austria (PRODEM) project, a multicenter dementia research project. A cohort of 221 AD patients (130 females; means: age 76 years, disease duration 34.4 months, MMSE 22.3) was included in a cross-sectional analysis. Everyday abilities were assessed with the Disability Assessment for Dementia scale, and cognitive functions with the CERAD plus neuropsychological test battery. Two models of multiple linear regressions were performed to find factors predicting functional decline, one entering demographical and disease related factors, and a joint model combining demographical and disease variables with neuropsychological scores.
Results: Non-cognitive factors explained 18%, whereas the adding of neuropsychological variables explained 39% of variance. Poor figural and verbal memory, constructional abilities, old age, longer disease duration, depression, and male gender were independent risk factors for reduced ADL. Instrumental and basic ADL were predicted by similar factors, except gender (predicting only instrumental ADL) and phonological fluency (predictor of basic ADL).
Conclusion: In addition to demographical factors, disease duration, and depression, neuropsychological variables are valuable predictors of the functional status in AD in an early disease stage.
Background: Alzheimer's disease (AD) is one of the most common age-related diseases in the western world. Gender differences in neuropsychological functions are seldom evaluated in AD.
Objective: Recent investigations suggested that gender may be an important modifying factor in the development and progression of AD. We examined gender-specific differences in the pattern of cognitive dysfunction of patients with mild to moderate AD.
Methods: We examined 113 males (mean age 78) and 173 females (mean age 80) of the prospective registry on dementia in Austria (PRODEM). We analyzed differences in the cognitive profile between male and female AD patients on the CERAD-Plus test battery.
Results: We found gender-related differences in the neuropsychological domains of verbal learning; the women tended to perform worse than men. Controlling for depression, stage and duration of dementia, and the level of education, there was still a significant effect of gender on verbal episodic memory.
Conclusion: There is an interaction between gender and cognitive function, most notable in verbal episodic memory; female patientsintheearlystageofADperformedworseonverbalepisodicmemorythanmen.Thisindicatesthatthegender-specificities of neuropsychological functions should be given careful consideration in clinical diagnosis of dementia.
The existence of a high co-morbidity between Alzheimer's disease (AD) and depression has been known for a long time. More interesting though are recent studies indicating that depression and number of depressive episodes earlier in life is associated with increased risk of AD development. This suggests the existence of common neuropathological mechanisms behind depression and AD. Here we propose that the brain changes associated with depressive episodes that compromise the brain's ability to cope with stress may constitute risk factors for development of AD. Furthermore, in individuals with a genetic linkage to depression, there may be an increased vulnerability towards the initiation of a detrimental neurodegenerative cascade. The following review will deal with the various observations reported within the different neurobiological systems known to be involved and affected in depression, like serotonergic and cholinergic system, hypothalamic-pituitary-adrenal axis and brain derived neurotrophic factor, and discussed in relation to AD.
Indoleamine 2,3-dioxygenase (IDO), an enzyme which is activated by pro-inflammatory cytokines, has been suggested as a potential link between neuroinflammatory processes in neurodegenerative diseases (like Alzheimer's disease) and depression. The present study aimed to determine whether neuroinflammation-induced increased IDO levels in the mammalian brain will lead to depressive-like behavior. Neuroinflammation was initiated in mice by a single intracerebroventricular injection of lipopolysaccharide (LPS). Cerebral inflammation was monitored 1, 2, 3 and 4 days after the injection with small-animal positron emission tomography (PET) using the inflammatory marker [11C]-PK11195. In the presence or absence of systemically applied 1-methyl-tryptophan (1-MT), a competitive IDO-inhibitor, we assessed the development of depressive-like behavioral symptoms in parallel with IDO expression and activity. The PK11195 PET signal reached a highly significant peak 3 days after LPS injection, while these animals displayed a significant increase of depressive-like behavior in the forced swim test compared to vehicle-injected animals. These findings were paralleled by a significant increase of IDO in the brainstem, and an increased kynurenine/tryptophan ratio in the serum. Moreover, we report here for the first time, that inhibition of IDO by 1-MT in centrally induced neuroinflammation under experimental conditions can prevent the development of depressive-like behavior.
The relationship between depression and Alzheimer's disease (AD) has always been relevant and controversial. Here, we briefly review epidemiological and biological studies that have investigated these disorders and then introduce our recent research about postmortem brains from patients with major depressive disorder (MDD). Our novel methodological approaches have revealed that MDD may be associated with an unknown type of myelin/myelination abnormalities in the frontopolar cortex. Based mainly on our findings, as well as on neuropathological observations by Braak and Braak (Acta Neuropathol 9, 197–201, 1996), we discuss the possible existence of an as yet unknown common mechanism linking the pathophysiologies underlying both depression and AD.
Depression is among the most common behavioral and psychological symptoms of dementia, and leads to more rapid decline and higher mortality. Treatment for depression in dementia has centered on conventional antidepressant drug treatment based around the monoamine hypothesis of depression. However, recent major studies have suggested that conventional antidepressant treatments that aim to correct underlying deficits in monoamine neurotransmitters are not effective for depression in dementia. Postmortem studies have also suggested that depression in dementia does not arise from serotonergic or noradrenergic abnormalities, or indeed from the degenerative pathology associated with Alzheimer's disease. In contrast, considerable recent evidence has suggested that alterations in glutamatergic transmission may contribute to the pathophysiology of depression. This supports the view that treatment-resistant depressed patients, such as many dementia patients, may benefit from agents affecting glutamate transmission. This review will thus draw together the wealth of pathological data examining the basis of depression in Alzheimer's disease and relate this to current thinking on treatment, with the aim of generating discussion on potential novel therapeutic strategies.
Even low levels of depressive symptoms are associated with an increased risk of cognitive decline in older adults without overt cognitive impairment (CN). Our objective was to examine whether very low, “subthreshold symptoms of depression” are associated with Alzheimer's disease (AD) biomarkers of neurodegeneration in CN adults and whether these associations are specific to particular depressive symptoms. We analyzed data from 248 community-dwelling CN older adults, including measurements of cortical amyloid burden, neurodegeneration markers of hippocampal volume (HV) and cerebral 18F-fluorodeoxyglucose (FDG) metabolism in a composite of AD-related regions and the 30-item Geriatric Depression Scale (GDS). Participants with GDS >10 were excluded. General linear regression models evaluated the cross-sectional relations of GDS to HV or FDG in separate backward elimination models. Predictors included GDS total score, age, gender, premorbid intelligence, a binary amyloid variable and its interaction with GDS. Principal component analyses of GDS item scores revealed three factors (the Dysphoria, Apathy-Anhedonia, and Anxiety-Concentration Factors). In secondary analyses, GDS total score was replaced with the three factor scores in repeated models. Higher GDS score (p=0.03) was significantly associated with lower HV and was marginally related (p=0.06) to FDG hypometabolism. In secondary models, higher Dysphoria (p=0.02) and Apathy-Anhedonia (p=0.05) were related to lower HV while higher Apathy-Anhedonia (p=0.003) was the sole factor related to FDG hypometabolism. Amyloid was not a significant predictor in any model. In conclusion, very low-level dysphoria, apathy and anhedonia may point to neurodegeneration in AD-related regions but this association appears to be independent of amyloid burden.
Background and Objectives: Decreased hippocampal volume in older adults is associated with neurodegenerative and psychiatric diseases. Several modifiable risk factors have been associated with the size of this structure, however the relative contribution of these factors to hippocampal atrophy is unclear. This study aimed to examine the relationship between modifiable risk factors and hippocampal volume in older adults at risk of cognitive decline.
Methods: Two hundred and eighteen participants (mean age=67.3 years, MMSE=28.6) with mood and/or memory complaints underwent clinical and neuropsychological assessment, and magnetic resonance imaging. Measures of depression, global cognitive functioning, exercise, vascular health, cognitive reserve, sleep, and memory were collected. Hippocampal volumes were derived using image segmentation as implemented by FMRIB Software Library.
Results: Smaller hippocampal volumes were strongly associated with poorer verbal learning and memory as well as diagnoses of either multiple or amnestic mild cognitive impairment. Based on univariate correlations, multivariable regressions were performed (controlling for age and total intracranial volume) to determine which modifiable risk factors were associated with hippocampal volume. For the left hippocampus, poor sleep efficiency and greater than five years untreated depressive illness remained significant predictors. For the right hippocampus, diabetes and low diastolic blood pressure remained significant predictors.
Conclusions: Although their contribution is small, lower sleep efficiency, low blood pressure, diabetes, and untreated depression are associated with reduced hippocampal volumes. Studies exploring the impact of early intervention for these risk factors on hippocampal integrity are warranted.
We examined whether late-life depression, including depressive symptoms and antidepressant use, was associated with smaller total brain volume, smaller hippocampal volume, and larger white matter hyperintensity (WMH) volume in a large community-based cohort of old persons without dementia. Within the Washington/Hamilton Height-Inwood Columbia Aging Project (WHICAP), a community-based cohort study in northern Manhattan, 630 persons without dementia (mean age 80 years, SD=5) had volumetric measures of the total brain, hippocampus, and WMH at 1.5 Tesla MRI and data on current depression, defined as a score of 4 or higher on the 10-item Center for Epidemiologic Studies-Depression (CES-D) scale, or use of antidepressants. Multiple linear regression analyses adjusted for age, gender, ethnicity, education, cardiovascular disease history, and MRI parameters showed that subjects with current depression had smaller relative total brain volume (B= −0.86%; 95% CI −1.68 to −0.05%; p<0.05), smaller relative hippocampal volume (B= −0.07ml; 95% CI −0.14 to 0.00ml; p=0.05), and larger relative WMH volume (natural logtransformed B=0.19ml; 95% CI 0.02 to 0.35ml; p<0.05). When examined separately, antidepressant use was significantly associated with smaller total brain, smaller hippocampal, and larger WMH volume, while high CES-D scores were not significantly associated with any of the brain measures, although the direction of association was similar as for antidepressant use. With the caveat that analyses were cross-sectional and we had no formal diagnosis of depression, our findings suggest that in this community-based sample of old persons without dementia, late-life depression is associated with more brain atrophy and more white matter lesions, which was mainly driven by antidepressant use.