Alpha-synuclein lesions in normal aging, Parkinson disease, and Alzheimer disease: evidence from the Baltimore Longitudinal Study of Aging (BLSA)

Alpha-synuclein (alpha-synuclein) lesions are characteristic of idiopathic Parkinson disease (PD) and other alpha-synucleinopathies. To study the frequency of alpha-synuclein lesions in normal aging and how frequently they coexist with lesions of Alzheimer disease (AD), we examined the autopsy brains from normal and demented subjects in the Baltimore Longitudinal Study of Aging (BLSA) (n = 117). We found that the overall frequency of alpha-synuclein lesions was 25%, with 100% in 7 cases of PD, 31.5% in 56 cases with AD lesions, and 8.3% among 36 older control brains. Among brains with AD lesions, the frequency of alpha-synuclein pathology was higher in those with higher scores for neuritic plaques, but not in those with higher scores for neurofibrillary tangles. Our observations indicate that alpha-synuclein lesions are uncommon in aged control subjects. Finally, the coexistence of Abeta amyloid and alpha-synuclein pathology in AD brains suggests that the pathogenic mechanism/s leading to the accumulation of Abeta and alpha-synuclein may be similar.     

Longitudinal analysis of the developmental process in chronically ill and healthy persons--empirical findings from the Bonn Longitudinal Study of Aging (BOLSA)

Chronically ill and healthy persons are compared as to social roles, dominant concerns, and in coping with stress. The comparison is based on a longitudinal analysis of data which was collected in the Bonn Longitudinal Study of Aging (BOLSA). The empirical analysis indicates that both groups show great success in mastering life situations and in coping with challenges and restrictions. This competence persists over the eight measurement points. The empirical analysis also makes clear that chronically ill patients often cope actively with stress, that they are able to accept restrictions and to look simultaneously for new possibilities in life. Social contacts have a predominant position in coping with chronic disease. Intrafamilial and extrafamilial contacts are important and helpful for chronically ill patients. As the longitudinal analysis reveals, coping with challenges and demands of life is influenced by the individual life-style. The analysis points to the aging process as a process of growth and of new potentials. This applies not only to persons who are in good health, but to chronically ill persons as well.     

Greater impairment of ability in the divided attention task is seen in Alzheimer's disease patients with depression than in those without depression

BACKGROUND: Recent studies have emphasized specific deficits of attention and executive functions, such as those of cognitive flexibility, divided attention, in geriatric patients with depression. In Alzheimer's disease (AD), depressive symptoms are known to occur even from an early stage of the disease. However, the nature of the impairment of executive functions in depression associated with AD remains unclear, because of the frequent occurrence of the apathy syndrome as a major confounding factor. METHOD: In this study, we conducted a comprehensive comparative neuropsychological assessment in AD patients with (n=21) and without (n=21) depression. The diagnosis of depression was based on provisional criteria proposed by Olin's group. RESULTS: In terms of apathy symptoms, both groups had a similar degree of deficits, which were mild as assessed according to Neuropsychiatric Inventory criteria. While no significant differences were observed in regard to the scores in general intellectual functioning, episodic memory and some attention and executive tasks between the two groups, AD patients with depression showed significantly lower scores in several attention and executive function tasks, such as the dual-task performance task administered to assess the capacity for divided attention, and the cognitive flexibility (Trail Making Test; Part B), than AD patients without depression. CONCLUSIONS: Our results suggest that depressive symptoms in AD patients increase the deficits of cognitive flexibility and divided attention. This is the first study to report a correlation between depressions, diagnosed based on the provisional criteria for depression in AD by Olin's group, and an impaired capacity for divided attention in AD patients.     

Sleep behaviours and multimorbidity occurrence in middle-aged and older adults: findings from the Canadian Longitudinal Study on Aging (CLSA)

ObjectivePoor sleep quality and reduced sleep duration impact over half of older adults and are associated with adverse health outcomes, such as multiple chronic conditions (multimorbidity) and reduced longevity. Our objective was to examine the relationship between sleep behaviours and multimorbidity in Canada.MethodsWe analysed data from the Canadian Longitudinal Study on Aging (CLSA), a cross-sectional national health survey of community-dwelling adults over the age of 45 years. A total of 30,011 participants had physiological and psychosocial data collected at baseline. Sleep measures included self-reported sleep duration (short: <6 h; normal: 6–8 h; long: >8 h) and sleep quality (dissatisfied/very dissatisfied; neutral; satisfied/very satisfied). Multimorbidity was defined using two definitions (public health and primary care) and two cut-points (2 or more and 3 or more chronic conditions).ResultsApproximately 70% were living with multimorbidity using the primary care definition (females: 67.9%; males 57.9%), whereas approximately 30% were living with multimorbidity using the public health definition (females: 30.9%; males: 24.0%). Adjusted analyses indicated that the odds of multimorbidity were higher for participants who selfreported either short or long sleep duration, as well as dissatisfaction with sleep quality. Associations were stronger among younger age groups (45–54 years and 55–64 years).ConclusionsDisrupted sleep may be a risk factor for multimorbidity across sexes and age groups. It is necessary to understand the potential impact of sleep on the risk of multimorbidity to inform both clinical and public health guidelines for the prevention and management of this major health issue.     

Attention and executive control predict Alzheimer disease in late life: results from the Berlin Aging Study (BASE).

OBJECTIVE: Longitudinal studies of neuropsychological changes in the preclinical phase of Alzheimer disease (AD) have yielded mixed results. Although some studies report tests of episodic memory, others report tests of attention and executive functions as reliable predictors of subsequent AD. Following theoretical models of neuropsychological processes before AD onset, the authors examined the predictive value of attention and executive function in the preclinical phase of AD in old age. METHODS: Authors studied the cognitive performance of 187 initially normal participants of the Berlin Aging Study, a community-based representative sample of Berlin citizens age 70 to 103, over a period of 4 years. Tests of attention and executive function (Digit Letter Test, Trailmaking Part B Test, Digit Symbol Substitution Test, and Identical Pictures Test) and of learning and recall functions (Activity Recall, Memory for Text, and Paired-Associate Learning) were administered at baseline. Diagnosis of AD was made according to NINCDS-ADRDA criteria (probable AD). Receiver operating characteristics curve analyses and Cox regression analyses were used to assess the diagnostic accuracy and predictive value of the neuropsychological tests at baseline for incident AD after 4 years. RESULTS: After 4 years, 15 participants had developed AD. Tests of attention and executive function discriminated best between nonconverters and incident AD cases. A similar pattern was found in survival analyses; attention and executive function tests, together with tests of learning and recall, significantly predicted incident AD over and above age, gender, and education. CONCLUSION: These results support theoretical models of attention and executive function in the preclinical phase of AD in old age.     

Cognitive response to pharmacological treatment for depression in Alzheimer disease: secondary outcomes from the depression in Alzheimer's disease study (DIADS).

OBJECTIVE: The authors assessed the cognitive effects of depression treatment with sertraline in patients with Alzheimer disease (AD) and major depression. METHODS: Forty-four patients with probable AD and major depression were enrolled in a double-blind, placebo-controlled clinical trial of sertraline. Cognitive testing was done at baseline and at 3-week intervals throughout the 12-week study. At the 12th week, subjects were categorized by treatment response (full, partial, or no response). Cognitive data from 41 participants who completed three or more testing sessions and 36 who completed all five study visits were included in the analyses. RESULTS: Neither improved mood nor use of sertraline was associated with cognitive change over time in AD patients. Post-hoc exploration of the data, however, suggested a sex difference in cognitive response to sertraline such that women treated with sertraline demonstrated improved cognition compared with women on placebo, whereas men treated with sertraline worsened significantly in cognition compared with men on placebo. CONCLUSIONS: In this study, among depressed AD patients after treatment with sertraline or placebo, there was no evidence that improved mood was associated with cognitive improvement. Future studies aimed at increasing power to detect mood as well as medication effects will be valuable in determining the relationship between cognition and treatment of depression in AD patients.     

Hospitalization,depression and dementia in community-dwelling older Americans: findings from the National Health and Aging Trends Study

Objective

The objective was to estimate the prevalence of both dementia and depression among community-dwelling older Americans and to determine if hospitalization is independently associated with dementia or depression in this population.

Method

This cross-sectional study utilized data from a nationally representative, population-based sample of 7197 community-dwelling adults ≥ 65 years old interviewed in 2011 as part of the National Health and Aging Trends Study. Information on hospitalizations was obtained from self- or proxy-report. Possible and probable dementia was assessed according to a validated algorithm. Depressive symptoms were assessed with the Patient Health Questionnaire-2.

Results

An estimated 3.1 million community-dwelling older Americans may have dementia, and approximately 5.3 million may have substantial depressive symptoms. After adjusting for demographic and social characteristics, medical diagnoses, smoking history, serious falls and pain symptoms, being hospitalized in the previous year was independently associated with greater odds of probable dementia (odds ratio [OR]: 1.42, 95% confidence interval [95% CI]: 1.16–1.73) and substantial depressive symptoms (OR: 1.60, 95% CI: 1.29–1.99).

Conclusions

Dementia and depression are common in community-dwelling older Americans, and hospitalization is associated with these conditions. Additional research increasing understanding of the bidirectional relationship between hospitalizations, dementia and depression, along with targeted interventions to reduce hospitalizations, is needed.     

Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease

The role of microglial cells in the pathogenesis of Alzheimer’s disease (AD) neurodegeneration is unknown. Although several works suggest that chronic neuroinflammation caused by activated microglia contributes to neurofibrillary degeneration, anti-inflammatory drugs do not prevent or reverse neuronal tau pathology. This raises the question if indeed microglial activation occurs in the human brain at sites of neurofibrillary degeneration. In view of the recent work demonstrating presence of dystrophic (senescent) microglia in aged human brain, the purpose of this study was to investigate microglial cells in situ and at high resolution in the immediate vicinity of tau-positive structures in order to determine conclusively whether degenerating neuronal structures are associated with activated or with dystrophic microglia. We used a newly optimized immunohistochemical method for visualizing microglial cells in human archival brain together with Braak staging of neurofibrillary pathology to ascertain the morphology of microglia in the vicinity of tau-positive structures. We now report histopathological findings from 19 humans covering the spectrum from none to severe AD pathology, including patients with Down’s syndrome, showing that degenerating neuronal structures positive for tau (neuropil threads, neurofibrillary tangles, neuritic plaques) are invariably colocalized with severely dystrophic (fragmented) rather than with activated microglial cells. Using Braak staging of Alzheimer neuropathology we demonstrate that microglial dystrophy precedes the spread of tau pathology. Deposits of amyloid-beta protein (Aβ) devoid of tau-positive structures were found to be colocalized with non-activated, ramified microglia, suggesting that Aβ does not trigger microglial activation. Our findings also indicate that when microglial activation does occur in the absence of an identifiable acute central nervous system insult, it is likely to be the result of systemic infectious disease. The findings reported here strongly argue against the hypothesis that neuroinflammatory changes contribute to AD dementia. Instead, they offer an alternative hypothesis of AD pathogenesis that takes into consideration: (1) the notion that microglia are neuron-supporting cells and neuroprotective; (2) the fact that development of non-familial, sporadic AD is inextricably linked to aging. They support the idea that progressive, aging-related microglial degeneration and loss of microglial neuroprotection rather than induction of microglial activation contributes to the onset of sporadic Alzheimer’s disease. The results have far-reaching implications in terms of reevaluating current treatment approaches towards AD.     

Alcohol drinking and cognitive functions: findings from the Cardiovascular Risk Factors Aging and Dementia (CAIDE) Study

BACKGROUND: Moderate alcohol drinking is suggested to be beneficial for cognitive functions, but the results of previous studies have varied greatly. Little is known about the effects of midlife alcohol drinking on the cognitive functions later in life. METHODS: Participants were derived from random, population-based samples studied in Eastern Finland in 1972, 1977, 1982, or 1987. A total of 1,341 participants were reexamined in 1998, after an average follow-up period of 21 years, at ages 65-79 years. RESULTS: The participants who did not drink alcohol at midlife had a poorer performance in episodic memory, psychomotor speed, and executive function in late life as compared with infrequent and frequent drinkers, adjusted for sociodemographic and vascular factors. Also late-life nondrinkers had poorer psychomotor speed and executive function. These findings were evident especially among nonsmokers. Further, no interactions between apolipoprotein E4 and alcohol or sex and alcohol were found. CONCLUSIONS: Alcohol drinking both at midlife and later is favorably related to the function in several cognitive domains, including episodic memory, psychomotor speed, and executive function, in late life. However, it is not clear whether the association is causal, what is the possible mechanism, and what would be a safe limit of drinking for the best cognitive function.     

A comparison of GMS-A/AGECAT,DSM-III-R for dementia and depression,including subthreshold depression (SD)--results from the Berlin Aging Study (BASE)

BACKGROUND: Empirical evaluation of the agreement between different diagnostic approaches is crucial for the understanding of epidemiological results in geriatric psychiatry. OBJECTIVES: In this paper, we analyse differences between widely used diagnostic approaches of dementia and depression and offer evidence that diagnostic thresholds vary substantially on quantitative dimensions, but that conceptual and other differences between approaches must also been taken into account. METHODS: In an epidemiological study of n = 516 persons, aged 70-103 years, we compared psychiatric diagnoses of dementia and depression obtained by GMS-A/HAS-AGECAT, DSM-III-R and clinician's diagnoses of subthreshold depression (SD). RESULTS: For depression, cumulative prevalence of clinician's diagnosis (including SD, GMS-A/HAS-AGECAT and DSM-III-R defined forms) was highest, followed by GMS-A/HAS-AGECAT-diagnosis and DSM-III-R, while for dementia DSM-III-R was followed by GMS-A/HAS-AGECAT. Overall agreement between DSM-III-R and GMS-A/HAS-AGECAT was moderate. Adapting thresholds for AGECAT resulted in slightly better diagnostic efficiency. Diagnostic disagreement was found predominantly for cases with intermediate symptom severity, supporting the hypothesis of differing thresholds between DSM-III-R and GMS-A/HAS-AGECAT, while cases with lower or higher symptom severity were similarly seen as cases or non-cases. CONCLUSION: Disagreement is not only caused by conceptual differences, but also different thresholds of diagnostic algorithms. Adaptation of threshold levels should be feasible, depending on the purpose of the analysis.     

Doublecortin (DCX) and doublecortin-like (DCL) are differentially expressed in the early but not late stages of murine neocortical development

During corticogenesis, radial glia-derived neural progenitors divide and migrate along radial fibers to their designated positions within the cortical plate. The microtubule-associated proteins doublecortin (DCX) and doublecortin-like (DCL) are critically involved in neuronal migration and division, and may function in a partially redundant pathway. Since little is known about the important early stages of corticogenesis, when neurogenesis is extensive, we addressed a possible differential role by examining spatiotemporal expression patterns of DCX, DCL, and the radial glia marker vimentin during murine development. We found expression patterns of DCL and DCX to differ remarkably prior to embryonic day (E)13. DCL was already expressed at E9 and largely overlapped with vimentin, whereas DCX expression started modestly from E10/E11 onward. DCL was mainly found in the ventricular zone, often in mitotic cells and in pial-oriented radial fibers. In contrast, DCX was expressed in tangential fibers in the outer cortical regions. After E13, DCX and DCL expression largely overlapped but DCL expression had disappeared from the ventricular zone. Also, DCL levels were attenuated, whereas DCX remained high beyond E17. In conclusion, DCX and DCL are differentially expressed, particularly during early corticogenesis, consistent with their different functional roles. Given its involvement in mitosis, DCL appears to have a unique role in the early neuroepithelium that is different from later developmental stages when DCX is coexpressed.