Manchester Longitudinal Study Of Cognition Research Articles

Depression in older adults and its associations with sleep and synaptic density

BackgroundDepression among older adults is a global concern, contributing to disability and overall illness burden. Understanding its trajectory, associated risk factors, and implications for mortality is essential for effective intervention. Moreover, the relationship between depression, sleep disturbances, and synaptic density in the ageing brain remains complex and poorly understood. MethodsUsing data from the University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort, comprising 6375 participants, we conducted comprehensive assessments of depression trajectories using generalized linear mixed models and mortality risks using Cox mixed-effects models. Generalized structural equation modelling was performed to explore longitudinal associations between sleep duration and depression. Lastly, associations between post-mortem synaptic density and depression were investigated. ResultsOur findings revealed that depression rates declined until age 80 before increasing again. Depression was associated with a 10 % increased risk of mortality in older adults. Reduced sleep was correlated with depression, and depression measured early in the study predicted future reduced sleep. Post-mortem analysis showed a global reduction in synaptic density associated with depression, particularly pronounced in the frontal lobe. LimitationsLimitations include recall bias, limiting generalizability due to dominantly including White British participants and difficulty in establishing causation between synaptic density and depression. ConclusionOur study underscores the significance of addressing depression in older adults, not only for mental health but also for mortality risk and neurobiological health. Early detection and intervention strategies are crucial for improving outcomes in elderly populations, potentially mitigating adverse effects on sleep, synaptic density, cognitive health, and longevity.

Associations between chronotype and employment status in a longitudinal study of an elderly population

ABSTRACT Individuals with an ‘evening’ chronotype tend to sleep and wake later than people described to be ‘morning’ type if given a free choice. Since early awakening times, due to school and occupation, may be more challenging for those with evening chronotype, they are expected to be at greater risk of adverse health, occupational and educational outcomes. Our objectives are to investigate associations between chronotype and occupational, educational and health outcomes in a longitudinal cohort. We use sleep, sociodemographic and health data from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, 1982 through 2010. The relationship between employment and longitudinal midsleep trajectories were estimated using linear mixed models. Associations between employment status and Cornell Medical Index, Beck Depression Inventory scores, cortisol concentrations at different times of the day stratified by chronotype were estimated using regression. The relationship between chronotype, occupational success, education, and cognition were also examined using regression methods. In older adults, compared to non-employed participants, employed participants get up 0.45 hours earlier. Evening-type employed individuals had earlier midsleep time compared to their non-employed counterparts and had abnormal longitudinal trajectories with an increasing trend as they aged. Employed individuals with evening chronotype had a higher risk of depression than employed morning-types. Moreover, employed individuals with evening chronotype had a higher cortisol concentration at 14:00 h than non-employed individuals. In addition, memory score was lower in individuals with morning chronotype, however processing speed was higher in individuals with morning chronotype compared to evening. Morning-types had a higher age when they finished full time education. Relative to evening-types, those with morning chronotype were 6.5% more likely to be in a job classed as professional or intermediate. Our findings suggest that evening-types are at a disadvantage with regards to occupational, educational and health outcomes in older adults due to their vulnerability to circadian and sleep disruption.

Telephone Interview for Cognitive Status Scores Associate with Cognitive Impairment and Alzheimer's Disease Pathology at Death.

Early diagnosis of Alzheimer's disease (AD) provides an opportunity for early intervention. Cognitive testing has proven to be a reliable way to identify individuals who may be at risk of AD. The Telephone Assessment for Cognitive Screening (TICS) is proficient in screening for cognitive impairment. However, its ability to identify those at risk of developing AD pathology is unknown. We aim to investigate associations between TICS scores, collected over a period of 13 years, and the cognitive status of participants at death. We also examine relationships between TICS scores and neuropathological indices of AD (CERAD score, Thal phase, and Braak stage). Between 2004 and 2017, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent cognitive assessment using TICS. Scores from four time points were available for analysis. Cognitive impairment and AD pathology at death was evaluated in 101 participants. TICS scores at time points 2, 3, and 4 were significantly lower in those cognitively impaired at death compared to those considered cognitively normal. There were significant negative correlations between TICS scores and CERAD score and Braak stage at time points 2 and 4. No correlations between Thal phase and TICS were found. Findings indicate that TICS could be used not only to screen for cognitive impairment, but also to identify individuals at risk of developing AD pathology, many years before any overt symptoms occur. Once identified, 'at risk' individuals could be targeted for early interventions which could attenuate the progression of the disease.

49 Longitudinal Change of Sleep in the Elderly and Its Associations with Health

Abstract Introduction In elderly populations, sleep quality deteriorates and sleep time shifts towards earlier times. These sleep characteristics have been associated with cardiovascular, metabolic and psychiatric disorders, cognitive decline and mortality. Our aims are to examine longitudinal changes of sleep in older adults and to investigate the relationship between sleep variations, general health and mortality. Methods The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort (6,375 participants, recruited in the North of England, between 1983 and 1993) was used. Mixed models were used to investigate individual sleep trajectories (5 waves in 30-year period). Sleep timing and efficiency trajectories were clustered using latent class analysis and analysed against daily habits, health and mortality. Results Older adults have decreased sleep efficiency (~20%) and early sleep time (~30 min) between 40 and 100 years of age. Those in the high sleep efficiency latent class had minimal decrease in their sleep efficiency as they aged. Belonging to the high sleep efficiency latent class was associated with having lower prevalence of hypertension, circulatory problems, arthritis, breathing problems and recurrent depression compared to the low efficiency latent class. Results showed a higher risk of hypertension and metabolic syndrome in the evening-type latent class compared to morning-type individuals. Evening class was associated with traits related to lower health such as reduced sport participation, increased risk of depression and psychoticism personality, late eating, increased smoking and alcohol usage. Survival analysis revealed that individuals in the evening class had 1.15-fold increased risk of all-cause mortality compared to those with morning preferences. Conclusion Ageing is associated with decreased sleep efficiency and early sleep timing. However, there are detectable subgroups of sleep traits that are related to prevalence of different diseases and longevity. Understating these subgroups may pave the way for new treatments for healthy sleeping habits in older population.

Influence of APOE genotype in primary age-related tauopathy

The term “Primary age-related tauopathy” (PART) was coined in 2014 to describe the common neuropathological observation of neurofibrillary tangles without associated beta-amyloid (Aβ) pathology. It is possible for PART pathology to be present in both cognitively normal and cognitively impaired individuals. Genetically, Apolipoprotein E (APOE) ε4 has been shown to occur less commonly in PART than in Alzheimer’s disease (AD). Here, we investigate the relationships between PART, AD and those pathologically normal for age, with an emphasis on APOE and cognition, using 152 selected participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age and the Manchester arm of the Brains for Dementia Research cohort. APOE genotype differed between PART and AD with APOE ε2 more common in the former and APOE ε4 more common in the latter. Individuals with definite PART were less likely to be cognitively impaired than those with AD and those with pathology considered pathologically normal for age. We postulate that the lack of Aβ in definite PART cases may be due either to an increased frequency of APOE ε2 or decreased frequency of APOE ε4 as their resulting protein isoforms have differing binding properties in relation to Aβ. Similarly, an increased frequency of APOE ε2 or decreased frequency of APOE ε4 may lead to decreased levels of cognitive impairment, which raises questions regarding the impact of Aβ pathology on overall cognition in elderly subjects. We suggest that it may be possible to use the increased frequency of APOE ε2 in definite PART to assist neuropathological diagnosis.

Mid to late-life scores of depression in the cognitively healthy are associated with cognitive status and Alzheimer's disease pathology at death.

ObjectivesEarly diagnosis of Alzheimer's disease (AD) is essential for early interventions. Symptoms of depression could represent a prodromal stage of AD. Very early mood alterations may help to stratify those at highest risk of late‐life AD. We aim to investigate associations between baseline/longitudinal scores for depression, presence of cognitive impairment and/or AD pathology at death.Methods/DesignBetween 1991 and 2015, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent 10 waves of assessment using the Geriatric Depression Scale (GDS). AD pathology at death was evaluated in 106 eligible cases. Analyses aimed to examine associations between GDS scores, cognitive status and AD pathology (as measured by Braak stage, Thal phase and CERAD).ResultsBaseline GDS scores were significantly higher for those cognitively impaired at death than those cognitively normal. Significantly higher baseline GDS scores were found for those with greater Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) scores than those with lower CERAD scores. Similarly, significantly higher baseline GDS scores were found for those with a greater Braak stage than those with lower tau burden. These correlations remained after controlling for age at death, education and APOE ε4, but were less robust. Mean longitudinal GDS scores associated with cognition but not pathology.ConclusionsGDS scores collected approximately 20 years before death were associated with cognitive status and AD pathology at death. We postulate that early AD‐related pathological change produces raised GDS scores due to an overlapping neural basis with depression, and that this may be considered as an early diagnostic marker for AD.

The Contribution of Vascular Pathology Toward Cognitive Impairment in Older Individuals with Intermediate Braak Stage Tau Pathology

The pathological features of Alzheimer's disease (AD) are well described but little is known as to how both neurodegeneration and vascular changes might interact in causing cognitive impairment. The present study aims to investigate relationships between vascular and AD pathology in cognitively healthy and cognitively impaired individuals with a particular emphasis on those at intermediate Braak tau stages. We investigated the interplay between Braak tau stage and measures of vascular pathology as described by the vascular cognitive impairment neuropathology guidelines (VCING) in 185 brains from the Brains for Dementia Research programme and The University of Manchester Longitudinal Study of Cognition in Healthy Old Age. VCING asserts that at least one large (>10 mm) infarct, moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, and moderate/severe arteriosclerosis in occipital white matter accurately predicts the contribution of cerebrovascular pathology to cognitive impairment. We found that the extent of arteriosclerosis in the occipital white matter did not differ between cognitive groups at intermediate (III-IV) Braak stages whereas moderate/severe leptomeningeal occipital cerebral amyloid angiopathy was greater in cognitively impaired than normal individuals at Braak stage III-IV. This finding remained significant after controlling for effects of age, sex, CERAD score, Thal phase, presence/severity of primary age-related tauopathy, presence/severity of limbic-predominant age-related TDP43 encephalopathy and small vessel disease in basal ganglia. Interventions targeting cerebral amyloid angiopathy may contribute to delay the onset of cognitive impairment in individuals with intermediate Alzheimer's type pathology.

Influence of APOE Genotype on Mortality and Cognitive Impairment.

While many studies have examined the associations between APOE genotype and mortality, findings have often been conflicting and it remains unclear whether APOE genotype affects longevity. Using selected individuals from the Manchester arm of the Brains for Dementia Research programme and University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, we investigated relationships between APOE genotype and age at death in both cognitively normal and cognitively impaired individuals. Results indicated that carrying the APOE ɛ4 allele led to a reduced chance in an individual reaching 80+ years and remaining cognitively healthy. Conversely, APOE ɛ2 carriers tended to live longer and remain cognitively normal. These findings add to the evidence that APOE genotype influences longevity, especially in cognitively impaired individuals who carry the APOE ɛ4 allele.

Longitudinal sleep efficiency in the elderly and its association with health.

The relationships between older age and sleep efficiency have traditionally been assessed using cross-sectional studies that ignore changes within individuals as they age. This research examines the determinants of sleep efficiency, the heterogeneity in an individual's sleep efficiency trajectory across a period of up to 27years in later life and its associations with health. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort (n=6,375; age 42-94 years) was used in this study. Depression and health data were collected using self-report validated instruments (Cornell Medical Index, Beck Depression Inventory and Geriatric Depression Scale). Longitudinal sleep and sociodemographic data were collected using a study-specific self-report questionnaire. A mixed-effect model was performed for sleep efficiency with adjustments for time-invariant and time-variant predictors. Latent class analysis was used to demonstrate subgroups of sleep efficiency trajectories and associations between sleep efficiency clusters and health history of the participants were investigated. Older adults have decreased sleep efficiency over time, with 18.6% decline between 40 and 100years of age. Three sleep efficiency trajectory clusters were identified: high (32%), medium (50%) and low sleep efficiency (18%). Belonging to the high sleep efficiency cluster was associated with having lower prevalence of hypertension, circulatory problems, general arthritis, breathing problems and recurrent episodes of depression compared to the low efficiency cluster. Overall, ageing decreases sleep efficiency. However, there are detectable subgroups of sleep efficiency that are related to prevalence of different diseases.

No association between head injury with loss of consciousness and Alzheimer disease pathology—Findings from the University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age

ObjectivesHead injury with loss of consciousness (HI‐LOC) is a common occurrence. Some studies have linked such injuries with an increased risk of Alzheimer disease (AD). However, recent large clinicopathologic studies have failed to find a clear relationship between HI‐LOC and the pathological changes associated with AD. The present study aims to further investigate the relationship between HI‐LOC and AD pathology in the elderly.Methods/DesignHistory of HI‐LOC in participants in the University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age was ascertained. The donated brains of 110 of these individuals were assessed for AD pathology using consensus guidelines. Analyses aimed to elucidate relationships between HI‐LOC and AD pathology.ResultsNo associations were found between incidence of HI‐LOC and regional AD pathology or any of the three established measures of the neuropathology associated with AD: CERAD score, Thal phase, or Braak stage.ConclusionsSingle incidences of HI‐LOC may not be sufficient to cause the pathology associated with late‐stage AD. Other routes of damage, such as diffuse axonal injury or Lewy body pathology, may play a greater role in causing cognitive impairment associated with head injury.

Pathological Correlates of Cognitive Impairment in The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age.

The neuropathological changes responsible for cognitive impairment and dementia remain incompletely understood. Longitudinal studies with a brain donation end point allow the opportunity to examine relationships between cognitive status and neuropathology. We report on the first 97 participants coming to autopsy with sufficient clinical information from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. This study began in 1983 and recruited 6,542 healthy individuals between 1983 and 1994, 312 of whom consented to brain donation. Alzheimer-type pathology was common throughout the cohort and generally correlated well with cognitive status. However, there was some overlap between cognitive status and measures of Alzheimer pathology with 26% of cognitively intact participants reaching either CERAD B or C, 11% reaching Thal phase 4 or 5, and 29% reaching Braak stage III- VI. Cerebral amyloid angiopathy(CAA), α-synuclein, and TDP-43 pathology was less common, but when present correlated well with cognitive status. Possession of APOEɛ4 allele(s) was associated with more severe Alzheimer-type and CAA pathology and earlier death, whereas possession of APOEɛ2 allele(s) had no effect on pathology but was more common in cognitively intact individuals. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort is pathologically representative when compared with similar studies. Cognitive impairment in life correlates strongly with all pathologies examined and the APOE status of an individual can affect pathology severity and longevity.

Scores Obtained from a Simple Cognitive Test of Visuospatial Episodic Memory Performed Decades before Death Are Associated with the Ultimate Presence of Alzheimer Disease Pathology

Background: Community- or population-based longitudinal studies of cognitive ability with a brain donation end point offer an opportunity to examine relationships between pathology and cognitive state prior to death. Discriminating the earliest signs of dementing disorders, such as Alzheimer disease (AD), is necessary to undertake early interventions and treatments. Methods: The neuropathological profile of brains donated from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, including CERAD (Consortium to Establish a Registry for Alzheimer’s Disease) and Braak stage, was assessed by immunohistochemistry. Cognitive test scores collected 20 years prior to death were correlated with the extent of AD pathology present at death. Results: Baseline scores from the Memory Circle test had the ability to distinguish between individuals who developed substantial AD pathology and those with no, or low, AD pathology. Predicted test scores at the age of 65 years also discriminated between these pathology groups. The addition of APOE genotype further improved the discriminatory ability of the model. Conclusions: The results raise the possibility of identifying individuals at future risk of the neuropathological changes associated with AD over 20 years before death using a simple cognitive test. This work may facilitate early interventions, therapeutics and treatments for AD by identifying at-risk and minimally affected (in pathological terms) individuals.

Life span decrements in fluid intelligence and processing speed predict mortality risk.

We examined life span changes in 5 domains of cognitive performance as predictive of mortality risk. Data came from the Manchester Longitudinal Study of Cognition, a 20-plus-year investigation of 6,203 individuals ages 42-97 years. Cognitive domains were general crystallized intelligence, general fluid intelligence, verbal memory, visuospatial memory, and processing speed. Life span decrements were evident across these domains, controlling for baseline performance at age 70 and adjusting for retest effects. Survival analyses stratified by sex and conducted independently by cognitive domain showed that lower baseline performance levels in all domains-and larger life span decrements in general fluid intelligence and processing speed-were predictive of increased mortality risk for both women and men. Critically, analyses of the combined predictive power of cognitive performance variables showed that baseline levels of processing speed (in women) and general fluid intelligence (in men), and decrements in processing speed (in women and in men) and general fluid intelligence (in women), accounted for most of the explained variation in mortality risk. In light of recent evidence from brain-imaging studies, we speculate that cognitive abilities closely linked to cerebral white matter integrity (such as processing speed and general fluid intelligence) may represent particularly sensitive markers of mortality risk. In addition, we presume that greater complexity in cognition-survival associations observed in women (in analyses incorporating all cognitive predictors) may be a consequence of longer and more variable cognitive declines in women relative to men.

The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, 1983 through 2003

This paper describes the participants, design, method and tests used during a 20-year longitudinal study of cognitive changes in increasing age experienced by 6542 healthy residents of Greater Manchester and Newcastle-upon-Tyne, then aged from 42 to 92 years. Information collected and updated includes demographics and health, scores on two, biennially alternated batteries of cognitive tests, repeated administrations of the Beck and Yesavage depression inventories and of self-reports of stressful life events, self-evaluation and locus of control questionnaires and detailed information on lifestyle, hobbies and occupations, physical and social activities, family circumstances and health history. Records have allowed investigation of rates of cognitive changes from 36 months to 20 years preceding death from a variety of causes. Collection of blood and saliva provide, blood chemistry and cortisol levels to analyse associations of rates of cognitive change to genetic factors, blood chemistry and cortisol levels. A random effects analysis confirms marked effects of drop-out and practice due to repeated testing and shows how true rates of change, and of increases in variability between individuals may be ascertained after these have been identified.