Cross-sectional association between posttraumatic stress and cognition is moderated by pulmonary functioning in world trade center responders.

BACKGROUND: Posttraumatic stress disorder (PTSD) symptomatology and poorer pulmonary function are highly prevalent psychiatric and medical conditions. In the present study, we tested for the individual, additive, and modifying associations of PTSD symptomatology and pulmonary function with cognitive performance. METHODS: In this cross-sectional study, a total of 1,401 World Trade Center (WTC) responders (mean age = 53, SD = 8 years, 92% males) participated in the study. Cogstate assessment measured cognitive performance. PTSD symptomatology was measured using the trauma-specific version of the posttraumatic stress disorder checklist (PCL-17) adapted for the WTC attacks. The 1-second forced expiratory volume and forced vital capacity (FEV1/FVC) ratio was used to measure pulmonary function. Linear regressions with cognitive performance as the outcome were conducted to assess individual, additive, and moderating associations of PTSD symptomatology and pulmonary function. RESULTS: Higher PTSD symptomatology and poorer pulmonary function were negatively associated with cognitive performance. A 10% increase on the FEV1/FVC ratio moderated the association between PTSD symptomatology and cognition, whereby its association with cognition was stronger when PTSD symptomatology was higher (est. = 0.01, 95%CI = 0.004, 0.01, p < 0.001). When stratified by responder type, these associations persisted in trained (est. = 0.01, 95%CI = 0.01, 0.02, p < 0.001), but not in non-trained (est. = 0.004, 95% C.I. = -0.01, 0.02, p = 0.39) responders. CONCLUSIONS: In the presence of higher PTSD, better pulmonary functioning is associated with better cognitive performance. Early intervention efforts to mitigate preventable cognitive decline in high-risk populations should be studied, especially since intervention in one modality may have an impact on others.

Correlates of Person-Specific Rates of Change in Sensor-Derived Physical Activity Metrics of Daily Living in the Rush Memory and Aging Project.

This study characterized person-specific rates of change of total daily physical activity (TDPA) and identified correlates of this change. TDPA metrics were extracted from multiday wrist-sensor recordings from 1083 older adults (average age 81 years; 76% female). Thirty-two covariates were collected at baseline. A series of linear mixed-effect models were used to identify covariates independently associated with the level and annual rate of change of TDPA. Though, person-specific rates of change varied during a mean follow-up of 5 years, 1079 of 1083 showed declining TDPA. The average decline was 16%/year, with a 4% increased rate of decline for every 10 years of age older at baseline. Following variable selection using multivariate modeling with forward and then backward elimination, age, sex, education, and 3 of 27 non-demographic covariates including motor abilities, a fractal metric, and IADL disability remained significantly associated with declining TDPA accounting for 21% of its variance (9% non-demographic and 12% demographics covariates). These results show that declining TDPA occurs in many very old adults. Few covariates remained correlated with this decline and the majority of its variance remained unexplained. Further work is needed to elucidate the biology underlying TDPA and to identify other factors that account for its decline.

Correlated decline of cognitive and motor phenotypes and ADRD pathologies in old age.

INTRODUCTION: Examining motor and cognitive decline in separate models may underestimate their associations. METHODS: In a single trivariate model, we examined the levels and rates of decline of three phenotypes, sensor-derived total daily physical activity, motor abilities, and cognition in 1007 older adults during 6 years of follow-up. In 477 decedents, we repeated the model adding fixed terms for indices of nine brain pathologies. RESULTS: Simultaneous rates of decline of all three phenotypes showed the strongest correlations with shared variance of up to 50%. Brain pathologies explained about 3% of the variance of declining daily physical activity, 9% of declining motor abilities, and 42% of cognitive decline. DISCUSSION: The rates of declining cognitive and motor phenotypes are strongly correlated and measures of brain pathologies account for only a small minority of their decline. Further work is needed to elucidate the biology underlying correlated cognitive and motor decline in aging adults.

Comparing Performance of Different Predictive Models in Estimating Disease Progression in Alzheimer Disease.

BACKGROUND: Automatic classification techniques provide tools to analyze complex data and predict disease progression. METHODS: A total of 305 cognitively normal; 475 patients with amnestic mild cognitive impairment (aMCI); and 162 patients with dementia were included in this study. We compared the performance of 3 different methods in predicting progression from aMCI to dementia: (1) index-based model; (2) logistic regression (LR); and (3) ensemble linear discriminant (ELD) machine learning models. LR and ELD models were trained using data from cognitively normal and dementia subgroups, and subsequently were applied to aMCI subgroup to predict their disease progression. RESULTS: Performance of ELD models were better than LR models in prediction of conversion from aMCI to Alzheimer dementia at all time frames. ELD models performed better when a larger number of features were used for prediction. CONCLUSION: Machine learning models have substantial potential to improve the predictive ability for cognitive outcomes.

Health-related Quality of Life, Cognitive Performance, and Incident Dementia in a Community-based Elderly Cohort.

BACKGROUND: We hypothesized that higher quality of life would be associated with better cognitive function and a reduced risk of incident all cause dementia and Alzheimer disease (AD) in older adults. MATERIALS AND METHODS: Participants included 1183 older adults with an average age of 78.2 (SD=5.3) from Einstein Aging Study. The 36-Item Short-Form Health Survey was used to measure health-related quality of life (HRQoL). We investigated baseline associations between the cognitive domains of memory, executive function, and general fluid ability with 8 subscales of the 36-Item Short-Form Health Survey (physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, social functioning, role limitations due to emotional problems, vitality, and general mental health) and the 2 component summary scores of physical component summary (PCS) and mental component summary (MCS). Next, we used Cox proportional hazard models to assess the predictive validity of HRQoL subscales for the onset of incident dementia and incident AD. RESULTS: At baseline, higher scores (better HRQoL) on MCS and its 4 subscales (social functioning, role limitations due to emotional problems, vitality, and general mental health) were associated with higher performance on both memory and executive function domains. Higher scores in role limitation due to physical problems, role limitation due to emotional problems, and general mental health subscales were associated with reduced risk of incident dementia. Higher MCS, but not PCS, predicted a reduced incident of all-cause dementia and AD. CONCLUSIONS: These findings suggest that diminution of HRQoL precedes the onset of diagnosable dementia and may be useful in the prediction of dementia onset.

Visual memory tests enhance the identification of amnestic MCI cases at greater risk of Alzheimer's disease.

OBJECTIVES: To investigate whether amnestic mild cognitive impairment (aMCI) identified with visual memory tests conveys an increased risk of Alzheimer's disease (risk-AD) and if the risk-AD differs from that associated with aMCI based on verbal memory tests. PARTICIPANTS: 4,771 participants aged 70.76 (SD = 6.74, 45.4% females) from five community-based studies, each a member of the international COSMIC consortium and from a different country, were classified as having normal cognition (NC) or one of visual, verbal, or combined (visual and verbal) aMCI using international criteria and followed for an average of 2.48 years. Hazard ratios (HR) and individual patient data (IPD) meta-analysis analyzed the risk-AD with age, sex, education, single/multiple domain aMCI, and Mini-Mental State Examination (MMSE) scores as covariates. RESULTS: All aMCI groups (n = 760) had a greater risk-AD than NC (n = 4,011; HR range = 3.66 - 9.25). The risk-AD was not different between visual (n = 208, 17 converters) and verbal aMCI (n = 449, 29 converters, HR = 1.70, 95%CI: 0.88, 3.27, p = 0.111). Combined aMCI (n = 103, 12 converters, HR = 2.34, 95%CI: 1.13, 4.84, p = 0.023) had a higher risk-AD than verbal aMCI. Age and MMSE scores were related to the risk-AD. The IPD meta-analyses replicated these results, though with slightly lower HR estimates (HR range = 3.68, 7.43) for aMCI vs. NC. CONCLUSIONS: Although verbal aMCI was most common, a significant proportion of participants had visual-only or combined visual and verbal aMCI. Compared with verbal aMCI, the risk-AD was the same for visual aMCI and higher for combined aMCI. Our results highlight the importance of including both verbal and visual memory tests in neuropsychological assessments to more reliably identify aMCI.

Neuropsychological latent classes at enrollment and postmortem neuropathology.

INTRODUCTION: We classified individuals based on their baseline performance on cognitive measures and investigated the association between cognitive classifications and neuropathological findings ∼7 years later, as an external validator. METHODS: Brain autopsies of 779 decedents were examined. Baseline latent class analysis on 10 neuropsychological measures was previously assigned: mixed-domains impairment (n = 39, 5%), memory-specific impairment (n = 210, 27%), frontal impairment (n = 113, 14.5%), average cognition (n = 360, 46.2%), and superior cognition (n = 57, 7.3%). Linear regressions and risks ratios were used to examine the relation of latent class assignment at enrollment with neuropathological indices. RESULTS: Amyloid ß, tau, and transactive response DNA-binding protein 43 were associated with mixed-domains impairment and memory-specific impairment classes ∼7 years before death. Moderate arteriolosclerosis was associated with membership in the frontal impairment class. DISCUSSION: Our findings support the use of latent class models that incorporate more comprehensive neuropsychological measures to classify cognitive impairment.

Identification of Heterogeneous Cognitive Subgroups in Community-Dwelling Older Adults: A Latent Class Analysis of the Einstein Aging Study.

OBJECTIVES: The aim of this study was to identify natural subgroups of older adults based on cognitive performance, and to establish each subgroup's characteristics based on demographic factors, physical function, psychosocial well-being, and comorbidity. METHODS: We applied latent class (LC) modeling to identify subgroups in baseline assessments of 1345 Einstein Aging Study (EAS) participants free of dementia. The EAS is a community-dwelling cohort study of 70+ year-old adults living in the Bronx, NY. We used 10 neurocognitive tests and 3 covariates (age, sex, education) to identify latent subgroups. We used goodness-of-fit statistics to identify the optimal class solution and assess model adequacy. We also validated our model using two-fold split-half cross-validation. RESULTS: The sample had a mean age of 78.0 (SD=5.4) and a mean of 13.6 years of education (SD=3.5). A 9-class solution based on cognitive performance at baseline was the best-fitting model. We characterized the 9 identified classes as (i) disadvantaged, (ii) poor language, (iii) poor episodic memory and fluency, (iv) poor processing speed and executive function, (v) low average, (vi) high average, (vii) average, (viii) poor executive and poor working memory, (ix) elite. The cross validation indicated stable class assignment with the exception of the average and high average classes. CONCLUSIONS: LC modeling in a community sample of older adults revealed 9 cognitive subgroups. Assignment of subgroups was reliable and associated with external validators. Future work will test the predictive validity of these groups for outcomes such as Alzheimer's disease, vascular dementia and death, as well as markers of biological pathways that contribute to cognitive decline. (JINS, 2018, 24, 511-523).

Cognitive Impairment and Dementia in Older Adults With Chronic Kidney Disease: A Review.

Individuals with chronic kidney disease (CKD), especially older adults, are at more risk of experiencing cognitive impairment, possibly leading to mild cognitive impairment and/or dementia. Studies report associations between CKD and cognitive impairment; although unclear, there seems to be a graded association between stage of CKD and affected cognitive domains, with executive function being affected earlier in the process than episodic memory and global ability. In CKD, dysexecutive mild cognitive impairment and vascular dementia are also more prominent than other subtypes. Explanations are directed toward traditional and nontraditional vascular factors, which may also explain or mediate the association between CKD and type of cognitive impairment. Future research is urged to focus on the longitudinal association between specific domains of cognitive function, including executive function and memory and CKD; to develop screening tools fit for every CKD stage in elderly individuals, and lastly, to use imaging methods that may help clarify the underlying mechanisms connecting the kidney and the brain.

Patterns and associates of cognitive function, psychosocial wellbeing and health in the Lothian Birth Cohort 1936.

BACKGROUND: Cognitive function, psychosocial wellbeing and health are important domains of function. Consistencies and inconsistencies in patterns of wellbeing across these domains may be informative about wellbeing in old age and the ways it is manifested amongst individuals. In this study we investigated whether there were groups of individuals with different profiles of scores across these domains. We also aimed to identify characteristics of any evident groups by comparing them on variables that were not used in identifying the groups. METHODS: The sample was the Lothian Birth Cohort 1936, which included 1091 participants born in 1936. They are a community-dwelling, narrow-age-range sample of 70-year-olds. Most had taken part in the Scottish Mental Survey 1947 at an average age of 11, making available a measure of childhood intelligence. We used latent class analysis (LCA) to explore possible profiles using 9 variables indicating cognitive functioning, psychosocial wellbeing and health status. Demographic, personality, and lifestyle variables - none of which were used in the LCA - were used to characterize the resulting profile groups. RESULTS: We accepted a 3-group solution, which we labeled High Wellbeing (65.3%), Low Cognition (20.3%), and Low Bio-Psychosocial (14.5%). Notably, the High Wellbeing group had significantly higher childhood IQ, lower Neuroticism scores, and a lower percentage of current smokers than the other 2 groups. CONCLUSION: The majority of individuals were functioning generally well; however, there was evidence of the presence of groups with different profiles, which may be explained in part in terms of cognitive ability differences. Results suggested that higher life-long intelligence, personality traits associated with less mental distress, and basic health practices such as avoiding smoking are important associates of wellbeing in old age.

Inferring Alzheimer's disease pathologic traits from clinical measures in living adults.

Background: Alzheimer's disease neuropathologic changes (AD-NC) are important for identify people with high risk for AD dementia (ADD) and subtyping ADD. Objective: Develop imputation models based on clinical measures to infer AD-NC. Methods: We used penalized generalized linear regression to train imputation models for four AD-NC traits (amyloid-ß, tangles, global AD pathology, and pathologic AD) in Rush Memory and Aging Project decedents, using clinical measures at the last visit prior to death as predictors. We validated these models by inferring AD-NC traits with clinical measures at the last visit prior to death for independent Religious Orders Study (ROS) decedents. We inferred baseline AD-NC traits for all ROS participants at study entry, and then tested if inferred AD-NC traits at study entry predicted incident ADD and postmortem pathologic AD. Results: Inferred AD-NC traits at the last visit prior to death were related to postmortem measures with R2=(0.188,0.316,0.262) respectively for amyloid-ß, tangles, and global AD pathology, and prediction Area Under the receiver operating characteristic Curve (AUC) 0.765 for pathologic AD. Inferred baseline levels of all four AD-NC traits predicted ADD. The strongest prediction was obtained by the inferred baseline probabilities of pathologic AD with AUC=(0.919,0.896) for predicting the development of ADD in 3 and 5 years from baseline. The inferred baseline levels of all four AD-NC traits significantly discriminated pathologic AD profiled eight years later with p-values<1.4 × 10-10. Conclusion: Inferred AD-NC traits based on clinical measures may provide effective AD biomarkers that can estimate the burden of AD-NC traits in aging adults.

A prospective study of the association of cognitive and motor function with odds of life space constriction in older adults.

BACKGROUND: Many studies indicate that smaller life space is related to worse cognitive and motor function. It is plausible that cognitive and motor function also predict life space constriction, thus long-term, prospective studies are needed of cognitive and motor function as predictors of life space. METHODS: A total of 1246 participants of the Rush Memory and Aging Project, who reported initial maximal life space and at least one follow-up assessment were included in this prospective study, with up to 19 years follow-up. The outcome of interest was the Modified version of the Life Space Questionnaire; which we categorized into large (beyond community), medium (neighborhood/community), and small (home/yard) life space. Participants also had detailed composite measures of global cognition and motor function as predictors and available at the first life space assessment. Life space transitions over one-year periods were modeled using multistate Markov modeling, including confounders and both predictors simultaneously. RESULTS: Better cognitive and motor function were broadly associated with lower odds of life space constriction (Cognitive: Large ➔ medium: OR = 0.91, 95% CI 0.83-1.00; Large ➔ small: OR = 0.85, 95% CI 0.74-0.97; Medium ➔ small: OR = 1.01, 95% CI 0.82-1.22. Motor: large ➔ medium: OR = 0.76, 95% CI 0.69-0.83; large ➔ small: OR = 0.58, 95% CI 0.51-0.67; medium ➔ small: OR = 0.71, 95% CI = 0.57-0.87). CONCLUSIONS: Combined with previous literature that life space predicts function, these results support the notion of complex inter-relations of cognitive function, motor function, and life space.

Inferring Alzheimer's Disease Pathologic Traits from Clinical Measures in Living Adults.

Background: Alzheimer's disease neuropathologic changes (AD-NC) are important to identify people with high risk for AD dementia (ADD) and subtyping ADD. Objective: Develop imputation models based on clinical measures to infer AD-NC. Methods: We used penalized generalized linear regression to train imputation models for four AD-NC traits (amyloid-ß, tangles, global AD pathology, and pathologic AD) in Rush Memory and Aging Project decedents, using clinical measures at the last visit prior to death as predictors. We validated these models by inferring AD-NC traits with clinical measures at the last visit prior to death for independent Religious Orders Study (ROS) decedents. We inferred baseline AD-NC traits for all ROS participants at study entry, and then tested if inferred AD-NC traits at study entry predicted incident ADD and postmortem pathologic AD. Results: Inferred AD-NC traits at the last visit prior to death were related to postmortem measures with R2 = (0.188,0.316,0.262) respectively for amyloid-ß, tangles, and global AD pathology, and prediction Area Under the receiver operating characteristic Curve (AUC) 0.765 for pathologic AD. Inferred baseline levels of all four AD-NC traits predicted ADD. The strongest prediction was obtained by the inferred baseline probabilities of pathologic AD with AUC = (0.919,0.896) for predicting the development of ADD in 3 and 5 years from baseline. The inferred baseline levels of all four AD-NC traits significantly discriminated pathologic AD profiled eight years later with p-values < 1.4×10-10. Conclusions: Inferred AD-NC traits based on clinical measures may provide effective AD biomarkers that can estimate the burden of AD-NC traits in aging adults.

Glycoproteome-Wide Discovery of Cortical Glycoproteins That May Provide Cognitive Resilience in Older Adults.

BACKGROUND AND OBJECTIVES: Molecular omics studies have identified proteins related to cognitive resilience but unrelated to Alzheimer disease and Alzheimer disease-related dementia (AD/ADRD) pathologies. Posttranslational modifications of proteins with glycans can modify protein function. In this study, we identified glycopeptiforms associated with cognitive resilience. METHODS: We studied brains from adults with annual cognitive testing with postmortem indices of 10 AD/ADRD pathologies and proteome-wide data from dorsal lateral prefrontal cortex (DLPFC). We quantified 11, 012 glycopeptiforms from DLPFC using liquid chromatography with tandem mass spectrometry. We used linear mixed-effects models to identify glycopeptiforms associated with cognitive decline correcting for multiple comparisons (p < 5 × 10-6). Then, we regressed out the effect of AD/ADRD pathologies to identify glycopeptiforms that may provide cognitive resilience. RESULTS: We studied 366 brains, average age at death 89 years, and 70% female with no cognitive impairment = 152, mild cognitive impairment = 93, and AD = 121 cognitive status at death. In models adjusting for age, sex and education, 11 glycopeptiforms were associated with cognitive decline. In further modeling, 8 of these glycopeptiforms remained associated with cognitive decline after adjusting for AD/ADRD pathologies: NPTX2a (Est., 0.030, SE, 0.005, p = 1 × 10-4); NPTX2b (Est.,0.019, SE, 0.005, p = 2 × 10-4) NECTIN1(Est., 0.029, SE, 0.009, p = 9 × 10-4), NPTX2c (Est., 0.015, SE, 0.004, p = 9 × 10-4), HSPB1 (Est., -0.021, SE, 0.006, p = 2 × 10-4), PLTP (Est., -0.027, SE, 0.009, p = 4.2 × 10-3), NAGK (Est., -0.027, SE, 0.008, p = 1.4 × 10-3), and VAT1 (Est., -0.020, SE, 0.006, p = 1.1 × 10-3). Higher levels of 4 resilience glycopeptiforms derived through glycosylation were associated with slower decline and higher levels of 4 derived through glycation were related to faster decline. Together, these 8 glycopeptiforms accounted for an additional 6% of cognitive decline over the 33% accounted for the 10 brain pathologies and demographics. All 8 resilience glycopeptiforms remained associated with cognitive decline after adjustments for the expression level of their corresponding protein. Exploratory gene ontology suggested that molecular mechanisms of glycopeptiforms associated with cognitive decline may involve metabolic pathways including pyruvate and NADH pathways and highlighted the importance of molecular mechanisms involved in glucose metabolism. DISCUSSION: Glycopeptiforms in aging brains may provide cognitive resilience. Targeting these glycopeptiforms may lead to therapies that maintain cognition through resilience.

Proteome-wide Analyses Identified Cortical Proteins Associated With Resilience for Varied Cognitive Abilities.

BACKGROUND AND OBJECTIVES: Prior work suggests that cognitive resilience may contribute to the heterogeneity of cognitive decline. This study examined whether distinct cortical proteins provide resilience for different cognitive abilities. METHODS: Participants were from the Religious Orders Study or the Rush Memory and Aging Project who had undergone annual assessments of 5 cognitive abilities and postmortem assessment of 9 Alzheimer disease and related dementia (ADRD) pathologies. Proteome-wide examination of the dorsolateral prefrontal cortex using tandem mass tag and liquid chromatography-mass spectrometry yielded 8,425 high-abundance proteins. We applied linear mixed-effect models to quantify residual cognitive change (cognitive resilience) of 5 cognitive abilities by regressing out cognitive decline related to age, sex, education, and indices of ADRD pathologies. Then we added terms for each of the individual proteins to identify cognitive resilience proteins associated with the different cognitive abilities. RESULTS: We included 604 decedents (69% female; mean age at death = 89 years) with proteomic data. A total of 47 cortical proteins that provide cognitive resilience were identified: 22 were associated with specific cognitive abilities, and 25 were common to at least 2 cognitive abilities. NRN1 was the only protein that was associated with more than 2 cognitive abilities (semantic memory: estimate = 0.020, SE = 0.004, p = 2.2 × 10-6; episodic memory: estimate = 0.029, SE = 0.004, p = 5.8 × 10-1; and working memory: estimate = 0.021, SE = 0.004, p = 1.2 × 10-7). Exploratory gene ontology analysis suggested that among top molecular pathways, mitochondrial translation was a molecular mechanism providing resilience in episodic memory, while nuclear-transcribed messenger RNA catabolic processes provided resilience in working memory. DISCUSSION: This study identified cortical proteins associated with various cognitive abilities. Differential associations across abilities may reflect distinct underlying biological pathways. These data provide potential high-value targets for further mechanistic and drug discovery studies to develop targeted treatments to prevent loss of cognition.

From theory to practice: translating the concept of cognitive resilience to novel therapeutic targets that maintain cognition in aging adults.

While the concept of cognitive resilience is well-established it has not been defined in a way that can be measured. This has been an impediment to studying its underlying biology and to developing instruments for its clinical assessment. This perspective highlights recent work that has quantified the expression of cortical proteins associated with cognitive resilience, thus facilitating studies of its complex underlying biology and the full range of its clinical effects in aging adults. These initial studies provide empirical support for the conceptualization of resilience as a continuum. Like other conventional risk factors, some individuals manifest higher-than-average cognitive resilience and other individuals manifest lower-than-average cognitive resilience. These novel approaches for advancing studies of cognitive resilience can be generalized to other aging phenotypes and can set the stage for the development of clinical tools that might have the potential to measure other mechanisms of resilience in aging adults. These advances also have the potential to catalyze a complementary therapeutic approach that focuses on augmenting resilience via lifestyle changes or therapies targeting its underlying molecular mechanisms to maintain cognition and brain health even in the presence of untreatable stressors like brain pathologies that accumulate in aging adults.

Alzheimer's Disease Pathology Outside of the Cerebrum Is Related to a Higher Odds of Dementia.

BACKGROUND: Assessments of Alzheimer's disease pathology do not routinely include lower brainstem, olfactory bulb, and spinal cord. OBJECTIVE: Test if amyloid-ß (Aß) and paired helical filament (PHF) tau-tangles outside the cerebrum are associated with the odds of dementia. METHODS: Autopsies were obtained in decedents with cognitive testing (n = 300). Aß plaques and PHF tau-tangles were assessed in 24 sites: cerebrum (n = 14), brainstem (n = 5), olfactory bulb, and four spinal cord levels. Since spinal Aß were absent in the first 165 cases, it was not assessed in the remaining cases. RESULTS: Age at death was 91 years old. About 90% had Aß in cerebrum and of these, half had Aß in the brainstem. Of the latter, 85% showed Aß in the olfactory bulb. All but one participant had tau-tangles in the cerebrum and 86% had brainstem tau-tangles. Of the latter, 80% had tau-tangles in olfactory bulb and 36% tau-tangles in one or more spinal cord levels. About 90% of adults with tau-tangles also had Aß in one or more regions. In a logistic model controlling for demographics, Aß and tau-tangles within the cerebrum, the presence of Aß in olfactory bulb [OR, 1.74(1.00, 3.05)]; tau-tangles in brainstem [OR, 4.00(1.1.57,10.21)]; and spinal cord [OR, 1.87 (1.21,3.11)] were independently associated with higher odds of dementia. CONCLUSION: Regional differences in Aß and tau-tangle accumulation extend beyond cerebrum to spinal cord and their presence outside the cerebrum are associated with a higher odds of dementia. Further studies are needed to clarify the extent, burden, and consequences of AD pathology outside of cerebrum.

Proteome-Wide Discovery of Cortical Proteins That May Provide Motor Resilience to Offset the Negative Effects of Pathologies in Older Adults.

BACKGROUND: Motor resilience proteins have not been identified. This proteome-wide discovery study sought to identify proteins that may provide motor resilience. METHODS: We studied the brains of older decedents with annual motor testing, postmortem brain pathologies, and proteome-wide data. Parkinsonism was assessed using 26 items of a modified United Parkinson Disease Rating Scale. We used linear mixed-effect models to isolate motor resilience, defined as the person-specific estimate of progressive parkinsonism after controlling for age, sex, and 10 brain pathologies. A total of 8 356 high-abundance proteins were quantified from dorsal lateral prefrontal cortex using tandem mass tag and liquid chromatography-mass spectrometry. RESULTS: There were 391 older adults (70% female), mean age 80 years at baseline and 89 years at death. Five proteins were associated with motor resilience: A higher level of AP1B1 (Estimate -0.504, SE 0.121, p = 3.12 × 10-5) and GNG3 (Estimate -0.276, SE 0.068, p = 4.82 × 10-5) was associated with slower progressive parkinsonism. By contrast, a higher level of TTC38 (Estimate 0.140, SE 0.029, p = 1.87 × 10-6), CARKD (Estimate 0.413, SE 0.100, p = 3.50 × 10-5), and ABHD14B (Estimate 0.175, SE 0.044, p = 6.48 × 10-5) was associated with faster progressive parkinsonism. Together, these 5 proteins accounted for almost 25% of the variance of progressive parkinsonism above the 17% accounted for by 10 indices of brain pathologies. DISCUSSION: Cortical proteins may provide more or less motor resilience in older adults. These proteins are high-value therapeutic targets for drug discovery that may lead to interventions that maintain motor function despite the accumulation of as yet untreatable brain pathologies.

Profiles of physical, emotional and psychosocial wellbeing in the Lothian birth cohort 1936.

BACKGROUND: Physical, emotional, and psychosocial wellbeing are important domains of function. The aims of this study were to explore the existence of separable groups among 70-year olds with scores representing physical function, perceived quality of life, and emotional wellbeing, and to characterise any resulting groups using demographic, personality, cognition, health and lifestyle variables. METHODS: We used latent class analysis (LCA) to identify possible groups. RESULTS: Results suggested there were 5 groups. These included High (n = 515, 47.2% of the sample), Average (n = 417, 38.3%), and Poor Wellbeing (n = 37, 3.4%) groups. The two other groups had contrasting patterns of wellbeing: one group scored relatively well on physical function, but low on emotional wellbeing (Good Fitness/ Low Spirits,n = 60, 5.5%), whereas the other group showed low physical function but relatively well emotional wellbeing (Low Fitness/Good Spirits, n = 62, 5.7%). Salient characteristics that distinguished all the groups included smoking and drinking behaviours, personality, and illness. CONCLUSIONS: Despite there being some evidence of these groups, the results also support a largely one-dimensional construct of wellbeing in old age--for the domains assessed here--though with some evidence that some individuals have uneven profiles.