Jeremiah F. Kelly

Neuropathology of older persons without cognitive impairment from two community-based studies

Objective: To examine the relation of National Institute on Aging–Reagan (NIA-Reagan) neuropathologic criteria of Alzheimer disease (AD) to level of cognitive function in persons without dementia or mild cognitive impairment (MCI). Methods: More than 2,000 persons without dementia participating in the Religious Orders Study or the Memory and Aging Project agreed to annual detailed clinical evaluation and brain donation. The studies had 19 neuropsychological performance tests in common that assessed five cognitive domains, including episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. A total of 134 persons without cognitive impairment died and underwent brain autopsy and postmortem assessment for AD pathology using NIA-Reagan neuropathologic criteria for AD, cerebral infarctions, and Lewy bodies. Linear regression was used to examine the relation of AD pathology to level of cognitive function proximate to death. Results: Two (1.5%) persons met NIA-Reagan criteria for high likelihood AD, and 48 (35.8%) met criteria for intermediate likelihood; 29 (21.6%) had cerebral infarctions, and 18 (13.4%) had Lewy bodies. The mean Mini-Mental State Examination score proximate to death was 28.2 for those meeting high or intermediate likelihood AD by NIA-Reagan criteria and 28.4 for those not meeting criteria. In linear regression models adjusted for age, sex, and education, persons meeting criteria for intermediate or high likelihood AD scored about a quarter standard unit lower on tests of episodic memory (p = 0.01). There were no significant differences in any other cognitive domain. Conclusions: Alzheimer disease pathology can be found in the brains of older persons without dementia or mild cognitive impairment and is related to subtle changes in episodic memory.

Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease

Alzheimers disease (AD) is an age-related disorder characterized by deposition of amyloid β-peptide (Aβ) and degeneration of neurons in brain regions such as the hippocampus, resulting in progressive cognitive dysfunction. The pathogenesis of AD is tightly linked to Aβ deposition and oxidative stress, but it remains unclear as to how these factors result in neuronal dysfunction and death. We report alterations in sphingolipid and cholesterol metabolism during normal brain aging and in the brains of AD patients that result in accumulation of long-chain ceramides and cholesterol. Membrane-associated oxidative stress occurs in association with the lipid alterations, and exposure of hippocampal neurons to Aβ induces membrane oxidative stress and the accumulation of ceramide species and cholesterol. Treatment of neurons with α-tocopherol or an inhibitor of sphingomyelin synthesis prevents accumulation of ceramides and cholesterol and protects them against death induced by Aβ. Our findings suggest a sequence of events in the pathogenesis of AD in which Aβ induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism which, in turn, triggers a neurodegenerative cascade that leads to clinical disease.

Chronic Psychological Distress and Risk of Alzheimer’s Disease in Old Age

Clinical and pathological data from the Rush Memory and Aging Project were used to test the hypothesis that distress proneness is associated with increased risk of Alzheimer’s disease (AD). More than 600 older persons without dementia completed a 6-item measure of neuroticism, a stable indicator of proneness to psychological distress. At annual intervals thereafter, they underwent uniform evaluations that included clinical classification of AD and administration of 18 cognitive tests. Those who died underwent brain autopsy from which composite measures of AD pathology were derived. During a mean of about 3 years of follow-up, 55 people were clinically diagnosed with AD. In analyses that controlled for age, sex, and education, persons with a high level of distress proneness (score = 24, 90th percentile) were 2.7 times more likely to develop AD than those not prone to distress (score = 6, 10th percentile). Adjustment for depressive symptomatology or frequency of cognitive, social, and physical activity did not substantially change this effect. Distress proneness was also associated with more rapid cognitive decline. Among 45 participants who died and underwent brain autopsy, distress proneness was unrelated to diverse measures of AD pathology and was inversely related to cognition after controlling for AD pathology. The results support the hypothesis that distress proneness is associated with increased risk of dementia and suggest that neurobiologic mechanisms other than AD pathology may underlie the association.

Statins, incident Alzheimer disease, change in cognitive function, and neuropathology

Objective: To examine the relation of statins to incident Alzheimer disease (AD) and change in cognition and neuropathology. Methods: Participants were 929 older Catholic clergy (68.7% women, mean baseline age 74.9 years, education 18.2 years, Mini-Mental State Examination 28.5) free of dementia, enrolled in the Religious Orders Study, a longitudinal clinical-pathologic study of AD. All agreed to brain autopsy at time of death and underwent annual structured clinical evaluations, allowing for classification of AD and assessment of cognition (based on 19 neuropsychological tests). Statins were identified by direct medication inspection. Neuropathologic data were available on 262 participants. All macroscopic chronic cerebral infarctions were recorded. A measure of global AD pathology was derived from silver stain, and separate measures of amyloid and tangles were based on immunohistochemistry. We examined the relation of statins to incident AD using Cox proportional hazards, change in cognition using mixed effects models, and pathologic indices using logistic and linear regression. Results: Statin use at baseline (12.8%) was not associated with incident AD (191 persons, up to 12 follow-up years), change in global cognition, or five separate cognitive domains (all p values > 0.20). Statin use any time prior to death (17.9%) was not related to global AD pathology. Persons taking statins were less likely to have amyloid (p = 0.02). However, among those with amyloid, there was no relation of statins to amyloid load. Statins were not related to tangles or infarction. Conclusions: Overall, statins were not related to incident Alzheimer disease (AD) or change in cognition, or continuous measures of AD pathology or infarction.

4-Hydroxynonenal, an aldehydic product of lipid peroxidation, impairs signal transduction associated with muscarinic acetylcholine and metabotropic glutamate receptors : Possible action on Gαq/11

Abstract: Considerable data indicate that oxidative stress and membrane lipid peroxidation contribute to neuronal degeneration in an array of age‐related neurodegenerative disorders. In contrast, the impact of subtoxic levels of membrane lipid peroxidation on neuronal function is largely unknown. We now report that 4‐hydroxy‐nonenal (HNE), an aldehydic product of lipid peroxidation, disrupts coupling of muscarinic cholinergic receptors and metabotropic glutamate receptors to phospholipase C‐linked GTP‐binding proteins in cultured rat cerebrocortical neurons. At subtoxic concentrations, HNE markedly inhibited GTPase activity, inositol phosphate release, and elevation of intracellular calcium levels induced by carbachol (muscarinic agonist) and (RS)‐3,5‐dihydroxyphenyl glycine (metabotropic glutamate receptor agonist). Maximal impairment of agonist‐induced responses occurred within 30 min of exposure to HNE. Other aldehydes, including malondialdehyde, had little effect on agonist‐induced responses. Antioxidants that suppress lipid peroxidation did not prevent impairment of agonist‐induced responses by HNE, whereas glutathione, which is known to bind and detoxify HNE, did prevent impairment of agonist‐induced responses. HNE itself did not induce oxidative stress. Immunoprecipitation‐western blot analysis using an antibody to HNE‐protein conjugates showed that HNE can bind to Gαq/11. HNE also significantly suppressed inositol phosphate release induced by aluminum fluoride. Collectively, our data suggest that HNE plays a role in altering receptor‐G protein coupling in neurons under conditions of oxidative stress that may occur both normally, and before cell degeneration and death in pathological settings.

Glial heme oxygenase-1 expression in Alzheimer disease and mild cognitive impairment.

We determined whether oxidative stress is an early event in the pathogenesis of sporadic Alzheimer disease (AD), and correlated oxidative stress with neuropsychological functions and neurofibrillary pathology in AD and mild cognitive impairment (MCI). Oxidative stress was measured as the percentage of astrocytes expressing heme oxygenase-1 (HO-1) in post mortem temporal cortex and hippocampus after dual HO-1/glial fibrillary acidic protein (GFAP) immunohistochemistry. Glial HO-1 expression in the MCI temporal cortex and hippocampus was significantly greater than in the non-demented group and did not differ from AD values. Astroglial HO-1 expression in the temporal cortex was associated with decreased scores for global cognition, episodic memory, semantic memory and working memory. Hippocampal astroglial HO-1 expression was associated with lower scores for global cognition, semantic memory and perceptual speed. Glial HO-1 immunoreactivity in the temporal cortex, but not hippocampus, correlated with the burden of neurofibrillary pathology. Cortical and hippocampal oxidative stress is a very early event in the pathogenesis of sporadic AD and correlates with the development of specific cognitive deficits in this condition.

Decision rules guiding the clinical diagnosis of Alzheimer's disease in two community-based cohort studies compared to standard practice in a clinic-based cohort study

We developed prediction rules to guide the clinical diagnosis of Alzheimer’s disease (AD) in two community-based cohort studies (the Religious Orders Study and the Rush Memory and Aging Project). The rules were implemented without informant interviews, neuroimaging, blood work or routine case conferencing. Autopsies were performed at death and the pathologic diagnosis of AD made with a modified version of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria. We compared the positive predictive value of the clinical diagnosis in the two community-based studies to the positive predictive value of the clinical diagnosis of AD made by standard clinical practice in a clinic-based cohort study using AD pathology as the gold standard. Of 306 clinic cases with probable AD, 286 (93.5%) met CERAD neuropathologic criteria for AD; the results were comparable for those with possible AD (51 of 54, 94.4%). Of 141 study subjects with probable AD, 130 (92.2%) met CERAD neuropathologic criteria for AD; the results were lower but acceptable for those with possible AD (26 of 37, 70.3%). The results were similar in secondary analyses using alternate neuropathologic criteria for AD. The clinical diagnosis of AD can be made in community-based studies without the use of informant interviews, neuroimaging, blood work or routine case conferencing. This approach holds promise for reducing the operational costs of epidemiologic studies of aging and AD.

Parkinsonian signs in subjects with mild cognitive impairment

BACKGROUND Parkinsonian signs such as gait disturbance, rigidity, bradykinesia, and tremor are common among individuals with dementia and are associated with negative outcomes, but little is known about parkinsonian signs among individuals with mild cognitive impairment (MCI). OBJECTIVE To examine the extent to which MCI is associated with parkinsonian signs and the relation between cognitive abilities and parkinsonism among individuals with MCI. METHODS Participants included 835 individuals from the Rush Memory and Aging Project, a clinical-pathologic study of common chronic conditions of old age. All participants underwent detailed clinical evaluations which included assessments of parkinsonian signs and cognitive function, and linear regression models were used to examine the associations of MCI and parkinsonism. RESULTS In a series of analyses controlled for age, sex, and education, individuals with MCI exhibited significantly more parkinsonism than individuals without cognitive impairment, particularly gait disturbance, bradykinesia, and rigidity. Among individuals with MCI, lower levels of cognitive function, particularly in perceptual speed, were associated with higher levels of parkinsonism; when classified according to MCI subtype, individuals with amnestic vs non-amnestic MCI differed from each other on only one parkinsonian sign, with non-amnestic MCI showing more gait disturbance. Because vascular factors can contribute to cognitive impairment and parkinsonian signs, the authors repeated the core analyses including terms for vascular risk factors and vascular disease and the associations between MCI and parkinsonism persisted. CONCLUSIONS Mild cognitive impairment (MCI) is accompanied by parkinsonian signs, which are related to the severity and type of cognitive impairment. The association between MCI and parkinsonism is not explained by vascular risk factors or vascular disease.

Relation of NSAIDs to incident AD, change in cognitive function, and AD pathology

Objective: To examine the relation of nonsteroidal anti-inflammatory drugs (NSAIDs) to incident Alzheimer disease (AD), change in cognition, and AD pathology. Methods: Participants were 1,019 older Catholic clergy followed up annually for up to 12 years (mean baseline age = 75.0 years, education = 18.1 years, Mini-Mental State Examination score = 28.5), enrolled in the Religious Orders Study, a longitudinal clinical–pathologic study of aging and AD. Clinical evaluations allowed for AD classification and assessment of global cognition and five cognitive domains. NSAIDs were identified by direct medication inspection at baseline and follow-up evaluations. Neuropathologic data were available on 328 deceased participants. AD pathology was summarized as a global measure and as measures of neuritic plaques, diffuse plaques, and neurofibrillary tangles. We used Cox proportional hazards models and mixed models for incident AD and cognitive decline, respectively, and logistic and linear regression for pathologic outcomes, adjusted for age, sex, and education. Results: Overall, we found no apparent relation of NSAIDs to incident AD (n = 209 cases), change in cognition, or AD pathology. The hazard ratio of incident AD was 1.19 (95% CI 0.87–1.62) comparing those using NSAIDs with those not using NSAIDs at baseline, and 0.84 (95% CI 0.63–1.11) for specific use of aspirin. Findings were similar in analyses in which we considered NSAID use during follow-up. NSAIDs were not related to change in cognition (all p values > 0.14). There was no relation of NSAIDs to global AD pathology or plaques or tangles. Conclusion: These data do not support a strong relation between nonsteroidal anti-inflammatory drugs and Alzheimer disease or cognition. Consistent findings across clinical and pathologic outcomes provide additional confidence in these results.

Association of Anxiety and Depression With Microtubule-Associated Protein 2– and Synaptopodin-Immunolabeled Dendrite and Spine Densities in Hippocampal CA3 of Older Humans

CONTEXT Chronic psychological distress has deleterious effects on many of the bodys physiological systems. In experimental animal models, chronic stress leads to neuroanatomic changes in the hippocampus, in particular a decrease in the length and branching of dendrites as well as a decrease in the number of dendritic spines. OBJECTIVES To examine whether analogous distress-related neuroanatomic changes occur in humans and whether such changes might also be related to cognitive dysfunction observed in older people who report greater psychological distress. DESIGN Postmortem study of brain tissues from participants of the Religious Orders Study, an ongoing population-based clinicopathological study of aging and cognition. SETTING The Rush University Religious Orders Study and the University of Pennsylvania Cellular and Molecular Neuropathology Program. PARTICIPANTS Seventy-two deceased participants of the Religious Orders Study. MAIN OUTCOME MEASURES Densities of microtubule-associated protein 2-immunolabeled dendrites and synaptopodin-immunolabeled dendritic spines in the CA3 subfield of the hippocampus, quantified using semiautomated image acquisition and analysis. RESULTS Higher levels of trait anxiety and longitudinal depression scores were associated with decreased densities of dendrites and spines in CA3. Dendrite and spine densities did not correlate with an index of global cognition or with densities of common age-related pathological changes. CONCLUSIONS Regressive neuronal changes occur in humans who experience greater psychological distress. These changes are analogous to neuronal changes in animal models of chronic stress.