Michael Wysocki

Role of the Neuropathology of Alzheimer Disease in Dementia in the Oldest-Old

BACKGROUND Neuritic plaques (NPs) and neurofibrillary tangles (NFTs) in the brain, especially in the hippocampus, entorhinal cortex, and isocortex, are hallmark lesions of Alzheimer disease and dementia in the elderly. However, this association has not been extensively studied in the rapidly growing population of the very old. OBJECTIVE To assess the relationship between estimates of cognitive function and NP and NFT pathologic conditions in 317 autopsied persons aged 60 to 107 years. DESIGN We studied the relationship between severity of dementia and the density of these characteristic lesions of Alzheimer disease in young-old, middle-old, and oldest-old persons. The relationship of the severity of dementia as measured by the Clinical Dementia Rating scale to the density of NPs and NFTs was then assessed in each age group. PARTICIPANTS Three hundred seventeen brains of persons aged 60 years and older were selected to have either no remarkable neuropathological lesions or only NP and NFT lesions. Brains with any other neuropathological conditions, either alone or in addition to Alzheimer disease findings, were excluded. The study cohort was then stratified into the youngest quartile (aged 60-80 years), middle 2 quartiles (aged 81-89 years), and oldest quartile (aged 90-107 years). RESULTS While the density of NPs and NFTs rose significantly by more than 10-fold as a function of the severity of dementia in the youngest-old group, significant increases in the densities of NPs and NFTs were absent in the brains of the oldest-old. This lack of difference in the densities of NPs and NFTs was due to reduced lesion densities in the brains of oldest-old persons with dementia rather than to increased density of these lesions in the brains of nondemented oldest-old persons. CONCLUSIONS These findings suggest that the neuropathological features of dementia in the oldest-old are not the same as those of cognitively impaired younger-old persons and compel a vigorous search for neuropathological indices of dementia in this most rapidly growing segment of the elderly population.

Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology

Objective: To examine the association between treatment for diabetes and Alzheimer disease (AD) neuropathology. Methods: This postmortem study matched 124 subjects with diabetes to 124 without diabetes from the Mount Sinai School of Medicine Brain Bank, on age (mean = 81.2 + 9.3), sex (57.3% F), and severity of dementia (Clinical Dementia Rating [CDR] 2.4 + 1.7). Densities of neuritic plaques (NPs) and of neurofibrillary tangles (NFTs) were assessed in several neocortical regions and in the hippocampus, entorhinal cortex, and amygdala. Diabetic subjects were classified according to their recorded lifetime antidiabetic medications: none (n = 29), insulin only (n = 49), diabetes medications other than insulin only (n = 28), or concomitant use of both insulin and any oral antidiabetic medications (n = 18). For each dependent variable, analysis of covariance controlling for age at death, sex, and CDR distinguished among the nondiabetic patients and four diabetic subgroups. Results: There were differences among the five groups for NP ratings in the entorhinal cortex (p = 0.003), amygdala (p = 0.009), and overall NP (p = 0.014) as well as counts of NPs in all regions examined (p values ranging from 0.009 to 0.04). NP ratings in the hippocampus (p = 0.057) and the combined neocortical measure (p = 0.052) approached significance. In each analysis, the concomitant medication group had significantly fewer NPs (∼20%) than any of the other groups, which were relatively similar. No significant NFT differences were found. Conclusion: The results of this study suggest that the combination of insulin with other diabetes medication is associated with substantially lower neuritic plaque density consistent with the effects of both on the neurobiology of insulin.

Cognitive Decline in Patients With Dementia as a Function of Depression

OBJECTIVE There is evidence that major depression increases the risk for dementia, but there is conflicting evidence as to whether depression may accelerate cognitive decline in dementia. The authors tested the hypothesis that decline in cognitive function over time is more pronounced in patients with dementia with comorbid depression, when compared with patients with dementia without depression history. DESIGN Prospective, longitudinal cohort study of aging. SETTING Nursing home. PARTICIPANTS Three hundred thirteen elderly nursing home residents (mean age at baseline: 86.99 years, standard deviation = 6.7; 83.1% women). At baseline, 192 residents were diagnosed with dementia, and another 27 developed dementia during follow-up. Thirty residents suffered from major depression at any point during the study, and 48 residents had a history of depression. MEASUREMENTS The authors measured cognitive decline using change in Mini-Mental State Examination (MMSE) scores over up to 36 months. The authors calculated multilevel regression models to estimate the effects of age, gender, education, dementia status, depression, depression history, and an interaction between dementia and depression, on change in MMSE scores over time. RESULTS Beyond the effects of age, gender, and education, residents showed steeper cognitive decline in the presence of dementia (β = -13.69, standard error = 1.38) and depression (β = -4.16, SE = 1.2), which was further accelerated by the presence of both depression and dementia (β = -2.72, SE = 0.65). CONCLUSIONS In dementia, the presence of depression corresponds to accelerated cognitive decline beyond gender and level of education, suggesting a unique influence of depression on the rate of cognitive decline in dementia.

Changes in Glycemic Control are Associated with Changes in Cognition in Non-Diabetic Elderly

The aim of the present study was to examine the relationship of changes in long term glucose levels as measured by Hemoglobin A1c (HbA1c) with simultaneous changes in cognition. The sample included in the present analysis consisted of 101 community dwelling non-diabetic elderly subjects participating in ongoing longitudinal studies of cognition. Subjects were included in this study if they were cognitively normal at baseline, had at least one co-temporaneous follow-up assessment of HbA1c and the Mini Mental State Exam (MMSE), and complete data on age, gender, race, and years of education. MMSE decline over time was the main outcome measure. In TOBIT mixed regression models, MMSE was the dependent variable and HbA1c the time-varying covariate. Sociodemographic (age, gender, and education), cardiovascular (hypertension and APOE4 status), and lifestyle (smoking and physical activity) covariates were included in the statistical model. After adjusting for age at follow-up, there was a decrease of 1.37 points in the MMSE (p = 0.0002) per unit increase in HbA1c. This result remained essentially unchanged after adjusting also for gender and education (p = 0.0005), cardiovascular factors (p = 0.0003), and lifestyle (p = 0.0006). Additionally, results remained very similar after excluding subjects with potentially incipient diabetes with HbA1c between 6 and 7. These findings suggest that in non-diabetic non-demented elderly subjects, an increase in HbA1c over time is associated with cognitive decline. Such results may have broad clinical applicability since manipulation of glucose control, even in non-diabetics, may affect cognitive performance, perhaps enabling preventive measures against dementia.

Hypertension is Associated With Cognitive Decline in Elderly People at High Risk for Dementia

Cardiovascular risk factors including hypertension (HTN) have been shown to increase the risk of Alzheimer disease. The current study investigated whether individuals with HTN are more susceptible to increased cognitive decline and whether the influence of HTN on cognitive decline varied as a function of dementia severity. A total of 224 nursing home and assisted living residents, with a mean age of 84.9 (±7.6) years, were assessed longitudinally with Mini Mental State Exams (MMSEs) and Clinical Dementia Ratings (CDR). Baseline dementia status was defined by the CDR score. As described in , MMSE scores in persons with HTN and questionable dementia (CDR = 0.5) declined significantly faster than nonhypertensive questionably demented persons. Hypertensive participants did not decline significantly faster than nonhypertensive participants in persons with intact cognition (CDR = 0) or frank dementia (CDR ≥ 1). These results suggest an increased risk of subsequent cognitive decline in hypertensive individuals who are especially vulnerable to developing dementia and raises the possibility that avoiding or controlling HTN might reduce the rate of cognitive decline in cognitively vulnerable individuals, potentially delaying their conversion to full-fledged dementia.

Absolute measurement of cerebral optical coefficients, hemoglobin concentration and oxygen saturation in old and young adults with near-infrared spectroscopy

We present near-infrared spectroscopy measurement of absolute cerebral hemoglobin concentration and saturation in a large sample of 36 healthy elderly (mean age, 85 ± 6 years) and 19 young adults (mean age, 28 ± 4 years). Non-invasive measurements were obtained on the forehead using a commercially available multi-distance frequency-domain system and analyzed using a diffusion theory model for a semi-infinite, homogeneous medium with semi-infinite boundary conditions. Our study included repeat measurements, taken five months apart, on 16 elderly volunteers that demonstrate intra-subject reproducibility of the absolute measurements with cross-correlation coefficients of 0.9 for absorption coefficient (μa), oxy-hemoglobin concentration ([HbO2]), and total hemoglobin concentration ([HbT]), 0.7 for deoxy-hemoglobin concentration ([Hb]), 0.8 for hemoglobin oxygen saturation (StO2), and 0.7 for reduced scattering coefficient (μs). We found significant differences between the two age groups. Compared to young subjects, elderly subjects had lower cerebral [HbO2], [Hb], [HbT], and StO2 by 10 ± 4 μM, 4 ± 3 μM, 14 ± 5 μM, and 6%±5%, respectively. Our results demonstrate the reliability and robustness of multi-distance near-infrared spectroscopy measurements based on a homogeneous model in the human forehead on a large sample of human subjects. Absolute, non-invasive optical measurements on the brain, such as those presented here, can significantly advance the development of NIRS technology as a tool for monitoring resting/basal cerebral perfusion, hemodynamics, oxygenation, and metabolism.

Corticosteroids, but not NSAIDs, are associated with less Alzheimer neuropathology

The objective of this study was to test the hypothesis that corticosteroid and nonsteroidal anti-inflammatory drug (NSAID) medications are associated with less global and regional Alzheimers disease (AD) neuropathology. This postmortem study was based on 694 brains of subjects from the Mount Sinai School of Medicine Brain Bank who did not have neuropathologies other than neuritic plaques (NPs), neurofibrillary tangles (NFTs), or cerebrovascular disease. Densities of NPs and of NFTs were assessed in several neocortical regions and in the hippocampus, entorhinal cortex, and amygdala. Counts of NPs in several neocortical regions were also assessed. For each neuropathology measure, analyses of covariance controlling for age at death and sex compared subjects who received only corticosteroids (n = 54) or those who received only NSAIDs (n = 56) to the same comparison group, subjects who received neither (n = 576). Subjects receiving corticosteroids had significantly lower ratings and counts of NPs for all neuropathological measures, and NFTs overall and in the cerebral cortex and amygdala. In contrast, no measures were significant for subjects who received NSAIDs. Use of corticosteroids was associated with approximately 50% fewer NPs and NFTs in most brain regions examined, compared with nonmedicated subjects. In contrast, use of NSAIDs was not substantially associated with the reductions in hallmark lesions of AD. Because corticosteroids have anti-inflammatory as well as a myriad of other neurobiological effects, more direct studies in model systems could reveal novel therapeutic targets and mechanisms for AD lesion reduction.

Diabetes is associated with increased rate of cognitive decline in questionably demented elderly.

Background: This study examines whether the association of diabetes with the rate of cognitive decline varies according to dementia severity. Methods: Longitudinal study on subjects residing in nursing homes and assisted living (n = 342). The Mini Mental State Examination (MMSE) was used to measure the rate of cognitive decline in diabetic and nondiabetic subjects who were nondemented (Clinical Dementia Rating, CDR = 0; n = 125), questionably demented (CDR = 0.5; n = 58) or frankly demented (CDR ≧1; n = 89) at baseline. Diagnosis of diabetes was ascertained by review of medical records and history. Results: Diabetes was associated with an increased rate of decline in the MMSE score of questionably demented subjects (p < 0.0001). In frankly demented subjects, diabetes tended to be associated with less cognitive decline (p = 0.04). Diabetes was not associated with the rate of MMSE decline in nondemented subjects (p = 0.89). Conclusion: In individuals with questionable dementia (CDR = 0.5), diabetes is associated with a faster rate of cognitive decline as measured by the MMSE, but not in nondemented (CDR = 0) or frankly demented (CDR ≧1) individuals.

Clinical Dementia Rating Performed Several Years prior to Death Predicts Regional Alzheimer’s Neuropathology

Aims: To assess the relationships between early and late antemortem measures of dementia severity and Alzheimer disease (AD) neuropathology severity. Methods: 40 residents of a nursing home, average age at death 82.0, participated in this longitudinal cohort study with postmortem assessment. Severity of dementia was measured by Clinical Dementia Rating (CDR) at two time points, averaging 4.5 and 1.0 years before death. Densities of postmortem neuritic plaques (NPs) and neurofibrillary tangles (NFTs) were measured in the cerebral cortex, hippocampus, and entorhinal cortex. Results: For most brain areas, both early and late CDRs were significantly associated with NPs and NFTs. CDRs assessed proximal to death predicted NFTs beyond the contribution of early CDRs. NPs were predicted by both early and late CDRs. NPs were predictive of both early and late CDRs after controlling for NFTs. NFTs were only associated significantly with late CDR in the cerebral cortex after controlling for NPs. Conclusions: Even if assessed several years before death, dementia severity is associated with AD neuropathology. NPs are more strongly associated with dementia severity than NFTs. NFTs consistently associate better with late than early CDR, suggesting that these neuropathological changes may occur relatively later in the course of the disease.

The association of age with rate of cognitive decline in elderly individuals residing in supporting care facilities.

ObjectivesThis study examines the effect of age on rate of cognitive decline in different stages of dementia, of nursing home and assisted-living residents. MethodsIn this longitudinal study, the Mini Mental State Examination (MMSE) was used to measure rate of cognitive decline in subjects who were nondemented [Clinical Dementia Rating (CDR)=0; n=353], questionably demented (CDR=0.5; n=121), or frankly demented (CDR≥1; n=213) at baseline. ResultsA generalized estimating equation was used to model the MMSE scores over time (mean follow-up 2.9±2.0 y). The generalized estimating equation model had the MMSE scores at successive follow-up time points as dependent variables and had linear and quadratic age, follow-up time from baseline, CDR at baseline, and all the interactions among them as independent variables, controlling for MMSE at baseline, sex, race, and education. The mean age of the entire sample was 85.2±7.4 years at baseline. There were no significant interactions of linear age effects with rate of cognitive decline. The analysis of interaction of quadratic age with rate of cognitive decline showed complex relationships: in the nondemented group, there was no substantial quadratic association of age with the rate of cognitive decline (P=0.13); in the questionable demented group, the oldest subjects declined relatively faster (P=0.02); and in the demented group, the youngest and oldest subjects tended to decline relatively less than subjects in the intermediate ages (P=0.07). ConclusionsThis study adds an additional aspect to the complexity of the association between age and rate of cognitive decline, showing that the direction and amplitude of this effect differs according to the stage along the course of cognitive decline.