Gerson T. Lesser

Dissociation of neuropathology from severity of dementia in late-onset Alzheimer disease

Background: Little is known about Alzheimer disease at advanced ages, although its incidence continues to increase at least through the ninth decade of life. Objective: To examine the effects of age on the relationship between clinical dementia severity and neuropathologic hallmarks in a large sample spanning the full age range. Methods: The authors assessed 81 subjects during life for dementia severity, and examined their brains. They analyzed plaque and tangle burden, as well as the activities of the cholinergic marker enzymes acetylcholinesterase (AChE) and choline acetyltransferase (ChAT), in relation to age at death and the clinical severity of dementia. Results: Dementia severity was strongly related to plaque and tangle burden in relatively young patients (aged <75 years), but this correlation diminished with age and disappeared in the ninth decade of life. Among the oldest patients studied, there was no difference in plaque and tangle load between the mild and severe dementia cases. This interaction (p < 0.0001 for plaque density) was not observed for the cholinergic markers ChAT and AChE. Conclusion: The nature or expression of Alzheimer disease may be different in severely demented older patients, who have equal cholinergic deficits but significantly lower plaque and tangle burden. If confirmed in a prospective study, these findings have diagnostic and therapeutic implications.

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.

Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons

Objective: To test the hypothesis that use of antihypertensive medication is associated with lower Alzheimer disease (AD) neuropathology. Methods: This was a postmortem study of 291 brains limited to those with normal neuropathology or with uncomplicated AD neuropathology (i.e., without other dementia-associated neuropathology) in persons with or without hypertension (HTN) who were and were not treated with antihypertensive medications. Neuritic plaque (NP) and neurofibrillary tangle (NFT) densities, quantified in selected brain regions according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropathologic criteria, with additional cortical NP counts, yielded 24 neuropathologic regional measures or summaries. Medicated hypertension (HTN-med; n = 77), nonmedicated HTN (HTN-nomed; n = 42), and non-HTN (no-HTN; n = 172) groups were compared by analyses of variance. Results: The HTN-med group had significantly less neuropathology than the no-HTN group. The no-HTN group averaged over 50% higher mean NP and NFT ratings, and double the mean NP count, of the HTN-med group. The HTN-nomed group had significantly more neuropathology than the HTN-med group, but not significantly less than the no-HTN group. Conclusions: There was substantially less Alzheimer disease (AD) neuropathology in the medicated hypertension group than the nonhypertensive group, which may reflect a salutary effect of antihypertensive medication against AD-associated neuropathology.

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.

Elevated Serum Total and LDL Cholesterol in Very Old Patients with Alzheimer’s Disease

The relationships of serum lipids with Alzheimer’s disease (AD) and other dementias in very old patients are not clear. All residents of an academic nursing home were studied clinically for dementia and for serum lipids. All those autopsied over a 7.7-year period had apolipoprotein E (apoE) genotyping and detailed neuropathological examination. Those with pathologically defined criteria for AD (n = 84) were compared to all others who also had clinical dementia but did not show AD changes (n = 22). In contrast to most other reports of serum lipids in very old patients with AD, total cholesterol (TC) and low density lipoprotein cholesterol levels were each significantly higher for those with AD. The lipid-AD associations were progressively stronger with increasing pathological certainty of AD diagnosis. These relationships remained significant after adjustment for apoE genotype and for other known risk factors. The lipid-AD associations in a very old cohort, and prior evidence that elevated TC in middle life is a risk factor for later dementia, prompt consideration of factors associated with lipid metabolism in the development of Alzheimer’s 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.

Mercurial Diuresis in Edematous Individuals

The electrolyte and water losses in 75 instances of diuresis following Mercuhydrin were studied in 17 edematous patients. The loss of potassium was appreciable following exhibition of the drug to patients who retained their dietary sodium almost completely. Occurrence of such clinical symptoms as weakness, nausea, and ventricular premature contractions might be attributed to this loss of potassium. The fluid lost by mercurial diuresis was isotonic with body fluids. The chloride concentration was fairly constant at 151 mEq. per liter. The concentrations of sodium and potassium were more variable, the average concentrations being 97 and 35 mEq. per liter, respectively. Loss of water and electrolyte in these concentrations leaves the patient in relative alkalosis, with a loss of intracellular potassium and a gain in intracellular sodium.

Serum Lipids Are Related to Alzheimer’s Pathology in Nursing Home Residents

Background: Studies of associations between serum lipids and Alzheimer’s disease (AD) or other dementias in the elderly show conflicting results, perhaps due to misclassification of the various dementias. Methods: For 358 nursing home residents, serum lipids were studied at admission and diagnoses established at autopsy. We used defined neuropathological criteria to distinguish the presence of AD and to avoid errors of clinical dementia assessment. Results: Residents with any AD pathology, as compared to those without AD pathology, had higher mean serum total cholesterol (TC; 200.4 vs. 185.9 mg/dl; p = 0.02) and higher mean low-density lipoprotein cholesterol (LDL; 124.5 vs. 111.5 mg/dl; p = 0.03). Further, mean TC, LDL and high-density lipoprotein cholesterol levels all increased progressively with increasing pathological certainty of AD (p for trend = 0.001, 0.02 and 0.02). Conclusions: TC and LDL were significantly related to pathologically defined AD. If serum lipids have a role in the pathogenesis of AD, interventions may modify the course of disease.

MEASUREMENT OF TOTAL BODY FAT IN MAN BY THE SIMULTANEOUS ABSORPTION OF TWO INERT GASES.

The need for an independent measurement of total body fat

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

has been emphasized by the necessity to examine the concept of a relatively constant composition of a fat-free body. Absorption of the inert highly fat soluble gas, cyclopropane, from a closed respiratory system of known volume made possible the measurement of body fat in the rat2 and the procedure was later adapted to man3s4 In small animals, the uptake of the inert gas from a closed respiratory system is observed to equilibrium, i.e., to that time when the body tissues contain the gas at the same partial pressure as exists in the respiratory circuit and no more gas is absorbed. After correcting for the small amount of gas taken up by the fat-free tissues, the remainder of the gas absorbed, assumed to be dissolved in body lipid, is divided by the known solubility of the gas in pooled rat lipid to obtain a value for total body fat (TABLE 1). In human experiments, however, the failure of the body tissues to attain essential gaseous equilibrium within a feasible experimental period of time necessitates extrapolation of the absorption curves to the equilibrium value necessary for the body fat calculation. As with any extrapolation based on a hypothetical model of physiological processes, a measure of uncertainty is introduced. Although the values obtained for body fat agreed quite well with those derived for fat from total body water measured by dilution of antipyrine, the gas absorption values tended to be systematically lower by about 13 per cent. In addition, cyclopropane absorption curves obtained in highly obese humans showed appreciable variation in gas uptake rates with time, and thus did not lend themselves to accurate analysis for measurement of total body fat. It was felt that the simultaneous observation of the uptake of cyclopropane and another inert gas, krypton