Daron G. Davis

Alzheimer Neuropathologic Alterations in Aged Cognitively Normal Subjects

The histopathologic changes distinguishing early Alzheimer disease (AD) from normal or pathologic aging are not clearly defined. This report describes the autopsy findings of 59 elderly, well-educated, volunteers. They were examined longitudinally with mental status testing, some for up to 8 years, as part of our normal aging study. This study reveals that (1) the brains of many subjects who did not show cognitive impairment on neuropsychologic testing contain abundant senile plaques (SP) and/or neurofibrillary tangles (NFT); (2) 29 subjects met Khachaturian criteria for AD, 15 met CERAD and 7 met National Institute on Aging-Reagan Institute guidelines; (3) Braak and Braak staging method included 9 in stage IV subjects, 4 in stage V, and 1 in stage VI; (4) there was a progression of NFT from entorhinal cortex to hippocampus and amygdala as a function of age; (5) 2 subjects met criteria for a diagnosis of dementia with Lewy bodies but were not demented; (6) cerebral amyloid angiopathy was present in leptomeningeal vessels in 75% of subjects and in parenchymal vessels in 62% of subjects; (7) only 10 of 59 subjects (17%) had no or few degenerative brain changes. Our study demonstrates that the brains of a large percentage of cognitively normal, relatively well-educated individuals contain numerous degenerative changes and only a small percentage are relatively free of these changes.

Neuropathology of nondemented aging: Presumptive evidence for preclinical Alzheimer disease

OBJECTIVE To determine the frequency and possible cognitive effect of histological Alzheimers disease (AD) in autopsied older nondemented individuals. DESIGN Senile plaques (SPs) and neurofibrillary tangles (NFTs) were assessed quantitatively in 97 cases from 7 Alzheimers Disease Centers (ADCs). Neuropathological diagnoses of AD (npAD) were also made with four sets of criteria. Adjusted linear mixed models tested differences between participants with and without npAD on the quantitative neuropathology measures and psychometric test scores prior to death. Spearman rank-order correlations between AD lesions and psychometric scores at last assessment were calculated for cases with pathology in particular regions. SETTING Washington University Alzheimers Disease Research Center. PARTICIPANTS Ninety-seven nondemented participants who were age 60 years or older at death (mean=84 years). RESULTS About 40% of nondemented individuals met at least some level of criteria for npAD; when strict criteria were used, about 20% of cases had npAD. Substantial overlap of Braak neurofibrillary stages occurred between npAD and no-npAD cases. Although there was no measurable cognitive impairment prior to death for either the no-npAD or npAD groups, cognitive function in nondemented aging appears to be degraded by the presence of NFTs and SPs. CONCLUSIONS Neuropathological processes related to AD in persons without dementia appear to be associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness. By age 80-85 years, many nondemented older adults have substantial AD pathology.

Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS <

Midlife hypertension is associated with later development of cognitive impairment, vascular dementia (VsD), and possibly Alzheimers disease (AD). Neuropathic cerebrovascular lesions and brain atrophy have been associated with elevated blood pressure (BP), however, to our knowledge there have been no prospective investigations of an association of blood pressure levels measured in midlife with the microscopic lesions of AD. We investigated the relationship of BP level in midlife to development of neurofibrillary tangles (NFT), neuritic plaques (NP), and low brain weight at autopsy among Japanese-American men who were members of the Honolulu Heart Program/Honolulu-Asia aging Study (HHP/HAAS) cohort. The HHP/HAAS is a population-based, longitudinal study of cognitive function and dementia with 36 years of follow-up. Neocortical and hippocampal NFT and NP were counted per mm(2), and fixed brain weight was measured for 243 decedents. Elevated systolic BP, (> or =160 mm Hg) in midlife was associated with low brain weight and greater numbers of NP in both neocortex and hippocampus. Diastolic BP elevation, (> or =95 mm Hg) was associated with greater numbers of NFT in hippocampus. Results indicate that in addition to the accepted association of high BP with neuropathic cerebrovascular lesions, there is a direct relationship with brain atrophy, NP and NFT.

“Preclinical” AD revisited Neuropathology of cognitively normal older adults

Objective: To classify neuropathologic alterations in the brains of nondemented older adults using current sets of criteria for AD. Background: AD neuropathologic alterations are found in the brains of some nondemented elderly subjects and suggest the possibility of presymptomatic AD. Three sets of guidelines have been developed to classify AD using senile plaques, neuritic plaques, and neurofibrillary tangles (NFT). Methods: Neuropathologic changes in 59 older adults followed longitudinally with a standard battery of mental status measures were investigated using Khachaturian, Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), and National Institute on Aging–Reagan Institute (NIA-RI) guidelines. AD neuropathologic markers were evaluated in neocortical and allocortical regions. Cases were categorized as neuropathologically “normal” or “AD-like” and compared for possible mental status differences. Results: Between 11 and 49% of cases met one or more of the three classifications of AD. With adjustments for multiple comparisons, only NFT in hippocampal CA1 region were associated with autopsy age, suggesting that this may represent a pathologic process associated with normal brain aging. Using the NIA-RI guidelines, subjects in the AD-like group performed less well on the immediate paragraph recall and word-list delayed recall than their counterparts who did not meet these guidelines. Conclusions: These data indicate that the prevalence of “preclinical” AD in our population is relatively low based on the NIA-RI classification. Although many subjects had AD-like changes based on CERAD and Khachaturian guidelines, they exhibited no differences in mental performance, suggesting that the aging brain may be able to withstand such structural changes without meaningful impact on mental functioning.

Cerebrovascular Pathology and Dementia in Autopsied Honolulu‐Asia Aging Study Participants

Abstract: Clinicopathologic data from 285 autopsies were analyzed. The decedents were long‐standing participants in the Honolulu‐Asia Aging Study, a prospective epidemiologic investigation of stroke, neurodegenerative diseases, and aging. We assessed the prevalence at death of four primary neuropathologic processes using specific microscopic lesions as indicators. An algorithm was developed to assign each decedent to one of six subsets, corresponding to pathologic dominance by microvascular lesions (14% of decedents), Alzheimer lesions (12%), hippocampal sclerosis (5%), cortical Lewy bodies (5%), codominance by two or more primary processes (9%), or without a dominant pathologic process recognized (55%). Definite or probable dementia had been identified in 118 of the decedents. The proportions of men in each subset identified as demented were (in the same order) 57%, 53%, 79%, 57%, 76%, and 25%. In this autopsied panel of older Japanese‐American men, the importance of microvascular lesions as a likely explanation for dementia was nearly equal to that of Alzheimer lesions. The cerebrovascular lesion type most essentially and inclusively related to dementia was multiple microinfarction.

AD lesions and infarcts in demented and non-demented Japanese-American men

Neocortical neuritic plaques and neurofibrillary tangles are hallmark neuropathological lesions of dementia. Concomitant cerebrovascular lesions increase dementia severity in patients meeting neuropathological criteria for Alzheimers disease and contribute to cognitive impairment in persons with mild entorhinal Alzheimer lesions. This study investigates whether individuals with sparse neocortical neuritic plaques experience increased odds of crossing the threshold to clinical dementia when they have coexistent cerebrovascular lesions. Dementia examinations were given to 3,734 men during the 1991–1993 Honolulu‐Asia Aging Study examination and to 2,603 men during the 1994–1996 examination. Lesion quantification was done without clinical data. Among 333 autopsied men, 120 had dementia, 115 had marginal results, and 98 had normal cognition. In men with neurofibrillary tangles, dementia frequency increased with increasing neuritic plaque density, and increased further in the presence of cerebrovascular lesions. The association was strongest in men with sparse neuritic plaques (1–3/mm2) where dementia frequency more than doubled with coexistent cerebrovascular lesions (45 vs 20%). Among all dementia cases, 24% were linked to cerebrovascular lesions. Findings suggest cerebrovascular lesions are associated with a marked excess of dementia in cases with low neuritic plaque frequency. Prevention of cerebrovascular lesions may be critically important in preserving late‐life cognitive function. Ann Neurol 2005

Brain Aging and Midlife Tofu Consumption

Objective: To examine associations of midlife tofu consumption with brain function and structural changes in late life. Methods: The design utilized surviving participants of a longitudinal study established in 1965 for research on heart disease, stroke, and cancer. Information on consumption of selected foods was available from standardized interviews conducted 1965–1967 and 1971–1974. A 4-level composite intake index defined “low-low” consumption as fewer than two servings of tofu per week in 1965 and no tofu in the prior week in 1971. Men who reported two or more servings per week at both interviews were defined as “high-high” consumers. Intermediate or less consistent “low” and “high” consumption levels were also defined. Cognitive functioning was tested at the 1991–1993 examination, when participants were aged 71 to 93 years (n=3734). Brain atrophy was assessed using neuroimage (n=574) and autopsy (n=290) information. Cognitive function data were also analyzed for wives of a sample of study participants (n=502) who had been living with the participants at the time of their dietary interviews. Results: Poor cognitive test performance, enlargement of ventricles and low brain weight were each significantly and independently associated with higher midlife tofu consumption. A similar association of midlife tofu intake with poor late life cognitive test scores was also observed among wives of cohort members, using the husband’s answers to food frequency questions as proxy for the wife’s consumption. Statistically significant associations were consistently demonstrated in linear and logistic multivariate regression models. Odds ratios comparing endpoints among “high-high” with “low-low” consumers were mostly in the range of 1.6 to 2.0. Conclusions: In this population, higher midlife tofu consumption was independently associated with indicators of cognitive impairment and brain atrophy in late life.

Bowel movement frequency in late-life and incidental Lewy bodies

It is not known if constipation is associated with the preclinical phase of Parkinsons disease (PD), often characterized by the presence of incidental Lewy bodies (ILB). Such an association could provide evidence that constipation is an early symptom of PD. The purpose of this report is to examine the association between late‐life bowel movement frequency and ILB. Bowel movement frequency was assessed from 1991 to 1993 in 245 men aged 71 to 93 years in the Honolulu‐Asia Aging Study who later received postmortem examinations. All were without clinical PD and dementia. Brains were examined for ILB in the substantia nigra and locus ceruleus. Among the decedents, 30 men had ILB (12.2%). After age‐adjustment, the percent of brains with ILB declined with increasing bowel movement frequency (P = 0.013). For men with <1, 1, and >1 bowel movement/day, corresponding percents were 24.1, 13.5, and 6.5%. Findings persisted after additional adjustment for time to death, mid‐life pack‐years of smoking and coffee intake, physical activity, and cognitive function. Infrequent bowel movements are associated with ILB. Findings provide evidence that constipation can predate the extrapyramidal signs of PD. Constipation could be one of the earliest markers of the beginning of PD processes.

Association of olfactory dysfunction with incidental Lewy bodies

Olfactory dysfunction is found in early Parkinsons disease (PD) and in asymptomatic relatives of PD patients. Incidental Lewy bodies (ILB), the presence of Lewy bodies in the brains of deceased individuals without a history of PD or dementia during life, are thought to represent a presymptomatic stage of PD. If olfactory dysfunction were associated with the presence of ILB, this would suggest that olfactory deficits may precede clinical PD. The purpose of this study was to determine the association of olfactory dysfunction during late life with ILB in the substantia nigra or locus ceruleus. Olfaction was assessed during the 1991–1994 and 1994–1996 examinations of elderly Japanese–American men participating in the longitudinal Honolulu–Asia Aging Study. Among those who later died and underwent a standardized postmortem examination, brains were examined for Lewy bodies in the substantia nigra and the locus ceruleus with hematoxylin and eosin stain. Lewy bodies in the brains of individuals without clinical PD or dementia were classified as ILB. There were 164 autopsied men without clinical PD or dementia who had olfaction testing during one of the examinations. Seventeen had ILB. The age‐adjusted percent of brains with ILB increased from 1.8% in the highest tertile of odor identification to 11.9% in the mid‐tertile to 17.4% in the lowest tertile (P = 0.019 in test for trend). Age‐adjusted relative odds of ILB for the lowest versus the highest tertile was 11.0 (P = 0.02). Olfactory dysfunction is associated with ILB. If incidental Lewy bodies represent presymptomatic stage of PD, olfactory testing may be a useful screening tool to identify those at high risk for developing PD.

Modeling the Association between 43 Different Clinical and Pathological Variables and the Severity of Cognitive Impairment in a Large Autopsy Cohort of Elderly Persons

We evaluated the association between mini‐mental status examination (MMSE) scores proximal to death and the values of 43 different clinical and pathological parameters. Studies were performed using data from 334 elderly, longitudinally evaluated research subjects who had undergone autopsy and satisfied inclusion criteria from an initial study group of 501. Interindividual variance in MMSE scores was used as a surrogate for the severity of cognitive impairment linked to aging (CILA). A statistical linear regression‐based model provided a framework for assessing the parameters with significant, direct impact on CILA severity. Strong association between CILA and Alzheimers disease (AD) pathology, especially isocortical neurofibrillary tangles, was evident. The pattern of association between AD lesion densities with cognitive impairment severity was biologically informative, with neuritic plaques having more impact in relatively high‐functioning individuals. Abundant isocortical Lewy bodies tended to be an additive pathology correlating with final MMSE scores approximately 10 points lower. In a subset of cases we found evidence for association between TDP‐43‐related pathology and CILA severity, independent of AD or hippocampal sclerosis. There was no support for independent association between CILA severity and most evaluated indices including diffuse plaques, argyrophilic grains, heart disease, education level, apolipoprotein E alleles or diabetes.