John Hardman

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.

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.

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.

Recent Clinical-Pathologic Research on the Causes of Dementia in Late Life: Update From the Honolulu-Asia Aging Study:

In this study, we compare neuropathological findings at autopsy with clinical dementia diagnoses, such as Alzheimer’s disease and vascular dementia. Participants consisted of 363 aged Japanese-American men from the Honolulu-Asia Aging Study. Results indicated that the correspondence between clinical and neuropathologic diagnosis was not great, with 56% of patients diagnosed with probable or possible Alzheimer’s disease during life but with only 19% having neuritic plaques and/or neurofibrillary tangles as the sole or dominant dementia-related lesions in the brain at autopsy. Although 16% of cases were attributed to mixed causes during life, almost 40% were found to have significant mixtures of dementia-related lesions at autopsy. Finally, both Alzheimer’s disease and non-Alzheimer’s disease neuropathologic lesions contributed independently to the explanation of variance on a test of overall cognitive performance. The results suggest that clinical diagnosis of dementia made during life may fail to reflect the pathogenic complexity of this condition in very elderly persons.

Parkinsonian signs and substantia nigra neuron density in decendents elders without PD

Substantia nigra (SN) neurons were counted on single, transverse caudal midbrain sections from 217 male participants in the Honolulu‐Asia Aging Study, aged 74–97 years at death. Quadrants areas within the SN were determined with a planimeter and neuronal density was expressed as neurons/mm2 for 10 Parkinsons disease (PD) cases, 29 incidental Lewy body cases, and 178 controls with neither condition. Mean densities in all quadrants were significantly lower in the PD group compared with the other groups (p = 0.006). This relationship was strongest in the ventrolateral quadrant. In a subgroup of 50 controls who were examined with the Unified Parkinsons Disease Rating Scale an average of 2.1 years prior to death, there was an association of stooped posture (p = 0.009), postural instability (p = 0.013), body bradykinesia (p = 0.048), and gait disturbance (p = 0.05) with neuron density in the dorsolateral quadrant; and impaired speech (p = 0.014), abnormal facial expression (p = 0.022), and difficulty rising from a chair (p = 0.032) with neuron density in the dorsomedial quadrant. There was a significant association of increasing number of signs present with decreasing neuron density in both quadrants (p = 0.001 for trend). Low SN neuron density may be the basis for parkinsonian signs in the elderly without PD. Ann Neurol 2004

Pathology of head trauma

This article reviews the essential primary and secondary injuries attributable to traumatic brain injury (TBI) which causes one third of all injury deaths in the United States. Motor vehicle crashes, falls, assaults, guns, sports, and recreational activities are the major causes of TBI. Secondary peak incidences of TBI occur in infants and children and the elderly. Conditions that increase risk for accidents include alcoholism, prior head injury, prior meningitis, seizure disorders, mental retardation, and psychiatric disorders. However, gunshot wounds to the head are steadily increasing and since 1990 have caused more deaths each year than motor vehicle accidents. The incidence, severity, etiology, and specific types of injuries have been assessed in clinicopathologic studies of head injuries. The pathologic features of both the primary and secondary lesions attributed to TBI should be understood by anyone caring for head-injured patients. The computed tomography (CT) and magnetic resonance (MR) images mirror the pathologic abnormalities found in head trauma. Radiologists must accurately interpret the CT and MR images of injured patients. Forensic pathologists have long appreciated the characteristic focal lesions, such as coup and contracoup contusions, that occur in falls or vehicle accidents, but the understanding of diffuse injuries has been more elusive. Understanding the nature of the focal and diffuse injuries is critical to understanding the morbidity and mortality of brain injury.

Associations of cortical astrogliosis with cognitive performance and dementia status.

We examined 204 decedents of the autopsy component of the Honolulu-Asia Aging Study, a longitudinal cohort study, who had been clinically assessed for dementia. A sensitive ELISA technique was used to quantify glial fibrillary acidic protein (GFAP), a marker for astrogliosis, in four specific cortical brain regions and assess associations between GFAP and 1) a measure of cognitive function, 2) several clinical dementia conditions, and 3) neuritic plaque (NP) and neurofibrillary tangle (NFT) formation. Cognitive function was inversely associated with GFAP in the occipital, parietal and temporal lobes, but not in the frontal lobe. This relationship remained significant when the contribution of NP and NFT counts was removed. Further, compared to brain samples from non-demented individuals, significantly greater GFAP levels were found in samples from individuals diagnosed with Alzheimers disease, mixed dementia, and vascular mediated dementia. Because elevated levels of GFAP reflect astroglial responses to even subtle forms of neural damage, our data indicate that increments in GFAP may provide independent, supporting evidence for the damage underlying dementia, even in the absence of other evidence of neuropathology such as the presence of NPs or NFTs. Our findings underscore the need to look beyond standard neuropathological measures putatively linked to specific neuropathological conditions in efforts to identify common cellular and molecular processes that contribute to dementia.

Immunocytochemical hormonal features of pituitary adenomas of aging wistar male rats

Pituitary adenomas were the most common grossly visible naturally occurring neoplasms found in over 27% of rats surviving beyond 17 months of age. Twenty-three pituitary adenomas, fixed in buffered neutral formalin and embedded in paraffin, were tested for the presence of prolactin (PRL), growth hormone (GH) and thyroid stimulating hormone (TSH) using the unlabeled peroxidase-antiperoxidase method. The adenoma cells in 6 (26%) of the 23 tumors stained with two or three of the tested hormones, but clear evidence that individual neoplastic cells contained more than one hormone was not found. These findings suggest that in aging male Wistar rats the spontaneous pituitary adenomas may originate from undifferentiated cells, PRL-, GH- and TSH-cells in a diminishing order of frequency.