Imaging Studies of Aging, Neurodegenerative Disease, and Alcoholism.

Neurodegenerative diseases such as Alzheimers disease, disorders such as alcoholism, and the aging process can lead to impaired cognitive function and dementia. Researchers and clinicians have used noninvasive imaging techniques to determine the structural and physiological alterations in the brain that are associated with these conditions. Analyses of the brains structure have found that shrinkage (atrophy) of the brain tissue is characteristic for all conditions associated with dementia, but that the specific locations of atrophied brain structures vary among different neurodegenerative diseases and alcohol-induced disorders. Similarly, studies analyzing the metabolism in various brain structures have found that, depending on whether dementia was induced by neurodegenerative diseases, alcoholism, or aging, the affected brain structures vary slightly. Based on such studies, researchers and clinicians now can more accurately define different types of dementia and predict their clinical course

P1–222: ApoE4 lipoprotein 4 reduces risk of dementia from high sensitivity C–reactive protein

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152633/1/alzjjalz200605599.pd

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No abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55888/1/21016_ftp.pd

Overeating Behavior and Striatal Dopamine with 6-[18F]-Fluoro-L-m-Tyrosine PET

Eating behavior may be affected by dopamine synthesis capacity. In this study, 6-[18F]-fluoro-L-m-tyrosine (FMT) positron emission tomography (PET) uptake in striatal subregions was correlated with BMI (kg/m2) and an estimate of the frequency of prior weight loss attempts in 15 healthy subjects. BMI was negatively correlated with FMT uptake in the dorsal caudate. Although the association between BMI and FMT uptake in the dorsal caudate was not significant upon correction for age and sex, the association fell within the range of a statistical trend. Weight loss attempts divided by years trying was also negatively correlated with FMT uptake in the dorsal putamen (P = .05). These results suggest an association between low dorsal striatal presynaptic dopamine synthesis capacity and overeating behavior

Cortical tau deposition follows patterns of entorhinal functional connectivity in aging.

Tau pathology first appears in the transentorhinal and anterolateral entorhinal cortex (alEC) in the aging brain. The transition to Alzheimer's disease (AD) is hypothesized to involve amyloid-β (Aβ) facilitated tau spread through neural connections. We contrasted functional connectivity (FC) of alEC and posteromedial EC (pmEC), subregions of EC that differ in functional specialization and cortical connectivity, with the hypothesis that alEC-connected cortex would show greater tau deposition than pmEC-connected cortex. We used resting state fMRI to measure FC, and PET to measure tau and Aβ in cognitively normal older adults. Tau preferentially deposited in alEC-connected cortex compared to pmEC-connected or non-connected cortex, and stronger connectivity was associated with increased tau deposition. FC-tau relationships were present regardless of Aβ, although strengthened with Aβ. These results provide an explanation for the anatomic specificity of neocortical tau deposition in the aging brain and reveal relationships between normal aging and the evolution of AD

Tau deposition is associated with functional isolation of the hippocampus in aging.

The tau protein aggregates in aging and Alzheimer disease and may lead to memory loss through disruption of medial temporal lobe (MTL)-dependent memory systems. Here, we investigated tau-mediated mechanisms of hippocampal dysfunction that underlie the expression of episodic memory decline using fMRI measures of hippocampal local coherence (regional homogeneity; ReHo), distant functional connectivity and tau-PET. We show that age and tau pathology are related to higher hippocampal ReHo. Functional disconnection between the hippocampus and other components of the MTL memory system, particularly an anterior-temporal network specialized for object memory, is also associated with higher hippocampal ReHo and greater tau burden in anterior-temporal regions. These associations are not observed in the posteromedial network, specialized for context/spatial information. Higher hippocampal ReHo predicts worse memory performance. These findings suggest that tau pathology plays a role in disconnecting the hippocampus from specific MTL memory systems leading to increased local coherence and memory decline

Regional brain hypometabolism is unrelated to regional amyloid plaque burden

In its original form, the amyloid cascade hypothesis of Alzheimer's disease holds that fibrillar deposits of amyloid are an early, driving force in pathological events leading ultimately to neuronal death. Early clinicopathological investigations highlighted a number of inconsistencies leading to an updated hypothesis in which amyloid plaques give way to amyloid oligomers as the driving force in pathogenesis. Rather than focusing on the inconsistencies, amyloid imaging studies have tended to highlight the overlap between regions that show early amyloid plaque signal on positron emission tomography and that also happen to be affected early in Alzheimer's disease. Recent imaging studies investigating the regional dependency between metabolism and amyloid plaque deposition have arrived at conflicting results, with some showing regional associations and other not. We extracted multimodal neuroimaging data from the Alzheimer's disease neuroimaging database for 227 healthy controls and 434 subjects with mild cognitive impairment. We analysed regional patterns of amyloid deposition, regional glucose metabolism and regional atrophy using florbetapir ((18)F) positron emission tomography, (18)F-fluordeoxyglucose positron emission tomography and T1-weighted magnetic resonance imaging, respectively. Specifically, we derived grey matter density and standardized uptake value ratios for both positron emission tomography tracers in 404 functionally defined regions of interest. We examined the relation between regional glucose metabolism and amyloid plaques using linear models. For each region of interest, correcting for regional grey matter density, age, education and disease status, we tested the association of regional glucose metabolism with (i) cortex-wide florbetapir uptake; (ii) regional (i.e. in the same region of interest) florbetapir uptake; and (iii) regional florbetapir uptake while correcting in addition for cortex-wide florbetapir uptake. P-values for each setting were Bonferroni corrected for 404 tests. Regions showing significant hypometabolism with increasing cortex-wide amyloid burden were classic Alzheimer's disease-related regions: the medial and lateral parietal cortices. The associations between regional amyloid burden and regional metabolism were more heterogeneous: there were significant hypometabolic effects in posterior cingulate, precuneus, and parietal regions but also significant positive associations in bilateral hippocampus and entorhinal cortex. However, after correcting for global amyloid burden, few of the negative associations remained and the number of positive associations increased. Given the wide-spread distribution of amyloid plaques, if the canonical cascade hypothesis were true, we would expect wide-spread, cortical hypometabolism. Instead, cortical hypometabolism appears to be linked to global amyloid burden. Thus we conclude that regional fibrillar amyloid deposition has little to no association with regional hypometabolism

Prevalence of Dementia in Older Latinos: The Influence of Type 2 Diabetes Mellitus, Stroke and Genetic Factors

To estimate dementia prevalence in older Mexican Americans, determine the distribution of dementia by etiology, and evaluate the contribution of type 2 diabetes mellitus, stroke, and apolipoprotein E (ApoE) genotype to dementia. DESIGN: Analysis of baseline data from an epidemiological cohort study. SETTING: Sacramento Valley, California. PARTICIPANTS: One thousand seven hundred eighty-nine Latinos aged 60 and older residing in targeted census tracts during 1998–99. MEASUREMENTS: Each subject was interviewed and screened for dementia and cardiovascular risk factors and diseases. Fasting blood samples were drawn for glucose, insulin, and lipids. Buccal cells were obtained for genetic analysis of ApoE. A three-stage process of screening was used to diagnose dementia, including cognitive testing, a clinical examination, and imaging to determine etiology. Presence of dementia was established according to National Institute of Neurological Disorders and Stroke/Alzheimers and Related Disorders Association criteria and California Alzheimer's Disease Diagnostic and Treatment Criteria. RESULTS: Overall dementia prevalence was 4.8%. Prevalence in those aged 85 and older was 31%. Education and Anglo cultural orientation was negatively associated with dementia risk. Risk of dementia was nearly eight times higher in those with both type 2 diabetes mellitus and stroke. Forty-three percent of dementia was attributable to type 2 diabetes mellitus, stroke, or a combination of the two. ApoE allele frequency was E2 5.9%, E3 90.1%, and E4 4%. Those with any E4 and 4–4 combinations had a higher risk for dementia than those with the E3–3 combination. CONCLUSIONS: Dementia prevalence in this ethnic group is similar to that reported in Canadian and European studies but lower than in Caribbean-Hispanics residing in the United States. The etiological fraction of dementia attributable to type 2 diabetes mellitus and stroke is substantial and points toward the need for intervention research and treatment with the goal of reducing neurological sequelae in groups with high prevalence of type 2 diabetes mellitus. The allele frequency of ApoE was similar to that in other published studies on Mexican Americans. The low frequency of the E4 allele may contribute to the difference in etiology of dementia in older Mexican Americans and older people of European background. Dementia in this ethnic group may be related to preventable causes, with a smaller genetic component than in Europeans.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66237/1/j.1532-5415.2003.51054.x.pd

Striatal dopamine synthesis and cognitive flexibility differ between hormonal contraceptive users and nonusers

In rodents and nonhuman primates, sex hormones are powerful modulators of dopamine (DA) neurotransmission. Yet less is known about hormonal regulation of the DA system in the human brain. Using positron emission tomography (PET), we address this gap by comparing hormonal contraceptive users and nonusers across multiple aspects of DA function: DA synthesis capacity via the PET radioligand 6-[18F]fluoro-m-tyrosine ([18F]FMT), baseline D2/3 receptor binding potential using [11C]raclopride, and DA release using methylphenidate-paired [11C]raclopride. Participants consisted of 36 healthy women (n = 15 hormonal contraceptive users; n = 21 naturally cycling/non users of hormonal contraception), and men (n = 20) as a comparison group. A behavioral index of cognitive flexibility was assessed prior to PET imaging. Hormonal contraceptive users exhibited greater DA synthesis capacity than NC participants, particularly in dorsal caudate, and greater cognitive flexibility. Furthermore, across individuals, the magnitude of striatal DA synthesis capacity was associated with cognitive flexibility. No group differences were observed in D2/3 receptor binding or DA release. Analyses by sex alone may obscure underlying differences in DA synthesis tied to women\u27s hormone status. Hormonal contraception (in the form of pill, shot, implant, ring, or intrauterine device) is used by ~400 million women worldwide, yet few studies have examined whether chronic hormonal manipulations impact basic properties of the DA system. Findings from this study begin to address this critical gap in women\u27s health