Glutamate decarboxylase (GAD), the enzyme that synthesizes the neurotransmitter gamma-aminobutyric acid (GABA), has been localized in the rat olfactory bulb by immunocytochemical methods with both light and electron microscopy. The light microscopic results demonstrated GAD-positive puncta concentrated in the external plexiform layer and in the glomeruli of the glomerular layer. In addition, GAD-positive reaction product stained the dentrites and somata of granule and periglomerular cells. The electron microscopic observations confirmed the presence of GAD-positive reaction product within granule and periglomerular somata and dendrites. In electron micrographs of the external plexiform layer, the gemmules which arise from the distal dentrites of granule cells were also observed to be filled with reaction product, and these structures corresponded in size and location to the puncta observed in light microscopic preparations. The gemmules were observed to form reciprocal dendrodentritic synaptic junctions with mitral cell dentrites which lacked reaction product. In the glomeruli, GAD-positive reaction product was observed in the dentritic shafts and gemmules of periglomerular cells which also formed reciprocal dendrodentritic synaptic contacts with mitral/tufted cell dentrites. The localization of GAD in known inhibitory neurons of the olfactory bulb supports the case that these local circuit neurons use GABA as their neurotransmitter. The present study demonstrates that GAD molecules located within certain neuronal somata and dentrites can be visualized with antisera prepared against GAD that was purified from synaptosomal fractions of mouse brains. This finding suggests that the lack of GAD staining within somata and dentrites of GABA-ergic neurons noted in previous studies of the cerebellum and spinal cord was probably due to low GAD concentrations, rather than to antigenic differences among GAD molecules located in different portions of the neuron. A striking differences among GAD molecules located in different portions of the neuron. A striking difference between the granule and periglomerular neurons of the olfactory bulb and the neurons of the cerebellum and spinal cord is that the former have presynaptic dentrites while the latter do not. Since GAD-positive reaction product can be detected in the somata and dentrites of GABA-ergic neurons which have presynaptic dentrites, it is suggested that these neurons may differ from other GABA-ergic neurons with respect to either transport or metabolism of GAD.

L-Glutamate decarboxylase (GAD, EC 4.1.1.15), the enzyme which catalyzes the alpha-decarboxylation of L-glutamate to form gamma-aminobutyric acid (GABA), was localized both light and electron microscopically in rat substantia nigra by an immunoperoxidase method. Large amounts of GAD-positive reaction produce were seen throughout the substantia nigra in light microscopic preparations, and it appeared to be localized in punctate structures that were apposed to dendrites and somata. Electron microscopic studies revealed that most of the axon terminals in the substantia nigra were filled with GAD-positive reaction product and formed both axodendritic and axosomatic synapses. Many dendrites were extensively surrounded by GAD-positive terminals which most commonly formed symmetric synaptic junctions, although some formed asymmetric synpatic junctions. The results of this investigation are consistent with biochemical, pharmacological and physiological data which have indicated that neurons of the neostriatum and globus pallidus exert a GABA-mediated, postsynaptic inhibition upon the neurons of the substantia nigra. These findings provide another example in the vertebrate central nervous system where Golgi I projection neurons are inhibitory and use GABA as their neurotransmitter.

Background

Despite tremendous advancements in the field, our understanding of mild cognitive impairment (MCI) and Alzheimer's disease (AD) among Mexican Americans remains limited.

Objective

The aim of this study was to characterize MCI and dementia among Mexican Americans and non-Hispanic whites.

Methods

Baseline data were analyzed from n = 1,705 (n = 890 Mexican American; n = 815 non-Hispanic white) participants enrolled in the Health and Aging Brain Study-Health Disparities (HABS-HD).

Results

Among Mexican Americans, age (OR = 1.07), depression (OR = 1.09), and MRI-based neurodegeneration (OR = 0.01) were associated with dementia, but none of these factors were associated with MCI. Among non-Hispanic whites, male gender (OR = 0.33), neighborhood deprivation (OR = 1.34), depression (OR = 1.09), and MRI-based neurodegeneration (OR = 0.03) were associated with MCI, while depression (OR = 1.09) and APOEɛ4 genotype (OR = 4.38) were associated with dementia.

Conclusion

Findings from this study revealed that the demographic, clinical, sociocultural and biomarker characteristics of MCI and dementia are different among Mexican Americans as compared to non-Hispanic whites.

Introduction

The APOEε4 allele is the single strongest genetic risk for late-onset Alzheimer's disease (AD). Prior work demonstrates that not only the APOEε4 allele varies by race/ethnicity but also the risk for AD and cognitive impairment conveyed by the APOEε4 allele varies by the racial/ethnic group as well as genetic ancestry. Here, we sought to examine the link between the APOEε4 and neuropsychological functioning among Mexican Americans (MAs).

Methods

Data were examined from 1,633 (852 MAs and 781 non-Hispanic Whites [NHWs]) participants of the Health & Aging Brain Study - Health Disparities (HABS-HD) and were enrolled with all requisite data to be included into the current analyses.

Results

The frequency of both ε4 and ε2 alleles was significantly lower among MAs as compared to NHWs. Among MAs, APOEε4 allele presence was associated specifically with poorer immediate and delayed memory (Wechsler Memory Scale - Third Edition [WMS-III] Logical Memory and Spanish-English Verbal Learning Test [SEVLT]). Among NHWs, APOEε4 allele presence was associated with poorer immediate and delayed memory as well as worse executive functioning (Trials B) and verbal fluency (Animal naming).

Discussion/conclusion

The APOEε4 allele was associated with poorer cognition across multiple domains among NHWs; however, allele presence was specifically associated with poorer memory performance among MAs. When combined with prior work, the current findings demonstrate that the risk factors associated with cognitive dysfunction differ among MAs as compared to NHWs and require additional investigation.

Introduction

Representation of Mexican Americans in Alzheimer's disease (AD) clinical research has been extremely poor.

Methods

Data were examined from the ongoing community-based, multi-ethnic Health & Aging Brain among Latino Elders (HABLE) study. Participants underwent functional exams, clinical labs, neuropsychological testing, and 3T magnetic resonance imaging of the brain. Fasting proteomic markers were examined for predicting mild cognitive impairment (MCI) and AD using support vector machine models.

Results

Data were examined from n = 1649 participants (Mexican American n = 866; non-Hispanic White n = 783). Proteomic profiles were highly accurate in detecting MCI (area under the curve [AUC] = 0.91) and dementia (AUC = 0.95). The proteomic profiles varied significantly between ethnic groups and disease state. Negative predictive value was excellent for ruling out MCI and dementia across ethnic groups.

Discussion

A blood-based screening tool can serve as a method for increasing access to state-of-the-art AD clinical research by bridging between community-based and clinic-based settings.

Patients with Alzheimer dementia display evidence of amyloid-related neurodegeneration. Our focus was to determine whether such patients also display evidence of a disease-targeting adaptive immune response mediated by CD4+ T cells. To test this hypothesis, we evaluated the CSF immune profiles of patients with Alzheimer clinical syndrome (ACS), who display clinically defined dementia. Innate and adaptive immune profiles of patients with ACS were measured using multicolor flow cytometry. CSF-derived CD4+ and CD8+ T-cell receptor repertoire genetics were measured using next-generation sequencing. Brain-specific autoantibody signatures of CSF-derived antibody pools were measured using array technology or ELISA. CSF from similar-age healthy controls (HCs) was used as a comparator cohort. Innate cells were expanded in the CSF of patients with ACS in comparison to HCs, and innate cell expansion increased with age in the patients with ACS, but not HCs. Despite innate cell expansion in the CSF, the frequency of total CD4+ T cells reduced with age in the patients with ACS. T-cell receptor repertoire genetics indicated that T-cell clonal expansion is enhanced, and diversity is reduced in the patients with ACS compared with similar-age HCs. Examination of CSF indicates that CD4+ T cell-mediated adaptive immune responses are altered in patients with ACS. Understanding the underlying mechanisms affecting adaptive immunity will help move us toward the goal of slowing cognitive decline.

Objective

Most investigations of pharmacotherapy for treating Alzheimer's disease focus on patients with mild-to-moderate symptoms, with little evidence to guide clinical decisions when symptoms become severe. We examined whether continuing donepezil, or commencing memantine, is cost-effective for community-dwelling, moderate-to-severe Alzheimer's disease patients.

Methods

Cost-effectiveness analysis was based on a 52-week, multicentre, double-blind, placebo-controlled, factorial clinical trial. A total of 295 community-dwelling patients with moderate/severe Alzheimer's disease, already treated with donepezil, were randomised to: (i) continue donepezil; (ii) discontinue donepezil; (iii) discontinue donepezil and start memantine; or (iv) continue donepezil and start memantine.

Results

Continuing donepezil for 52 weeks was more cost-effective than discontinuation, considering cognition, activities of daily living and health-related quality of life. Starting memantine was more cost-effective than donepezil discontinuation. Donepezil-memantine combined is not more cost-effective than donepezil alone.

Conclusions

Robust evidence is now available to inform clinical decisions and commissioning strategies so as to improve patients' lives whilst making efficient use of available resources. Clinical guidelines for treating moderate/severe Alzheimer's disease, such as those issued by NICE in England and Wales, should be revisited. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.

Introduction

Mexican Americans remain severely underrepresented in Alzheimer's disease (AD) research. The Health & Aging Brain among Latino Elders (HABLE) study was created to fill important gaps in the existing literature.

Methods

Community-dwelling Mexican Americans and non-Hispanic White adults and elders (age 50 and above) were recruited. All participants underwent comprehensive assessments including an interview, functional exam, clinical labs, informant interview, neuropsychological testing, and 3T magnetic resonance imaging (MRI) of the brain. Amyloid and tau positron emission tomography (PET) scans were added at visit 2. Blood samples were stored in the Biorepository.

Results

Data was examined from n = 1705 participants. Significant group differences were found in medical, demographic, and sociocultural factors. Cerebral amyloid and neurodegeneration imaging markers were significantly different between Mexican Americans and non-Hispanic Whites.

Discussion

The current data provide strong support for continued investigations that examine the risk factors for and biomarkers of AD among diverse populations.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.