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Objectives: Many survivors of sepsis suffer long-term cognitive impairment, but the mechanisms of this association remain unknown. The objective of this study was to determine whether sepsis is associated with cerebral microinfarcts on brain autopsy., Design: Retrospective cohort study., Setting and Subjects: Five-hundred twenty-nine participants of the Adult Changes in Thought, a population-based prospective cohort study of older adults carried out in Kaiser Permanente Washington greater than or equal to 65 years old without dementia at study entry and who underwent brain autopsy., Measurements and Main Results: Late-life sepsis hospitalization was identified using administrative data. We identified 89 individuals with greater than or equal to 1 sepsis hospitalization during study participation, 80 of whom survived hospitalization and died a median of 169 days after discharge. Thirty percent of participants with one or more sepsis hospitalization had greater than two microinfarcts, compared with 19% participants without (χ p = 0.02); 20% of those with sepsis hospitalization had greater than two microinfarcts in the cerebral cortex, compared with 10% of those without (χ p = 0.01). The adjusted relative risk of greater than two microinfarcts was 1.61 (95% CI, 1.01-2.57; p = 0.04); the relative risk for having greater than two microinfarcts in the cerebral cortex was 2.12 (95% CI, 1.12-4.02; p = 0.02). There was no difference in Braak stage for neurofibrillary tangles or consortium to establish a registry for Alzheimer's disease score for neuritic plaques between, but Lewy bodies were less significantly common in those with sepsis., Conclusions: Sepsis was specifically associated with moderate to severe vascular brain injury as assessed by microvascular infarcts. This association was stronger for microinfarcts within the cerebral cortex, with those who experienced severe sepsis hospitalization being more than twice as likely to have evidence of moderate to severe cerebral cortical injury in adjusted analyses. Further study to identify mechanisms for the association of sepsis and microinfarcts is needed.

Diseases that commonly cause dementia in the general population are Alzheimer's disease, microvascular brain injury, and Lewy body disease. Each of these is a chronic disease with latent, prodromal, and dementia stages. Here I present outcomes from validated neuropathologic assessments and cerebrospinal fluid biomarkers to estimate the prevalence of the latent stage of diseases that commonly contribute to the dementia syndrome. The latent stage of diseases that commonly cause dementia is highly prevalent in the adult population, highlighting the need for prevention strategies and longitudinal studies.

Beta-methylamino-L-alanine (BMAA) has been proposed as a global contributor to neurodegenerative diseases, including Parkinson-dementia complex (PDC) of Guam and Alzheimer's disease (AD). The literature on the effects of BMAA is conflicting with some but not all in vitro data supporting a neurotoxic action, and experimental animal data failing to replicate the pattern of neurodegeneration of these human diseases, even at very high exposures. Recently, BMAA has been reported in human brain from individuals afflicted with PDC or AD. Some of the BMAA in human tissue reportedly is freely extractable (free) while some is protein-associated and liberated by techniques that hydrolyze the peptide bond. The latter is especially intriguing since BMAA is a non-proteinogenic amino acid that has no known tRNA. We attempted to replicate these findings with techniques similar to those used by others; despite more than adequate sensitivity, we were unable to detect free BMAA. Recently, using a novel stable isotope dilution assay, we again were unable to detect free or protein-associated BMAA in human cerebrum. Here we review the development of our new assay for tissue detection of BMAA and show that we are able to detect free BMAA in liver but not cerebrum, nor do we detect any protein-associated BMAA in mice fed this amino acid. These studies demonstrate the importance of a sensitive and specific assay for tissue BMAA and seriously challenge the proposal that BMAA is accumulating in human brain.

In February 2004, we initiated an epidemiological investigation within a US state to enhance autopsy surveillance for clinically suspected prion disease. During the first 30 months, 30 cases of suspected prion disease were referred from throughout Washington. Of these, 18 cases had prion disease, and all of these were classified as either familial or sporadic Creutzfeldt-Jakob disease (CJD); there was no case of variant CJD. This represents a death rate of approximately 1.1 cases of sporadic CJD per 1 million people per year in Washington. Our results do not support the hypotheses that variant CJD is an emerging illness in Washington or that sporadic CJD is more common in this state than in other regions of the world.