Background: Inhalation of airborne particulate matter (PM) derived from urban traffic is associated with pathology in the arteries, heart, and lung; effects on brain are also indicated but are less documented.Objective: We evaluated rodent brain responses to urban nanoscale (< 200 nm) PM (nPM).Methods: Ambient nPM collected near an urban freeway was transferred to aqueous suspension and reaerosolized for 10-week inhalation exposure of mice or directly applied to rat brain cell cultures.Results: Free radicals were detected by electron paramagnetic resonance in the nPM 30 days after initial collection. Chronic inhalation of reaerosolized nPM altered selected neuronal and glial activities in mice. The neuronal glutamate receptor subunit (GluA1) was decreased in hippocampus, whereas glia were activated and inflammatory cytokines were induced [interleukin-1α (IL-1α), tumor necrosis factor-α (TNFα)] in cerebral cortex. Two in vitro models showed effects of nPM suspensions within 24–48 hr of exposure that involved glutamatergic functions. In hippocampal slice cultures, nPM increased the neurotoxicity of NMDA (N-methyl-d-aspartic acid), a glutamatergic agonist, which was in turn blocked by the NMDA antagonist AP5 [(2R)-amino-5-phosphonopentanoate]. In embryonic neuron cultures, nPM impaired neurite outgrowth, also blocked by AP5. Induction of IL-1α and TNFα in mixed glia cultures required higher nPM concentrations than did neuronal effects. Because conditioned media from nPM-exposed glia also impaired outgrowth of embryonic neurites, nPM can act indirectly, as well as directly, on neurons in vitro.Conclusions: nPM can affect embryonic and adult neurons through glutamatergic mechanisms. The interactions of nPM with glutamatergic neuronal functions suggest that cerebral ischemia, which involves glutamatergic excitotoxicity, could be exacerbated by nPM.

Objectives To assess whether MIND at Home, a community-based, multicomponent, care coordination intervention, reduces unmet caregiving needs and burden in informal caregivers of persons with memory disorders. Design 18-month randomized controlled trial of 289 community-living care recipient (CR)/caregiver dyads. Setting 28 postal code areas of Baltimore, MD. Participants Informal caregivers (i.e., an unpaid individual who is regularly relied on by the CR for assistance). Intervention All dyads and the CR's primary care physician received the written needs assessment results and intervention recommendations. Intervention dyads then received an 18-month care coordination intervention delivered by non-clinical community-workers to address unmet care needs through individualized care planning; referral and linkage to dementia services; provision of caregiver dementia education and skill building strategies; and care progress monitoring by an interdisciplinary team. Measurements Primary outcome was total percent of unmet caregiver needs at 18 months. Secondary outcomes included objective and subjective caregiver burden measures, quality of life (QOL), and depression. Results Total percent of unmet caregiver needs declined in both groups from baseline to 18 months, but there was no statistically significant between-group difference. There were no significant group differences in most caregiver burden measures, depression, or QOL. There was a potentially clinically- relevant reduction in self-reported number of hours caregivers spent with the CR for MIND participants compared with controls. Conclusions No statistically significant impacts on caregiver outcomes were found after multiple comparison adjustments. Yet, MIND appeared to have had a modest, and clinically-meaningful, impact on informal caregiver time spent with CRs.

Early-onset (age &lt; 65) Alzheimer’s disease is associated with greater non-amnestic cognitive symptoms and neuropathological burden than late-onset disease. It is not fully understood whether these groups also differ in the associations between molecular pathology, neurodegeneration, and cognitive performance. We studied amyloid-positive patients with early-onset (n = 60, mean age 58 ± 4, MMSE 21 ± 6, 58% female) and late-onset (n = 53, mean age 74 ± 6, MMSE 23 ± 5, 45% female) Alzheimer’s disease who underwent neurological evaluation, neuropsychological testing, 11C- Pittsburgh Compound B PET (amyloid-PET), and 18F-flortaucipir PET (tau-PET). 18F-fluorodeoxyglucose PET (brain glucose metabolism PET) was also available in 74% (n = 84) of participants. Composite scores for episodic memory, semantic memory, language, executive function, and visuospatial domains were calculated based on cognitively unimpaired controls. Voxel-wise regressions evaluated correlations between PET biomarkers and cognitive scores, and early-onset versus late-onset differences were tested with a PET*age group interaction. Mediation analyses estimated direct and indirect (18F-fluorodeoxyglucose mediated) local associations between 18F-flortaucipir binding and cognitive scores in domain-specific regions-of-interest. We found that early-onset patients had higher 18F-flortaucipir binding in parietal, lateral temporal, and lateral frontal cortex; more severe 18F-fluorodeoxyglucose hypometabolism in the precuneus and angular gyrus; and greater 11C- Pittsburgh Compound B binding in occipital regions compared to late-onset patients. In our primary analyses, PET-cognition correlations did not meaningfully differ between age groups.18F-flortaucipir and 18F-fluorodeoxyglucose, but not 11C- Pittsburgh Compound B, were significantly associated with cognition in expected domain-specific patterns in both age groups (e.g., left perisylvian/language, frontal/executive, occipital/visuospatial). 18F-fluorodeoxyglucose mediated the relationship between 18F-flortaucipir and cognition in both age groups across all domains except episodic memory in late-onset patients. Additional direct effects of 18F-flortaucipir were observed for executive function in all age groups, language in early-onset Alzheimer’s disease and in the total sample, and visuospatial function in the total sample. In conclusion, tau and neurodegeneration, but not amyloid, were similarly associated with cognition in both early and late-onset Alzheimer’s disease. Tau had an association with cognition independent of neurodegeneration in language, executive, and visuospatial functions in the total sample. Our findings support tau PET as a biomarker that captures both the clinical severity and molecular pathology specific to Alzheimer’s disease across the broad spectrum of ages and clinical phenotypes in Alzheimer’s disease.

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