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Principal Investigator: JOSHUA A SONNEN
Organization: TUFTS UNIVERSITY MEDFORD
Fiscal Year: 2024
Award: $594,130
Funding agency: National Institute of Environmental Health Sciences
Project Summary
1) Objectives: We will define associations and pathways through which exposure to PM2.5 and metals
contribute to dementia-associated neuropathology (DAN), incident dementia, and cognitive function. We will do
so by leveraging resources from the Adult Changes in Thought (ACT) study, an ongoing, prospective cohort
study of brain aging and dementia in older adults who are cognitively intact at enrollment. Every two years
since 1994, ACT has collected vetted data on dementia, other brain health measures, physical health, lifestyle,
medications, and residential history for over 5000 participants, following them until incident dementia or death.
At each timepoint, ACT assesses dementia using the Cognitive Abilities Screening Instrument (CASI) and
consensus diagnosis using DSM-IV criteria. AD is also assessed based on NINCDS criteria. For participants
who consent to autopsy (~25%), ACT performs a neuropathological examination of their brains, including
confirmation of dementia diagnoses. Our study will build on these data and resources to achieve 3 primary
aims: (1) to characterize PM2.5 and metal concentrations within the olfactory bulb (OB), olfactory tract (OT), and
brain tissues of ~140 human donors to establish whether the OB is a pathway through which air pollutants
reach the brain; (2) to investigate the OB as a pathway for DAN within the OBs and brains of these donors; and
(3) to assess the association of PM2.5, metals with incident dementia - including for pathologically-defined AD,
μVBI, LBD, and mixed dementia – and cognitive function, controlling for key confounders and examining effect
modification by sex, race/ethnicity, socio-economics, and health conditions and mediation by health conditions.
2) Approach: We will test our aims following a multi-disciplinary approach that relies on (1) our detailed
analysis of brains and OB for particles, metals and DAN indicators for ACT participants who consented to
autopsy and (2) our epidemiological analyses of the association of long-term ambient PM2.5 and metal
exposures with incident dementia, AD, μVBI, and LBD for the entire ACT cohort and for the subset with
neuropathology confirmed dementia diagnoses. For both, we will leverage ACT’s rich database of clinical and
functional health measures, behaviors, and residential histories. We, for example, will use the residential
histories to estimate long-term ambient PM2.5 and associated metal exposures for each ACT participant using
novel spatio-temporal models. We will also use health and behavioral data to control for key confounders and
predictors and health data to assess modification and mediation of the pollutant-dementia associations.
3) Expected Results: We will provide new evidence of the risks posed by airborne metals to incident dementia
and of the pathways through which airborne metals cause damage. In so doing, results from our study will help
identify targeted interventions to block pathways to dementia by type and mitigate the severe and growing
burden of AD and other dementias.
Terms: <21+ years old><AD dementia><Active Follow-up><Adult><Adult Human><Aging><Air Pollutants><Air Pollution><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Amentia><Anatomic Sites><Anatomic structures><Anatomy><Apo-E><ApoE><ApoE protein><Apolipoprotein E><Autopsy><Behavior><Behavioral><Biometrics><Biometry><Biostatistics><Blood Plasma><Brain><Brain Nervous System><Brain Vascular Disorders><Brain Vascular Trauma><Brain region><Cerebellum><Cerebrovascular Disease><Cerebrovascular Disorders><Cerebrovascular Trauma><Cessation of life><Clinical><Cognition><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Collaborations><Consensus><Consent><Coupled><DSM-4><DSM-IV><DSM4><Data><Death><Dementia><Diagnosis><Diagnostic and Statistical Manual of Mental Disorders, 4th edition><Diagnostic and Statistical Manual of Mental Disorders-IV><Discipline><Disease><Disorder><Disturbance in cognition><Drugs><Encephalon><Enrollment><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology><Epidemiology Research><Ethnic Origin><Ethnicity><Evaluation><Exposure to><Gender><Genotype><Gliosis><Health><Health Care Costs><Health Costs><Healthcare Costs><History><Human><Impaired cognition><Intervention><Intervention Strategies><Intracranial Vascular Diseases><Intracranial Vascular Disorders><Knowledge><LB disease><LB disorder><Lewy Bodies><Lewy Body Disease><Lewy body disorder><Lewy disease><Lewy disorder><Life Style><Lifestyle><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Mediating><Mediation><Medication><Metal exposure><Metals><Modeling><Modern Man><Modification><Morbidity><Morbidity - disease rate><Negotiating><Negotiation><Nerve Degeneration><Network Analysis><Neuron Degeneration><Olfactory Pathways><Olfactory system><Olfactory tract><Outcome><PM2.5><Participant><Pathologic><Pathology><Pathway Analysis><Pathway interactions><Pharmaceutical Preparations><Plasma><Plasma Serum><Population><Primary Senile Degenerative Dementia><Prospective, cohort study><Psychometrics><Race><Races><Recording of previous events><Research><Research Resources><Resources><Reticuloendothelial System, Serum, Plasma><Risk><Risk Factors><Sampling><Scanning Electron Microscopy><Science><Testing><Toxicology><United States><Vascular Brain Injury><Vascular Diseases><Vascular Disorder><Visit><active followup><adulthood><aged brain><aging brain><ambient air pollution><blood vessel disorder><brain health><brain tissue><brain vascular disease><brain vascular dysfunction><cerebral vascular disease><cerebral vascular dysfunction><cerebrovascular dysfunction><clinical database><cognitive ability><cognitive dysfunction><cognitive function><cognitive loss><cognitive performance><cohort><dementia burden><drug/agent><enroll><epidemiologic><epidemiologic investigation><epidemiological><epidemiology study><exposure to metal><fine particles><fine particulate matter><follow up><follow-up><followed up><followup><glial activation><glial cell activation><health data><histories><instrument><interdisciplinary approach><interventional strategy><intracranial vascular dysfunction><malleable risk><mixed dementia><mixed etiology dementia><mixed pathology dementia><mixed type dementia><modifiable risk><mortality><multidisciplinary approach><multiple etiology dementia><multiple pathology dementia><multiple type dementia><necropsy><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neuronal degeneration><neuropathologic><neuropathological><neuropathology><novel><older adult><older adulthood><older men><older women><olfactory bulb><olfactory circuitry><olfactory circuits><outdoor air pollution><particle><particle exposure><pathway><physical conditioning><physical health><pollutant><postmortem><primary degenerative dementia><prospective><racial><racial background><racial origin><screening><screenings><senile dementia of the Alzheimer type><sex><socio-economic><socio-economically><socioeconomically><socioeconomics><spatiotemporal><systemic inflammation><systemic inflammatory response><vascular dysfunction><vasculopathy>