Modelling Small Vessel Disease Using Regional MRI Markers, and Mediating Effects on Cognitive Decline.

Background: The location of proposed brain MRI markers of small vessel disease (SVD) might reflect their pathogenesis and may translate into differential associations with cognition. We derived regional MRI markers of SVD and studied: (i) associations with cognitive performance, (ii) patterns most likely to reflect underlying SVD, (iii) mediating effects on the relationships of age and cardiovascular disease (CVD) risk with cognition.

Method: In 891 participants from The Multi‐Ethnic Study of Atherosclerosis, we segmented enlarged perivascular spaces (ePVS), white matter hyperintensities (WMH) and microbleeds (MBs) using deep learning‐based algorithms, and calculated white matter (WM) microstructural integrity measures of fractional anisotropy (FA), trace (TR) and free water (FW) using automated DTI‐processing pipelines.

Decreased entropy of functional MRI signals in individuals with mild cognitive impairment compared to cognitively normal controls.

Background: Mild cognitive impairment (MCI) is a clinical cognitive deficit that is not severe enough to meet the threshold for Alzheimer's Disease (AD); however, MCI patients have an increased risk of developing AD. Therefore, a diagnosis of MCI may represent a critical turning point in the trajectory of developing AD. Establishing neurological signatures of MCI using network control theory (NCT) may allow more informed diagnosis, and an understanding of its underlying mechanisms could pave the way for novel treatments.

Comparison of olfactory and cognitive measures to neuroimaging biomarkers in the prediction of cognitive decline and dementia in the MCSA cohort.

Background: Inexpensive, non‐invasive tests may improve the identification of persons at increased risk for cognitive decline and dementia. We compared impairment in odor identification and global cognition with neuro‐imaging biomarkers to predict cognitive decline and dementia in the population‐based Mayo Clinic Study of Aging (MCSA).

Method: At the 2008 assessment, 647 participants who were ≥ 55 years old with at least one follow‐up had the following procedures: modified Blessed Information‐Memory‐Concentration Test (BIMCT), 12‐item Brief Smell Identification Test (BSIT), brain magnetic resonance imaging (MRI), and Positron Emission Tomography (PET) amyloid imaging with 11C‐Pittsburgh compound B (11C‐PiB).

Performance of a smell identification test vs. the mini‐mental status exam for the detection of dementia and cognitive impairment among ethnically diverse persons with cognitive concerns in primary care.

Background: Early detection of dementia and cognitive impairment is recommended for persons 65 years and older during wellness primary care visits. The importance of early detection has increased with the availability of new treatments for early Alzheimer's disease (AD). However, there is no clear approach for early detection in primary care.

Design, Characteristics, and Resources from the Diabetes Prevention Program Outcomes Study (DPPOS) AD/ADRD project.

Background: Persons with prediabetes and type 2 diabetes (T2D) are known to have higher risk of cognitive impairment (CI), including age‐related cognitive decline, mild cognitive impairment (MCI), and dementia; however, the characteristics of CI and the determinants and mechanisms in prediabetes and T2D remain unclear. Addressing these gaps is critical since over half of the U.S.

Integrating NACC UDSv3 into non AD/ADRD Cohorts: The Diabetes Prevention Program Outcomes Study in Alzheimer’s Diseases and Related Dementias (DPPOS)‐AD/ADRD Project Experience.

Background: The Diabetes Prevention Program (DPP) was a randomized trial for prevention of diabetes in adults with prediabetes (PreD). The DPP Outcomes Study (DPPOS) is the long‐term epidemiological follow‐up of this cohort, studied continuously for over 25 years. DPPOS Phase 4 (DPPOS‐AD/ADRD) began in 2022, with a primary focus on the nature and determinants of cognitive impairment in the surviving cohort.

Implementation of a standardized Video‐based Asynchronous Neurological Examination (VANE) in a multi‐center study of AD/ADRD: Findings from The Diabetes Prevention Program Outcomes Study (DPPOS) AD/ADRD Project.

Background: The Diabetes Prevention Program Outcomes Study (DPPOS) is an established cohort of aging persons (mean age 72 years) with prediabetes and diabetes with a mean of 23 (range 21‐25) years of follow‐up. DPPOS added neuropsychological testing using the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDSv3) forms. Using the NACC UDS required implementing a standardized neurological examination across 25 US clinical sites, administered by project coordinators (PC).

Subclinical Vascular Disorders in Relation to Cognitive Decline and Impairment: The Multi‐Ethnic Study of Atherosclerosis.

Background: Vascular disorders are proposed as modifiable risk factors for dementia; yet, physiologic mechanisms connecting vascular disorders to cognitive impairment remain unknown. We examined subclinical cardiovascular measures to determine which predict global cognitive decline and domain specific cognitive impairment and point to potential pathways linking subclinical vascular disease and dementia.

Methods: MESA includes a diverse cohort of 6,814 participants free from clinical cardiovascular disease with follow‐up over 6 clinical examinations and annual follow‐up calls.

Subclinical Vascular Risk Composites and Dementia Imaging Biomarkers 17‐20 years later in the Multi‐Ethnic Study of Atherosclerosis (MESA).

Background: Vascular risk factors captured in midlife represent modifiable features of cardiovascular disease (CVD), stroke, dementia, and dementia‐related neuropathology. Subclinical measures of CVD may help identify specific structural and function aspects underlying vascular contributions to cognitive impairment and dementia over and above conventional dementia risk scores.

Method: The MESA study followed a diverse cohort of 6,814 adults aged 45‐84 years over 6 clinical examinations and annual follow‐up calls since baseline, 2000‐2002.

Total and Structural Carotid Artery Stiffness are related to Cognitive Decline and ADRD Pathology: The Multi‐Ethnic Study of Atherosclerosis (MESA).

Background: Stiffening of the large elastic arteries is an emerging age‐related risk factor for Alzheimer’s disease (AD) and related dementia (ADRD). Arterial stiffness is associated with pathological changes underlying AD/ADRD, and total arterial stiffness (T‐PWV) can be subdivided into two main mechanisms. Structural stiffening (S‐PWV) is due to intrinsic remodeling of the artery wall, and load‐dependent stiffening (LD‐PWV) is due to increased blood pressure without intrinsic changes to the artery wall.

Remote associations between beta‐amyloid and tau are mediated by between‐network connectivity.

Background: The accumulation of tau tangles and beta‐amyloid (Aβ) are hallmarks of Alzheimer's disease (AD). Despite the hypothesis that Aβ may trigger tau spread across remote brain regions, the specific pathological processes remain unclear.

Methods: Our study utilized 18F‐Florbetaben Aβ positron emission tomography (PET), 18F‐MK6240 tau PET, and resting‐state functional magnetic resonance imaging (rs‐fMRI).

Modelling Small Vessel Disease Using Regional MRI Markers, and Mediating Effects on Cognitive Decline.

Background: The location of proposed brain MRI markers of small vessel disease (SVD) might reflect their pathogenesis and may translate into differential associations with cognition. We derived regional MRI markers of SVD and studied: (i) associations with cognitive performance, (ii) patterns most likely to reflect underlying SVD, (iii) mediating effects on the relationships of age and cardiovascular disease (CVD) risk with cognition.

Method: In 891 participants from The Multi‐Ethnic Study of Atherosclerosis, we segmented enlarged perivascular spaces (ePVS), white matter hyperintensities (WMH) and microbleeds (MBs) using deep learning‐based algorithms, and calculated white matter (WM) microstructural integrity measures of fractional anisotropy (FA), trace (TR) and free water (FW) using automated DTI‐processing pipelines.

Pharmacological thiamine (Vitamin B1) as a treatment for alzheimer’s disease.

Background: Abnormal glucose metabolism in AD brains correlates with cognitive deficits. The glucose changes are consistent with brain thiamine (vitamin B1) deficiency. In animals, thiamine deficiency causes multiple AD‐like changes including memory loss, neuron loss, brain inflammation, enhanced phosphorylation of tau, exaggerated plaque formation and elevated advanced glycation end products (AGE).

A Seamless Phase 2A‐Phase 2B Multi‐Center Trial to Test the Benefits of Benfotiamine on the Progression of Alzheimer’s Disease‐Benfoteam: Design and Methods.

Background: Benfotiamine, a prodrug of thiamine, raises blood levels by 50‐100 times to achieve pharmacologic effects. It provides a novel therapeutic direction addressing a well‐characterized brain tissue thiamine deficiency and related changes in glucose metabolism in AD. BenfoTeam is a seamless phase 2A‐2B “proof of concept” (POC), double‐blind, placebo‐controlled RCT investigating tolerability, safety, and efficacy of benfotiamine, as a first‐in‐class small molecule treatment for early AD.

Long-term impact of Diabetes Prevention Program interventions on walking endurance.

Objectives: Type 2 diabetes (T2D) and prediabetes are associated with poor walking endurance, a marker of physical function. We aimed to examine the long-term effects of metformin or intensive lifestyle intervention in adults at high risk of T2D on their 6-min walk test (6MWT) performance.

Methods: Participants were randomized in the 3-year Diabetes Prevention Program (DPP) to one of the three groups: lifestyle intervention, metformin, or placebo, and were subsequently followed in the DPP Outcomes Study.

Urinary Metal Levels, Cognitive Test Performance, and Dementia in the Multi-Ethnic Study of Atherosclerosis.

Importance: Metals are established neurotoxicants, but evidence of their association with cognitive performance at low chronic exposure levels is limited.

Objective: To investigate the association of urinary metal levels, individually and as a mixture, with cognitive tests and dementia diagnosis, including effect modification by apolipoprotein ε4 allele (APOE4).

Design, Setting, And Participants: The multicenter prospective cohort Multi-Ethnic Study of Atherosclerosis (MESA) was started from July 2000 to August 2002, with follow-up through 2018.

Association of circulating ketone bodies with cognitive performance and dementia in the Multi-Ethnic Study of Atherosclerosis (MESA).

Introduction: Growing interest centers on the association between circulating ketone bodies (KB) and cognitive function, notably in aging and neurodegenerative diseases.

Methods: Associations of plasma KB with incident dementia and cognitive performances were examined among Multi-Ethnic Study of Atherosclerosis (MESA) participants. KB were measured using plasma samples collected following an overnight fasting at Exam 1 (2000-02) and detailed cognitive testing at Exam 5 (2010-2012,  = 4392), Exam 6 (2016-2018,  = 1838), and in MESA-MIND (2019-2021,  = 2060).

Metformin as a Potential Prevention Strategy for Alzheimer's Disease and Alzheimer's Disease Related Dementias.

Background: Metformin is a safe and effective medication for type 2 diabetes (T2D) that has been proposed to decrease the risk of aging related disorders including Alzheimer's disease (AD) and Alzheimer's disease related disorders(ADRD).

Objective: This review seeks to summarize findings from studies examining the association of metformin with AD/ADRD related outcomes.

Methods: This is a narrative review of human studies, including observational studies and clinical trials, examining the association of metformin with cognitive and brain outcomes.

Comparison of brief olfactory and cognitive assessments to neuroimaging biomarkers in the prediction of cognitive decline and dementia in the MCSA cohort.

Introduction: We evaluated impaired odor identification and global cognition as simple, cost-effective alternatives to neuroimaging biomarkers to predict cognitive decline and dementia in the Mayo Clinic Study of Aging.

Methods: Six hundred forty-seven participants (mean 8.1, standard deviation 3.

The lucidity in dementia experience: perspectives from family and professional caregivers.

Background: Family and professional caregivers of individuals with dementia often witness care-receiver's lucidity events.

Objective: A qualitative data analysis was performed of documented family and professional caregivers' experiences and their respective appraisals of lucidity events.

Research Design And Methods: Using a reduction method of selection, data from 10 in-home family caregivers and 20 professional caregivers to long-term care residents was content-coded and analysed.

Increased between-network connectivity: A risk factor for tau elevation and disease progression.

One of the pathologic hallmarks of Alzheimer's disease (AD) is neurofibrillary tau tangles. Despite our knowledge that tau typically initiates in the medial temporal lobe (MTL), the mechanisms driving tau to spread beyond MTL remain unclear. Emerging evidence reveals distinct patterns of functional connectivity change during aging and preclinical AD: while connectivity within-network decreases, connectivity between-network increases.

Plasma Biomarkers of Brain Injury and Their Association With Brain MRI and Cognition in Type 1 Diabetes.

Objective: To evaluate associations between plasma biomarkers of brain injury and MRI and cognitive measures in participants with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study.

Research Design And Methods: Plasma amyloid-β-40, amyloid-β-42, neurofilament light chain (NfL), phosphorylated Tau-181 (pTau-181), and glial fibrillary acidic protein (GFAP) were measured in 373 adults who participated in the DCCT/EDIC study. MRI assessments included total brain and white matter hyperintensity volumes, white matter mean fractional anisotropy, and indices of Alzheimer disease (AD)-like atrophy and predicted brain age.