Advances in molecular positron emission tomography (PET) have enabled anatomic tracking of brain pathology in longitudinal studies of normal aging and dementia, including assessment of the central model of Alzheimer’s disease (AD) pathogenesis, according to which TAU pathology begins focally but expands catastrophically under the influence of amyloid-β (Aβ) pathology to mediate neurodegeneration and cognitive decline. Initial TAU deposition occurs many years before Aβ in a specific area of the medial temporal lobe. Building on recent work that enabled focus of molecular PET measurements on specific TAU-vulnerable convolutional temporal lobe anatomy, we applied an automated anatomic sampling method to quantify TAU PET signal in 443 adult participants from several observational studies of aging and AD, spanning a wide range of ages, Aβ burdens, and degrees of clinical impairment. We detected initial cortical emergence of tauopathy near the rhinal sulcus in clinically normal people and, in a subset with longitudinal 2-year follow-up data (n = 104), tracked Aβ-associated spread of TAU from this site first to nearby neocortex of the temporal lobe and then to extratemporal regions. Greater rate of TAU spread was associated with baseline measures of both global Aβ burden and medial temporal lobe TAU. These findings are consistent with clinicopathological correlation studies of Alzheimer’s tauopathy and enable precise tracking of AD-related TAU progression for natural history studies and prevention therapeutic trials.

CONCLUSIONS: In a patient with suspected PD, a high PD probability on smell testing favours the diagnosis of PD, and a low PD probability strengthens the indication for dopamine transporter imaging.

Background and Objective:Loneliness is common and its prevalence is rising. The relationship of loneliness with subsequent dementia and the early preclinical course of Alzheimer disease and related dementia (ADRD) remains unclear. Thus, the primary objective of this study was to determine the association of loneliness with 10-year all-cause dementia risk and early cognitive and neuroanatomic imaging markers of ADRD vulnerability.Methods:Retrospective analysis of prospectively collected data from the population-based Framingham Study cohorts (09/09/1948-12/31/2018). Eligible participants had loneliness assessed and were dementia-free at baseline. Loneliness was recorded using the Center for Epidemiologic Studies Depression Scale; defined conservatively as feeling lonely ≥3 days in the past week. The main outcomes were incident dementia over a 10-year period, cognition, and MRI brain volumes and white-matter injury.Results:Of 2308 participants (mean age, 73 [SD, 9] years; 56% women) who met eligibility in the dementia sample, 14% (329/2308) developed dementia; 6% (144/2308) were lonely. Lonely (versus not lonely) adults had higher 10-year dementia risk (age-, sex-, and education-adjusted hazard ratio, 1.54; 95% CI, 1.06-2.24). Lonely participants younger than age 80 without APOE ε4 alleles had a three-fold greater risk (adjusted hazard ratio, 3.03; 95% CI, 1.63-5.62). Among 1875 persons without dementia who met eligibility in the cognition sample (mean age, 62 [SD, 9] years; 54% women), loneliness associated with poorer executive function, lower total cerebral volume, and greater white-matter injury.Discussion:Over 10 years of close clinical dementia surveillance in this cohort study, loneliness was associated with increased dementia risk; this tripled in adults whose baseline risk would otherwise be relatively low based on age and genetic risk, representing a majority of the US population. Loneliness was also associated with worse neurocognitive markers of ADRD vulnerability, suggesting an early pathogenic role. These findings may have important clinical and public health implications given observed loneliness trends.Classification of Evidence:This study provides Class I evidence that loneliness increases the 10-year risk of developing dementia.

Background: Adherence to the Mediterranean-DASH for Neurodegenerative Delay (MIND) diet has previously been associated with cognitive decline and dementia. To our knowledge, no prior study has investigated the association between the MIND diet and measures of brain volume, silent brain infarcts (SBIs), or brain atrophy. Objective: We evaluated whether adherence to the MIND diet associated with superior cognitive function, larger brain volumes, fewer SBIs, and less cognitive decline in the community-based Framingham Heart Study. Methods: 2,092 participants (mean±SD, age 61±9) completed Food Frequency Questionnaires, averaged across a maximum of 3-time points (examination cycles 5, 6, and 7), cognitive testing at examination cycle 7 (present study baseline: 1998–2001) and after a mean±SD of 6.6±1.1 years from baseline (n = 1,584). A subset of participants also completed brain magnetic resonance imaging (MRI) at examination cycle 7 (n = 1,904). In addition, participants with dementia, stroke, and other relevant neurological diseases such as significant head trauma, subdural hematoma, or multiple sclerosis were excluded from the analyses. Results: Higher MIND diet scores were associated with better global cognitive function (β±SE,+0.03SD±0.01; p = 0.004), verbal memory, visual memory, processing speed, verbal comprehension/reasoning, and with larger total brain volume (TBV) following adjustments for clinical, lifestyle and demographic covariates, but not with other brain MRI measures (i.e., hippocampal volume, lateral ventricular volume, white matter hyperintensity volume, SBIs) or cognitive decline. Conclusion: Higher MIND diet scores associated with better cognitive performance and larger TBV at baseline, but not with cognitive decline. Clinical trials are needed to ascertain whether adopting the MIND diet affects trajectories of cognitive decline.

Objective: Women have a higher lifetime risk of Alzheimer's disease (AD) than men. Among cognitively normal (CN) older adults, women exhibit elevated tau positron emission tomography (PET) signal compared with men. We explored whether menopause exacerbates sex differences in tau deposition in middle-aged adults. Methods: 328 CN participants from the Framingham Study (mean age = 57 years (AE10 years), 161 women, of whom, 104 were post-menopausal) underwent tau and β-amyloid (Aβ)-PET neuroimaging. We examined global Aβ-PET, and tau-PET signal in 5 regions identified a priori as demonstrating significant sex differences in older adults (in temporal, inferior parietal, middle frontal, and lateral occipital regions). We examined sex and menopause status-related differences in each region-of-interest, using linear regressions, as well as interactions with Aβ and APOEε4 genotype. Results: Women exhibited higher tau-PET signal (p < 0.002), and global Aβ-PET (p = 0.010), than men in inferior parietal, rostral middle frontal, and lateral occipital regions. Compared with age-matched men, post-menopausal women showed significantly higher tau-PET signal in parieto-occipital regions (p < 0.0001). By contrast, no differences in tau-PET signal existed between pre-menopausal women and men. Aβ-PET was not associated with menopausal status or age. Neither Aβ-PET nor APOEε4 status moderated sex or menopause associations with tau-PET. Interpretation: Clear divergence in tauopathy between the sexes are apparent approximately 20 years earlier than previously reported. Menopause status moderated sex differences in Aβ and tau-PET burden, with tau first appearing post-menopause. Sex and menopause differences consistently appeared in middle frontal and parieto-occipital regions but were not moderated by Aβ burden or APOEε4, suggesting that menopause-related tau vulnerability may be independent of AD-related pathways.

The duration and lifetime pattern of hypertension is related to risk of stroke and dementia. In turn, cerebral small vessel disease (CSVD) is the most frequent form of cerebrovascular disease underlying dementia and stroke. Thus, study of the relation of mid to late life hypertension trends with CSVD late in life will help understand hypertension’s role and inform preventive efforts of CSVD consequences. We studied 1686 Framingham Heart Study Offspring cohort participants free of stroke and dementia, who were examined in mid and late life, and had available brain magnetic resonance imaging during late life. We related hypertension trends between mid and late life (normotension–normotension N-N, normotension-hypertension N-H, hypertension-hypertension H-H) to cerebral microbleeds and covert brain infarcts (CBI), overall and stratified by brain topography. We used multivariable logistic regression analyses to calculate odds ratio and 95% CIs for CSVD measures. The prevalence of CSVD in late life was 8% for cerebral microbleeds and 13% for covert brain infarcts and increased with longer hypertension exposure across all brain regions. Compared with the trend pattern of N-N, both N-H and H-H trends had higher odds of mixed cerebral microbleeds (2.71 [1.08–6.80], and 3.44 [1.39–8.60], respectively); H-H also had higher odds of any cerebral microbleeds or covert brain infarcts (1.54 [1.12–2.20]), and any covert brain infarcts (1.55 [1.08–2.20]). The burden of CSVD also increased with longer hypertension exposure. Our results highlight hypertension having a major role in subclinical CSVD, across subtypes and brain regions, and call attention to improve recognition and treatment of hypertension early in life.

IMPORTANCE Cognitive resilience refers to the general capacity of cognitive processes to be less susceptible to differences in brain structure from age-and disease-related changes. Studies suggest that supportive social networks reduce Alzheimer disease and related disorder (ADRD) risk by enhancing cognitive resilience, but data on specific social support mechanisms are sparse. OBJECTIVE To examine the association of individual forms of social support with a global neuroanatomical measure of early ADRD vulnerability and cognition. DESIGN, SETTING, AND PARTICIPANTS This retrospective cross-sectional analysis used prospectively collected data from Framingham Study participants without dementia, stroke, or other neurological conditions who underwent brain magnetic resonance imaging and neuropsychological testing at the same visit. Data from this large, population-based, longitudinal cohort were collected

Normal cardiac function is directly associated with the maintenance of cerebrovascular health. Whether the Mediterranean-Dietary Approach to Systolic Hypertension Intervention for Neurodegenerative Delay (MIND) diet, designed for the maintenance of neurocognitive health, is associated with cardiac remodeling is unknown. We evaluated 2512 Framingham Offspring Cohort participants who attended the 8th examination cycle and had available dietary and echocardiographic data (mean age 66 years; 55% women). Using multivariable regression, we related the cumulative MIND diet score (independent variable) to left ventricular (LV) ejection fraction, left atrial emptying fraction, LV mass (LVM), E/e’ ratio (dependent variables; primary), global longitudinal strain, global circumferential strain (GCS), mitral annular plane systolic excursion, longitudinal segmental synchrony, LV hypertrophy, and aortic root diameter (secondary). Adjusting for age, sex, and energy intake, higher cumulative MIND diet scores were associated with lower values of indices of LV diastolic (E/e’ ratio: logβ=-0.03) and systolic function (GCS: β=-0.04), and with higher values of LVM (logβ=0.02), all P≤0.01. We observed effect modification by age in the association between the cumulative MIND diet score and GCS. When we further adjusted for clinical risk factors, the associations of the cumulative MIND diet score with GCS in participants ≥66 years (β=-0.06, P=0.005) and LVM remained significant. In our community-based sample, relations between the cumulative MIND diet score and cardiac remodeling differ among indices of LV structure and function. Our results suggest that favorable associations between a higher cumulative MIND diet score and indices of LV function may be influenced by cardiometabolic and lifestyle risk factors.