AmyloidPETNet: Classification of Amyloid Positivity in Brain PET Imaging Using End-to-End Deep Learning.

Background Visual assessment of amyloid PET scans relies on the availability of radiologist expertise, whereas quantification of amyloid burden typically involves MRI for processing and analysis, which can be computationally expensive. Purpose To develop a deep learning model to classify minimally processed brain PET scans as amyloid positive or negative, evaluate its performance on independent data sets and different tracers, and compare it with human visual reads. Materials and Methods This retrospective study used 8476 PET scans (6722 patients) obtained from late 2004 to early 2023 that were analyzed across five different data sets. A deep learning model, AmyloidPETNet, was trained on 1538 scans from 766 patients, validated on 205 scans from 95 patients, and internally tested on 184 scans from 95 patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) fluorine 18 (18F) florbetapir (FBP) data set. It was tested on ADNI scans using different tracers and scans from independent data sets. Scan amyloid positivity was based on mean cortical standardized uptake value ratio cutoffs. To compare with model performance, each scan from both the Centiloid Project and a subset of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study were visually interpreted with a confidence level (low, intermediate, high) of amyloid positivity/negativity. The area under the receiver operating characteristic curve (AUC) and other performance metrics were calculated, and Cohen κ was used to measure physician-model agreement. Results The model achieved an AUC of 0.97 (95% CI: 0.95, 0.99) on test ADNI 18F-FBP scans, which generalized well to 18F-FBP scans from the Open Access Series of Imaging Studies (AUC, 0.95; 95% CI: 0.93, 0.97) and the A4 study (AUC, 0.98; 95% CI: 0.98, 0.98). Model performance was high when applied to data sets with different tracers (AUC ≥ 0.97). Other performance metrics provided converging evidence. Physician-model agreement ranged from fair (Cohen κ = 0.39; 95% CI: 0.16, 0.60) on a sample of mostly equivocal cases from the A4 study to almost perfect (Cohen κ = 0.93; 95% CI: 0.86, 1.0) on the Centiloid Project. Conclusion The developed model was capable of automatically and accurately classifying brain PET scans as amyloid positive or negative without relying on experienced readers or requiring structural MRI. Clinical trial registration no. NCT00106899 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Bryan and Forghani in this issue.

Functional outcomes of diets in multiple sclerosis (FOOD for MS): Protocol for a parallel arm randomized feeding trial for low glycemic load and calorie restriction.

BACKGROUND: Pilot trials indicate that both a low glycemic load (GL) diet and calorie restriction (CR) can be implemented successfully in people with multiple sclerosis (pMS) and may improve MS symptoms and physical function, but large randomized clinical trials (RCTs) have not yet been conducted. The purpose of this study is to test these interventions alone and in combination to determine their efficacy for improving clinical and patient reported outcomes (PROs) in pMS. METHODS: This 32-week, two-arm, RCT at two centers will randomly assign 100 adults with relapsing-remitting or secondary progressive MS to a low GL diet (n = 50) or a standard GL diet (n = 50). Both diet groups will complete two study phases: a eucaloric phase (16 weeks) and a CR phase (16 weeks). Groceries for the study meal plans will be delivered to participants' homes weekly. The primary outcome is physical function, measured by timed 25-ft walk test. Secondary outcomes are pain, fatigue, mood, and anxiety. DISCUSSION: This will be the most rigorous intervention trial to date of a low GL diet and CR in adults with MS, and among the first to assess the impact of intentional weight loss on MS symptoms. Results will provide valuable insight for recommending dietary change, weight loss, or both to adults with MS. These non-drug interventions pose few risks and have potential to yield significant improvements in MS symptoms. TRIAL REGISTRATION ID: NCT05327322.

Exercise-Related Physical Activity Relates to Brain Volumes in 10,125 Individuals.

BACKGROUND: The potential neuroprotective effects of regular physical activity on brain structure are unclear, despite links between activity and reduced dementia risk. OBJECTIVE: To investigate the relationships between regular moderate to vigorous physical activity and quantified brain volumes on magnetic resonance neuroimaging. METHODS: A total of 10,125 healthy participants underwent whole-body MRI scans, with brain sequences including isotropic MP-RAGE. Three deep learning models analyzed axial, sagittal, and coronal views from the scans. Moderate to vigorous physical activity, defined by activities increasing respiration and pulse rate for at least 10 continuous minutes, was modeled with brain volumes via partial correlations. Analyses adjusted for age, sex, and total intracranial volume, and a 5% Benjamini-Hochberg False Discovery Rate addressed multiple comparisons. RESULTS: Participant average age was 52.98±13.04 years (range 18-97) and 52.3% were biologically male. Of these, 7,606 (75.1%) reported engaging in moderate or vigorous physical activity approximately 4.05±3.43 days per week. Those with vigorous activity were slightly younger (p < 0.00001), and fewer women compared to men engaged in such activities (p = 3.76e-15). Adjusting for age, sex, body mass index, and multiple comparisons, increased days of moderate to vigorous activity correlated with larger normalized brain volumes in multiple regions including: total gray matter (Partial R = 0.05, p = 1.22e-7), white matter (Partial R = 0.06, p = 9.34e-11), hippocampus (Partial R = 0.05, p = 5.96e-7), and frontal, parietal, and occipital lobes (Partial R = 0.04, p≤1.06e-5). CONCLUSIONS: Exercise-related physical activity is associated with increased brain volumes, indicating potential neuroprotective effects.

Longitudinal White and Gray Matter Response to Precision Medicine-Guided Intervention for Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a debilitating condition that is widely known to adversely affect gray matter (GM) and white matter (WM) tracts within the brain. Recently, precision medicine has shown promise in alleviating the clinical and gross morphological trajectories of patients with AD. However, regional morphological changes have not yet been adequately characterized. OBJECTIVE: Investigate regional morphological responses to a precision medicine-guided intervention with regards to white and gray matter in AD and mild cognitive impairment (MCI). METHODS: Clinical and neuroimaging data were compiled over a 9-month period from 25 individuals who were diagnosed with AD or MCI receiving individualized treatment plans. Structural T1-weighted MRI scans underwent segmentation and volumetric quantifications via Neuroreader. Longitudinal changes were calculated via annualized percent change of WM or GM ratios. RESULTS: Montreal Cognitive Assessment scores (p < 0.001) and various domains of the Computerized Neurocognitive Screening Vital Signs significantly improved from baseline to 9-month follow-up. There was regional variability in WM and GM atrophy or hypertrophy, but none of these observed changes were statistically significant after correction for multiple comparisons.

Paving the Way for Alzheimer's Disease Prevention: A Systematic Review of Global Open-Access Neuroimaging Datasets in Healthy Individuals.

BACKGROUND: Given the advent of large-scale neuroimaging data-driven endeavors for Alzheimer's disease, there is a burgeoning need for well-characterized neuroimaging databases of healthy individuals. With the rise of initiatives around the globe for the rapid and unrestricted sharing of data resources, there is now an abundance of open-source neuroimaging datasets available to the research community. However, there is not yet a systematic review that fully details the demographic information and modalities actually available in all open access neuroimaging databases around the globe. OBJECTIVE: This systematic review aims to provide compile a list of MR structural imaging databases encompassing healthy individuals across the lifespan. METHODS: In this systematic review, we searched EMBASE and PubMed until May 2022 for open-access neuroimaging databases containing healthy control participants of any age, race, with normal development and cognition having at least one structural T1-weighted neuroimaging scan. RESULTS: A total of 403 databases were included, for up to total of 48,268 participants with all available demographic information and imaging modalities detailed in Supplementary Table 1. There were significant trends noted when compiling normative databases for this systematic review, notably that 11.7% of databases included reported ethnicity in their participants, with underrepresentation of many socioeconomic groups globally. CONCLUSIONS: As efforts to improve primary prevention of AD may require a broader perspective including increased relevance of earlier stages in life, and strategies in addressing modifiable risk factors may be individualized to specific demographics, improving data characterization to be richer and more rigorous will greatly enhance these efforts.

T1 and FLAIR signal intensities are related to tau pathology in dominantly inherited Alzheimer disease.

Carriers of mutations responsible for dominantly inherited Alzheimer disease provide a unique opportunity to study potential imaging biomarkers. Biomarkers based on routinely acquired clinical MR images, could supplement the extant invasive or logistically challenging) biomarker studies. We used 1104 longitudinal MR, 324 amyloid beta, and 87 tau positron emission tomography imaging sessions from 525 participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study to extract novel imaging metrics representing the mean (µ) and standard deviation (σ) of standardized image intensities of T1-weighted and Fluid attenuated inversion recovery (FLAIR) MR scans. There was an exponential decrease in FLAIR-µ in mutation carriers and an increase in FLAIR and T1 signal heterogeneity (T1-σ and FLAIR-σ) as participants approached the symptom onset in both supramarginal, the right postcentral and right superior temporal gyri as well as both caudate nuclei, putamina, thalami, and amygdalae. After controlling for the effect of regional atrophy, FLAIR-µ decreased and T1-σ and FLAIR-σ increased with increasing amyloid beta and tau deposition in numerous cortical regions. In symptomatic mutation carriers and independent of the effect of regional atrophy, tau pathology demonstrated a stronger relationship with image intensity metrics, compared with amyloid pathology. We propose novel MR imaging intensity-based metrics using standard clinical T1 and FLAIR images which strongly associates with the progression of pathology in dominantly inherited Alzheimer disease. We suggest that tau pathology may be a key driver of the observed changes in this cohort of patients.

Snoring and risk of dementia: a prospective cohort and Mendelian randomization study.

Background: The association between snoring, a very common condition that increases with age, and dementia risk is controversial. Snoring is linked to obstructive sleep apnoea and cardiometabolic conditions, both of which are associated with an increased risk of dementia. However, snoring also increases with body mass index (BMI), which in late life is linked to lower dementia risk, possibly due to metabolic changes during prodromal dementia. Methods: The prospective cohort study used data from 450,027 UK Biobank participants with snoring measured at baseline (2006 - 2010), and followed up for dementia diagnosis (censored at 2022). Two-sample Mendelian randomization (MR) analysis used summary statistics for genome-wide association studies of Alzheimer's disease (AD) (n = 94,437; cases = 35,274) and snoring (n = 408,317; snorers = 151,011). Results: During a median follow-up of 13.5 years, 7,937 individuals developed dementia. Snoring was associated with an 8% lower risk of all-cause dementia (hazard ratio [HR] 0.92; 95% confidence interval [CI] 0.88 to 0.97) and AD (HR 0.92; 95% CI 0.86 to 0.99). The association was stronger in older individuals, APOE ε4 allele carriers, and during shorter follow-up periods. MR analyses suggested no causal effect of snoring on AD, however, genetic liability to AD was associated with a lower risk of snoring. Multivariable MR indicated that the effect of AD on snoring was primarily driven by BMI. Conclusions: The phenotypic association between snoring and lower dementia risk likely stems from reverse causation, with genetic predisposition to AD associated with reduced snoring. This may be driven by weight loss in prodromal AD.

Visceral and Subcutaneous Abdominal Fat Predict Brain Volume Loss at Midlife in 10,001 Individuals.

Abdominal fat is increasingly linked to brain health. A total of 10,001 healthy participants were scanned on 1.5T MRI with a short whole-body MR imaging protocol. Deep learning with FastSurfer segmented 96 brain regions. Separate models segmented visceral and subcutaneous abdominal fat. Regression analyses of abdominal fat types and normalized brain volumes were evaluated, controlling for age and sex. Logistic regression models determined the risk of brain total gray and white matter volume loss from the highest quartile of visceral fat and lowest quartile of these brain volumes. This cohort had an average age of 52.9 ± 13.1 years with 52.8% men and 47.2% women. Segmented visceral abdominal fat predicted lower volumes in multiple regions including: total gray matter volume (r = -.44, p<.001), total white matter volume (r =-.41, p<.001), hippocampus (r = -.39, p< .001), frontal cortex (r = -.42, p<.001), temporal lobes (r = -.44, p<.001), parietal lobes (r = -.39, p<.001), occipital lobes (r =-.37, p<.001). Women showed lower brain volumes than men related to increased visceral fat. Visceral fat predicted increased risk for lower total gray matter (age 20-39: OR = 5.9; age 40-59, OR = 5.4; 60-80, OR = 5.1) and low white matter volume: (age 20-39: OR = 3.78; age 40-59, OR = 4.4; 60-80, OR = 5.1). Higher subcutaneous fat is related to brain volume loss. Elevated visceral and subcutaneous fat predicted lower brain volumes and may represent novel modifiable factors in determining brain health.

Impact of Eating a Carbohydrate-Restricted Diet on Cortical Atrophy in a Cross-Section of Amyloid Positive Patients with Alzheimer's Disease: A Small Sample Study.

BACKGROUND: A carbohydrate-restricted diet aimed at lowering insulin levels has the potential to slow Alzheimer's disease (AD). Restricting carbohydrate consumption reduces insulin resistance, which could improve glucose uptake and neural health. A hallmark feature of AD is widespread cortical thinning; however, no study has demonstrated that lower net carbohydrate (nCHO) intake is linked to attenuated cortical atrophy in patients with AD and confirmed amyloidosis. OBJECTIVE: We tested the hypothesis that individuals with AD and confirmed amyloid burden eating a carbohydrate-restricted diet have thicker cortex than those eating a moderate-to-high carbohydrate diet. METHODS: A total of 31 patients (mean age 71.4±7.0 years) with AD and confirmed amyloid burden were divided into two groups based on a 130 g/day nCHO cutoff. Cortical thickness was estimated from T1-weighted MRI using FreeSurfer. Cortical surface analyses were corrected for multiple comparisons using cluster-wise probability. We assessed group differences using a two-tailed two-independent sample t-test. Linear regression analyses using nCHO as a continuous variable, accounting for confounders, were also conducted. RESULTS: The lower nCHO group had significantly thicker cortex within somatomotor and visual networks. Linear regression analysis revealed that lower nCHO intake levels had a significant association with cortical thickness within the frontoparietal, cingulo-opercular, and visual networks. CONCLUSIONS: Restricting carbohydrates may be associated with reduced atrophy in patients with AD. Lowering nCHO to under 130 g/day would allow patients to follow the well-validated MIND diet while benefiting from lower insulin levels.

Alzheimer Disease Pathology and Neurodegeneration in Midlife Obesity: A Pilot Study.

Obesity and excess adiposity at midlife are risk factors for Alzheimer disease (AD). Visceral fat is known to be associated with insulin resistance and a pro-inflammatory state, the two mechanisms involved in AD pathology. We assessed the association of obesity, MRI-determined abdominal adipose tissue volumes, and insulin resistance with PET-determined amyloid and tau uptake in default mode network areas, and MRI-determined brain volume and cortical thickness in AD cortical signature in the cognitively normal midlife population. Thirty-two middle-aged (age: 51.27±6.12 years, 15 males, body mass index (BMI): 32.28±6.39 kg/m2) cognitively normal participants, underwent bloodwork, brain and abdominal MRI, and amyloid and tau PET scan. Visceral and subcutaneous adipose tissue (VAT, SAT) were semi-automatically segmented using VOXel Analysis Suite (Voxa). FreeSurfer was used to automatically segment brain regions using a probabilistic atlas. PET scans were acquired using [11C]PiB and AV-1451 tracers and were analyzed using PET unified pipeline. The association of brain volumes, cortical thicknesses, and PiB and AV-1451 standardized uptake value ratios (SUVRs) with BMI, VAT/SAT ratio, and insulin resistance were assessed using Spearman's partial correlation. VAT/SAT ratio was associated significantly with PiB SUVRs in the right precuneus cortex (p=0.034) overall, controlling for sex. This association was significant only in males (p=0.044), not females (p=0.166). Higher VAT/SAT ratio and PiB SUVRs in the right precuneus cortex were associated with lower cortical thickness in AD-signature areas predominantly including bilateral temporal cortices, parahippocampal, medial orbitofrontal, and cingulate cortices, with age and sex as covariates. Also, higher BMI and insulin resistance were associated with lower cortical thickness in bilateral temporal poles. In midlife cognitively normal adults, we demonstrated higher amyloid pathology in the right precuneus cortex in individuals with a higher VAT/SAT ratio, a marker of visceral obesity, along with a lower cortical thickness in AD-signature areas associated with higher visceral obesity, insulin resistance, and amyloid pathology.

Benefits of a 12-Week Non-Drug "Brain Fitness Program" for Patients with Attention-Deficit/Hyperactive Disorder, Post-Concussion Syndrome, or Memory Loss.

Background: Non-pharmacologic interventions can potentially improve cognitive function, sleep, and/or mood in patients with attention-deficit/hyperactive disorder (ADHD), post-concussion syndrome (PCS), or memory loss. Objective: We evaluated the benefits of a brain rehabilitation program in an outpatient neurology practice that consists of targeted cognitive training, lifestyle coaching, and electroencephalography (EEG)-based neurofeedback, twice weekly (90 minutes each), for 12 weeks. Methods: 223 child and adult patients were included: 71 patients with ADHD, 88 with PCS, and 64 with memory loss (mild cognitive impairment or subjective cognitive decline). Patients underwent a complete neurocognitive evaluation, including tests for Verbal Memory, Complex Attention, Processing Speed, Executive Functioning, and Neurocognition Index. They completed questionnaires about sleep, mood, diet, exercise, anxiety levels, and depression-as well as underwent quantitative EEG-at the beginning and the end of the program. Results: Pre-post test score comparison demonstrated that all patient subgroups experienced statistically significant improvements on most measures, especially the PCS subgroup, which experienced significant score improvement on all measures tested (p≤0.0011; dz≥0.36). After completing the program, 60% to 90% of patients scored higher on cognitive tests and reported having fewer cognitive and emotional symptoms. The largest effect size for pre-post score change was improved executive functioning in all subgroups (ADHD dz= 0.86; PCS dz= 0.83; memory dz= 1.09). Conclusion: This study demonstrates that a multimodal brain rehabilitation program can have benefits for patients with ADHD, PCS, or memory loss and supports further clinical trials in this field.

Preliminary validation of a structural magnetic resonance imaging metric for tracking dementia-related neurodegeneration and future decline.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and atrophy in the medial temporal lobe (MTL) and subsequent brain regions. Structural magnetic resonance imaging (sMRI) has been widely used in research and clinical care for diagnosis and monitoring AD progression. However, atrophy patterns are complex and vary by patient. To address this issue, researchers have made efforts to develop more concise metrics that can summarize AD-specific atrophy. Many of these methods can be difficult to interpret clinically, hampering adoption. In this study, we introduce a novel index which we call an "AD-NeuroScore," that uses a modified Euclidean-inspired distance function to calculate differences between regional brain volumes associated with cognitive decline. The index is adjusted for intracranial volume (ICV), age, sex, and scanner model. We validated AD-NeuroScore using 929 older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, with a mean age of 72.7 years (SD = 6.3; 55.1-91.5) and cognitively normal (CN), mild cognitive impairment (MCI), or AD diagnoses. Our validation results showed that AD-NeuroScore was significantly associated with diagnosis and disease severity scores (measured by MMSE, CDR-SB, and ADAS-11) at baseline. Furthermore, baseline AD-NeuroScore was associated with both changes in diagnosis and disease severity scores at all time points with available data. The performance of AD-NeuroScore was equivalent or superior to adjusted hippocampal volume (AHV), a widely used metric in AD research. Further, AD-NeuroScore typically performed as well as or sometimes better when compared to other existing sMRI-based metrics. In conclusion, we have introduced a new metric, AD-NeuroScore, which shows promising results in detecting AD, benchmarking disease severity, and predicting disease progression. AD-NeuroScore differentiates itself from other metrics by being clinically practical and interpretable.

Neuroinflammation: A Modifiable Pathway Linking Obesity, Alzheimer's disease, and Depression.

Obesity, depression and Alzheimer's disease (AD) are three major interrelated modern health conditions with complex relationships. Early-life depression may serve as a risk factor for AD, while late-life depression may be a prodrome of AD. Depression affects approximately 23% of obese individuals, and depression itself raises the risk of obesity by 37%. Mid-life obesity independently increases AD risk, while late-life obesity, particularly metabolically healthy obesity, may offer protection against AD pathology. Chronic inflammation serves as a key mechanism linking obesity, AD, and depression, encompassing systemic inflammation from metabolic disturbances, immune dysregulation through the gut microbiome, and direct interactions with amyloid pathology and neuroinflammation. In this review, we explore the biological mechanisms of neuroinflammation in relation to obesity, AD, and depression. We assess the efficacy of therapeutic interventions targeting neuroinflammation and discuss current and future radiological imaging initiatives for studying neuroinflammation. By comprehending the intricate interplay among depression, obesity, and AD, especially the role of neuroinflammation, we can advance our understanding and develop innovative strategies for prevention and treatment.

Longitudinal Patterns of Brain Changes in a Community Sample in Relation to Aging and Cognitive Status.

BACKGROUND: Aging and Alzheimer's disease (AD) are characterized by widespread cortical and subcortical atrophy. Though atrophy patterns between aging and AD overlap considerably, regional differences between these two conditions may exist. Few studies, however, have investigated these patterns in large community samples. OBJECTIVE: Elaborate longitudinal changes in brain morphometry in relation to aging and cognitive status in a well-characterized community cohort. METHODS: Clinical and neuroimaging data were compiled from 72 participants from the Cardiovascular Health Study-Cognition Study, a community cohort of healthy aging and probable AD participants. Two time points were identified for each participant with a mean follow-up time of 5.36 years. MRI post-processing, morphometric measurements, and statistical analyses were performed using FreeSurfer, Version 7.1.1. RESULTS: Cortical volume was significantly decreased in the bilateral superior frontal, bilateral inferior parietal, and left superior parietal regions, among others. Cortical thickness was significantly reduced in the bilateral superior frontal and left inferior parietal regions, among others. Overall gray and white matter volumes and hippocampal subfields also demonstrated significant reductions. Cortical volume atrophy trajectories between cognitively stable and cognitively declined participants were significantly different in the right postcentral region. CONCLUSION: Observed volume reductions were consistent with previous studies investigating morphometric brain changes. Patterns of brain atrophy between AD and aging may be different in magnitude but exhibit widespread spatial overlap. These findings help characterize patterns of brain atrophy that may reflect the general population. Larger studies may more definitively establish population norms of aging and AD-related neuroimaging changes.

Childhood obesity is linked to putative neuroinflammation in brain white matter, hypothalamus, and striatum.

Neuroinflammation is both a consequence and driver of overfeeding and weight gain in rodent obesity models. Advances in magnetic resonance imaging (MRI) enable investigations of brain microstructure that suggests neuroinflammation in human obesity. To assess the convergent validity across MRI techniques and extend previous findings, we used diffusion basis spectrum imaging (DBSI) to characterize obesity-associated alterations in brain microstructure in 601 children (age 9-11 years) from the Adolescent Brain Cognitive DevelopmentSM Study. Compared with children with normal-weight, greater DBSI restricted fraction (RF), reflecting neuroinflammation-related cellularity, was seen in widespread white matter in children with overweight and obesity. Greater DBSI-RF in hypothalamus, caudate nucleus, putamen, and, in particular, nucleus accumbens, correlated with higher baseline body mass index and related anthropometrics. Comparable findings were seen in the striatum with a previously reported restriction spectrum imaging (RSI) model. Gain in waist circumference over 1 and 2 years related, at nominal significance, to greater baseline RSI-assessed restricted diffusion in nucleus accumbens and caudate nucleus, and DBSI-RF in hypothalamus, respectively. Here we demonstrate that childhood obesity is associated with microstructural alterations in white matter, hypothalamus, and striatum. Our results also support the reproducibility, across MRI methods, of findings of obesity-related putative neuroinflammation in children.

Prospective Longitudinal Perfusion in Probable Alzheimer's Disease Correlated with Atrophy in Temporal Lobe.

Reduced cerebral blood flow (CBF) in the temporoparietal region and gray matter volumes (GMVs) in the temporal lobe were previously reported in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, the temporal relationship between reductions in CBF and GMVs requires further investigation. This study sought to determine if reduced CBF is associated with reduced GMVs, or vice versa. Data came from 148 volunteers of the Cardiovascular Health Study Cognition Study (CHS-CS), including 58 normal controls (NC), 50 MCI, and 40 AD who had perfusion and structural MRIs during 2002-2003 (Time 2). Sixty-three of the 148 volunteers had follow-up perfusion and structural MRIs (Time 3). Forty out of the 63 volunteers received prior structural MRIs during 1997-1999 (Time 1). The relationships between GMVs and subsequent CBF changes, and between CBF and subsequent GMV changes were investigated. At Time 2, we observed smaller GMVs (p<0.05) in the temporal pole region in AD compared to NC and MCI. We also found associations between: (1) temporal pole GMVs at Time 2 and subsequent declines in CBF in this region (p=0.0014) and in the temporoparietal region (p=0.0032); (2) hippocampal GMVs at Time 2 and subsequent declines in CBF in the temporoparietal region (p=0.012); and (3) temporal pole CBF at Time 2 and subsequent changes in GMV in this region (p = 0.011). Therefore, hypoperfusion in the temporal pole may be an early event driving its atrophy. Perfusion declines in the temporoparietal and temporal pole follow atrophy in this temporal pole region.

Twelve Weeks of Intermittent Caloric Restriction Diet Mitigates Neuroinflammation in Midlife Individuals with Multiple Sclerosis: A Pilot Study with Implications for Prevention of Alzheimer's Disease.

BACKGROUND: Multiple sclerosis (MS) is a prototype neuroinflammatory disorder with increasingly recognized role for neurodegeneration. Most first-line treatments cannot prevent the progression of neurodegeneration and the resultant disability. Interventions can improve symptoms of MS and might provide insights into the underlying pathology. OBJECTIVE: To investigate the effect of intermittent caloric restriction on neuroimaging markers of MS. METHODS: We randomized ten participants with relapsing remitting MS to either a 12-week intermittent calorie restriction (iCR) diet (n = 5) or control (n = 5). Cortical thickness and volumes were measured through FreeSurfer, cortical perfusion was measured by arterial spin labeling and neuroinflammation through diffusion basis spectrum imaging. RESULTS: After 12 weeks of iCR, brain volume increased in the left superior and inferior parietal gyri (p: 0.050 and 0.049, respectively) and the banks of the superior temporal sulcus (p: 0.01). Similarly in the iCR group, cortical thickness improved in the bilateral medial orbitofrontal gyri (p: 0.04 and 0.05 in right and left, respectively), the left superior temporal gyrus (p: 0.03), and the frontal pole (p: 0.008) among others. Cerebral perfusion decreased in the bilateral fusiform gyri (p: 0.047 and 0.02 in right and left, respectively) and increased in the bilateral deep anterior white matter (p: 0.03 and 0.013 in right and left, respectively). Neuroinflammation, demonstrated through hindered and restricted water fractions (HF and RF), decreased in the left optic tract (HF p: 0.02), and the right extreme capsule (RF p: 0.007 and HF p: 0.003). CONCLUSION: These pilot data suggest therapeutic effects of iCR in improving cortical volume and thickness and mitigating neuroinflammation in midlife adults with MS.

Cortical atrophy and leukoaraiosis, imaging markers of cerebrovascular small vessel disease, are associated with driving behavior changes among cognitively normal older adults.

BACKGROUND: Cerebral small vessel disease (CSVD) as measured by cortical atrophy and white matter hyperintensities [leukoaraiosis], captured via magnetic resonance imaging (MRI) are increasing in prevalence due to the growth of the aging population and an increase in cardiovascular risk factors in the population. CSVD impacts cognitive function and mobility, but it is unclear if it affects complex, functional activities like driving. METHODS: In a cohort of 163 cognitively normal, community-dwelling older adults (age ≥ 65), we compared naturalistic driving behavior with mild/moderate leukoaraiosis, cortical atrophy, or their combined rating in a clinical composite termed, aging-related changes to those without any, over a two-and-a-half-year period. RESULTS: Older drivers with mild or moderate cortical atrophy and aging-related changes (composite) experienced a greater decrease in the number of monthly trips which was due to a decrease in the number of trips made within a one-to-five-mile diameter from their residence. Older drivers with CSVD experience a larger reduction in daily driving behaviors than drivers without CSVD, which may serve as an early neurobehavioral marker for functional decline. CONCLUSIONS: As CSVD markers, leukoaraiosis and cortical atrophy are standard MRI metrics that are widely available and can be used for screening individuals at higher risk for driving safety risk and decline in community mobility.

Handgrip Strength Is Related to Hippocampal and Lobar Brain Volumes in a Cohort of Cognitively Impaired Older Adults with Confirmed Amyloid Burden.

BACKGROUND: Strength and mobility are essential for activities of daily living. With aging, weaker handgrip strength, mobility, and asymmetry predict poorer cognition. We therefore sought to quantify the relationship between handgrip metrics and volumes quantified on brain magnetic resonance imaging (MRI). OBJECTIVE: To model the relationships between handgrip strength, mobility, and MRI volumetry. METHODS: We selected 38 participants with Alzheimer's disease dementia: biomarker evidence of amyloidosis and impaired cognition. Handgrip strength on dominant and non-dominant hands was measured with a hand dynamometer. Handgrip asymmetry was calculated. Two-minute walk test (2MWT) mobility evaluation was combined with handgrip strength to identify non-frail versus frail persons. Brain MRI volumes were quantified with Neuroreader. Multiple regression adjusting for age, sex, education, handedness, body mass index, and head size modeled handgrip strength, asymmetry and 2MWT with brain volumes. We modeled non-frail versus frail status relationships with brain structures by analysis of covariance. RESULTS: Higher non-dominant handgrip strength was associated with larger volumes in the hippocampus (p = 0.02). Dominant handgrip strength was related to higher frontal lobe volumes (p = 0.02). Higher 2MWT scores were associated with larger hippocampal (p = 0.04), frontal (p = 0.01), temporal (p = 0.03), parietal (p = 0.009), and occipital lobe (p = 0.005) volumes. Frailty was associated with reduced frontal, temporal, and parietal lobe volumes. CONCLUSION: Greater handgrip strength and mobility were related to larger hippocampal and lobar brain volumes. Interventions focused on improving handgrip strength and mobility may seek to include quantified brain volumes on MR imaging as endpoints.