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IntroductionUnderstanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise Alzheimer’s progression assessment strategies.MethodsWe examined the temporal order of changes in plasma amyloid-β ratio (Aβ42/Aβ40), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau ratios (p-tau181/Aβ42, p-tau231/Aβ42) relative to11C-Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB−/+). Participants (n = 199) were cognitively normal at index visit with a median 6.1-year follow-up.ResultsPiB groups exhibited different rates of longitudinal change in Aβ42/Aβ40(β= 5.41 × 10-4, SE = 1.95 × 10-4,p= 0.0073). Change in brain amyloid correlated with change in GFAP (r= 0.5, 95% CI = [0.26, 0.68]). Greatest relative decline in Aβ42/Aβ40(-1%/year) preceded brain amyloid positivity by 41 years (95% CI = [32, 53]).DiscussionPlasma Aβ42/Aβ40may begin declining decades prior to brain amyloid accumulation, whereas p-tau ratios, GFAP, and NfL increase closer in time.

We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer’s dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.

It is estimated that short association fibers running immediately beneath the cortex may make up as much as 60% of the total white matter volume. However, these have been understudied relative to the long-range association, projection, and commissural fibers of the brain. This is largely because of limitations of diffusion MRI fiber tractography, which is the primary methodology used to non-invasively study the white matter connections. Inspired by recent anatomical considerations and methodological improvements in superficial white matter (SWM) tractography, we aim to characterize changes in these fiber systems in cognitively normal aging, which provide insight into the biological foundation of age-related cognitive changes, and a better understanding of how age-related pathology differs from healthy aging. To do this, we used three large, longitudinal and cross-sectional datasets (N = 1293 subjects, 2711 sessions) to quantify microstructural features and length/volume features of several SWM systems. We find that axial, radial, and mean diffusivities show positive associations with age, while fractional anisotropy has negative associations with age in SWM throughout the entire brain. These associations were most pronounced in the frontal, temporal, and temporoparietal regions. Moreover, measures of SWM volume and length decrease with age in a heterogenous manner across the brain, with different rates of change in inter-gyri and intra-gyri SWM, and at slower rates than well-studied long-range white matter pathways. These features, and their variations with age, provide the background for characterizing normal aging, and, in combination with larger association pathways and gray matter microstructural features, may provide insight into fundamental mechanisms associated with aging and cognition.

Background In older persons, neuropsychological function, especially sensorimotor function, is strongly associated with mobility. Hearing impairment is related to poor mobility, and we hypothesize that such relationships would be stronger in persons with compromised sensorimotor function than those with preserved sensorimotor function. Methods We analyzed 601 cognitively normal (Mini-Mental State Examination ≥24 or free of cognitive impairment/dementia) Baltimore Longitudinal Study of Aging participants aged 50 or older with concurrent data on hearing (better ear pure-tone average [PTA]), mobility (6 m usual gait, 400 m endurance walk), and neuropsychological function including attention via Trail Making Test (TMT)-A, executive function via the difference between TMT-A and B, and Digit Symbol Substitution Test, and manual dexterity via Pegboard performance. We examined the association of PTA, each cognitive measure, and their interaction with mobility using multivariable linear regression, adjusted for covariates. Results After covariate adjustment, there were significant interactions between PTA and all cognitive measures in the association with 400 m endurance walking speed as the outcome. There was also a significant interaction between PTA and pegboard nondominant hand performance in the association with 6 m gait as the outcome. In all these cases, the PTA–mobility relationship was stronger among participants with lower cognition. Conclusion Impaired hearing more strongly relates to poor mobility among those with compromised neuropsychological performance, especially manual dexterity reflecting the motor–cognitive interface and sensorimotor function, than those with preserved neuropsychological performance. Future longitudinal studies are needed to test whether hearing impairment more strongly predicts mobility decline over time in older persons with compromised neuropsychological function.

Background In the medical imaging domain, deep learning-based methods have yet to see widespread clinical adoption, in part due to limited generalization performance across different imaging devices and acquisition protocols. The deviation between estimated brain age and biological age is an established biomarker of brain health and such models may benefit from increased cross-site generalizability. Purpose To develop and evaluate a deep learning-based image harmonization method to improve cross-site generalizability of deep learning age prediction. Study type Retrospective. Population Eight thousand eight hundred and seventy-six subjects from six sites. Harmonization models were trained using all subjects. Age prediction models were trained using 2739 subjects from a single site and tested using the remaining 6137 subjects from various other sites. Field strength/sequence Brain imaging with magnetization prepared rapid acquisition with gradient echo or spoiled gradient echo sequences at 1.5 T and 3 T. Assessment StarGAN v2, was used to perform a canonical mapping from diverse datasets to a reference domain to reduce site-based variation while preserving semantic information. Generalization performance of deep learning age prediction was evaluated using harmonized, histogram matched, and unharmonized data. Statistical tests Mean absolute error (MAE) and Pearson correlation between estimated age and biological age quantified the performance of the age prediction model. Results Our results indicated a substantial improvement in age prediction in out-of-sample data, with the overall MAE improving from 15.81 (±0.21) years to 11.86 (±0.11) with histogram matching to 7.21 (±0.22) years with generative adversarial network (GAN)-based harmonization. In the multisite case, across the 5 out-of-sample sites, MAE improved from 9.78 (±6.69) years to 7.74 (±3.03) years with histogram normalization to 5.32 (±4.07) years with GAN-based harmonization. Data conclusion While further research is needed, GAN-based medical image harmonization appears to be a promising tool for improving cross-site deep learning generalization. Level of evidence 4 TECHNICAL EFFICACY: Stage 1.

Significance Epidemiological studies have demonstrated that improved air quality may improve respiratory health and reduce mortality. Increasing data support late-life exposure to air pollution as a modifiable risk factor for dementia, but whether improved ambient air quality translates to lower dementia risk is unclear. In this study on a geographically diverse cohort of US community-dwelling older women, we found that long-term improvement in ambient air quality in late life was associated with reduced dementia risk. The associations did not significantly differ by age, education, geographic region, Apolipoprotein E e4 genotypes, or cardiovascular risk factors. These findings strengthen the causal association between late-life exposure to air pollution and dementia risk., Late-life ambient air pollution is a risk factor for brain aging, but it remains unknown if improved air quality (AQ) lowers dementia risk. We studied a geographically diverse cohort of older women dementia free at baseline in 2008 to 2012 (n = 2,239, aged 74 to 92). Incident dementia was centrally adjudicated annually. Yearly mean concentrations of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) were estimated using regionalized national universal kriging models and averaged over the 3-y period before baseline (recent exposure) and 10 y earlier (remote exposure). Reduction from remote to recent exposures was used as the indicator of improved AQ. Cox proportional hazard ratios (HRs) for dementia risk associated with AQ measures were estimated, adjusting for sociodemographic, lifestyle, and clinical characteristics. We identified 398 dementia cases during follow up (median = 6.1 y). PM2.5 and NO2 reduced significantly over the 10 y before baseline. Larger AQ improvement was associated with reduced dementia risks (HRPM2.5 0.80 per 1.78 μg/m3, 95% CI 0.71–0.91; HRNO2 0.80 per 3.91 parts per billion, 95% CI 0.71–0.90), equivalent to the lower risk observed in women 2.4 y younger at baseline. Higher PM2.5 at baseline was associated with higher dementia risk (HRPM2.5 1.16 per 2.90 μg/m3, 95% CI 0.98–1.38), but the lower dementia risk associated with improved AQ remained after further adjusting for recent exposure. The observed associations did not substantially differ by age, education, geographic region, Apolipoprotein E e4 genotypes, or cardiovascular risk factors. Long-term AQ improvement in late life was associated with lower dementia risk in older women.

The cranial meninges are membranes enveloping the brain. The space between these membranes contains mainly cerebrospinal fluid. It is of interest to study how the volumes of this space change with respect to normal aging. In this work, we propose to combine convolutional neural networks (CNNs) with nested topology-preserving geometric deformable models (NTGDMs) to reconstruct meningeal surfaces from magnetic resonance (MR) images. We first use CNNs to predict implicit representations of these surfaces then refine them with NTGDMs to achieve sub-voxel accuracy while maintaining spherical topology and the correct anatomical ordering. MR contrast harmonization is used to match the contrasts between training and testing images. We applied our algorithm to a subset of healthy subjects from the Baltimore Longitudinal Study of Aging for demonstration purposes and conducted longitudinal statistical analysis of the intracranial volume (ICV) and subarachnoid space (SAS) volume. We found a statistically significant decrease in the ICV and an increase in the SAS volume with respect to normal aging.

Background Higher energetic costs for mobility are associated with declining gait speed, and slow gait is linked to cognitive decline and Alzheimer’s disease. However, the physiological underpinnings of gait and brain health have not been well explored. We examined the associations of the energetic cost of walking with brain volume in cognitively unimpaired adults from the Baltimore Longitudinal Study of Aging. Methods We used brain magnetic resonance imaging (MRI) data from 850 participants (mean baseline age 66.3 ± 14.5 years), of whom 451 had longitudinal MRI data (2.8 ± 1.0 MRI scans over 4.0 ± 2.0 years). The energetic cost of walking was assessed as the average energy expended (V̇O2) during 2.5 minutes of customary-paced overground walking. Multivariable linear mixed-effects models examined the associations between baseline energetic cost of walking and regional brain volumes adjusting for covariates. Results At baseline, higher energetic cost of walking was cross-sectionally associated with lower gray and white matter volumes within the frontal, parietal, and temporal lobes, as well as hippocampal, total brain, and larger ventricular volumes (all false-discovery rate [FDR] p < .05). A baseline energetic cost of walking × time interaction demonstrated that participants with higher energetic cost of walking had faster annual decline in hippocampal volume (FDR p = .02) and accelerated annual increase in ventricular volumes (FDR p = .02). Conclusions The energetic cost of walking is associated with gray and white matter volumes and subsequent hippocampal atrophy and ventricular enlargement. Collectively, these data suggest the energetic cost of walking may be an early marker of neurodegeneration that contributes to the gait brain connection.

BackgroundSeveral studies have demonstrated that age-related hearing loss is associated with cognitive decline. We investigated whether subclinical hearing loss (SCHL) or imperfect hearing traditionally categorized as normal (pure-tone average ≤25 dB) may be similarly linked to cognitive decline and risk of incident mild cognitive impairment (MCI)/dementia.MethodsParticipants from the Baltimore Longitudinal Study of Aging were cognitively normal adults at least 50 years old with cognitive assessments from 1991 to 2019 and pure-tone average ≤25 dB measured between 1991 and 1994 (n = 263). The exposure was hearing based on the better ear pure-tone average. Outcomes were test scores in various cognitive domains. Multivariable linear-mixed effects models were developed to analyze the association between hearing and change in cognition over time, adjusting for age, sex, education, vascular burden, and race. Kaplan–Meier survival curves and Cox proportional hazards models portrayed associations between hearing and incident MCI/dementia diagnosis based on predefined criteria.ResultsOf 263 participants, 145 (55.1%) were female; mean age was 68.3 years (SD = 8.9). Follow-up ranged up to 27.7 years (mean = 11.7 years). Adjusting for multiple comparisons, a 10-dB increase in hearing loss was associated with an annual decline of −0.02 SD (95% confidence interval: −0.03, −0.01) in Letter Fluency. No significant relationships were observed between hearing and incident MCI/dementia.ConclusionsA relationship between SCHL and cognitive decline was observed for the Letter Fluency test. Further studies are necessary to determine where in the spectrum of hearing loss there begins to be an observable relationship between hearing and cognitive decline.

Cognitive aging varies tremendously across individuals and is often accompanied by regionally specific reductions in gray matter (GM) volume, even in the absence of disease. Rhesus monkeys provide a primate model unconfounded by advanced neurodegenerative disease, and the current study used a recognition memory test (delayed non-matching to sample; DNMS) in conjunction with structural imaging and voxel-based morphometry (VBM) to characterize age-related differences in GM volume and brain-behavior relationships. Consistent with expectations from a long history of neuropsychological research, DNMS performance in young animals prominently correlated with the volume of multiple structures in the medial temporal lobe memory system. Less anticipated correlations were also observed in the cingulate and cerebellum. In aged monkeys, significant volumetric correlations with DNMS performance were largely restricted to the prefrontal cortex and striatum. Importantly, interaction effects in an omnibus analysis directly confirmed that the associations between volume and task performance in the MTL and prefrontal cortex are age-dependent. These results demonstrate that the regional distribution of GM volumes coupled with DNMS performance changes across the lifespan, consistent with the perspective that the aged primate brain retains a substantial capacity for structural reorganization.

Background Epigenetic age acceleration (AgeAccel), which indicates faster biological aging relative to chronological age, has been associated with lower cognitive function. However, the association of AgeAccel with mild cognitive impairment (MCI) or dementia is not well-understood. We examined associations of 4 AgeAccel measures with incident MCI and dementia. Methods This prospective analysis included 578 older women from the Women’s Health Initiative Memory Study selected for a case–cohort study of coronary heart disease (CHD). Women were free of CHD and cognitive impairment at baseline. Associations of AgeAccel measures (intrinsic AgeAccel [IEAA], extrinsic AgeAccel [EEAA], AgeAccelPheno, and AgeAccelGrim) with risks for incident adjudicated diagnoses of MCI and dementia overall and stratified by incident CHD status were evaluated. Results IEAA was not significantly associated with MCI (HR, 1.23; 95% CI, 0.99–1.53), dementia (HR, 1.10; 95% CI, 0.88–1.38), or cognitive impairment (HR, 1.18; 95% CI, 0.99–1.40). In stratified analysis by incident CHD status, there was a 39% (HR, 1.39; 95% CI, 1.07–1.81) significantly higher risk of MCI for every 5-year increase in IEAA among women who developed CHD during follow-up. Other AgeAccel measures were not significantly associated with MCI or dementia. Conclusions IEAA was not significantly associated with cognitive impairment overall but was associated with impairment among women who developed CHD. Larger studies designed to examine associations of AgeAccel with cognitive impairment are needed, including exploration of whether associations are stronger in the setting of underlying vascular pathologies.

Background While Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis. Methods and findings We used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = 4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72–1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose–response relationship between BAS use and risk of VaD (p-trend = 0.045) in males. Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings. Conclusions We combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia., Vijay Varma and co-workers study cholesterol and bile acid metabolism in dementia., Author summary Why was this study done? Hypercholesterolemia is associated with increased risk of Alzheimer disease (AD) and vascular dementia (VaD). However, cholesterol is impermeable to the blood–brain barrier (BBB), and it is unclear how peripheral cholesterol mediates risk of dementia. While prior research has examined the relationship between de novo cholesterol biosynthesis and dementia, few studies have assessed the role of cholesterol catabolism and its principal breakdown products, oxysterols, and primary bile acids (BAs) in dementia. What did the researchers do and find? We examined the role of cholesterol catabolism in dementia pathogenesis by first testing the association between serum oxysterols and BAs and neuroimaging markers of dementia. We also tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia in a large, real-world clinical dataset. Finally, we tested plausible mechanisms underlying these associations by examining whether primary BAs and mRNA of their receptors were altered in the brain in dementia. We found that lower serum levels of 7α-hydroxycholesterol (7α-OHC) and primary BAs were associated with higher brain amyloid deposition, faster WML accumulation, and faster brain atrophy mainly in males. Consistent with this finding, we observed a sex difference in the association between use of BAS and risk of VaD. We found that primary BAs were detectable in the brain, and levels of gene expression of BA receptors were altered in AD mainly in males. What do these findings mean? Our findings suggest that cholesterol catabolism and BA synthesis may impact dementia progression through sex-specific effects on signaling pathways in the brain. These results set the stage for experimental studies to test whether BA signaling in the brain may be a novel therapeutic target in dementia.

The hippocampus and underlying cortices are highly susceptible to pathologic change with increasing age. Using an associative face-scene (Face-Place) encoding task designed to target these regions, we investigated activation and connectivity patterns in cognitively normal older adults. Functional MRI scans were collected in 210 older participants (mean age = 76.4 yrs) in the Baltimore Longitudinal Study of Aging (BLSA). Brain activation patterns were examined during encoding of novel Face-Place pairs. Functional connectivity of the hippocampus was also examined during encoding, with seed regions placed along the longitudinal axis in the head, body and tail of the structure. In the temporal lobe, task activation patterns included coverage of the hippocampus and underlying ventral temporal cortices. Extensive activation was also seen in frontal, parietal and occipital lobes of the brain. Functional connectivity analyses during overall encoding showed that the head of the hippocampus was connected to frontal and anterior/middle temporal regions, the body with frontal, widespread temporal and occipital regions, and the tail with posterior temporal and occipital cortical regions. Connectivity limited to encoding of subsequently remembered stimuli showed a similar pattern for the hippocampal body, but differing patterns for the head and tail regions. These results show that the Face-Place task produces activation along the occipitotemporal visual pathway including medial temporal areas. The connectivity results also show that patterns of functional connectivity vary throughout the anterior-posterior extent of the hippocampus during memory encoding. As these patterns include regions vulnerable to pathologic change in early stages of Alzheimer’s disease, continued longitudinal assessment of these individuals can provide valuable information regarding changes in brain-behavior relationships that may occur with advancing age and the onset of cognitive decline.

Objective:To compare the predictive validity of learning and retention measures from the picture version of the Free and Cued Selective Reminding Test with Immediate Recall (pFCSRT + IR) for identifying incident mild cognitive impairment (MCI).Methods:Learning was defined by the sum of free recall (FR) and retention by delayed free recall (DFR) tested 15–20 min later. Totally, 1422 Baltimore Longitudinal Study of Aging (BLSA) participants (mean age 69.6 years, 54% male, mean 16.7 years of education) without dementia or MCI received the pFCSRT + IR at baseline and were followed longitudinally. Cox proportional hazards models were used to evaluate the effect of baseline learning and retention on risk of MCI.Results:In total, 187 participants developed MCI over a median of 8.1 years of follow-up. FR and DFR each predicted incident MCI adjusting for age, sex, and education. Also, each independently predicted incident MCI in the presence of the other with similar effect sizes: around 20% decrease in the hazard of MCI corresponding to one standard deviation increase in FR or DFR.Conclusion:The practice of preferring retention over learning to predict incident MCI should be reconsidered. The decision to include retention should be guided by time constraints and patient burden.

The interrelationships among long-term ambient air pollution exposure, emotional distress and cognitive decline in older adulthood remain unclear. Long-term exposure may impact cognitive performance and subsequently impact emotional health. Conversely, exposure may initially be associated with emotional distress followed by declines in cognitive performance. Here we tested the inter-relationship between global cognitive ability, emotional distress, and exposure to PM2.5 (particulate matter with aerodynamic diameter

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Studies suggest that concussions may be related to increased risk of neurodegenerative diseases, such as Chronic Traumatic Encephalopathy and Alzheimer's Disease. Most neuroimaging studies show effects of concussions in frontal and temporal lobes of the brain, yet the long-term impacts of concussions on the aging brain have not been well studied. We examined neuroimaging data from 51 participants (mean age at first imaging visit=65.1 ± 11.23) in the Baltimore Longitudinal Study of Aging (BLSA) who reported a concussion in their medical history an average of 23 years prior to the first imaging visit, and compared them to 150 participants (mean age at first imaging visit=66.6 ± 10.97) with no history of concussion. Participants underwent serial structural MRI over a mean of 5.17±6.14 years and DTI over a mean of 2.92±2.22 years to measure brain structure, as well as 15O-water PET over a mean of 5.33±2.19 years to measure brain function. A battery of neuropsychological tests was also administered over a mean of 11.62±7.41 years. Analyses of frontal and temporal lobe regions were performed to examine differences in these measures between the concussion and control groups at first imaging visit and in change over time. Compared to those without concussion, participants with a prior concussion had greater brain atrophy in temporal lobe white matter and hippocampus at first imaging visit, which remained stable throughout the follow-up visits. Those with prior concussion also showed differences in white matter microstructure using DTI, including increased radial and axial diffusivity in the fornix/stria terminalis, anterior corona radiata, and superior longitudinal fasciculus at first imaging visit. In 15O-water PET, higher resting cerebral blood flow was seen at first imaging visit in orbitofrontal and lateral temporal regions, and both increases and decreases were seen in prefrontal, cingulate, insular, hippocampal, and ventral temporal regions with longitudinal follow-up. There were no significant differences in neuropsychological performance between groups. Most of the differences observed between the concussed and non-concussed groups were seen at the first imaging visit, suggesting that concussions can produce long-lasting structural and functional alterations in temporal and frontal regions of the brain in older individuals. These results also suggest that many of the reported short-term effects of concussion may still be apparent later in life.

Introduction Relationships between brain atrophy patterns of typical aging and Alzheimer's disease (AD), white matter disease, cognition, and AD neuropathology were investigated via machine learning in a large harmonized magnetic resonance imaging database (11 studies; 10,216 subjects). Methods Three brain signatures were calculated: Brain-age, AD-like neurodegeneration, and white matter hyperintensities (WMHs). Brain Charts measured and displayed the relationships of these signatures to cognition and molecular biomarkers of AD. Results WMHs were associated with advanced brain aging, AD-like atrophy, poorer cognition, and AD neuropathology in mild cognitive impairment (MCI)/AD and cognitively normal (CN) subjects. High WMH volume was associated with brain aging and cognitive decline occurring in an ≈10-year period in CN subjects. WMHs were associated with doubling the likelihood of amyloid beta (Aβ) positivity after age 65. Brain aging, AD-like atrophy, and WMHs were better predictors of cognition than chronological age in MCI/AD. Discussion A Brain Chart quantifying brain-aging trajectories was established, enabling the systematic evaluation of individuals' brain-aging patterns relative to this large consortium.

While it is well known that the vestibular system is responsible for maintaining balance, posture and coordination, there is increasing evidence that it also plays an important role in cognition. Moreover, a growing number of epidemiological studies are demonstrating a link between vestibular dysfunction and cognitive deficits in older adults; however, the exact pathways through which vestibular loss may affect cognition are unknown. In this cross-sectional study, we sought to identify relationships between vestibular function and variation in morphometry in brain structures from structural neuroimaging. We used a subset of 80 participants from the Baltimore Longitudinal Study of Aging, who had both brain MRI and vestibular physiological data acquired during the same visit. Vestibular function was evaluated through the cervical vestibular-evoked myogenic potential (cVEMP). The brain structures of interest that we analyzed were the hippocampus, amygdala, thalamus, caudate nucleus, putamen, insula, entorhinal cortex (ERC), trans-entorhinal cortex (TEC) and perirhinal cortex, as these structures comprise or are connected with the putative “vestibular cortex.” We modeled the volume and shape of these structures as a function of the presence/absence of cVEMP and the cVEMP amplitude, adjusting for age and sex. We observed reduced overall volumes of the hippocampus and the ERC associated with poorer vestibular function. In addition, we also found significant relationships between the shape of the hippocampus (p = 0.0008), amygdala (p = 0.01), thalamus (p = 0.008), caudate nucleus (p = 0.002), putamen (p = 0.02), and ERC-TEC complex (p = 0.008) and vestibular function. These findings provide novel insight into the multiple pathways through which vestibular loss may impact brain structures that are critically involved in spatial memory, navigation and orientation., Vestibular, MRI, volume, Shape, Diffeomorphometry, Cognition, Aging, Epidemiology, Eye-Ear-Nose-Throat, Medical Imaging

Deep learning has emerged as a powerful approach to constructing imaging signatures of normal brain ageing as well as of various neuropathological processes associated with brain diseases. In particular, MRI-derived brain age has been used as a comprehensive biomarker of brain health that can identify both advanced and resilient ageing individuals via deviations from typical brain ageing. Imaging signatures of various brain diseases, including schizophrenia and Alzheimer’s disease, have also been identified using machine learning. Prior efforts to derive these indices have been hampered by the need for sophisticated and not easily reproducible processing steps, by insufficiently powered or diversified samples from which typical brain ageing trajectories were derived, and by limited reproducibility across populations and MRI scanners. Herein, we develop and test a sophisticated deep brain network (DeepBrainNet) using a large (n = 11 729) set of MRI scans from a highly diversified cohort spanning different studies, scanners, ages and geographic locations around the world. Tests using both cross-validation and a separate replication cohort of 2739 individuals indicate that DeepBrainNet obtains robust brain-age estimates from these diverse datasets without the need for specialized image data preparation and processing. Furthermore, we show evidence that moderately fit brain ageing models may provide brain age estimates that are most discriminant of individuals with pathologies. This is not unexpected as tightly-fitting brain age models naturally produce brain-age estimates that offer little information beyond age, and loosely fitting models may contain a lot of noise. Our results offer some experimental evidence against commonly pursued tightly-fitting models. We show that the moderately fitting brain age models obtain significantly higher differentiation compared to tightly-fitting models in two of the four disease groups tested. Critically, we demonstrate that leveraging DeepBrainNet, along with transfer learning, allows us to construct more accurate classifiers of several brain diseases, compared to directly training classifiers on patient versus healthy control datasets or using common imaging databases such as ImageNet. We, therefore, derive a domain-specific deep network likely to reduce the need for application-specific adaptation and tuning of generic deep learning networks. We made the DeepBrainNet model freely available to the community for MRI-based evaluation of brain health in the general population and over the lifespan.

IMPORTANCE: Genetic studies of Alzheimer disease have focused on the clinical or pathologic diagnosis as the primary outcome, but little is known about the genetic basis of the preclinical phase of the disease. OBJECTIVE: To examine the underlying genetic basis for brain amyloidosis in the preclinical phase of Alzheimer disease. DESIGN, SETTING, AND PARTICIPANTS: In the first stage of this genetic association study, a meta-analysis was conducted using genetic and imaging data acquired from 6 multicenter cohort studies of healthy older individuals between 1994 and 2019: the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study, the Berkeley Aging Cohort Study, the Wisconsin Registry for Alzheimer’s Prevention, the Biomarkers of Cognitive Decline Among Normal Individuals cohort, the Baltimore Longitudinal Study of Aging, and the Alzheimer Disease Neuroimaging Initiative, which included Alzheimer disease and mild cognitive impairment. The second stage was designed to validate genetic observations using pathologic and clinical data from the Religious Orders Study and Rush Memory and Aging Project. Participants older than 50 years with amyloid positron emission tomographic (PET) imaging data and DNA from the 6 cohorts were included. The largest cohort, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (n = 3154), was the PET screening cohort used for a secondary prevention trial designed to slow cognitive decline associated with brain amyloidosis. Six smaller, longitudinal cohort studies (n = 1160) provided additional amyloid PET imaging data with existing genetic data. The present study was conducted from March 29, 2019, to February 19, 2020. MAIN OUTCOMES AND MEASURES: A genome-wide association study of PET imaging amyloid levels. RESULTS: From the 4314 analyzed participants (age, 52-96 years; 2478 participants [57%] were women), a novel locus for amyloidosis was noted within RBFOX1 (β = 0.61, P = 3 × 10(−9)) in addition to APOE. The RBFOX1 protein localized around plaques, and reduced expression of RBFOX1 was correlated with higher amyloid-β burden (β = −0.008, P = .002) and worse cognition (β = 0.007, P = .006) during life in the Religious Orders Study and Rush Memory and Aging Project cohort. CONCLUSIONS AND RELEVANCE: RBFOX1 encodes a neuronal RNA-binding protein known to be expressed in neuronal tissues and may play a role in neuronal development. The findings of this study suggest that RBFOX1 is a novel locus that may be involved in the pathogenesis of Alzheimer disease.

Background: Alzheimer’s disease (AD) is now understood to have a long preclinical phase in which pathology starts to accumulate in the absence of clinical symptoms. Identifying the temporal stages of accelerated cognitive decline in this phase may help in developing more sensitive neuropsychological tools for early screening of preclinical cognitive decline. Change-point analyses are increasingly used to characterize the temporal stages of accelerated cognitive decline in the preclinical stages of AD. However, statistical comparisons of change-points between specific cognitive measures have not been reported. Objective: To characterize and compare the temporal stages of accelerated decline in performance on multiple cognitive tests in a sample of participants from the Baltimore Longitudinal Study on Aging (BLSA) who later developed AD. Methods: 165 older adults (baseline age range: 61.1–91.2) from the Baltimore Longitudinal Study of Aging developed AD during follow-up. Linear and non-linear mixed models were fit for 11 cognitive measures to determine change-points in rates of decline before AD diagnosis. Bootstrapping was used to compare the timing of change-points across cognitive measures. Results: Change-points followed by accelerated decline ranged from 15.5 years (Standard Error (S.E.) = 1.72) for Card Rotations to 1.9 years (S.E. = 0.68) for the Trail-Making A test before AD diagnosis. Accelerated decline in Card Rotations occurred significantly earlier than all other measures, including learning and memory measures. Conclusion: Results suggest that visuospatial ability, as assessed by Card Rotations, may have the greatest utility as an early predictive tool in identifying preclinical AD.

Amyloid β (Aβ) plays a critical role in the pathogenesis of Alzheimer’s disease. Nevertheless, its distribution and clearance before Aβ plaque formation needs to be elucidated. Using an optimized immunofluorescent staining method, we examined the distribution of Aβ in the post-mortem parietal cortex of 35 subjects, 30 to 65 years of age, APOE ε3/ε3, without AD lesions. We used 11A1, an antibody against an Aβ conformer which forms neurotoxic oligomers. 11A1 immunoreactivity (IR) was present in cortical neurons, pericapillary spaces, astrocytes and the extracellular compartment at 30 years of age. The percentage of neurons with 11A1 IR did not change with age, but the number and percentage of astrocytes with 11A1 IR gradually increased. Notably, the percentage of pericapillary spaces labeled with 11A1 IR declined significantly in the 5th decade of the life, at the same time that 11A1 IR increased in the extracellular space. Our findings indicate that the Aβ toxic conformer is normally present in various cell types and brain parenchyma, and appears to be constitutively produced, degraded, and cleared from the inferior parietal cortex. The decrease in pericapillary Aβ and the concomitant increase of extracellular Aβ may reflect an age-associated impairment in Aβ clearance from the brain.

Introduction Biomarker discovery of dementia and cognitive impairment is important to gather insight into mechanisms underlying the pathogenesis of these conditions. Methods In 997 adults from the InCHIANTI study, we assessed the association of 1301 plasma proteins with dementia and cognitive impairment. Validation was conducted in two Alzheimer's disease (AD) case‐control studies as well as endophenotypes of AD including cognitive decline, brain amyloid burden, and brain volume. Results We identified four risk proteins that were significantly associated with increased odds (peptidase inhibitor 3 (PI3), trefoil factor 3 (TFF3), pregnancy associated plasma protein A (PAPPA), agouti‐related peptide (AGRP)) and two protective proteins (myostatin (MSTN), integrin aVb5 (ITGAV/ITGB5)) with decreased odds of baseline cognitive impairment or dementia. Of these, four proteins (MSTN, PI3, TFF3, PAPPA) were associated cognitive decline in subjects that were cognitively normal at baseline. ITGAV/ITGB5 was associated with lower brain amyloid burden, MSTN and ITGAV/ITGB5 were associated with larger brain volume and slower brain atrophy, and PI3, PAPPA, and AGRP were associated with smaller brain volume and/or faster brain atrophy. Discussion These proteins may be useful as non‐invasive biomarkers of dementia and cognitive impairment.

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Publisher's version (útgefin grein), Importance: Dual decline in both memory and gait speed may characterize a group of older individuals at high risk for future dementia. Objective: To assess the risk of dementia in older persons who experience parallel declines in memory and gait speed compared with those who experience no decline or decline in either memory or gait speed only. Design, Setting, and Participants: A multicohort meta-analysis was performed of 6 prospective cohort studies conducted between 1997 and 2018 in the United States and Europe. Participants were 60 years or older, had an initial gait speed of more than 0.6 m/s (ie, free of overt dismobility), with repeated measures of memory and gait speed before dementia diagnosis during a mean follow-up of 6.6 to 14.5 years. Within each study, participants were divided into 4 groups: memory decline only, gait speed decline only, dual decline, or no decline (hereafter referred to as usual agers). Gait decline was defined as a loss of 0.05 m/s or more per year; memory decline was defined as being in the cohort-specific lowest tertile of annualized change. Main Outcomes and Measures: Risk of incident dementia according to group membership was examined by Cox proportional hazards regression with usual agers as the reference, adjusted for baseline age, sex, race/ethnicity, educational level, study site, and baseline gait speed and memory. Results: Across the 6 studies of 8699 participants, mean age ranged between 70 and 74 years and mean gait speed ranged between 1.05 and 1.26 m/s. Incident dementia ranged from 5 to 21 per 1000 person-years. Compared with usual agers, participants with only memory decline had 2.2 to 4.6 times higher risk for developing dementia (pooled hazard ratio, 3.45 [95% CI, 2.45-4.86]). Those with only gait decline had 2.1 to 3.6 times higher risk (pooled hazard ratio, 2.24 [95% CI, 1.62-3.09]). Those with dual decline had 5.2 to 11.7 times the risk (pooled hazard ratio, 6.28 [95% CI, 4.56-8.64]). Conclusions and Relevance: In this study, dual decline of memory and gait speed was associated with increased risk of developing dementia among older individuals, which might be a potentially valuable group for preventive or therapeutic interventions. Why dual decline is associated with an elevated risk of dementia and whether these individuals progress to dementia through specific mechanisms should be investigated by future studies., This research work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (Drs Tian, Resnick, Launer, Simonsick, Studenski, and Ferrucci). The BLSA was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. The AGES-Reykjavik Study was funded by contract N01-AG-12100 from the National Institutes of Health; by the Intramural Research Program of the National Institute on Aging; and by the Icelandic Heart Association and the Icelandic Parliament. The Health ABC study was supported by National Institute on Aging contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; National Institute on Aging grant R01-AG028050; and National Institute of Nursing Research grant R01-NR012459, and was funded in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. The MCSA was supported by funding from the National Institutes of Health, National Institute on Aging (U01 AG006786), the Gerald and Henrietta Rauenhorst Foundation, and the Mayo Foundation for Medical Education and Research; and was made possible by the Rochester Epidemiology Project (R01 AG034676). The SNAC-K was supported by the funders of the Swedish National Study on Aging and Care; the Ministry of Health and Social Affairs, Sweden; the participating County Councils and Municipalities; and the Swedish Research Council. The InCHIANTI study was supported by National Institute on Aging contracts 263MD9164 (Dr Ferrucci) and 263 MD 821336, N01-AG-1-1, N01-AG-10211, and N01-AG-5-0002 (Dr Bandinelli), and partially supported by grant n PE 2011 02350413 of the Italian Ministry of Health (Dr Cherubini).

Increasing reliance on electronic medical records at large medical centers provides unique opportunities to perform population level analyses exploring disease progression and etiology. The massive accumulation of diagnostic, procedure, and laboratory codes in one place has enabled the exploration of co-occurring conditions, their risk factors, and potential prognostic factors. While most of the readily identifiable associations in medical records are (now) well known to the scientific community, there is no doubt many more relationships are still to be uncovered in EMR data. In this paper, we introduce a novel finding index to help with that task. This new index uses data mined from real-time PubMed abstracts to indicate the extent to which empirically discovered associations are already known (i.e., present in the scientific literature). Our methods leverage second-generation p-values, which better identify associations that are truly clinically meaningful. We illustrate our new method with three examples: Autism Spectrum Disorder, Alzheimer's Disease, and Optic Neuritis. Our results demonstrate wide utility for identifying new associations in EMR data that have the highest priority among the complex web of correlations and causalities. Data scientists and clinicians can work together more effectively to discover novel associations that are both empirically reliable and clinically understudied.

BACKGROUND: Hearing loss (HL) and menopausal hormone therapy (conjugated equine estrogens [CEE] and/or medroxyprogesterone acetate [MPA]) are separately associated with cognitive decline and increased risk of incident cognitive impairment. Joint effects of HL and HT could be associated with additive or synergistic decline in global cognition and risk of incident cognitive impairment among postmenopausal women. METHODS: Using the Women’s Health Initiative (WHI) Memory Study, 7,220 postmenopausal women with measures of HL, global cognition (Modified Mini-Mental State Examination score), and cognitive impairment (centrally adjudicated diagnoses of mild cognitive impairment and dementia) from 1996 to 2009. Multivariable linear mixed-effects models were used to analyze rate of change in global cognition. Accelerated failure time models were used to evaluate time to incident cognitive impairment, stratified by HT. RESULTS: Within the CEE-Alone trial, observed adverse effects of CEE-Alone on change in global cognition did not differ by HL, and estimated joint effects of HL and CEE-Alone were not associated with incident cognitive impairment. Within the CEE+MPA trial, while HL did not independently accelerate time to cognitive impairment, the adverse effect of CEE+MPA on global cognition was heightened in older women with HL. Older women on CEE+MPA either with HL (time ratio [TR] = 0.82, 95% confidence interval [CI]: 0.71, 0.94) or with normal hearing (TR = 0.86, 95% CI: 0.76, 0.97) had faster time to cognitive impairment than those with normal hearing and placebo. CONCLUSIONS: HL may accentuate the adverse effect of CEE+MPA, not CEE-Alone, on global cognitive decline, not incident cognitive impairment, among postmenopausal women on HT.

Prior studies suggesting associations between cortical brain areas and gait speed has been largely cross-sectional and limited to one modality neuroimaging. Using machine learning from 506 cognitively normal BLSA participants aged 55+ who had repeated measures of brain volumes, diffusion tensor imaging (DTI), and gait speed, we examined multimodal neuroimaging predictors of gait decline, accounting for demographics, body composition, and grip strength. Significant predictors of gait decline included changes in volumes and DTI measures of gray matter in selected frontal, parietal, temporal, and subcortical areas, as well as white matter changes in both fractional anisotropy and diffusivity of tracts connecting frontal areas to subcortical motor areas. This predictive model highlights the importance of atrophy and microstructural deterioration in selected frontal and subcortical motor areas in predicting gait speed decline.

Medial temporal tau pathology is frequently observed in individuals over 70 regardless of cognitive status. To understand the link between tau and cognitive performance, we evaluated tau pathology using 18F-flortaucipir positron emission tomography among 95 cognitively normal participants from the Baltimore Longitudinal Study of Aging. We examined tau levels in early Braak regions (entorhinal cortex and hippocampus) in relation to verbal episodic memory performance concurrent with and prior to the tau scan using linear mixed effects models adjusted for age, sex, amyloid status, and time from PET scan. Higher hippocampal tau burden had a trend-level association with lower concurrent memory performance (p=0.05). Greater tau pathology in the hippocampus and entorhinal cortex was associated with steeper decline in memory performance prior to tau scan (p=0.013 and 0.026, respectively). These findings suggest that therapeutic interventions targeting tau pathology may need to be administered early among cognitively normal individuals to prevent memory decline.

Detailed whole brain segmentation is an essential quantitative technique in medical image analysis, which provides a non-invasive way of measuring brain regions from a clinical acquired structural magnetic resonance imaging (MRI). Recently, deep convolution neural network (CNN) has been applied to whole brain segmentation. However, restricted by current GPU memory, 2D based methods, downsampling based 3D CNN methods, and patch-based high-resolution 3D CNN methods have been the de facto standard solutions. 3D patch-based high resolution methods typically yield superior performance among CNN approaches on detailed whole brain segmentation (>100 labels), however, whose performance are still commonly inferior compared with state-of-the-art multi-atlas segmentation methods (MAS) due to the following challenges: (1) a single network is typically used to learn both spatial and contextual information for the patches, (2) limited manually traced whole brain volumes are available (typically less than 50) for training a network. In this work, we propose the spatially localized atlas network tiles (SLANT) method to distribute multiple independent 3D fully convolutional networks (FCN) for high-resolution whole brain segmentation. To address the first challenge, multiple spatially distributed networks were used in the SLANT method, in which each network learned contextual information for a fixed spatial location. To address the second challenge, auxiliary labels on 5111 initially unlabeled scans were created by multi-atlas segmentation for training. Since the method integrated multiple traditional medical image processing methods with deep learning, we developed a containerized pipeline to deploy the end-to-end solution. From the results, the proposed method achieved superior performance compared with multi-atlas segmentation methods, while reducing the computational time from >30 h to 15 min. The method has been made available in open source ( https://github.com/MASILab/SLANTbrainSeg ).

Objective Amyloid positivity is a biomarker of AD pathology, yet the associations between amyloid positivity and brain volumetric changes, especially in the hippocampus, are inconsistent. We hypothesize that sex differences in associations may contribute to inconsistent findings among cognitively normal older adults. Methods Using linear mixed effects models, we examined the association of amyloid positivity with prospective volumetric changes (mean = 3.3 visits) of parahippocampal gyrus (phg), hippocampus, entorhinal cortex (erc), precuneus, and fusiform gyrus among 171 Baltimore Longitudinal Study of Aging participants aged ≥55 years. Amyloid positivity was defined by a mean 11C-Pittsburgh Compound B (PiB) distribution volume ratio (DVR) cut-off of 1.062. All analyses included age, race, sex, education, APOE e4 carrier status, and two-way interactions of these covariates with time. Two-way interaction between sex and PiB+/− status and three-way interaction of sex and PiB+/− status with time were added to assess whether sex modified associations. Results PiB+ status was associated with greater volumetric declines in the phg (β = −0.036, SE = 0.011, p = 0.001) and erc (β = −0.019, SE = 0.009, p = 0.045). Sex modified the association of PiB+ status and rates of volumetric declines in fusiform (β = −0.117, SE = 0.049, p = 0.019). PiB+ males had steeper rates of volumetric declines in phg (β = −0.051, SE = 0.013, p, Highlights • Amyloid positivity is related to volume loss in regions of early AD pathology. • Sex modified the association of amyloid positivity and brain volumetric changes. • Amyloid-positive males were vulnerable to volume loss in regions of early AD. • Females with and without amyloid positivity had similar volume changes.

Background Idiopathic Parkinson’s disease (IPD) has a long preclinical phase. Research question This study assesses data on prediagnostic markers of IPD from a longitudinal, natural history study of aging. Methods Participants were selected from the database of the Baltimore Longitudinal Study of Aging, and included 10 prediagnosed IPD cases (eight men and two women) and 30 age and sex matched healthy controls. Patients with prediagnosed IPD had already had an assessment for IPD 2.6 ± 1.3 years (range 1.0–5.3 years) before the actual diagnosis, including: gait speed (six-meter corridor walk), spatio-temporal gait parameters using Vicon motion capture, balance, upper-limb motor skills, neuropsychological profile, and non-motor symptoms. Results Prediagnosed IPD cases compared to controls had slower gait speed (Δ=-0.13 m.s−1, p = 0.03) due to shorter step length (Δ=−5 cm, p = 0.004), worse visuospatial ability (card rotation test, Δ=-42, p = 0.0001) and worse executive function (category fluency test, Δ=-2.6, p = 0.04). Significance Our findings identify dimensions that merit further study as prediagnostic markers of Idiopathic Parkinson’s disease to identify patients who might benefit from future neuroprotective therapy in order to delay, or prevent, clinical manifestations.

Introduction In a geographically diverse sample of women, we asked whether cognitive reserve (CR) is best viewed as a general or cognitive domain-specific construct and whether some cognitive reserve domains but not others exert protective effects on risk of developing mild cognitive impairment (MCI) or dementia. Methods Estimates of general and domain-specific CR were derived via variance decomposition in 972 cognitively intact women from the Women's Health Initiative Study of Cognitive Aging and Women's Health Memory Study Magnetic Resonance Imaging. Women were then followed up for 13 years. Results General CR was the strongest predictor of reduced risk for both MCI and dementia, compared to domain-specific CR measures. Verbal memory, figural memory, and spatial CR were independently protective of MCI, but only verbal memory was independently associated with reduced risk for dementia. Discussion Cognitive reserve is a heterogenous construct with valid quantitative measures identifiable across different neuropsychological processes associated with MCI and dementia.

Given conflicting evidence, the relationship between cognitive function (CF) and physical activity (PA) remains unclear. We investigated the association between standardized cognitive scores for: memory, language, executive functioning, attention, and visuospatial processing, and three accelerometer-based PA metrics: total volume of daily activity on the log scale (TLAC), total daily activity counts (TAC), log total daily activity count (LTAC), and activity fragmentation (AF) among 714 BLSA participants aged > 50 years (49.6% men, age: 71.88 ± 9.99). In multivariable regression models adjusted for age, gender, and years of education, there was no association between executive function and any of the mtrics (p>0.05 for all). Language was associated with all four metrics, memory and visuospatial scores with AF and TLAC, and attention with LTAC, TAC and AF (p

Previous studies reported the association of increased dementia risk with depressive symptoms assessed at one-time point, neglecting the inter-individual differences and intra-individual variability in the profiles of symptoms over time. We examined the association between longitudinal trajectories of depressive symptoms and cognitive impairment among participants from the Women’s Health Initiative Study of Cognitive Aging without prior depression (n=2,081; aged 73.4 ± 3.8 years), including a subsample (n=1,050) with 1.5-T brain MRI measures of small-vessel-ischemic-diseases (SVID) and spatial patterns of grey matter atrophy in Alzheimer’s disease (i.e., AD pattern similarity [AD-PS] score; Casanova 2013). Latent-class mixed models (LCMMs) were used to identify clusters with similar individual trajectories of symptoms assessed annually by the 15-item Geriatric Depression Scale (GDS). Using Cox-proportional hazard regression, we estimated the association between GDS-defined classes and global cognitive decline in the Modified Mini-Mental State [3MS] score;>10-point drop) and incident dementia. Multinomial logistic regressions estimated the associations between GDS classes and brain MRI measures. Compared to the resilient group with minimal symptoms (N=739;35.5%), the other two clusters with low-levels of depressive symptoms that either emerged (N=314;15.1%) in late life or sustained (N=1028;49.4%) during the follow-up were at increased risks for 3MS decline (HRemerging=1.93, p=0.02; HRsustained=2.51,p

In long-term studies of cognitive aging, assessment protocols may change. It is of great interest to model trajectories of cognitive function spanning these different protocols in order to identify risk factors related to changes in cognitive function, particularly from midlife into later ages. The Women’s Health Initiative Memory Study (WHIMS) switched from an in-person interview (Modified Mini-Mental State Exam) to a telephone-based interview (Telephone Interview for Cognitive Status) for assessing global cognitive function. We ranked annual scores from N=2,561 individuals (aged 75–92 years) according to age- and race/ethnicity-adjusted performance levels and used group-based trajectory modeling to identify five clusters of trajectories across the ten years spanning the change in protocols. These groups differed significantly according to three known risk factors for cognitive decline -- education level, APOE-e4 genotype, and type 2 diabetes –and a novel brain MRI biomarker developed by supervised machine learning and validated with the Alzheimer’s Disease Neuroimaging Initiative data that linked spatial patterns of brain atrophy to increased risks for cognitive decline and clinical Alzheimer’s disease in WHIMS. Participants with consistently low relative levels of cognitive function over time and those whose relative performance over time declined to these low levels tended to have poorer risk factor profiles. We conclude that longitudinal measures of an individual’s relative performance across different assessment protocols for global cognitive function can be used to identify trajectories of change over time that appear to have internal validity with respect to known risk factors.

Background: Surgical removal of malignancies may enhance the risk of recurrence but mechanisms remain poorly understood. Neutrophils, first line responders after surgical stress, can facilitate cancer progression. Neutrophils can expel nuclear DNA studded with proteins to form web-like structures known as Neutrophil Extracellular Traps (NETs) in response to stress. Here we aim to characterize the role of NETs in promoting metastatic cancer growth after surgical stress that is currently entirely unknown. Methods: We used a standardized mouse model of partial hepatic ischemia reperfusion, to stimulate surgical stress, directly or five days after splenic injection of MC38 colon carcinoma cells. Results: We found that NET formation is significantly increased in the immediate post-operative period in humans undergoing curative liver resection for colorectal cancer metastases. The risk of liver metastases recurrence was 4.22 times higher in patients with increased post-operative NET formation. In the murine model, we demonstrated increased NET deposition after surgical stress and this was associated with both increased formation of metastases and growth of already established micrometastatic disease. In vitro, NETs increase growth, invasion, migration and adhesion in multiple cancer cell lines. All the above effects were abrogated by NET inhibition with DNAse. NETs exert their pro-tumorigenic effects by releasing HMGB1 and activating TLR-9 dependent pathways in the cancer cells. In addition, as metastatic tumors continue to grow, hypoxia within the tumor microenvironment induces further neutrophil recruitment and NET formation that further accelerates tumor growth. Conclusions: These findings implicate NETs in the process of cancer metastasis progression and recurrence after surgery and identifies NETs as potential therapeutic targets. Citation Format: Samer Tohme, Hai Huang, Alexis Chidi, Richard Simmons, Allan Tsung. The role of neutrophil extracellular traps in promoting metastatic cancer following surgical stress. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A30.