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Background: The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) cohort study of the Canadian Consortium on Neurodegeneration in Aging (CCNA) is a national initiative to catalyze research on dementia, set up to support the research agendas of CCNA teams. This cross-country longitudinal cohort of 2310 deeply phenotyped subjects with various forms of dementia and mild memory loss or concerns, along with cognitively intact elderly subjects, will test hypotheses generated by these teams., Methods: The COMPASS-ND protocol, initial grant proposal for funding, fifth semi-annual CCNA Progress Report submitted to the Canadian Institutes of Health Research December 2017, and other documents supplemented by modifications made and lessons learned after implementation were used by the authors to create the description of the study provided here., Results: The CCNA COMPASS-ND cohort includes participants from across Canada with various cognitive conditions associated with or at risk of neurodegenerative diseases. They will undergo a wide range of experimental, clinical, imaging, and genetic investigation to specifically address the causes, diagnosis, treatment, and prevention of these conditions in the aging population. Data derived from clinical and cognitive assessments, biospecimens, brain imaging, genetics, and brain donations will be used to test hypotheses generated by CCNA research teams and other Canadian researchers. The study is the most comprehensive and ambitious Canadian study of dementia. Initial data posting occurred in 2018, with the full cohort to be accrued by 2020., Conclusion: Availability of data from the COMPASS-ND study will provide a major stimulus for dementia research in Canada in the coming years.

Background: Harmonized protocols to collect imaging data must be devised, employed, and maintained in multicentric studies to reduce interscanner variability in subsequent analyses., Purpose: To present a standardized protocol for multicentric research on dementia linked to neurodegeneration in aging, harmonized on all three major vendor platforms. The protocol includes a common procedure for qualification, quality control, and quality assurance and feasibility in large-scale studies., Study Type: Prospective., Subjects: The study involved a geometric phantom, a single individual volunteer, and 143 cognitively healthy, mild cognitively impaired, and Alzheimer's disease participants in a large-scale, multicentric study., Field Strength/sequences: MRI was perform with 3T scanners (GE, Philips, Siemens) and included 3D T 1 w, PD/T 2 w, T 2 * , T 2 w-FLAIR, diffusion, and BOLD resting state acquisitions., Assessment: Measures included signal- and contrast-to-noise ratios (SNR and CNR, respectively), total brain volumes, and total scan time., Statistical Tests: SNR, CNR, and scan time were compared between scanner vendors using analysis of variance (ANOVA) and Tukey tests, while brain volumes were tested using linear mixed models., Results: Geometric phantom T 1 w SNR was significantly (P < 0.001) higher in Philips (mean: 71.4) than Siemens (29.5), while no significant difference was observed between vendors for T 2 w (32.0 and 37.2, respectively, P = 0.243). Single individual volunteer T 1 w CNR was higher in subcortical regions for Siemens (P < 0.001), while Philips had higher cortical CNR (P =  0.044). No significant difference in brain volumes was observed between vendors (P = 0.310/0.582/0.055). The average scan time was 41.0 minutes (SD: 2.8) and was not significantly different between sites (P = 0.071) and cognitive groups (P = 0.853)., Data Conclusion: The harmonized Canadian Dementia Imaging Protocol suits the needs of studies that need to ensure quality MRI data acquisition for the measurement of brain changes across adulthood, due to aging, neurodegeneration, and other etiologies. A detailed description, exam cards, and operators' manual are freely available at the following site: www.cdip-pcid.ca., Level of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:456-465., (© 2018 International Society for Magnetic Resonance in Medicine.)

Objectives: To analyze age representation trends over time in antiepileptic drug (AED) trials and to assess trial design elements as possible barriers to enrollment of elderly patients., Materials and Methods: We searched MEDLINE, EMBASE, and PsycINFO, and meta-analyzed demographic data of cohorts enrolled in randomized controlled trials (RCTs) of AEDs published since 1991. Data analysis included trends of age representation over time and trial design elements associated with average age of enrolled cohorts., Results: We identified 187 studies (n = 48,077); 184 studies were included in the meta-analysis. The mean age of participants enrolled increased steadily from a mean age of 27.0 years (SD 5.7, range 21.0-38.4) in 1991-1992, to a mean age of 41.9 years (SD 11.4, range 28.8-71.4) in 2015-2016 (r = 0.868, p < 0.0001). Maximum age limit for inclusion of participants was present in 83 trials (44%). There was no significant decrease in the use of upper age limit over time (r = 0.072, p = 0.8161). Among the eligibility criteria assessed, only the exclusion of neurological conditions other than epilepsy was associated with a significant reduction of the average age of enrolled cohorts (-2.1 years, 95% CI -4.1 to -0.1)., Conclusions: Despite a progressive increase in the average age of participants enrolled in AED trials over time, elderly patients are still largely underrepresented. Successful strategies to increase representation of elderly patients in these trials will likely need to involve more than minimal protocol modifications of eligibility criteria., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: One of the central features of brain aging is the accumulation of multiple age-related structural changes, which occur heterogeneously in individuals and can have immediate or potential clinical consequences. Each of these deficits can coexist and interact, producing both independent and additive impacts on brain health. Many of the changes can be visualized using MRI. To collectively assess whole-brain structural changes, the MRI-based Brain Atrophy and Lesion Index (BALI) has been developed. In this study, we validate this whole-brain health assessment approach using several clinical MRI examinations., Materials and Methods: Data came from three independent studies: the Alzheimer's Disease Neuroimaging Initiative Phase II (n=950; women =47.9%; age =72.7±7.4 years); the National Alzheimer's Coordinating Center (n=722; women =55.1%; age =72.7±9.9 years); and the Tianjin Medical University General Hospital Research database on older adults (n=170; women =60.0%; age =62.9±9.3 years). The 3.0-Tesla MRI scans were evaluated using the BALI rating scheme on the basis of T1-weighted (T1WI), T2-weighted (T2WI), T2-weighted fluid-attenuated inversion recovery (T2-FLAIR), and T2*-weighted gradient-recalled echo (T2*GRE) images., Results: Atrophy and lesion changes were commonly seen in each MRI test. The BALI scores based on different sequences were highly correlated (Spearman r 2 >0.69; P <0.00001). They were associated with age ( r 2 >0.29; P <0.00001) and differed by cognitive status ( χ 2 >26.48, P <0.00001). T2-FLAIR revealed a greater level of periventricular ( χ 2 =29.09) and deep white matter ( χ 2 =26.65, P <0.001) lesions than others, but missed revealing certain dilated perivascular spaces that were seen in T2WI ( P <0.001). Microhemorrhages occurred in 15.3% of the sample examined and were detected using only T2*GRE., Conclusion: The T1WI- and T2WI-based BALI evaluations consistently identified the burden of aging and dementia-related decline of structural brain health. Inclusion of additional MRI tests increased lesion differentiation. Further research is to integrate MRI tests for a clinical tool to aid the diagnosis and intervention of brain aging., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Mobility limitations are common and hazardous in community-dwelling older adults but are largely understudied, particularly regarding the role of the central nervous system (CNS). This has limited development of clearly defined pathophysiology, clinical terminology, and effective treatments. Understanding how changes in the CNS contribute to mobility limitations has the potential to inform future intervention studies., Methods: A conference series was launched at the 2012 conference of the Gerontological Society of America in collaboration with the National Institute on Aging and the University of Pittsburgh. The overarching goal of the conference series is to facilitate the translation of research results into interventions that improve mobility for older adults., Results: Evidence from basic, clinical, and epidemiological studies supports the CNS as an important contributor to mobility limitations in older adults without overt neurologic disease. Three main goals for future work that emerged were as follows: (a) develop models of mobility limitations in older adults that differentiate aging from disease-related processes and that fully integrate CNS with musculoskeletal contributors; (b) quantify the contribution of the CNS to mobility loss in older adults in the absence of overt neurologic diseases; (c) promote cross-disciplinary collaboration to generate new ideas and address current methodological issues and barriers, including real-world mobility measures and life-course approaches., Conclusions: In addition to greater cross-disciplinary research, there is a need for new approaches to training clinicians and investigators, which integrate concepts and methodologies from individual disciplines, focus on emerging methodologies, and prepare investigators to assess complex, multisystem associations.

Cerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE)., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: Determine whether white matter signal fluctuation on T2* weighted BOLD contrast images are associated with aging and cerebral small vessel disease (SVD)., Methodology: Resting state BOLD data were collected with a 250 ms repetition time (TR) to achieve unaliased, ungated cardiac sampled BOLD (cs-BOLD) images on 11 young adult controls, 10 healthy older adult controls and 7 adults with extensive white matter hyperintensities (WMH) from SVD. Tissue classes (WM and GM) were segmented on T1 images. WMH were identified on FLAIR images in the SVD group. Raw physiological noise (σphysio) and cardiac pulsatility (i.e. fluctuations at the cardiac frequency) were calculated voxel wise and group differences were tested by ANOVA. It was also possible to calculate σphysio in 2s TR cardiac aliased whole-brain BOLD (wb-BOLD) data (N = 84) obtained from the International Consortium for Brain Mapping., Results: CS-BOLD metrics showed an aging and SVD effects (p<0.0005). Covariates such as thermal noise, WM volume and partial volume did not influence the significant aging effect seen on the cardiac pulsatility metric (p<0.017) but did influence the σphysio (p = 0.184). As a verification of the cs-BOLD findings, the wb-BOLD also showed a linear aging effect of σphysio in WM. In the SVD adults, cardiac pulsatility and σphysio were lower in WMH regions compared to normal appearing white matter (NAWM) regions (p<0.0013 and p<0.002, respectively). Cardiac pulsatility was better able to distinguish WMH regions from NAWM than σphysio as measured by effect size (Cohen's d 2.2 and 0.88, respectively)., Conclusion: NAWM was found to have graded increases in cardiac pulsations due to age and SVD, independently. Within SVD participants, WMH lesions had reduced physiological noise compared to NAWM. Cardiac pulsatility in resting BOLD data may provide a complementary dynamic measure of WM integrity to add to static FLAIR anatomical images.

Unlabelled: Measurement of gait is essential for identifying underlying deficits contributing to gait dysfunction, guiding clinical decisions and measuring rehabilitation outcomes. Velocity is commonly used to measure gait, however, its interpretation in patient populations is complicated by the confound of age. Gait symmetry may be an additional and valuable measure since it may not feature the same age-related changes as velocity. The purpose of this study was to determine if gait symmetry is related to age., Methods: Spatiotemporal gait parameters were recorded for 172 individuals with stroke and 81 healthy adults walking across a pressure sensitive mat at their preferred speed. Swing time, stance time and step length symmetry ratios were calculated. The relationship of age to velocity and symmetry was examined using Pearson correlations., Results: There was a significant negative association between velocity and age in the healthy group (r=-0.57, p<0.01). There were no significant relationships between age and any of the three symmetry ratios for either the stroke or healthy groups., Conclusions: The main finding of the current study is that gait symmetry ratios are not significantly associated with age in either a healthy or a post-stroke group. Gait symmetry ratios may therefore, allow the clinician and the researcher to make judgments about the effects of disease (such as stroke) on the control of an individual's gait without the confound of age., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Subcortical hyperintensities (SHs) on brain magnetic resonance imaging are associated with cognitive and gait impairment in elderly but their impact on dual-tasking (performing cognitive tasks while walking) in patients with Alzheimer disease (AD) is unknown. This study explored the costs of dual-tasking in relation to SH severity in AD and normal controls (NCs). Cadence while walking on a treadmill, and speed-accuracy-tradeoff (SAT), on 3 working memory tasks, were measured during single-task and dual-task conditions. Dual-task costs (DTC) on SAT, cadence, and overall DTC were measured for each of these tasks. On visual rating of SH severity, AD and NC groups were subdivided into high-SH and low-SH subgroups. Compared with the NC, the AD group performed poorly on all working memory tasks across both conditions, decreased cadence on dual-tasking, and showed a decrement in overall DTC (all P<0.01). When grouped according to SH severity, the low-SH-NC group performed superiorly on working memory tasks (P<0.001) and the high-SH-AD group (P=0.001) showed a decrease in dual-task costs of cadence. Although the AD group showed a decrement in overall DTC (P<0.01) compared with NC, when assessed in terms of SH severity, the high-SH-AD group showed the largest decrement in DTC (P<0.01). Greater SH severity is associated with a decrement in overall dual-tasking ability in AD.

Changes in gait parameters induced by the concomitant performance of one of two cognitive tasks activating working memory and spatial attention, was examined in healthy young adults (YA) and older adults (OA). There was a main effect of task condition on gait-speed (p = .02), stride-length (p < .001) and double-support time (p = .04) independent of the group. There were no significant differences between working memory and spatial attention associated gait changes. Working-memory and spatial-attention dual-tasking led to a decrease in gait-speed (p = .09 and 0.01) and stride-length (p = .04 and 0.01) and increase in double-support time (p = .01 and 0.03) in YA and decrease in stride-length (p = .04 and 0.01) alone in OA. Cognitive task associated changes in gait may be a function of limited attentional resources irrespective of the type of cognitive task.

Spatial and temporal gait parameters in 40 patients with early Alzheimer's disease (AD) were compared to that of 34 normal controls (NC) on a level ground and on a treadmill. Over-ground velocity, cycle-time, cadence, stride-length, stride-width and double-support time were captured on an electronic walkway. On the treadmill, cadence, cycle-time and double-support time were recorded at a preferred velocity using footswitches. The AD group were significantly slower on the Timed Up and Go task compared to NC (p<0.05). AD patients differed significantly from the NC on their over-ground gait velocity (99+/-19 cm/s vs 119+15 cm/s, p<0.001), cadence (101+/-9 steps/min vs 109+/-9 steps/min, p=0.001) and stride-length (118+/-18 cm vs 131+/-17 cm, p<0.01). On the treadmill, only preferred speed was significantly different in the AD group compared to the NC group (60+/-20 cm/s vs 74+/-23 cm/s, p=0.02). These results indicate that patients with early AD walk slower and with shorter strides than healthy older adults.

Background and Purpose: Limited information is available on the effect of age on stroke management and care delivery. Our aim was to determine whether access to stroke care, delivery of health services, and clinical outcomes after stroke are affected by age., Methods: This was a prospective cohort study of patients with acute ischemic stroke in the province of Ontario, Canada, admitted to stroke centers participating in the Registry of the Canadian Stroke Network between July 1, 2003 and March 31, 2005. Primary outcomes were the following selected indicators of quality stroke care: (1) use of thrombolysis; (2) dysphagia screening; (3) admission to a stroke unit; (4) carotid imaging; (5) antithrombotic therapy; and (6) warfarin for atrial fibrillation at discharge. Secondary outcomes were risk-adjusted stroke fatality, discharge disposition, pneumonia, and length of hospital stay., Results: Among 3631 patients with ischemic stroke, 1219 (33.6%) were older than 80 years. There were no significant differences in stroke care delivery by age group. Stroke fatality increased with age, with a 30-day risk adjusted fatality of 7.1%, 6.5%, 8.8%, and 14.8% for those aged 59 or younger, 60 to 69, 70 to 79, and 80 years or older, respectively. Those aged older than 80 years had a longer length of hospitalization, increased risk of pneumonia, and higher disability at discharge compared to those younger than 80. This group was also less likely to be discharged home., Conclusions: In the context of a province-wide coordinated stroke care system, stroke care delivery was similar across all age groups with the exception of slightly lower rates of investigations in the very elderly. Increasing age was associated with stroke severity and stroke case-fatality.

This study assessed the convergent validity of a virtual environment (VE) navigation learning task, the Groton Maze Learning Test (GMLT), and selected traditional neuropsychological tests performed in a group of healthy elderly adults (n = 24). The cohort was divided equally between males and females to explore performance variability due to sex differences, which were subsequently characterized and reported as part of the analysis. To facilitate performance comparisons, specific "efficiency" scores were created for both the VE navigation task and the GMLT. Men reached peak performance more rapidly than women during VE navigation and on the GMLT and significantly outperformed women on the first learning trial in the VE. Results suggest reasonable convergent validity across the VE task, GMLT, and selected neuropsychological tests for assessment of spatial memory.

Background/aims: The relationship between subcortical hyperintensities (SH) on brain MRI and gait parameters in aging and Alzheimer's disease (AD) is unclear. This study compared gait in 42 mild AD patients to 22 normal controls (NC) based on their SH severity and correlated them to SH burden in these groups., Methods: Gait velocity, stride length, cadence and step width were captured on an automated walkway. Severity of SH on MRI was visually scored, which was used to dichotomize the AD and NC groups into high and low SH severity subgroups. Correlations between gait parameters and total and regional distribution of SH were explored., Results: Compared to both AD subgroups and the NC subgroup with high SH severity, the NC subgroup with low SH severity had a significantly faster velocity (127 cm/s). Overall SH severity correlated significantly with stride length and velocity in the AD (r = -0.4, p = 0.01) and NC (r = -0.4, p = 0.02) groups, respectively, specifically with SH severity in the frontal and basal ganglion regions., Conclusion: SH burden may have a relatively stronger association with slower gait velocity in NC than in patients with mild AD. The fronto-subcortical SH load may influence gait in AD and aging., (2009 S. Karger AG, Basel.)

This study explored possible deficits in selective attention brought about by Dementia of Alzheimer Type (DAT). In three experiments, we tested patients with early DAT, healthy elderly, and young adults under low memory demands to assess perceptual filtering, conflict resolution, and set switching abilities. We found no evidence of impaired perceptual filtering nor evidence of impaired conflict resolution in early DAT. In contrast, early DAT patients did exhibit a global cost in set switching consistent with an inability to maintain the goals of the task (mental set). We discuss these findings in relation to the DAT literature on executive attention, dual-tasking, and working memory.

Background and Purpose: MRI-based quantification of gray and white matter volume is common in studies involving elderly patient populations. The aim of the present study was to describe the effects of not accounting for subcortical white matter hyperintensities (WMH) on tissue volumes in Alzheimer Disease patients with varying degrees of WMH (mild: n=19, moderate: n=22, severe: n=18)., Methods: An automated tissue segmentation protocol that was optimized for an elderly population, a brain regional parcellation procedure, and a lesion segmentation protocol were applied to measure tissue volumes (whole brain and regional lobar volumes) with and without lesion segmentation to quantify the volume of misclassified tissue., Results: After application of the tissue segmentation protocol and lesion analysis, mean total percentage misclassified volume across all subjects was 2% (17.9 cm(3)) of whole brain volume (corrected for total intracranial capacity). Mean percentage of misclassified tissue volumes for the severe group was 4.8% of whole brain, which translates to a mean volume 42.2 cm(3). Gray matter volume was most overestimated in the severe group, where 6.4% of the total gray matter volume was derived from misclassified WMH. The regional analysis showed that frontal (41%, 7.4 cm(3)) and inferior parietal (18%, 3.25 cm(3)) lobes were most affected by tissue misclassification., Conclusions: MRI-based volumetric studies of Alzheimer Disease that do not account for WMH can expect an erroneous inflation of gray or white matter volumes, especially in the frontal and inferior parietal regions. To avoid this source of error, MRI-based volumetric studies in patient populations susceptible to hyperintensities should include a WMH segmentation protocol.

By combining a flanker task and a cuing task into a single paradigm, the authors assessed the effects of orienting and alerting on conflict resolution and explored how normal aging and Alzheimer's disease (AD) modulate these attentional functions. Orienting failed to enhance conflict resolution; alerting was most beneficial for trials without conflict, as if acting on response criterion rather than on information processing. Alerting cues were most effective in the older groups--healthy aging and AD. Conflict resolution was impaired only in AD. Orienting remained unchanged across groups. These findings provide evidence of different life span developmental and clinical trajectories for each attentional network.

Application of magnetic resonance imaging (MRI) techniques reveals that human brain aging varies across cortical regions. One area particularly sensitive to normal aging is the frontal lobes. In vitro neuropathological studies and behavioral measures in a canine model of aging previously suggested that the frontal lobes of the dog might be sensitive to aging. In the present study, MRI scans were acquired to compare age-related changes in frontal lobe volume with changes in executive functions and beta-amyloid pathology in the frontal cortex of beagle dogs aged 3 months to 15 years. Decreases in total brain volume appeared only in senior dogs (aged 12 years and older), whereas frontal lobe atrophy developed earlier, appearing in the old dogs (aged 8-11 years). Hippocampal volume also declined with age, but not occipital lobe volume past maturity. Reduced frontal lobe volume correlated with impaired performance on measures of executive function, including inhibitory control and complex working memory, and with increased beta-amyloid accumulation in the frontal cortex. Age-related hippocampal atrophy also correlated with complex working memory but not inhibitory control, whereas occipital lobe volume did not correlate with any cognitive measure. These findings are consistent with the frontal lobe theory of aging in humans, which suggests that the frontal lobes and functions subserved by this region are compromised early in aging.

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson's, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.

IntroductionWe examined whether sex modifies the association between APOE ε2 and cognitive decline in two independent samples.MethodsWe used observational data from cognitively unimpaired non-Hispanic White (NHW) and non-Hispanic Black (NHB) adults. Linear mixed models examined interactive associations of APOE genotype (ε2 or ε4 carrier vs. ε3/ε3) and sex on cognitive decline in NHW and NHB participants separately.ResultsIn both Sample 1 (N = 9766) and Sample 2 (N = 915), sex modified the association between APOE ε2 and cognitive decline in NHW participants. Specifically, relative to APOE ε3/ε3, APOE ε2 protected against cognitive decline in men but not women. Among APOE ε2 carriers, men had slower decline than women. Among APOE ε3/ε3 carriers, cognitive trajectories did not differ between sexes. There were no sex-specific associations of APOE ε2 with cognition in NHB participants (N = 2010).DiscussionIn NHW adults, APOE ε2 may protect men but not women against cognitive decline.HighlightsWe studied sex-specific apolipoprotein E (APOE) ε2 effects on cognitive decline. In non-Hispanic White (NHW) adults, APOE ε2 selectively protects men against decline. Among men, APOE ε2 was more protective than APOE ε3/ε3. In women, APOE ε2 was no more protective than APOE ε3/ε3. Among APOE ε2 carriers, men had slower decline than women. There were no sex-specific APOE ε2 effects in non-Hispanic Black (NHB) adults.

A large interventional trial, the Systolic Blood Pressure Intervention Trial sub-study termed Memory and Cognition in Decreased Hypertension (SPRINT-MIND), found reduced risk of cognitive impairment in older adults with intensive, relative to standard, blood-pressure-lowering targets (systolic BP  80 years), will maximize external validity and global implementation of trial findings. New biomarkers will improve phenotyping to stratify patients to optimal treatments. Currently no antihypertensive drug class stands out for dementia risk reduction. Multi-domain interventions, incorporating lifestyle change (exercise, diet) alongside medications, may maximize global impact. Given the low cost and wide availability of antihypertensive drugs, intensive BP reduction may be a cost-effective means to reduce dementia risk in diverse, aging populations worldwide.

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.

The APOE locus is strongly associated with risk for developing Alzheimer's disease and dementia with Lewy bodies. In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2466 dementia with Lewy bodies cases versus 2928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association study approach, we found that GBA is associated with risk for dementia with Lewy bodies in patients without APOE ε4 (P = 6.58 × 10-9, OR = 3.41, 95% CI = 2.25-5.17), but not with dementia with Lewy bodies with APOE ε4 (P = 0.034, OR = 1.87, 95%, 95% CI = 1.05-3.37). We then divided 495 neuropathologically examined dementia with Lewy bodies cases into three groups based on the extent of concomitant Alzheimer's disease co-pathology: pure dementia with Lewy bodies (n = 88), dementia with Lewy bodies with intermediate Alzheimer's disease co-pathology (n = 66) and dementia with Lewy bodies with high Alzheimer's disease co-pathology (n = 341). In each group, we tested the association of the APOE ε4 against the 2928 neurologically healthy controls. Our examination found that APOE ε4 was associated with dementia with Lewy bodies + Alzheimer's disease (P = 1.29 × 10-32, OR = 4.25, 95% CI = 3.35-5.39) and dementia with Lewy bodies + intermediate Alzheimer's disease (P = 0.0011, OR = 2.31, 95% CI = 1.40-3.83), but not with pure dementia with Lewy bodies (P = 0.31, OR = 0.75, 95% CI = 0.43-1.30). In conclusion, although deep clinical data were not available for these samples, our findings do not support the notion that APOE ε4 is an independent driver of α-synuclein pathology in pure dementia with Lewy bodies, but rather implicate GBA as the main risk gene for the pure dementia with Lewy bodies subgroup.

ObjectiveTo evaluate whether orthostatic hypotension (OH) or supine hypertension (SH) is associated with brain atrophy and white matter hyperintensities (WMH), we analyzed clinical and radiologic data from a large multicenter consortium of patients with Parkinson disease (PD) and dementia with Lewy bodies (DLB).MethodsSupine and orthostatic blood pressure (BP) and structural MRI data were extracted from patients with PD and DLB evaluated at 8 tertiary-referral centers in the United States, Canada, Italy, and Japan. OH was defined as a systolic/diastolic BP fall ≥20/10 mm Hg within 3 minutes of standing from the supine position (severe ≥30/15 mm Hg) and SH as a BP ≥140/90 mm Hg with normal sitting BP. Diagnosis-, age-, sex-, and disease duration-adjusted differences in global and regional cerebral atrophy and WMH were appraised with validated semiquantitative rating scales.ResultsA total of 384 patients (310 with PD, 74 with DLB) met eligibility criteria, of whom 44.3% (n = 170) had OH, including 24.7% (n = 42) with severe OH and 41.7% (n = 71) with SH. OH was associated with global brain atrophy (p = 0.004) and regional atrophy involving the anterior-temporal (p = 0.001) and mediotemporal (p = 0.001) regions, greater in severe vs nonsevere OH (p = 0.001). The WMH burden was similar in those with and without OH (p = 0.49). SH was not associated with brain atrophy (p = 0.59) or WMH (p = 0.72).ConclusionsOH, but not SH, was associated with cerebral atrophy in Lewy body disorders, with prominent temporal region involvement. Neither OH nor SH was associated with WMH.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

IntroductionWe examine whether distinct brain atrophy patterns (using brain parenchymal fraction [BPF]) differentially predict functional performance and decline in Alzheimer's disease (AD), and are independently moderated by (1) a key AD genetic risk marker (apolipoprotein E [APOE]), (2) sex, and (3) high-risk group (women APOE ɛ4 carriers).MethodsWe used a 2-year longitudinal sample of AD patients (baseline N = 170; mean age = 71.3 [9.1] years) from the Sunnybrook Dementia Study. We applied latent class analysis, latent growth modeling, and path analysis. We aimed to replicate our findings (N = 184) in the Alzheimer's Disease Neuroimaging Initiative.ResultsWe observed that high brain atrophy class predicted lower functional performance and steeper decline. This association was moderated by APOE, sex, and high-risk group. Baseline findings as moderated by APOE and high-risk group were replicated.DiscussionWomen APOE ɛ4 carriers may selectively be at a greater risk of functional impairment with higher brain atrophy.

The Worldwide Alzheimer's Disease Neuroimaging Initiative (WW-ADNI) is a collaborative effort to investigate imaging and biofluid markers that can inform Alzheimer's disease treatment trials. It is a public-private partnership that spans North America, Argentina, Australia, Canada, China, Japan, Korea, Mexico, and Taiwan. In 2004, ADNI researchers began a naturalistic, longitudinal study that continues today around the globe. Through several successive phases (ADNI-1, ADNI-GO, ADNI-2, and ADNI-3), the study has fueled amyloid and tau phenotyping and refined neuroimaging methodologies. WW-ADNI researchers have successfully standardized analyses and openly share data without embargo, providing a rich data set for other investigators. On August 26, 2020, the Alzheimer's Association convened WW-ADNI researchers who shared updates from ADNI-3 and their vision for ADNI-4.

BackgroundFrontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72.MethodsIn this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried.FindingsData were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even more by family membership (66%, 56-75, for age at onset; 74%, 65-82, for age at death). In the GRN group, only 2% (0-10) of the variability of age at onset and 9% (3-21) of that of age of death was explained by the specific mutation, whereas 14% (9-22) of the variability of age at onset and 20% (12-30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11-26) of the variability of age at onset and 19% (12-29) of that of age at death.InterpretationOur study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates.FundingUK Medical Research Council, National Institute for Health Research, and Alzheimer's Society.

Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.

ObjectiveTo estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants.MethodsWe conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-β pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models.ResultsAmyloid-β positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p

BackgroundLoss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers.MethodsThe study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p

BackgroundSeveral sets of diagnostic criteria have been published for vascular dementia since the 1960s. The continuing ambiguity in vascular dementia definition warrants a critical reexamination.MethodsParticipants at a special symposium of the International Society for Vascular Behavioral and Cognitive Disorders (VASCOG) in 2009 critiqued the current criteria. They drafted a proposal for a new set of criteria, later reviewed through multiple drafts by the group, including additional experts and the members of the Neurocognitive Disorders Work Group of the fifth revision of Diagnostic and Statistical Manual (DSM-5) Task Force.ResultsCognitive disorders of vascular etiology are a heterogeneous group of disorders with diverse pathologies and clinical manifestations, discussed broadly under the rubric of vascular cognitive disorders (VCD). The continuum of vascular cognitive impairment is recognized by the categories of Mild Vascular Cognitive Disorder, and Vascular Dementia or Major Vascular Cognitive Disorder. Diagnostic thresholds are defined. Clinical and neuroimaging criteria are proposed for establishing vascular etiology. Subtypes of VCD are described, and the frequent cooccurrence of Alzheimer disease pathology emphasized.ConclusionsThe proposed criteria for VCD provide a coherent approach to the diagnosis of this diverse group of disorders, with a view to stimulating clinical and pathologic validation studies. These criteria can be harmonized with the DSM-5 criteria such that an international consensus on the criteria for VCD may be achieved.

We studied behavioral variant frontotemporal dementia (bvFTD) using object alternation (OA) as a novel probe of cognition. This task was adopted from animal models and is sensitive to ventrolateral-orbitofrontal and medial frontal function in humans. OA was administered to bvFTD patients, normal controls, and a dementia control group with Alzheimer disease (AD). Two other frontal lobe measures adopted from animal models were administered: delayed response (DR) and delayed alternation (DA). Brain volumes were measured using the semiautomatic brain region extraction method. Compared with the normal controls, bvFTD patients were significantly impaired on OA and DR. For OA and DR, sensitivities and specificities were 100% and 51.5% (cutoff=22.5 errors) and 9.5% and 98% (cutoff=1.5 errors), respectively. Negative predictive value (NPV) for OA was 100% at all prevalence rates. Comparing AD with bvFTD, there were no significant differences on OA, DR, or DA. Nevertheless, positive predictive value (PPV) and NPV were good at all prevalence rates for OA (cutoff=36.5 errors) and DA (cutoff=6 errors); PPV was good for DR (cutoff=9 errors). Error scores above cutoffs favored diagnosis of AD. Performance on OA was significantly related to medial frontal gray matter atrophy. OA, together with DR and DA, may facilitate assessment of bvFTD as a novel probe of medial frontal function.

Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, ¹⁸F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured ("metric": visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR-), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR- between 0.25 and 0.08, whereas prognostic LR+ and LR- were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR- from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR-. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR-. Within markers, the largest proportion of diagnostic LR+ and LR- variability was within ¹⁸F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.

In this study, hyperpolarized 13C MRI (HP‐13C MRI) was used to investigate changes in the uptake and metabolism of pyruvate with age. Hyperpolarized 13C‐pyruvate was administered to healthy aging individuals (N = 35, ages 21–77) and whole‐brain spatial distributions of 13C‐lactate and 13C‐bicarbonate production were measured. Linear mixed‐effects regressions were performed to compute the regional percentage change per decade, showing a significant reduction in both normalized 13C‐lactate and normalized 13C‐bicarbonate production with age: −7%±2% per decade for 13C‐lactate and −9%±4% per decade for 13C‐bicarbonate. Certain regions, such as the right medial precentral gyrus, showed greater rates of change while the left caudate nucleus had a flat 13C‐lactate versus age and a slightly increasing 13C‐bicarbonate versus age. The results show that both the production of lactate (visible as 13C‐lactate signal) as well as the consumption of monocarboxylates to make acetyl‐CoA (visible as 13C‐bicarbonate signal) decrease with age and that the rate of change varies by brain region. [ABSTRACT FROM AUTHOR]

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Copyright of Applied Physiology, Nutrition & Metabolism is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: One of the central features of brain aging is the accumulation of multiple age-related structural changes, which occur heterogeneously in individuals and can have immediate or potential clinical consequences. Each of these deficits can coexist and interact, producing both independent and additive impacts on brain health. Many of the changes can be visualized using MRI. To collectively assess whole-brain structural changes, the MRI-based Brain Atrophy and Lesion Index (BALI) has been developed. In this study, we validate this whole-brain health assessment approach using several clinical MRI examinations. Materials and methods: Data came from three independent studies: the Alzheimer's Disease Neuroimaging Initiative Phase II (n=950; women =47.9%; age =72.7±7.4 years); the National Alzheimer's Coordinating Center (n=722; women =55.1%; age =72.7±9.9 years); and the Tianjin Medical University General Hospital Research database on older adults (n=170; women =60.0%; age =62.9±9.3 years). The 3.0-Tesla MRI scans were evaluated using the BALI rating scheme on the basis of T1-weighted (T1WI), T2-weighted (T2WI), T2-weighted fluid-attenuated inversion recovery (T2-FLAIR), and T2*-weighted gradient-recalled echo (T2*GRE) images. Results: Atrophy and lesion changes were commonly seen in each MRI test. The BALI scores based on different sequences were highly correlated (Spearman r².0.69; P<0.00001). They were associated with age (r².0.29; P<0.00001) and differed by cognitive status (ϲ>.26.48, P<0.00001). T2-FLAIR revealed a greater level of periventricular (ϲ=29.09) and deep white matter (ϲ=26.65, P<0.001) lesions than others, but missed revealing certain dilated perivascular spaces that were seen in T2WI (P<0.001). Microhemorrhages occurred in 15.3% of the sample examined and were detected using only T2*GRE. Conclusion: The T1WI- and T2WI-based BALI evaluations consistently identified the burden of aging and dementia-related decline of structural brain health. Inclusion of additional MRI tests increased lesion differentiation. Further research is to integrate MRI tests for a clinical tool to aid the diagnosis and intervention of brain aging. [ABSTRACT FROM AUTHOR]

Introduction Cerebral small vessel disease (CSVD) is a highly prevalent condition associated with diffuse ischemic damage and cognitive dysfunction particularly in executive function and attention. Functional brain imaging studies can reveal mechanisms of cognitive impairment in CSVD, although findings are mixed. Methods A systematic review integrating findings from functional magnetic resonance imaging and electroencephalography in CSVD is involved. Results CSVD damages long-range white matter tracts connecting nodes within distributed brain networks. It also disrupts frontosubcortical circuits and cholinergic fiber tracts mediating attentional processes. These changes, illustrated within a model of network dynamics, synergistically relate to neurodegenerative pathology contributing to dementia. Discussion The effects of CSVD on attention and executive functioning are best understood within a network model of cognition as revealed by functional neuroimaging. Analysis of network function in CSVD can improve characterization of disease severity and treatment effects, and it can inform theoretical models of brain function. [ABSTRACT FROM AUTHOR]

Although white matter hyperintensities (WMH), markers of cerebral small vessel disease (SVD), are believed to generally increase over time, some studies have shown sharp decreases after therapeutic intervention, suggesting that WMH progression may be more dynamic than previously thought. Our primary goal was to examine dynamic progression of WMH in a real-world sample of Alzheimer's disease (AD) patients and normal elderly (NC), with varying degrees of SVD. WMH volumes from serial magnetic resonance imaging (MRI; mean = 1.8 years) were measured from NC (n = 44) and AD patients (n = 113) with high and low SVD burden. Dynamic progression for each individual was measured using spatial overlap images to assess shrinkage, growth, and stable WMH volumes. Significant group differences were found for shrinkage (p < 0.001), growth (p < 0.001) and stable (p < 0.001) WMH, where the AD high SVD group showed the largest changes relative to low SVD and NC. Our results suggest spatial progression measured at the individual patient level may be more sensitive to the dynamic nature of WMH. [ABSTRACT FROM AUTHOR]

Given the recent acknowledgement of the complex mixed pathologies that contribute to the clinical expression of dementia, various cohort studies have aimed to examine Alzheimer's disease and cerebrovascular disease as comorbid pathologies, with neuroimaging playing a central role in these studies. Using white matter hyperintensities (WMH) as a biomarker of cerebrovascular disease, we compared WMH burden between the Sunnybrook Dementia Study, the Alzheimer's Disease Neuroimaging Initiative (ADNI-1), the Three-City Study, and various other studies around the world. Based on our findings, it was evident that ADNI-1 had minimal WMH burden relative to other large studies that examine aging and dementia. This low WMH burden in ADNI-1 may be considered as both an advantage, representing a relatively “pure” sample with little confounding vasculopathy, and a disadvantage, as it limits generalizability to “real-world” patient populations with mixed pathologies and to nondemented groups with baseline vascular disease. We explore possible reasons for this distinction, including management of vascular risk factors, gaps in diagnostic criteria, and future directions for clinical research. [ABSTRACT FROM AUTHOR]

Background: A brain atrophy and lesion index (BALI) based on high-field magnetic resonance imaging (MRI) has recently been validated to evaluate structural changes in the aging brain. The present study investigated the two-year progression of brain structural deficits in people with Alzheimer's disease (AD) and mild cognitive impairment (MCI), and in healthy control older adults (HC) using the BALI rating. Methods: T1-weighted high-resolution anatomical imaging data using 3 Tesla MRI at baseline (AD = 39, MCI = 82, HC = 58) and at 24-months were obtained from the Alzheimer's disease Neuroimaging Initiative database. Lesions in various brain structures, including the infratentorial and basal ganglia areas, and the periventricular and deep white matter and global atrophy, were evaluated and combined into the BALI scale. Results: Mean progression of brain deficits over two years was evident in all diagnostic groups (p < 0.001) and was statistically greater in MCI-AD converters than in the non-converters (p = 0.044). An increase in the BALI score was significantly associated with cognitive test scores (p = 0.008 for the Mini-Mental State Examination MMSE and p = 0.013 for the Alzheimer's Disease Assessment Scale-Cognitive Subscale ADAS-cog) in a model that adjusted for age, sex, and education. Conclusion: The BALI rating quantified the progression of brain deficits over two years, which is associated with cognitive decline. BALI ratings may be used to help summarize AD-associated structural variations. [ABSTRACT FROM AUTHOR]