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Introduction: Melanopsin is a photopigment with roles in mediating sleep and circadian-related processes, which are often disrupted in Alzheimer's disease (AD). Melanopsin also impacts cognition and synaptogenesis. This study investigated the associations between melanopsin genetic variants, sleep, and markers of brain health., Methods: Linear regression analyses examined the relationship of single-nucleotide polymorphisms (SNPs) within the melanopsin gene ( OPN4 ), with cortical amyloid beta (Aβ), cognition, brain volumes, and self-reported sleep traits in cognitively unimpaired older adults. Further analyses assessed whether sleep traits x OPN4 SNP interactions were associated with markers of brain health., Results: OPN4 SNPs rs2355009 and rs3740334 were associated with attention and processing speed and ventricular volume and language, respectively. Furthermore, rs3740334 and rs1079610 showed significant interactions with sleep traits in association with language., Discussion: This study shows associations of OPN4 genetic variants with markers of brain health, and suggests that these variants interact with sleep to exacerbate cognitive effects., Highlights: The relationships between melanopsin gene ( OPN4 ) variants and markers of brain health were examined cross-sectionally in cognitively unimpaired older individuals.Variation within OPN4 is associated with differences in cognition and ventricular volume.rs2355009 and rs3740334 show small-moderate associations with differences in attention and processing speed. Further to this, rs2355009 and rs3740334 were associated with ventricular volumes and language performance, respectively.The interactions between rs3740334 and rs1079610 and sleep traits also showed small-moderate associations with differences in language performance., Competing Interests: A.M.A., E.O., T.P., V.D., P.B., S.R.R.S., and S.M.L. report no disclosures. V.L.V. is and has been a consultant or paid speaker at sponsored conference sessions for Eli Lilly, Life Molecular Imaging, ACE Barcelona, and IXICO. P.M. is a full‐time employee of Cogstate Ltd. C.C.R. has served on scientific advisory boards for Bayer Pharma, Elan Corporation, GE Healthcare, and AstraZeneca; has received speaker honoraria from Bayer Pharma and GE Healthcare; and has received research support from Bayer Pharma, GE Healthcare, Piramal Lifesciences, and Avid Radiopharmaceuticals. Author disclosures are available in the Supporting Information., (© 2025 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Blood biomarkers are an emerging diagnostic and prognostic tool that reflect a range of neuropathological processes following traumatic brain injury (TBI). Their effectiveness in identifying long-term neuropathological processes after TBI is unclear. Studying biomarkers in the chronic phase is vital because elevated levels in TBI might result from distinct neuropathological mechanisms during acute and chronic phases. Here, we examine plasma biomarkers in the chronic period following TBI and their association with amyloid and tau PET, white matter microarchitecture, brain age and cognition. We recruited participants ≥40 years of age who had suffered a single moderate-severe TBI ≥10 years previously between January 2018 and March 2021. We measured plasma biomarkers using single molecule array technology [ubiquitin C-terminal hydrolase L1 (UCH-L1), neurofilament light (NfL), tau, glial fibrillary acidic protein (GFAP) and phosphorylated tau (P-tau181)]; PET tracers to measure amyloid-β (18F-NAV4694) and tau neurofibrillary tangles (18F-MK6240); MRI to assess white matter microstructure and brain age; and the Rey Auditory Verbal Learning Test to measure verbal-episodic memory. A total of 90 post-TBI participants (73% male; mean = 58.2 years) were recruited on average 22 years (range = 10-33 years) post-injury, and 32 non-TBI control participants (66% male; mean = 57.9 years) were recruited. Plasma UCH-L1 levels were 67% higher {exp(b) = 1.67, P = 0.018, adjusted P = 0.044, 95% confidence interval (CI) [10% to 155%], area under the curve = 0.616} and P-tau181 were 27% higher {exp(b) = 1.24, P = 0.011, adjusted P = 0.044, 95% CI [5% to 46%], area under the curve = 0.632} in TBI participants compared with controls. Amyloid and tau PET were not elevated in TBI participants. Higher concentrations of plasma P-tau181, UCH-L1, GFAP and NfL were significantly associated with worse white matter microstructure but not brain age in TBI participants. For TBI participants, poorer verbal-episodic memory was associated with higher concentration of P-tau181 {short delay: b = -2.17, SE = 1.06, P = 0.043, 95% CI [-4.28, -0.07]; long delay: bP-tau = -2.56, SE = 1.08, P = 0.020, 95% CI [-4.71, -0.41]}, tau {immediate memory: bTau = -6.22, SE = 2.47, P = 0.014, 95% CI [-11.14, -1.30]} and UCH-L1 {immediate memory: bUCH-L1 = -2.14, SE = 1.07, P = 0.048, 95% CI [-4.26, -0.01]}, but was not associated with functional outcome. Elevated plasma markers related to neuronal damage and accumulation of phosphorylated tau suggest the presence of ongoing neuropathology in the chronic phase following a single moderate-severe TBI. Plasma biomarkers were associated with measures of microstructural brain disruption on MRI and disordered cognition, further highlighting their utility as potential objective tools to monitor evolving neuropathology post-TBI., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: In early Alzheimer disease (AD), β-amyloid (Aβ) deposition is associated with volume loss in the basal forebrain (BF) and cognitive decline. However, the extent to which Aβ-related BF atrophy manifests as cognitive decline is not understood. This study sought to characterize the relationship between BF atrophy and the decline in memory and attention in patients with early AD., Methods: Participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study who completed Aβ-PET imaging and repeated MRI and cognitive assessments were included. At baseline, participants were classified based on their clinical dementia stage and Aβ status, yielding groups that were cognitively unimpaired (CU) Aβ-, CU Aβ+, and mild cognitive impairment (MCI) Aβ+. Linear mixed-effects models were used to assess changes in volumetric measures of BF subregions and the hippocampus and changes in AIBL memory and attention composite scores for each group compared with CU Aβ- participants. Associations between Aβ burden, brain atrophy, and cognitive decline were evaluated and explored further using mediation analyses., Results: The cohort included 476 participants (72.6 ± 5.9 years, 55.0% female) with longitudinal data from a median follow-up period of 6.1 years. Compared with the CU Aβ- group (n = 308), both CU Aβ+ (n = 107) and MCI Aβ+ (n = 61) adults showed faster decline in BF and hippocampal volumes and in memory and attention (Cohen d = 0.73-1.74). Rates of atrophy in BF subregions and the hippocampus correlated with cognitive decline, and each individually mediated the impact of Aβ burden on memory and attention decline. When all mediators were considered simultaneously, hippocampal atrophy primarily influenced the effect of Aβ burden on memory decline (β [SE] = -0.139 [0.032], proportion mediated [PM] = 28.0%) while the atrophy of the posterior nucleus basalis of Meynert in the BF (β [SE] = -0.068 [0.029], PM = 13.1%) and hippocampus (β [SE] = -0.121 [0.033], PM = 23.4%) distinctively influenced Aβ-related attention decline., Discussion: These findings highlight the significant role of BF atrophy in the complex pathway linking Aβ to cognitive impairment in early stages of AD. Volumetric assessment of BF subregions could be essential in elucidating the relationships between the brain structure and behavior in AD.

I SYSTEMIC DISCRIMINATION IN THE LEGAL PROFESSION 84 II THE LAW SOCIETY'S EVOLVING MANDATE 85 III THE LAW SOCIETY IS ENTITLED TO DEFERENCE 88 IV RECOGNIZING A STATUTORY MANDATE TO [...], The Law Society of Ontario ("LSO") has been subjected to vocal criticism for its recent efforts to promote diversity in the legal profession. According to some detractors, this mission oversteps the LSO's jurisdiction based on its statutory mandate, which has traditionally focused on regulating the standards of practice for legal professionals. This split in the legal profession invites an examination of the proper role of the LSO with respect to addressing the systemic discrimination that persists in legal practice. The main contention of this article is that the LSO has a statutory mandate to promote diversity in the legal profession, based on the language of its governing statute, the LSO's own public commitment to this objective, and supporting policy rationales. Although no specific action or policy is prescribed, the LSO has an overarching duty to pursue this proper and constitutional objective. In particular, the Statement of Principles requirement it has implemented for licensees is a justifiable and constitutional course of action in fulfilling this mandate. The overall effect of this mandate is that the legal profession, their clients, and society should expect the LSO to be proactive in resolving issues of diversity and discrimination in legal practice. KEYWORDS Law Society; diversity; legal profession regulation; public interest; Statement of Principles

Introduction: The current study evaluated the relationship between habitual physical activity (PA) levels and brain amyloid beta (Aβ) over 15 years in a cohort of cognitively unimpaired older adults., Methods: PA and Aβ measures were collected over multiple timepoints from 731 cognitively unimpaired older adults participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Aging. Regression modeling examined cross-sectional and longitudinal relationships between PA and brain Aβ. Moderation analyses examined apolipoprotein E (APOE) ε4 carriage impact on the PA-Aβ relationship., Results: PA was not associated with brain Aβ at baseline (β = -0.001, p = 0.72) or over time (β = -0.26, p = 0.24). APOE ε4 status did not moderate the PA-Aβ relationship over time (β = 0.12, p = 0.73). Brain Aβ levels did not predict PA trajectory (β = -54.26, p = 0.59)., Discussion: Our study did not identify a relationship between habitual PA and brain Aβ levels., Highlights: Physical activity levels did not predict brain amyloid beta (Aβ) levels over time in cognitively unimpaired older adults (≥60 years of age). Apolipoprotein E (APOE) ε4 carrier status did not moderate the physical activity-brain Aβ relationship over time. Physical activity trajectories were not impacted by brain Aβ levels., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Objectives: While the highest prevalence of dementia occurs in individuals older than 80 years, most imaging studies focused on younger populations. The rates of β-amyloid (Aβ) accumulation and the effect of Alzheimer disease (AD) pathology on progression to dementia in this age group remain unexplored. In this study, we examined the relationship between changes in Aβ deposition over time and incident dementia in nondemented individuals followed during a period of 11 years., Methods: We examined 94 participants (age 85.9 + 2.8 years) who had up to 5 measurements of Pittsburgh compound-B (PiB)-PET and clinical evaluations from 2009 to 2020. All 94 participants had 2 PiB-PET scans, 76 participants had 3 PiB-PET scans, 18 participants had 4 PiB-PET scans, and 10 participants had 5 PiB-PET scans. The rates of Aβ deposition were compared with 120 nondemented individuals younger than 80 years (69.3 ± 5.4 years) from the Australian Imaging, Biomarker, and Lifestyle (AIBL) study who had 3 or more annual PiB-PET assessments., Results: By 2020, 49% of the participants developed dementia and 63% were deceased. There was a gradual increase in Aβ deposition in all participants whether they were considered Aβ positive or negative at baseline. In a Cox model controlled for age, sex, education level, APOE-4 allele, baseline Mini-Mental State Examination, and mortality, short-term change in Aβ deposition was not significantly associated with incident dementia (HR 2.19 (0.41-11.73). However, baseline Aβ burden, cortical thickness, and white matter lesions volume were the predictors of incident dementia. Aβ accumulation was faster ( p = 0.01) in the older cohort (5.6%/year) when compared with AIBL (4.1%/year). In addition, baseline Aβ deposition was a predictor of short-term change (mean time 1.88 years)., Discussion: There was an accelerated Aβ accumulation in cognitively normal individuals older than 80 years. Baseline Aβ deposition was a determinant of incident dementia and short-term change in Aβ deposition suggesting that an active Aβ pathologic process was present when these participants were cognitively normal. Consequently, age may not be a limiting factor for the use of the emergent anti-Aβ therapies.

Background and Objectives: There are limited validated biomarkers in Parkinson disease (PD) which substantially hinders the ability to monitor disease progression and consequently measure the efficacy of disease-modifying treatments. Imaging biomarkers, such as vesicular monoamine transporter type 2 (VMAT2) PET, enable enhanced diagnostic accuracy and detect early neurodegenerative changes associated with prodromal PD. This study sought to assess whether 18 F-AV-133 VMAT2 PET is sensitive enough to monitor and quantify disease progression over a 2-year window., Methods: 18 F-AV-133 PET scans were performed on participants with PD and REM sleep behavior disorder (RBD) and neurologic controls (NC). All participants were scanned twice ∼26 months apart. Regional tracer retention was calculated with a primary visual cortex reference region and expressed as the standard uptake volume ratio. Regions of interest included caudate, anterior, and posterior putamen. At the time of scanning, participants underwent clinical evaluation including UPDRS MOTOR test, Sniffin' Sticks, and Hospital Anxiety and Depression Score., Results: Over the 26-month interval, a significant decline in PET signal was observed in all 3 regions in participants with PD (N = 26) compared with NC (N = 12), consistent with a decrease in VMAT2 level and ongoing neurodegeneration. Imaging trajectory calculations suggest that the neurodegeneration in PD occurs over ∼33 years [CI: 27.2-39.5], with ∼10.5 years [CI: 9.1-11.3] of degeneration in the posterior putamen before it becomes detectable on a VMAT2 PET scan, a further ∼6.5 years [CI: 1.6-12.7] until symptom onset, and a further ∼3 years [CI: 0.3-8.7] until clinical diagnosis., Discussion: Over a 2-year period, 18 F-AV-133 VMAT2 PET was able to detect progression of nigrostriatal degeneration in participants with PD, and it represents a sensitive tool to identify individuals at risk of progression to PD, which are currently lacking using clinical readouts. Trajectory models propose that there is nigrostriatal degeneration occurring for 20 years before clinical diagnosis. These data demonstrate that VMAT2 PET provides a sensitive measure to monitor neurodegenerative progression of PD which has implications for PD diagnostics and subsequently clinical trial patient stratification and monitoring., Classification of Evidence: This study provides Class IV evidence that VMAT2 PET can detect patients with Parkinson disease and quantify progression over a 2-year window., (© 2023 American Academy of Neurology.)

The author addresses two perennial problems in Canadian administrative law: the choice of a standard of review and the inconsistent application of the reasonableness standard. With these problems in mind, [...]

A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer's disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study (n = 1,325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired individuals who were amyloid PET-positive (A + ) and tau PET-positive (T + ) in the medial temporal lobe (A + T MTL + ) and/or in the temporal neocortex (A + T NEO-T + ) and compared them with A + T - and A - T - groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A + T NEO-T + (hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9-33.7), A + T MTL + (HR = 14.6, 95% CI = 8.1-26.4) and A + T - (HR = 2.4, 95% CI = 1.4-4.3) groups versus the A - T - (reference) group. Both A + T MTL + (HR = 6.0, 95% CI = 3.4-10.6) and A + T NEO-T + (HR = 7.9, 95% CI = 4.7-13.5) groups also showed faster clinical progression to mild cognitive impairment than the A + T - group. Linear mixed-effect models indicated that the A + T NEO-T + (β = -0.056 ± 0.005, T = -11.55, P < 0.001), A + T MTL + (β = -0.024 ± 0.005, T = -4.72, P < 0.001) and A + T - (β = -0.008 ± 0.002, T = -3.46, P < 0.001) groups showed significantly faster longitudinal global cognitive decline compared to the A - T - (reference) group (all P < 0.001). Both A + T NEO-T + (P < 0.001) and A + T MTL + (P = 0.002) groups also progressed faster than the A + T - group. In summary, evidence of advanced Alzheimer's disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3-5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance., (© 2022. The Author(s).)

Cholesterol levels have been repeatedly linked to Alzheimer's Disease (AD), suggesting that high levels could be detrimental, but this effect is likely attributed to Low-Density Lipoprotein (LDL) cholesterol. On the other hand, High-Density Lipoproteins (HDL) cholesterol levels have been associated with reduced brain amyloidosis and improved cognitive function. However, recent findings have suggested that HDL-functionality, which depends upon the HDL-cargo proteins associated with HDL, rather than HDL levels, appears to be the key factor, suggesting a quality over quantity status. In this report, we have assessed the HDL-cargo (Cholesterol, ApoA-I, ApoA-II, ApoC-I, ApoC-III, ApoD, ApoE, ApoH, ApoJ, CRP, and SAA) in stable healthy control (HC), healthy controls who will convert to MCI/AD (HC-Conv) and AD patients (AD). Compared to HC we observed an increased cholesterol/ApoA-I ratio in AD and HC-Conv, as well as an increased ApoD/ApoA-I ratio and a decreased ApoA-II/ApoA-I ratio in AD. Higher cholesterol/ApoA-I ratio was also associated with lower cortical grey matter volume and higher ventricular volume, while higher ApoA-II/ApoA-I and ApoJ/ApoA-I ratios were associated with greater cortical grey matter volume (and for ApoA-II also with greater hippocampal volume) and smaller ventricular volume. Additionally, in a clinical status-independent manner, the ApoE/ApoA-I ratio was significantly lower in APOE ε4 carriers and lowest in APOE ε4 homozygous. Together, these data indicate that in AD patients the composition of HDL is altered, which may affect HDL functionality, and such changes are associated with altered regional brain volumetric data., (© 2022 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Background and Objectives: Traumatic brain injury (TBI) has been promoted as a risk factor for Alzheimer disease (AD). There is evidence of elevated β-amyloid (Aβ) and tau, the pathologic hallmarks of AD, immediately following TBI. It is not clear whether Aβ and tau remain elevated in the chronic period. To address this issue, we assessed Aβ and tau burden in long-term TBI survivors and healthy controls using PET imaging., Methods: Using a cross-sectional design, we recruited individuals following a single moderate to severe TBI at least 10 years previously from an inpatient rehabilitation program. A demographically similar healthy control group was recruited from the community. PET data were acquired using 18 F-NAV4694 (Aβ) and 18 F-MK6240 (tau) tracers. Aβ deposition was quantified using the Centiloid scale. Tau deposition was quantified using the standardized uptake value ratio (SUVR) in 4 regions of interest (ROIs). As a secondary measure, PET scans were also visually read as positive or negative. We examined PET data in relation to time since injury and age at injury. PET data were analyzed in a series of regression analyses., Results: The sample comprised 87 individuals with TBI (71.3% male; 28.7% female; mean 57.53 years, SD 11.53) and 59 controls (59.3% male; 40.7% female; mean 60.34 years, SD 11.97). Individuals with TBI did not have significantly higher 18 F-NAV4694 Centiloid values ( p = 0.067) or 18 F-MK6240 tau SUVRs in any ROI ( p ≤ 0.001; SUVR greater for controls). Visual assessment was consistent with the quantification; individuals with TBI were not more likely than controls to have a positive Aβ ( p = 0.505) or tau scan ( p = 0.221). No associations were identified for Aβ or tau burden with time since injury ( p = 0.057 to 0.332) or age at injury., Discussion: A single moderate to severe TBI was not associated with higher burden of Aβ or tau pathologies in the chronic period relative to healthy controls. Aβ and tau burden did not show a significant increase with years since injury, and burden did not appear to be greater for those who were older at the time of injury., (© 2022 American Academy of Neurology.)

Mounting evidence implicates insulin resistance (IR) with reduced cognition, increased dementia risk and changes in Alzheimer's disease biomarkers. It's unclear how, and at what stage IR has the greatest impact on Alzheimer's disease biomarker progression indicative of cognitive decline. Exploration of potential factors influencing this relationship continue. We have previously reported IR to be associated with cognitive function, and increased CSF tau in a cognitively unimpaired cohort. Now, we aimed to determine if CSF total (t-tau) or phosphorylated tau (p-tau) mediated the relationship between HOMA-IR and cognition, and explore sex or amyloid-β (Aβ) biomarkers as moderators of this relationship. Mediation analysis demonstrated that CSF tau does not directly influence the association between HOMA-IR and cognition. Moderation analysis revealed CSF Aβ42 moderates the relationships between HOMA-IR and CSF tau. The combination of lower CSF Aβ42 and higher HOMA-IR was associated with increases in CSF tau. The CSF Aβ42 moderation finding has potential to be considered when assessing type 2 diabetic risk for tau pathology and cognitive decline., (Copyright © 2022. Published by Elsevier Inc.)

Previous studies have indicated that physical activity may be beneficial in reducing the risk for Alzheimer's disease (AD), although the underlying mechanisms are not fully understood. The goal of this study was to evaluate the relationship between habitual physical activity levels and brain amyloid deposition and AD-related blood biomarkers (i.e., measured using a novel high-performance mass spectrometry-based assay), in apolipoprotein E (APOE) ε4 carriers and noncarriers. We evaluated 143 cognitively normal older adults, all of whom had brain amyloid deposition assessed using positron emission tomography and had their physical activity levels measured using the International Physical Activity Questionnaire (IPAQ). We observed an inverse correlation between brain amyloidosis and plasma beta-amyloid (Aβ) 1-42 but found no association between brain amyloid and plasma Aβ 1-40 and amyloid precursor protein (APP) 669-711 . Additionally, higher levels of physical activity were associated with lower plasma Aβ 1-40 , Aβ 1-42 , and APP 669-711 levels in APOE ε4 noncarriers. The ratios of Aβ 1-40 /Aβ 1-42 and APP 669-711 /Aβ 1-42 , which have been associated with higher brain amyloidosis in previous studies, differed between APOE ε4 carriers and non-carriers. Taken together, these data indicate a complex relationship between physical activity and brain amyloid deposition and potential blood-based AD biomarkers in cognitively normal older adults. In addition, the role of APOE ε4 is still unclear, and more studies are necessary to bring further clarification., Competing Interests: NK was employed by Shimadzu Corporation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pedrini, Chatterjee, Nakamura, Tegg, Hone, Rainey-Smith, Rowe, Dore, Villemagne, Ames, Kaneko, Gardener, Taddei, Fernando, Martins, Bharadwaj, Sohrabi, Masters, Brown and Martins.)

Objective: To determine the proportional genetic contribution to the variability of cerebral β-amyloid load in older adults using the classic twin design., Methods: Participants (n=206) comprising 61 monozygotic (MZ) twin pairs (68 (55.74%) females; mean age (SD): 71.98 (6.43) years), and 42 dizygotic (DZ) twin pairs (56 (66.67%) females; mean age: 71.14 (5.15) years) were drawn from the Older Australian Twins Study. Participants underwent detailed clinical and neuropsychological evaluations, as well as MRI, diffusion tensor imaging (DTI) and amyloid PET scans. Fifty-eight participants (17 MZ pairs, 12 DZ pairs) had PET scans with 11 Carbon-Pittsburgh Compound B, and 148 participants (44 MZ pairs, 30 DZ pairs) with 18 Fluorine-NAV4694. Cortical amyloid burden was quantified using the centiloid scale globally, as well as the standardised uptake value ratio (SUVR) globally and in specific brain regions. Small vessel disease (SVD) was quantified using total white matter hyperintensity volume on MRI, and peak width of skeletonised mean diffusivity on DTI. Heritability ( h 2 ) and genetic correlations were measured with structural equation modelling under the best fit model, controlling for age, sex, tracer and scanner., Results: The heritability of global amyloid burden was moderate (0.41 using SUVR; 0.52 using the centiloid scale) and ranged from 0.20 to 0.54 across different brain regions. There were no significant genetic or environmental correlations between global amyloid burden and markers of SVD., Conclusion: Amyloid deposition, the hallmark early feature of Alzheimer's disease, is under moderate genetic influence, suggesting a major environmental contribution that may be amenable to intervention., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The blood-brain barrier (BBB) is formed by a high-density lining of endothelial cells, providing a border between circulating blood and the brain interstitial fluid. This structure plays a key role in protecting the brain microenvironment by restricting passage of certain molecules and circulating pathogens., Objective: To identify associations between brain volumetric changes and a set of 355 BBB-related single nucleotide polymorphisms (SNP)., Method: In a population of 721 unrelated individuals, linear mixed effect models were used to assess if specific variants were linked to regional rates of atrophy over a 12-year time span. Four brain regions were investigated, including cortical grey matter, cortical white matter, ventricle, and hippocampus. Further, we also investigated the potential impact of history of hypertension, diabetes, and the incidence of stroke on regional brain volume change., Results: History of hypertension, diabetes, and stroke was not associated with longitudinal brain volume change. However, we identified a series of genetic variants associated with regional brain volume changes. The associations were independent of variation due to the APOEɛ4 allele and were significant post correction for multiple comparisons., Conclusion: This study suggests that key genes involved in the regulation of BBB integrity may be associated with longitudinal changes in specific brain regions. The derived polygenic risk scores indicate that these interactions are multigenic. Further research needs to be conducted to investigate how BBB functions maybe compromised by genetic variation.

Background: Arterial spin labeling (ASL) is an emerging MRI technique for noninvasive measurement of cerebral blood flow (CBF) that has been used to show hemodynamic changes in the brains of people with Alzheimer's disease (AD). CBF changes have been measured using positron emission tomography (PET) across the AD spectrum, but ASL showed limited success in measuring CBF variations in the preclinical phase of AD, where amyloid β (Aβ) plaques accumulate in the decades prior to symptom onset., Purpose: To investigate the relationship between CBF measured by multiphase-pseudocontinuous-ASL (MP-PCASL) and Aβ burden as measured by 11 C-PiB PET imaging in a study of cognitively normal (CN) subjects age over 65., Study Type: Cross-sectional., Population: Forty-six CN subjects including 33 with low levels of Aβ burden and 13 with high levels of Aβ., Field Strength/sequence: 3T/3D MP-PCASL., Assessment: The MP-PCASL method was chosen because it has a high signal-to-noise ratio. Furthermore, the data were analyzed using an efficient processing pipeline consisting of motion correction, ASL motion correction imprecision removal, temporal and spatial filtering, and partial volume effect correction., Statistical Tests: General Linear Model., Results: In CN subjects positive for Aβ burden (n = 13), we observed a positive correlation between CBF and Aβ burden in the hippocampus, amygdala, caudate (P < 0.01), frontal, temporal, and insula (P < 0.05)., Data Conclusion: To the best of our knowledge, this is the first study using MP-PCASL in the study of AD, and the results suggest a potential compensatory hemodynamic mechanism that protects against pathology in the early stages of AD., Level of Evidence: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:505-513., (© 2019 International Society for Magnetic Resonance in Medicine.)