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1. Brain structure and allelic associations in Alzheimer's disease

   https://doi.org/10.1111/cns.14073  

   Moon, Seok Woo ; Zhao, Lu ; Matloff, William ; Hobel, Sam ; Berger, Ryan ; Kwon, Daehong ; Kim, Jaebum ; Toga, Arthur W. ; Dinov, Ivo D. ; for the Alzheimer's Disease Neuroimaging Initiative ( December 2022 , CNS Neuroscience & Therapeutics)

   Alzheimer's disease (AD), the most prevalent form of dementia, affects 6.5 million Americans and over 50 million people globally. Clinical, genetic, and phenotypic studies of dementia provide some insights of the observed progressive neurodegenerative processes, however, the mechanisms underlying AD onset remain enigmatic.

   This paper examines late‐onset dementia‐related cognitive impairment utilizing neuroimaging‐genetics biomarker associations.

   The participants, ages 65–85, included 266 healthy controls (HC), 572 volunteers with mild cognitive impairment (MCI), and 188 Alzheimer's disease (AD) patients. Genotype dosage data for AD‐associated single nucleotide polymorphisms (SNPs) were extracted from the imputed ADNI genetics archive using sample‐major additive coding. Such 29 SNPs were selected, representing a subset of independent SNPs reported to be highly associated with AD in a recent AD meta‐GWAS study by Jansen and colleagues.

   We identified the significant correlations between the 29 genomic markers (GMs) and the 200 neuroimaging markers (NIMs). The odds ratios and relative risks for AD and MCI (relative to HC) were predicted using multinomial linear models.

   In the HC and MCI cohorts, mainly cortical thickness measures were associated with GMs, whereas the AD cohort exhibited different GM‐NIM relations. Network patterns within the HC and AD groups were distinct in cortical thickness, volume, and proportion of White to Gray Matter (pct), but not in the MCI cohort. Multinomial linear models of clinical diagnosis showed precisely the specific NIMs and GMs that were most impactful in discriminating between AD and HC, and between MCI and HC.

   This study suggests that advanced analytics provide mechanisms for exploring the interrelations between morphometric indicators and GMs. The findings may facilitate further clinical investigations of phenotypic associations that support deep systematic understanding of AD pathogenesis.

    

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2. Diffusion MRI tractography of the locus coeruleus‐transentorhinal cortex connections using GO‐ESP

   https://doi.org/10.1002/mrm.29088  

   Solders, Seraphina K. ; Galinsky, Vitaly L. ; Clark, Alexandra L. ; Sorg, Scott F. ; Weigand, Alexandra J. ; Bondi, Mark W. ; Frank, Lawrence R. ( November 2021 , Magnetic Resonance in Medicine)

   The locus coeruleus (LC) is implicated as an early site of protein pathogenesis in Alzheimer's disease (AD). Tau pathology is hypothesized to propagate in a prion‐like manner along the LC‐transentorhinal cortex (TEC) white matter (WM) pathway, leading to atrophy of the entorhinal cortex and adjacent cortical regions in a progressive and stereotypical manner. However, WM damage along the LC‐TEC pathway may be an earlier observable change that can improve detection of preclinical AD.

   Diffusion‐weighted MRI (dMRI) allows reconstruction of WM pathways in vivo, offering promising potential to examine this pathway and enhance our understanding of neural mechanisms underlying the preclinical phase of AD. However, standard dMRI analysis tools have generally been unable to reliably reconstruct this pathway. We apply a novel method, geometric‐optics based entropy spectrum pathways (GO‐ESP) and produce a new measure of connectivity: the equilibrium probability (EP).

   We demonstrated reliable reconstruction of LC‐TEC pathways in 50 cognitively normal older adults and showed a negative association between LC‐TEC EP and cerebrospinal fluid tau. Using Human Connectome Project data, we demonstrated replicability of the method across acquisition schemes and scanners. Finally, we compared our findings with the only other existing LC‐TEC tractography template, and replicated their pathway as well as investigated the source of these discrepant findings.

   AD‐related tau pathology may be detectable within GO‐ESP‐identified LC‐TEC pathways. Furthermore, there may be multiple possible routes from LC to TEC, raising important questions for future research on the LC‐TEC connectome and its role in AD pathogenesis.

    

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3. What’s the cut-point?: a systematic investigation of tau PET thresholding methods

   https://doi.org/10.1186/s13195-022-00986-w  

   Weigand, Alexandra J. ; Maass, Anne ; Eglit, Graham L. ; Bondi, Mark W. ( April 2022 , Alzheimer's Research & Therapy)

   Tau positron emission tomography (PET) is increasing in popularity for biomarker characterization of Alzheimer’s disease (AD), and recent frameworks rely on tau PET cut-points to stage individuals along the AD continuum. Given the lack of standardization in tau PET thresholding methods, this study sought to systematically canvass and characterize existing studies that have derived tau PET cut-points and then directly assess different methods of tau PET thresholding in terms of their concurrent validity.

   First, a literature search was conducted in PubMed to identify studies of AD and related clinical phenotypes that used the Flortaucipir (AV-1451) tau PET tracer to derive a binary cut-point for tau positivity. Of 540 articles screened and 47 full-texts reviewed, 23 cohort studies met inclusion criteria with a total of 6536 participants. Second, we derived and compared tau PET cut-points in a 2 × 2 × 2 design that systematically varied region (temporal meta-ROI and entorhinal cortex), analytic method (receiver operating characteristics and 2 standard deviations above comparison group), and criterion/comparison variable (amyloid-beta negative cognitively unimpaired or cognitively unimpaired only) using a sample of 453 older adults from the Alzheimer’s Disease Neuroimaging Initiative.

   For the systematic review, notable variability in sample characteristics, preprocessing methods, region of interest, and analytic approach were observed, which were accompanied by discrepancy in proposed tau PET cut points. The empirical follow-up indicated the cut-point derived based on 2 standard deviations above a either comparison group in either ROI best differentiated tau positive and negative groups on cerebrospinal fluid phosphorylated tau, Mini-Mental State Examination score, and delayed memory performance.

   Given the impact of discrepant thresholds on tau positivity rates, biomarker staging, and eligibility for future clinical treatment trials, recommendations are offered to select cut-point derivations based on the unique goals and priorities of different studies.

    

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4. Observation of Reduced Homeostatic Metabolic Activity and/or Coupling in White Matter Aging

   https://doi.org/10.1111/jon.12744  

   Anderson, Valerie C. ; Tagge, Ian J. ; Li, Xin ; Quinn, Joseph F. ; Kaye, Jeffrey A. ; Bourdette, Dennis N. ; Spain, Rebecca I. ; Riccelli, Louis P. ; Sammi, Manoj K. ; Springer, Jr, Charles S. ; et al ( June 2020 , Journal of Neuroimaging)

   Transvascular water exchange plays a key role in the functional integrity of the blood–brain barrier (BBB). In white matter (WM), a variety of imaging modalities have demonstrated age‐related changes in structure and metabolism, but the extent to which water exchange is altered remains unclear. Here, we investigated the cumulative effects of healthy aging on WM capillary water exchange.

   A total of 38 healthy adults (aged 36‐80 years) were studied using 7T dynamic contrast enhanced MRI. Blood volume fraction (v_b) and capillary water efflux rate constant (k_po) were determined by fitting changes in the¹H₂O longitudinal relaxation rate constant (R₁) during contrast agent bolus passage to a two‐compartment exchange model. WM volume was determined by morphometric analysis of structural images.

   R₁values and WM volume showed similar trajectories of age‐related decline. Among all subjects,v_bandk_poaveraged 1.7 (±0.5) mL/100 g of tissue and 2.1 (±1.1) s⁻¹, respectively. Whilev_bshowed minimal changes over the 40‐year‐age span of participants,k_podeclined 0.06 s⁻¹(ca. 3%) per year (r= −.66;P < .0005), from near 4 s⁻¹at age 30 to ca. 2 s⁻¹at age 70. The association remained significant after controlling for WM volume.

   Previous studies have shown thatk_potracks Na⁺, K⁺‐ATPase activity‐dependent water exchange at the BBB and likely reflects neurogliovascular unit (NGVU) coupled metabolic activity. The age‐related decline ink_poobserved here is consistent with compromised NGVU metabolism in older individuals and the dysregulated cellular bioenergetics that accompany normal brain aging.

    

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5. Cerebellar atrophy and its contribution to cognition in frontotemporal dementias

   https://doi.org/10.1002/ana.25271  

   Chen, Yu ; Kumfor, Fiona ; Landin‐Romero, Ramon ; Irish, Muireann ; Hodges, John R. ; Piguet, Olivier ( August 2018 , Annals of Neurology)

   Increasing evidence suggests that cerebellar damage impacts on cognitive functions. Frontotemporal dementias (FTDs) are neurodegenerative brain conditions, primarily affecting the frontal and/or temporal lobe. Three main phenotypes are recognized, each with a distinct clinical and cognitive profile: behavioral‐variant FTD (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). The severity of cerebellar changes and their relation to cognition in FTD, however, remain unclear. This study aimed to establish cerebellar gray matter changes on magnetic resonance imaging (MRI) and their relation to profiles of cognitive deficits in FTD subtypes.

   Ninety‐six FTD patients (45 bvFTD, 28 SD, and 23 PNFA), meeting current clinical diagnostic criteria, and 35 age‐, sex‐, and education‐matched controls underwent brain MRI and cognitive assessment. Cerebral and cerebellar gray matter integrity were investigated using voxel‐based morphometry.

   Compared with controls, widespread bilateral cerebellar changes were observed in all FTD subtypes, with the greatest atrophy present in bvFTD. Significant associations were found between cerebellar integrity and cognitive performance in attention and working memory in bvFTD, visuospatial function in SD, and language‐motor function in PNFA. Bilateral atrophy of crus and lobule VI were most commonly associated with cognitive deficits, irrespective of FTD phenotype.

   This study is the first to identify distinct patterns of cerebellar atrophy across FTD syndromes, which in turn relate to discrete cognitive dysfunctions, after accounting for the effect of cerebral atrophy. These findings extend our understanding of the cerebellum and point to its involvement across an array of processes beyond the domain of motor function. Ann Neurol 2018;83:98–109

    

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