Atrophy Measures Research Articles

Lifetime brain atrophy estimated from a single MRI: measurement characteristics and genome-wide correlates.

A measure of lifetime brain atrophy (LBA) obtained from a single magnetic resonance imaging (MRI) scan could be an attractive candidate to boost statistical power in uncovering novel genetic signals and mechanisms of neurodegeneration. We analysed data from five young and old adult cohorts (MRi-Share, Human Connectome Project, UK Biobank, Generation Scotland Subsample, and Lothian Birth Cohort 1936 [LBC1936]) to test the validity and utility of LBA inferred from cross-sectional MRI data, i.e., a single MRI scan per participant. LBA was simply calculated based on the relationship between total brain volume (TBV) and intracranial volume (ICV), using three computationally distinct approaches: the difference ( ICV-TBV ), ratio ( TBV / ICV ), and regression-residual method (TBV∼ICV). LBA derived with all three methods were substantially correlated with well-validated neuroradiological atrophy rating scales ( r = 0.37-0.44). Compared with the difference or ratio method, LBA computed with the residual method most strongly captured phenotypic variance associated with cognitive decline ( r = 0.36), frailty ( r = 0.24), age-moderated brain shrinkage ( r = 0.45), and longitudinally-measured atrophic changes ( r = 0.36). LBA computed using a difference score was strongly correlated with baseline (i.e., ICV; r = 0.81) and yielded GWAS signal similar to ICV ( r g = 0.75). We performed the largest genetic study of LBA to date ( N = 43,110), which was highly heritable ( h 2 SNP GCTA = 41% [95% CI = 38-43%]) and had strong polygenic signal (LDSC h 2 = 26%; mean χ2 = 1.23). The strongest association in our genome-wide association study (GWAS) implicated WNT16 , a gene previously linked with neurodegenerative diseases such as Alzheimer, and Parkinson disease, and amyotrophic lateral sclerosis. This study is the first side-by-side evaluation of different computational approaches to estimate lifetime brain changes and their measurement characteristics. Careful assessment of methods for LBA computation had important implications for the interpretation of existing phenotypic and genetic results, and showed that relying on the residual method to estimate LBA from a single MRI scan captured brain shrinkage rather than current brain size. This makes this computationally-simple definition of LBA a strong candidate for more powerful analyses, promising accelerated genetic discoveries by maximising the use of available cross-sectional data.

Comparison of Geographic Atrophy Measurements Between Blue-Light Heidelberg Standard Field and Green-Light Optos Ultrawide Field Autofluorescence.

This study compared geographic atrophy (GA) measurements in the macula using standard 30° field and ultrawide field (UWF) fundus autofluorescence (FAF) imaging. Participants from Age-Related Eye Disease Study 2 (AREDS2) and Optos PEripheral RetinA (OPERA) studies with GA were included for comparison between standard field FAF with Heidelberg Spectralis and Optos 200Tx UWF FAF. Two time points 5years apart were evaluated. GA area (mm2) was recorded in the macular area for both imaging types and in the peripheral field for UWF. Of 102 paired images (73 subjects), the mean (SD) baseline GA area was 5.32 (6.36)mm2 with standard and 4.79 (5.87)mm2 with UWF FAF (P < 0.001). The mean difference between the two modalities was 0.52mm2 (95% confidence interval, -2.41 to 1.37). Progression of GA in 25 eyes over 5years showed a median annual growth rate of 1.28mm2 (range, 0.02 to 4.7) for standard and 1.34mm2 (range, 0.04 to 5.3) for UWF FAF (P = 0.49). The measurement of GA is larger on standard than on UWF FAF imaging. The observed difference may be due to image averaging and the use of blue versus green FAF. Similar GA progression with standard and UWF FAF suggests either may be used longitudinally, although not interchangeably. Further investigation is required with updated UWF technology. With the increasing adoption of UWF imaging modalities, this study suggests that Optos UWF FAF may be used longitudinally as an alternative to standard field FAF to monitor GA.

Greater baseline cortical atrophy in the dorsal attention network predicts faster clinical decline in Posterior Cortical Atrophy.

Posterior Cortical Atrophy (PCA) is a clinical syndrome characterized by progressive visuospatial and visuoperceptual impairment. As the neurodegenerative disease progresses, patients lose independent functioning due to the worsening of initial symptoms and development of symptoms in other cognitive domains. The timeline of clinical progression is variable across patients, and the field currently lacks robust methods for prognostication. Here, evaluated the utility of MRI-based cortical atrophy as a predictor of longitudinal clinical decline in a sample of PCA patients. PCA patients were recruited through the Massachusetts General Hospital Frontotemporal Disorders Unit PCA Program. All patients had cortical thickness estimates from baseline MRI scans, which were used to predict longitudinal change in clinical impairment assessed by the CDR Sum-of-Boxes (CDR-SB) score. Multivariable linear regression was used to estimate the magnitude of cortical atrophy in PCA patients relative to a group of amyloid-negative cognitively unimpaired participants. Linear mixed-effects models were used to test hypotheses about the utility of baseline cortical atrophy for predicting longitudinal clinical decline. Data acquired from 34 PCA patients (mean age = 65.41 ± 7.90, 71% females) and 24 controls (mean age = 67.34 ± 4.93, 50% females) were analyzed. Sixty-two percent of the PCA patients were classified as having mild cognitive impairment (CDR 0.5) at baseline, with the rest having mild dementia (CDR 1). Each patient had at least one clinical follow-up, with the mean duration of 2.78 ± 1.62 years. Relative to controls, PCA patients showed prominent baseline atrophy in the posterior cortical regions, with the largest effect size observed in the visual network of the cerebral cortex. Cortical atrophy localized to the dorsal attention network, which supports higher-order visuospatial function, selectively predicted the rate of subsequent clinical decline. These results demonstrate the utility of a snapshot measure of cortical atrophy of the dorsal attention network for predicting the rate of subsequent clinical decline in PCA. If replicated, this topographically-specific MRI-based biomarker could be useful as a clinical prognostication tool that facilitates personalized care planning.

Quantitative comparison of automated OCT and conventional FAF-based geographic atrophy measurements in the phase 3 OAKS/DERBY trials

With the approval of the first two substances for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD), a standardized monitoring of patients treated with complement inhibitors in clinical practice is needed. Optical coherence tomography (OCT) provides high-resolution access to the retinal pigment epithelium (RPE) and neurosensory layers, such as the ellipsoid zone (EZ), which further enhances the understanding of disease progression and therapeutic effects in GA compared to conventional fundus autofluorescence (FAF). In addition, artificial intelligence-based methodology allows the identification and quantification of GA-related pathology on OCT in an objective and standardized manner. The purpose of this study was to comprehensively evaluate automated OCT monitoring for GA compared to reading center-based manual FAF measurements in the largest successful phase 3 clinical trial data of complement inhibitor therapy to date. Automated OCT analysis of RPE loss showed a high and consistent correlation to manual GA measurements on conventional FAF. EZ loss on OCT was generally larger than areas of RPE loss, supporting the hypothesis that EZ loss exceeds underlying RPE loss as a fundamental pathophysiology in GA progression. Automated OCT analysis is well suited to monitor disease progression in GA patients treated in clinical practice and clinical trials.

Association of quantitative histopathology measurements with antemortem medial temporal lobe cortical thickness in the Alzheimer’s disease continuum

The medial temporal lobe (MTL) is a hotspot for neuropathology, and measurements of MTL atrophy are often used as a biomarker for cognitive decline associated with neurodegenerative disease. Due to the aggregation of multiple proteinopathies in this region, the specific relationship of MTL atrophy to distinct neuropathologies is not well understood. Here, we develop two quantitative algorithms using deep learning to measure phosphorylated tau (p-tau) and TDP-43 (pTDP-43) pathology, which are both known to accumulate in the MTL and are associated with MTL neurodegeneration. We focus on these pathologies in the context of Alzheimer’s disease (AD) and limbic predominant age-related TDP-43 encephalopathy (LATE) and apply our deep learning algorithms to distinct histology sections, on which MTL subregions were digitally annotated. We demonstrate that both quantitative pathology measures show high agreement with expert visual ratings of pathology and discriminate well between pathology stages. In 140 cases with antemortem MR imaging, we compare the association of semi-quantitative and quantitative postmortem measures of these pathologies in the hippocampus with in vivo structural measures of the MTL and its subregions. We find widespread associations of p-tau pathology with MTL subregional structural measures, whereas pTDP-43 pathology had more limited associations with the hippocampus and entorhinal cortex. Quantitative measurements of p-tau pathology resulted in a significantly better model of antemortem structural measures than semi-quantitative ratings and showed strong associations with cortical thickness and volume. By providing a more granular measure of pathology, the quantitative p-tau measures also showed a significant negative association with structure in a severe AD subgroup where semi-quantitative ratings displayed a ceiling effect. Our findings demonstrate the advantages of using quantitative neuropathology to understand the relationship of pathology to structure, particularly for p-tau, and motivate the use of quantitative pathology measurements in future studies.

Disability independent of cerebral white matter demyelination in progressive multiple sclerosis

The pathogenic mechanisms contributing to neurological disability in progressive multiple sclerosis (PMS) are poorly understood. Cortical neuronal loss independent of cerebral white matter (WM) demyelination in myelocortical MS (MCMS) and identification of MS patients with widespread cortical atrophy and disability progression independent of relapse activity (PIRA) support pathogenic mechanisms other than cerebral WM demyelination. The three-dimensional distribution and underlying pathology of myelinated T2 lesions were investigated in postmortem MCMS brains. Postmortem brain slices from previously characterized MCMS (10 cases) and typical MS (TMS) cases (12 cases) were co-registered with in situ postmortem T2 hyperintensities and T1 hypointensities. T1 intensity thresholds were used to establish a classifier that differentiates MCMS from TMS. The classifier was validated in 36 uncharacterized postmortem brains and applied to baseline MRIs from 255 living PMS participants enrolled in SPRINT-MS. Myelinated T2 hyperintensities in postmortem MCMS brains have a contiguous periventricular distribution that expands at the occipital poles of the lateral ventricles where a surface-in gradient of myelinated axonal degeneration was observed. The MRI classifier distinguished pathologically confirmed postmortem MCMS and TMS cases with an accuracy of 94%. For SPRINT-MS patients, the MRI classifier identified 78% as TMS, 10% as MCMS, and 12% with a paucity of cerebral T1 and T2 intensities. In SPRINT-MS, expanded disability status scale and brain atrophy measures were similar in MCMS and TMS cohorts. A paucity of cerebral WM demyelination in 22% of living PMS patients raises questions regarding a primary role for cerebral WM demyelination in disability progression in all MS patients and has implications for clinical management of MS patients and clinical trial outcomes in PMS. Periventricular myelinated fiber degeneration provides additional support for surface-in gradients of neurodegeneration in MS.

Leptin bioavailability and markers of brain atrophy and vascular injury in the middle age.

We investigated the associations of leptin markers with cognitive function and magnetic resonance imaging (MRI) measures of brain atrophy and vascular injury in healthy middle-aged adults. We included 2262 cognitively healthy participants from the Framingham Heart Study with neuropsychological evaluation; of these, 2028 also had available brain MRI. Concentrations of leptin, soluble leptin receptor (sOB-R), and their ratio (free leptin index [FLI]), indicating leptin bioavailability, were measured using enzyme-linked immunosorbent assays. Cognitive and MRI measures were derived using standardized protocols. Higher sOB-R was associated with lower fractional anisotropy (FA, β=-0.114±0.02, p<0.001), and higher free water (FW, β=0.091±0.022, p<0.001) and peak-width skeletonized mean diffusivity (PSMD, β=0.078±0.021, p<0.001). Correspondingly, higher FLI was associated with higher FA (β=0.115±0.027, p<0.001) and lower FW (β=-0.096±0.029, p=0.001) and PSMD (β=-0.085±0.028, p=0.002). Higher leptin bioavailability was associated with better white matter (WM) integrity in healthy middle-aged adults, supporting the putative neuroprotective role of leptin in late-life dementia risk. Higher leptin bioavailability was related to better preservation of white matter microstructure. Higher leptin bioavailability during midlife might confer protection against dementia. Potential benefits might be even stronger for individuals with visceral obesity. DTI measures might be sensitive surrogate markers of subclinical neuropathology.

Interreader and Intermodality Variability in Macular Atrophy Quantification in Neovascular Age-related Macular Degeneration: Comparison of 6 Imaging Modalities

Macular atrophy is a common complication in neovascular age-related macular degeneration (AMD) and is associated with poorer visual outcomes. This study evaluated interreader and intermodality variability in measuring macular atrophy in previously treated neovascular AMD eyes without exudation using 6 imaging modalities. Prospective, cohort study. Thirty participants with previously treated neovascular AMD showing no signs of exudation at the time of enrollment and exhibiting macular atrophy. During the same clinic visit, patients were imaged using 6 different imaging modalities: color fundus photography (CFP; Clarus, Carl Zeiss Meditec), near-infrared imaging (NIR; Spectralis, Heidelberg Engineering), structural OCT (Spectralis, Heidelberg Engineering), green fundus autofluorescence (GAF; Clarus, Carl Zeiss Meditec), blue fundus autofluorescence (BAF; Spectralis, Heidelberg Engineering), and pseudocolor imaging (MultiColor; Spectralis, Heidelberg Engineering). Two readers independently measured the macular atrophy area. Interreader and intermodality agreement. The 95% coefficient of repeatability was 5.98 mm2 for CFP, 4.46 mm2 for MultiColor, 3.90 mm2 for BAF, 3.92 mm2 for GAF, 4.86 mm2 for NIR, and 3.55 mm2 for OCT. Similarly, the coefficient of variation was lowest for OCT-based grading at 0.08 and highest for NIR-based grading at 0.28. Accordingly, the intraclass correlation coefficient was 0.742 for CFP, 0.805 for MultiColor, 0.857 for BAF, 0.850 for GAF, 0.755 for NIR, and 0.917 for OCT. The 6 different imaging modalities presented measurements with different mean values, with only a limited number of comparisons not significantly different between the instruments, although measurements were correlated. The largest size of macular atrophy was measured with structural OCT-based grading (median= 4.65 mm2; interquartile range [IQR]= 4.78 mm2) and the smallest was with CFP-based grading (median= 3.86 mm2; IQR= 5.06 mm2). Inconsistencies arose from various factors. In patients with neovascular AMD, macular atrophy measurements vary significantly depending on the imaging technique used. Color fundus photography-based assessments yielded the smallest macular atrophy sizes, whereas structural OCT-based assessments produced the largest. These discrepancies stem from both the inherent limitations of each modality in assessing retinal pigment epithelial atrophy and factors related to neovascularization, such as the coexistence of fibrosis. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The evolving contribution of MRI measures towards the prediction of secondary progressive multiple sclerosis

BackgroundIn multiple sclerosis (MS), both lesion accrual and brain atrophy predict clinical outcomes. However, it is unclear whether these prognostic features are equally relevant throughout the course of MS. Among...

Global left frontal cortex connectivity attenuates the adverse effect of brain atrophy on global cognition in non-dementia participants

Aim: To investigate whether higher global left frontal cortex (gLFC) connectivity, a potential neural substrate of cognitive reserve (CR), mitigates the impact of brain atrophy on cognition in non-dementia participants. Methods: A total of 43 clinically diagnostic normal controls (NC), 63 subjective cognitive decline (SCD) and 30 mild cognitive impairment (MCI) were recruited, who underwent resting-state fMRI and structural MRI scans. The gLFC connectivity was defined as the average positive functional connectivity between the left frontal cortex and each voxel in the gray matter. Hippocampus, parahippocampal gyrus, and amygdala volume volumes/intracranial volume ratio (HpVR, PhgVR, and AmyVR) values were computed as measures of brain atrophy. In general linear analysis, interaction term gLFC connectivity × brain atrophy on global cognition performance were tested, which were repeated in women and men separately. The Trial registration number is NCT03370744. Results: Significant interaction effects of HpVR * gLFC connectivity (P = 0.031) and PhgVR * gLFC connectivity (P = 0.006) were observed, while AmyVR * gLFC connectivity (P = 0.088) showed a marginal significance. After accounting for APOE ε4 carrying status or diagnosis based on amyloidosis, the significant results still existed. In separate analysis, the significant interaction effects of HpVR * gLFC connectivity (P = 0.004), PhgVR * gLFC connectivity (P = 0.017), and AmyVR * gLFC connectivity (P = 0.027) were only observed in men, not in women. Conclusion: The gLFC connectivity is associated with greater resilience against the adverse effect of specified brain atrophy on global cognition, which is more effective in men.

The subcortical basis of subjective sleep quality.

To assess the association between self-reported sleep quality and cortical and subcortical local morphometry. Sleep and neuroanatomical data from the full release of the young adult Human Connectome Project dataset were analyzed. Sleep quality was operationalized with the Pittsburgh Sleep Quality Index (PSQI). Local cortical and subcortical morphometry was measured with subject-specific segmentations resulting in voxelwise thickness measurements for cortex and relative (i.e., cross-sectional) local atrophy measurements for subcortical regions. Relative atrophy across several subcortical regions, including bilateral pallidum, striatum, and thalamus, was negatively associated with both global PSQI score and sub-components of the index related to sleep duration, efficiency, and quality. Conversely, we found no association between cortical morphometric measurements and self-reported sleep quality. This work shows that subcortical regions such as the bilateral pallidum, thalamus, and striatum, might be interventional targets to ameliorate self-reported sleep quality.

Genetic variability of FOXP2 and its targets CNTNAP2 and PRNP in frontotemporal dementia: A pilot study in a southern Italian population

The Forkhead box P2 (FOXP2) is an evolutionary conserved transcription factor involved in the maintenance of neuronal networks, implicated in language disorders. Some evidence suggests a possible link between FOXP2 genetic variability and frontotemporal dementia (FTD) pathology and related endophenotypes. To shed light on this issue, we analysed the association between single-nucleotide polymorphisms (SNPs) in FOXP2 and FTD in 113 patients and 223 healthy controls. In addition, we investigated SNPs in two putative targets of FOXP2, CNTNAP2, Contactin-associated protein-like 2 and PRNP, prion protein genes. Overall, 27 SNPs were selected by a tagging approach. FOXP2-rs17213159-C/T resulted associated with disease risk (OR = 2.16, P = 0.0004), as well as with age at onset and severity of dementia. Other FOXP2 markers were associated with semantic and phonological fluency scores, cognitive levels (MMSE) and neuropsychological tests. Associations with language, cognitive and brain atrophy measures were found with CNTNAP2 and PRNP genetic variability. Overall, although preliminary, results here presented suggest an influence of regulatory pathways centred on FOXP2 as a molecular background of FTD affecting neurological function of multiple brain areas.

Correlation Between Blue Fundus Autofluorescence and SD-OCT Measurements of Geographic Atrophy in Dry Age-Related Macular Degeneration

To compare fundus autofluorescence (FAF) and spectral domain optical coherence tomography (OCT) measurements of geographic atrophy (GA) area and to analyze lesion area changes measured by spectral domain OCT in GATHER1. An assessment reliability analysis using prospective, randomized, double-masked phase 2/3 clinical trial data. GATHER1 examined the efficacy and safety of avacincaptad pegol (ACP) for GA treatment. A post hoc analysis was performed to identify correlations between FAF- and OCT-based measurements of GA. GA area was measured on blue-light FAF images using semiautomatic segmentation software with support from OCT and near-infrared imaging. Machine-learning enhanced, multilayer segmentation of OCT scans were reviewed by human readers, and segmentation errors were corrected as needed. GA area was defined as total RPE loss on cross-sectional B scans. Time points included Months 0, 6, 12, and 18. Additionally, OCT-based GA-area changes between ACP and sham were analyzed. There was a strong correlation (r = 0.93) between FAF and OCT GA area measurements that persisted through 18 months. Mean (SD) differences between OCT and FAF GA measurements were negligible: 0.11 mm2 (1.42) at Month 0, 0.03 mm2 (1.62) at Month 6, -0.17 mm2 (1.81) at Month 12, and -0.07 mm2 (1.78) at Month 18. OCT assessments of GA growth revealed a 30% and 27% reduction at Months 12 and 18, respectively, between ACP and sham, replicating FAF measurements from GATHER1. The strong correlation between blue FAF and OCT measurements of GA area supports OCT as a reliable method to measure GA lesion area in clinical trials.

Circulating sphingolipids and subclinical brain pathology: the cardiovascular health study.

Sphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults. Brain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40% male; and 25% APOE ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP. In the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [β = 0.05, false-discovery rate corrected P (PFDR) = 0.004 and β = 0.06, PFDR = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex (P for interaction = <0.001), such that ceramide d18:1/20:0 associated with higher odds for infarcts in women [OR = 1.26 (95%CI: 1.07, 1.49), PFDR = 0.03]. We did not observe any associations with GFAP blood levels, white matter grade, ventricular grade, mean bilateral hippocampal volume, or total brain volume. Overall, our comprehensive investigation supports the evidence that ceramides and sphingomyelins are associated with increased aging brain pathology and that the direction of association depends on the fatty acid attached to the sphingosine backbone.

Precise prediction of cerebrospinal fluid amyloid beta protein for early Alzheimer's disease detection using multimodal data.

Alzheimer's disease (AD) constitutes a neurodegenerative disorder marked by a progressive decline in cognitive function and memory capacity. The accurate diagnosis of this condition predominantly relies on cerebrospinal fluid (CSF) markers, notwithstanding the associated burdens of pain and substantial financial costs endured by patients. This study encompasses subjects exhibiting varying degrees of cognitive impairment, encompassing individuals with subjective cognitive decline, mild cognitive impairment, and dementia, constituting a total sample size of 82 participants. The primary objective of this investigation is to explore the relationships among brain atrophy measurements derived from magnetic resonance imaging, atypical electroencephalography (EEG) patterns, behavioral assessment scales, and amyloid β-protein (Aβ) indicators. The findings of this research reveal that individuals displaying reduced Aβ1-42/Aβ-40 levels exhibit significant atrophy in the frontotemporal lobe, alongside irregularities in various parameters related to EEG frequency characteristics, signal complexity, inter-regional information exchange, and microstates. The study additionally endeavors to estimate Aβ1-42/Aβ-40 content through the application of a random forest algorithm, amalgamating structural data, electrophysiological features, and clinical scales, achieving a remarkable predictive precision of 91.6%. In summary, this study proposes a cost-effective methodology for acquiring CSF markers, thereby offering a valuable tool for the early detection of AD.

Characterization of monoamine oxidase-B (MAO-B) as a biomarker of reactive astrogliosis in Alzheimer’s disease and related dementias

Reactive astrogliosis accompanies the two neuropathological hallmarks of Alzheimer’s disease (AD)—Aβ plaques and neurofibrillary tangles—and parallels neurodegeneration in AD and AD-related dementias (ADRD). Thus, there is growing interest in developing imaging and fluid biomarkers of reactive astrogliosis for AD/ADRD diagnosis and prognostication. Monoamine oxidase-B (MAO-B) is emerging as a target for PET imaging radiotracers of reactive astrogliosis. However, a thorough characterization of MAO-B expression in postmortem control and AD/ADRD brains is lacking. We sought to: (1) identify the primary cell type(s) expressing MAO-B in control and AD brains; (2) quantify MAO-B immunoreactivity in multiple brain regions of control and AD donors as a proxy for PET radiotracer uptake; (3) correlate MAO-B level with local AD neuropathological changes, reactive glia, and cortical atrophy; (4) determine whether the MAOB rs1799836 SNP genotype impacts MAO-B expression level; (5) compare MAO-B immunoreactivity across AD/ADRD, including Lewy body diseases (LBD) and frontotemporal lobar degenerations with tau (FTLD-Tau) and TDP-43 (FTLD-TDP). We found that MAO-B is mainly expressed by subpial and perivascular cortical astrocytes as well as by fibrous white matter astrocytes in control brains, whereas in AD brains, MAO-B is significantly upregulated by both cortical reactive astrocytes and white matter astrocytes across temporal, frontal, and occipital lobes. By contrast, MAO-B expression level was unchanged and lowest in cerebellum. Cortical MAO-B expression was independently associated with cortical atrophy and local measures of reactive astrocytes and microglia, and significantly increased in reactive astrocytes surrounding Thioflavin-S+ dense-core Aβ plaques. MAO-B expression was not affected by the MAOB rs1799836 SNP genotype. MAO-B expression was also significantly increased in the frontal cortex and white matter of donors with corticobasal degeneration, Pick’s disease, and FTLD-TDP, but not in LBD or progressive supranuclear palsy. These findings support ongoing efforts to develop MAO-B-based PET radiotracers to image reactive astrogliosis in AD/ADRD.

Longitudinal Relationship Between Brain Atrophy Patterns, Cognitive Decline, and Cerebrospinal Fluid Biomarkers in Alzheimer's Disease Explored by Orthonormal Projective Non-Negative Matrix Factorization.

Longitudinal magnetic resonance imaging (MRI) has been proposed for tracking the progression of Alzheimer's disease (AD) through the assessment of brain atrophy. Detection of brain atrophy patterns in patients with AD as the longitudinal disease tracker. We used a refined version of orthonormal projective non-negative matrix factorization (OPNMF) to identify six distinct spatial components of voxel-wise volume loss in the brains of 83 subjects with AD from the ADNI3 cohort relative to healthy young controls from the ABIDE study. We extracted non-negative coefficients representing subject-specific quantitative measures of regional atrophy. Coefficients of brain atrophy were compared to subjects with mild cognitive impairment and controls, to investigate the cross-sectional and longitudinal associations between AD biomarkers and regional atrophy severity in different groups. We further validated our results in an independent dataset from ADNI2. The six non-overlapping atrophy components represent symmetric gray matter volume loss primarily in frontal, temporal, parietal and cerebellar regions. Atrophy in these regions was highly correlated with cognition both cross-sectionally and longitudinally, with medial temporal atrophy showing the strongest correlations. Subjects with elevated CSF levels of TAU and PTAU and lower baseline CSF Aβ42 values, demonstrated a tendency toward a more rapid increase of atrophy. The present study has applied a transferable method to characterize the imaging changes associated with AD through six spatially distinct atrophy components and correlated these atrophy patterns with cognitive changes and CSF biomarkers cross-sectionally and longitudinally, which may help us better understand the underlying pathology of AD.

Structural and functional correlates of disability, motor and cognitive performances in multiple sclerosis: Focus on the globus pallidus

ObjectivesTo explore structural and functional alterations of external (GPe) and internal (GPi) globus pallidus in people with multiple sclerosis (pwMS) compared to healthy controls (HC) and analyze their relationship with measures of clinical disability, motor and cognitive impairment. MethodsSixty pwMS and 30 HC comparable for age and sex underwent 3.0T MRI, including conventional, diffusion tensor MRI and resting state (RS) functional MRI. Expanded Disability Status Scale (EDSS) scores were rated and timed 25-foot walk (T25FW) test, nine-hole peg test (9HPT), and paced auditory serial addition test (PASAT) were administered. Two operators segmented the GP into GPe and GPi. Volumes, T1/T2 ratio, diffusivity indices and seed-based RS functional connectivity (FC) of the GP and its components were assessed. ResultsPwMS had no atrophy or altered diffusivity measures of the GP. Compared to HC, pwMS had higher T1/T2 ratio in both GP regions, which correlated with EDSS score (r = 0.26–0.39, p = 0.01–0.05). RS FC analysis highlighted component-specific functional alterations in pwMS: the GPe had decreased RS FC with fronto-parietal cortices, whereas the GPi had decreased intra-GP RS FC and increased RS FC with the thalamus. Worse EDSS, 9HPT, T25FW and PASAT scores were associated with GP RS FC modifications (r=-0.51‒0.51, p < 0.001). ConclusionsStructural GP involvement in MS was homogeneous across its portions. Increased T1/T2 ratio values, possibly representing iron accumulation, were related to more severe disability. RS FC alterations of the GPe and GPi were consistent with their roles within the basal ganglia network and correlated with worse functional status, suggesting less efficient communication between structures.

Alzheimer's disease progression detection based on optical fluence rate measurements using alternative laser wavelengths.

Alzheimer's disease (AD) levels have increased globally, which is considered the sixth reason for deaths. So, a requirement exists for economic and quantitative methods to follow up the gradual progression of AD. The current study presents a simulation for a non-irradiated, safe, wearable, and noninvasive mobile approach for detecting the progression of Alzheimer's brain atrophy using the optical diffusion technique and for investigating the difference between the normal and the diseased brain. The virtual study was accomplished using COMSOL Multiphysics. The simulated head is implemented as the following: scalp, skull, cerebrospinal fluid, gray matter, and white matter. The optical properties of the heterogeneous tissue are observed using the fluence rate after irradiating the head with different wavelengths (630, 700, 810, 915, and 1000 nm) of lasers. Two assessment techniques were applied to evaluate the brain atrophy measurements; the first technique was an array of photodetectors, which were lined at the head posterior, while a matrix of photodetectors was applied over the head surface in the second technique. The results show that the surface photodetectors approach differentiates the normal from AD brains without measuring the brain atrophy percentages by applying 630 nm. The array of photodetectors distinguishes normal from AD brains without detecting the brain atrophy percentages when the wavelengths 630, 700, and 810 nm were applied. The line detector at 1000 nm evaluates the brain atrophy percentages with AD. The future explores applying those techniques in vivo and analyzing the information by the spectrometer for extensively safer early detection of neural disorders.

Resting-state functional connectivity and structural differences between smokers and healthy non-smokers

Previous studies have shown an association between cigarette use and altered resting-state functional connectivity (rsFC) in many large-scale networks, sometimes complemented by measures of cortical atrophy. In this study, we aimed to further explore the neural differences between smokers and healthy non-smokers through the integration of functional and structural analyses. Imaging data of fifty-two smokers and forty-five non-smokers were analyzed through an independent component analysis for group differences in rsFC. Smokers showed lower rsFC within the dorsal attention network (DAN) in the left superior and middle frontal gyrus and left superior division of the lateral occipital cortex compared to non-smokers; moreover, cigarette use was found to be associated with reduced grey matter volume in the left superior and middle frontal gyrus and right orbitofrontal cortex, partly overlapping with functional findings. Within smokers, daily cigarette consumption was positively associated with increased rsFC within the cerebellar network and the default mode network and decreased rsFC within the visual network and the salience network, while carbon monoxide level showed a positive association with increased rsFC within the sensorimotor network. Our results suggest that smoking negatively impacts rsFC within the DAN and that changes within this network might serve as a circuit-based biomarker for structural deficits.