There is both clinical and neuroanatomical variability at the single-subject level in Alzheimer's disease, complicating our understanding of brain-behaviour relationships and making it challenging to ...develop neuroimaging biomarkers to track disease severity, progression, and response to treatment. Prior work has shown that both group-level atrophy in clinical dementia syndromes and complex neurological symptoms in patients with focal brain lesions localize to brain networks. Here, we use a new technique termed 'atrophy network mapping' to test the hypothesis that single-subject atrophy maps in patients with a clinical diagnosis of Alzheimer's disease will also localize to syndrome-specific and symptom-specific brain networks. First, we defined single-subject atrophy maps by comparing cortical thickness in each Alzheimer's disease patient versus a group of age-matched, cognitively normal subjects across two independent datasets (total Alzheimer's disease patients = 330). No more than 42% of Alzheimer's disease patients had atrophy at any given location across these datasets. Next, we determined the network of brain regions functionally connected to each Alzheimer's disease patient's location of atrophy using seed-based functional connectivity in a large (n = 1000) normative connectome. Despite the heterogeneity of atrophied regions at the single-subject level, we found that 100% of patients with a clinical diagnosis of Alzheimer's disease had atrophy functionally connected to the same brain regions in the mesial temporal lobe, precuneus cortex, and angular gyrus. Results were specific versus control subjects and replicated across two independent datasets. Finally, we used atrophy network mapping to define symptom-specific networks for impaired memory and delusions, finding that our results matched symptom networks derived from patients with focal brain lesions. Our study supports atrophy network mapping as a method to localize clinical, cognitive, and neuropsychiatric symptoms to brain networks, providing insight into brain-behaviour relationships in patients with dementia.
IntroductionWhile Huntington’s disease (HD) disproportionately impacts those of European descent, greater awareness has encouraged increased counseling and diagnoses in Black, Hispanic, and Asian ...patients. This study aims to identify indices of disease burden and progression in HD among race groups.MethodsData from Enroll-HD periodic data set 5 was used to assess racial differences in HD patients at baseline and longitudinally. A data set of over 20,000 participants was reduced to 624 participants to account for disproportionate sample size per racial group. The race groups were matched by CAP score, using Asian, the group with the smallest sample size, as the base group. All other groups were matched by a 1:1 or 2:1 ratio depending on the available sample size. HD progression was measured by cognitive, motor, and functional scales. We performed logistic regression and mixed effect model analyses to assess longitudinal progression, controlling for age and CAG repeats.ResultsCompared to White participants at baseline, Black participants had greater severity in several clinical markers: TMS (p=0.0003), TMC (p=0.0013), TFC (p=0.02), SWRT (p=0.002), SDMT (p=0.0007), and c-UDHRS (p=0.0003).ConclusionsWe note that Black participants in Enroll-HD at baseline have increased disease severity compared to other races. There are no differences in disease progression among racial groups over time. We suspect that these findings reflect either delayed diagnosis of Black participants or a selection bias to clinical research for participants with greater disease burden. Our analyses are limited by a paucity of non-European participant data. We suggest revising the self-identification of race in Enroll-HD.
Reduced diffusion along perivascular spaces in adults with Alzheimer's-disease-related-dementias has been reported and attributed to reduced glymphatic function.
To apply quantitative measures of ...diffusion along, and orthogonal to, perivascular spaces in a cohort of older adults with and without clinical symptoms of alpha-synuclein related neurodegeneration.
181 adults with Parkinson disease (PD) or essential tremor (ET) additionally sub-classified by the presence of cognitive impairment underwent 3 T MRI. Diffusion-tensor-imaging (spatial resolution = 2x2x2 mm; b-value = 1000 s/mm2; directions = 33) measures of diffusion (mm2/s) parallel and orthogonal to perivascular spaces at the level of the medullary veins, and the ratio of these measures (ALPS-index), were calculated. Regions were identified by a board-certified neuroradiologist from T1-weighted and T2-weighted MRI. Evaluations of motor impairment and mild cognitive impairment (MCI) were interpreted by a board-certified neurologist and neuropsychologist, respectively. Multiple regression with false discovery rate correction was applied to understand how diffusion metrics related to (i) disease category (PD vs. ET), (ii) cognition (MCI status), and (iii) white matter disease severity from the Fazekas score.
The ALPS-index was reduced in PD compared to ET participants (p = 0.037). No association between the ALPS-index and MCI status, but an inverse association between the ALPS-index and Fazekas score (p = 0.002), was observed. The ALPS-index was inversely associated with age (p = 0.007).
Diffusion aberrations near perivascular spaces are evident in patients with alpha-synuclein related neurodegenerative disorders, and are related to age and white matter disease severity.
•The DTI-ALPS method is purported to contain information related to glymphatic function.•ALPS-index scores are reduced in Parkinson patients compared to essential tremor patients.•Findings parallel prior results demonstrating reduced ALPS-index scores in Alzheimer's disease.•Altered perivascular fluid transport in PD may be a mechanism of underlying (α-synuclein) accumulation.
Conventional regions of interest (ROIs)—level resting state fMRI (functional magnetic resonance imaging) response analyses do not rigorously model the underlying spatial correlation within each ROI. ...This can result in misleading inference. Moreover, they tend to estimate the temporal covariance matrix with the assumption of stationary time series, which may not always be valid. To overcome these limitations, we propose a double‐wavelet approach that simplifies temporal and spatial covariance structure because wavelet coefficients are approximately uncorrelated under mild regularity conditions. This property allows us to analyze much larger dimensions of spatial and temporal resting‐state fMRI data with reasonable computational burden. Another advantage of our double‐wavelet approach is that it does not require the stationarity assumption. Simulation studies show that our method reduced false positive and false negative rates by properly taking into account spatial and temporal correlations in data. We also demonstrate advantages of our method by using resting‐state fMRI data to study the difference in resting‐state functional connectivity between healthy subjects and patients with major depressive disorder.
This study investigated the temporal dynamics of pancreas volume and microstructure in children and adolescents with recent-onset type 1 diabetes (T1D) and individuals without diabetes, including a ...subset expressing autoantibodies associated with the early stages of T1D.
MRI was performed in individuals with recent-onset stage 3 T1D (
= 51; median age 13 years) within 100 days after diagnosis (mean 67 days), 6 months, and 1 year postdiagnosis. Longitudinal MRI measurements were also made in similarly aged control participants (
= 57) and in autoantibody-positive individuals without diabetes (
= 20). The MRI protocol consisted of anatomical imaging to determine pancreas volume and quantitative MRI protocols interrogating tissue microstructure and composition.
Within 100 days of diabetes onset, individuals with T1D had a smaller pancreas (median volume 28.6 mL) than control participants (median volume 48.4 mL;
< 0.001), including when normalized by individual weight (
< 0.001). Longitudinal measurements of pancreas volume increased in control participants over the year, consistent with adolescent growth, but pancreas volume declined over the first year after T1D diagnosis (
< 0.001). In multiple autoantibody-positive individuals, the pancreas volume was significantly larger than that of the T1D cohort (
= 0.017) but smaller than that of the control cohort (
= 0.04). Diffusion-weighted MRI showed that individuals with recent-onset T1D had a higher apparent diffusion coefficient (
= 0.012), suggesting a loss of cellular structural integrity, with heterogeneous pancreatic distribution.
These results indicate that pancreas volume is decreased in stages 1, 2, and 3 of T1D and decreases during the first year after diabetes onset and that this loss of pancreatic volume is accompanied by microstructural changes.
Background Semiquantitative methods such as the standardized uptake value ratio (SUVR) require normalization of the radiotracer activity to a reference tissue to monitor changes in the accumulation ...of amyloid-beta (Abeta) plaques measured with positron emission tomography (PET). The objective of this study was to evaluate the effect of reference tissue normalization in a test-retest .sup.18F-florbetapir SUVR study using cerebellar gray matter, white matter (two different segmentation masks), brainstem, and corpus callosum as reference regions. Methods We calculated the correlation between .sup.18F-florbetapir PET and concurrent cerebrospinal fluid (CSF) Abeta.sub.1-42 levels in a late mild cognitive impairment cohort with longitudinal PET and CSF data over the course of 2 years. In addition to conventional SUVR analysis using mean and median values of normalized brain radiotracer activity, we investigated a new image analysis technique--the weighted two-point correlation function (wS.sub.2)--to capture potentially more subtle changes in Abeta-PET data. Results Compared with the SUVRs normalized to cerebellar gray matter, all cerebral-to-white matter normalization schemes resulted in a higher inverse correlation between PET and CSF Abeta.sub.1-42, while the brainstem normalization gave the best results (high and most stable correlation). Compared with the SUVR mean and median values, the wS.sub.2 values were associated with the lowest coefficient of variation and highest inverse correlation to CSF Abeta.sub.1-42 levels across all time points and reference regions, including the cerebellar gray matter. Conclusions The selection of reference tissue for normalization and the choice of image analysis method can affect changes in cortical .sup.18F-florbetapir uptake in longitudinal studies.
Objectives: The aim of this study is to develop novel semi-quantitative image analysis approaches that eliminate the reference region normalization of Tau-PET data, which poses a major challenge in ...Alzheimer’s disease (AD) and several other tauopathies. Methods: We developed a weighted two-point correlation analysis (wS2) to characterize the topographic features of cross-sectional 18FAV-1451 images. This method was validated with imaging data of cognitively normal (CN) subjects from Alzheimer’s disease neuroimaging initiative (ADNI) database. The wS2 analysis is performed by sampling randomly distributed voxel-pairs (events) within each subject’s PET image. All events are weighted based on the intensity ratios between the sampled voxel-pairs and parsed by their corresponding distances to obtain the characteristiccurves. We used several methods to quantitatively characterize the shape of the curves. These included both linear slopes of wS2 log-plots and multi-rate decay models. A linear regression was used to determine the associations between wS2 features and other biomarkers. Results: We found significant associations between wS2 features and MMSE (Rs=0.32, P=0.005) and CSF-Aβ (Rs=0.43, P=0.04). The association between wS2 and CSF-tau (Rs=0.29, P=0.09) and CSF-ptau (Rs=0.2, P=0.08) reached marginal significance. For comparison, the SUVR values from the AD-signature ROIs provided similar associations to MMSE and CSF-Aβ but no significant correlation to tau and ptau. Conclusion: We have developed a novel PET analysis that can be used to characterize tau accumulation without using any reference region normalization.
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