Brain regions showing white matter loss in Huntington's Disease are enriched for synaptic and metabolic genes

Background The earliest white matter changes in Huntington’s disease are seen before disease onset in the premanifest stage around the striatum, within the corpus callosum, and in posterior white matter tracts. While experimental evidence suggests that these changes may be related to abnormal gene transcription, we lack an understanding of the biological processes driving this regional vulnerability. Methods Here, we investigate the relationship between regional transcription in the healthy brain, using the Allen Institute for Brain Science transcriptome atlas, and regional white matter connectivity loss at three time points over 24 months in subjects with premanifest Huntington’s disease relative to control participants. The baseline cohort included 72 premanifest Huntington’s disease participants and 85 healthy control participants. Results We show that loss of corticostriatal, interhemispheric, and intrahemispheric white matter connections at baseline and over 24 months in premanifest Huntington’s disease is associated with gene expression profiles enriched for synaptic genes and metabolic genes. Corticostriatal gene expression profiles are predominately associated with motor, parietal, and occipital regions, while interhemispheric expression profiles are associated with frontotemporal regions. We also show that genes with known abnormal transcription in human Huntington’s disease and animal models are overrepresented in synaptic gene expression profiles, but not in metabolic gene expression profiles. Conclusions These findings suggest a dual mechanism of white matter vulnerability in Huntington’s disease, in which abnormal transcription of synaptic genes and metabolic disturbance not related to transcription may drive white matter loss

Disease Onset in Huntington's Disease: When Is the Conversion?

International audienceBackground: Determination of disease onset in Huntington's disease is made by clinical experience. The diagnostic confidence level is an assessment regarding the certainty about the clinical diagnosis based on motor signs. A level of 4 means the rater has ≥99% confidence motor abnormalities are unequivocal signs of disease. However, it does not state which motor abnormalities are signs of disease and how many must be present. Objective: Our aim is to explore how accurate the diagnostic confidence level is in estimating disease onset using the Enroll-HD data set. For clinical disease onset we use a cutoff total motor score >5 of the Unified Huntington's Disease Rating Scale. This score is used in the TRACK-HD study, with ≤5 indicating no substantial motor signs in premanifests. Methods Methods: At baseline premanifest participants who converted to manifest (converters) and non-converters were compared for clinical symptoms and diagnostic confidence level. Clinical symptoms and diagnostic confidence levels were longitudinally displayed in converters.Results: Of 3731 eligible participants, 455 were converters and 3276 non-converters. Baseline diagnostic confidence levels were significantly higher in converters compared to non-converters (P 5 (mean = 6.7). Converters had significantly more baseline clinical symptoms, and higher disease burden compared to non-converters (P < 0.001). Diagnostic confidence level before disease onset ranged between 1 and 3 in converters. Conclusions: According to this data the diagnostic confidence level is not an accurate instrument to determine phenoconversion. With trials evaluating disease modifying therapies it is important to develop more reliable diagnostic criteria

The Relationship Between Fear of Falling, respectively, Fear of Choking and Emotional and Cognitive Functioning in Huntington’s Disease, Parkinson’s Disease and Dementia:a Review

Context: Choking and accidental falls are common incidents in patients with Huntington’s disease (HD). It is not clear which emotional and cognitive factors contribute to the development of fear of choking (FoC) or fear of falling (FoF). Objective: To explore the relationship between cognition, awareness and anxiety and experiencing FoC or FoF in HD, Parkinson’s disease (PD) and dementia. As the literature on HD is expected to be limited, the study population will be expanded by also looking at PD and dementia, both of which are neurodegenerative diseases that share symptoms and signs with HD. Methods: A systematic review of English, German and Dutch articles using the electronic databases: MEDLINE, Embase, CINAHL and Psychinfo. Only studies describing the influence of cognition, awareness and anxiety on the outcome measures FoF and FoC in patients with HD, PD or dementia were included Results: For HD, no reports were found related to the objective of the study and no studies on FoC were found for PD or dementia. The results of studies addressing FoF in PD and dementia were contradictory as far as the relationship with cognition (PD n=5; dementia n=8) and anxiety (PD n=2) was concerned. No study on FoF in relation to awareness was found in any patient group. Conclusions: Although dysphagia and accidental falls are common symptoms of HD, PD and dementia, data on emotional and cognitive factors and their relationship with FoC and FoF are limited. Available data are inconsistent. Future research focusing specifically on these topics might lead to better insight into the relationship between FoC, FoF and cognitive, emotional and behavioral functioning of patients with these diseases. Better insight in these subjects could result in therapeutic options for patients or guidelines for caregivers, with regard to prevention and coping strategies, to improve quality of care

Early grey matter changes in structural covariance networks in Huntington's disease

Background: Progressive subcortical changes are known to occur in Huntington's disease (HD), a hereditary neurodegenerative disorder. Less is known about the occurrence and cohesion of whole brain grey matter changes in HD. Objectives: We aimed to detect network integrity changes in grey matter structural covariance networks and examined relationships with clinical assessments. Methods: Structural magnetic resonance imaging data of premanifest HD (n = 30), HD patients (n = 30) and controls (n = 30) was used to identify ten structural covariance networks based on a novel technique using the co-variation of grey matter with independent component analysis in FSL. Group differences were studied controlling for age and gender. To explore whether our approach is effective in examining grey matter changes, regional voxel-based analysis was additionally performed. Results: Premanifest HD and HD patients showed decreased network integrity in two networks compared to controls. One network included the caudate nucleus, precuneous and anterior cingulate cortex (in HD p < 0.001, in pre-HD p = 0.003). One other network contained the hippocampus, premotor, sensorimotor, and insular cortices (in HD p < 0.001, in pre-HD p = 0.023). Additionally, in HD patients only, decreased network integrity was observed in a network including the lingual gyrus, intracalcarine, cuneal, and lateral occipital cortices (p = 0.032). Changes in network integrity were significantly associated with scores of motor and neuropsychological assessments. In premanifest HD, voxel-based analyses showed pronounced volume loss in the basal ganglia, but less prominent in cortical regions. Conclusion: Our results suggest that structural covariance might be a sensitive approach to reveal early grey matter changes, especially for premanifest HD

Progressive microstructural changes of the occipital cortex in Huntington’s disease

In this study we longitudinally investigated the rate of microstructural alterations in the occipital cortex in different stages of Huntington’s disease (HD) by applying an automated atlas-based approach to diffusion MRI data. Twenty-two premanifest (preHD), 10 early manifest HD (early HD) and 24 healthy control subjects completed baseline and two year follow-up scans. The preHD group was stratified based on the predicted years to disease onset into a far (preHD-A) and near (preHD-B) to disease onset group. Clinical and behavioral measures were collected per assessment time point. An automated atlas-based DTI analysis approach was used to obtain the mean, axial and radial diffusivities of the occipital cortex. We found that the longitudinal rate of diffusivity change in the superior occipital gyrus (SOG), middle occipital gyrus (MOG), and inferior occipital gyrus (IOG) was significantly higher in early HD compared to both preHD and controls (all p’s ≤ 0.005), which can be interpreted as an increased rate of microstructural degeneration. Furthermore, the change rate in the diffusivity of the MOG could significantly discriminate between preHD-B compared to preHD-A and the other groups (all p’s ≤ 0.04). Finally, we found an inverse correlation between the Stroop Word Reading task and diffusivities in the SOG and MOG (all p’s ≤ 0.01). These findings suggest that measures obtained from the occipital cortex can serve as sensitive longitudinal biomarkers for disease progression in preHD-B and early HD. These could in turn be used to assess potential effects of proposed disease modifying therapies

Association of vascular amyloid β and cells of the mononuclear phagocyte system in hereditary cerebral hemorrhage with amyloidosis (Dutch) and Alzheimer disease

Arterial and arteriolar amyloid-β (Aβ) deposition in hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D) and Alzheimer disease (AD) cerebral amyloid angiopathy (CAA) were studied as to morphology, extent, and association with mononuclear phagocyte system (MPS) cells using Aβ, a- smooth muscle actin, and monocyte/macrophage marker (HLA-DR, CD68, CD11c, CD45) immunohistochemistry. The HCHWA-D/AD arterial/arteriolar media showed compact Aβ deposits, first appearing at the media/adventitia junction, and concomitant smooth muscle loss. Only HCHWA-D CAA featured (a) severe involvement of larger arteries and (b) arterioles showing a single or double ring of radial Aβ surrounding compact Aβ. Radial Aβ appeared to develop at the media/adventitia junction. Monocyte/macrophage marker-positive foci/cells co-localized with HCHWA-D arterial Aβ. Focal HLA-DR/CD11c positivity was observed at the media/adventitia junction of AD/HCHWA-D arteries in the absence of local Aβ, but not in controls. Monocyte/macrophage marker positivity co-localizing with radial Aβ appeared continuous with perivascular cells and microglia clustering perivascularly. These results suggest that (a) MPS cells are topographically associated with HCHWA-D arterial Aβ and radial arteriolar Aβ, and (b) HLA-DR/CD11c immunoreactivity may appear at the media/adventitia junction prior to Aβ. The latter finding and the assumed formation of radial Aβ at the media/adventitia junction may relate to involvement of the abluminal basement membrane in CAA pathogenesis. The role of MPS cells in this process remains to be established