Mini-Exome Coupled to Read-Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias.

Next-generation sequencing (NGS) has an established diagnostic value for inherited ataxia. However, the need of a rigorous process of analysis and validation remains challenging. Moreover, copy number variations (CNV) or dynamic expansions of repeated sequence are classically considered not adequately detected by exome sequencing technique. We applied a strategy of mini-exome coupled to read-depth based CNV analysis to a series of 33 patients with probable inherited ataxia and onset <50 years. The mini-exome consisted of the capture of 4,813 genes having associated clinical phenotypes. Pathogenic variants were found in 42% and variants of uncertain significance in 24% of the patients. These results are comparable to those from whole exome sequencing and better than previous targeted NGS studies. CNV and dynamic expansions of repeated CAG sequence were identified in three patients. We identified both atypical presentation of known ataxia genes (ATM, NPC1) and mutations in genes very rarely associated with ataxia (ERCC4, HSD17B4). We show that mini-exome bioinformatics data analysis allows the identification of CNV and dynamic expansions of repeated sequence. Our study confirms the diagnostic value of the proposed genetic analysis strategy. We also provide an algorithm for the multidisciplinary process of analysis, interpretation, and validation of NGS data.

Styloid and hyoid bone proximity is a risk factor for cervical carotid artery dissection.

BACKGROUND AND PURPOSE: Carotid artery dissection (CAD) is more common with increased styloid process length. Our goal was to determine whether proximity of the styloid process and the hyoid bone to the internal carotid artery (ICA) was a risk factor for CAD. METHODS: We studied axial slices on computed tomography angiograms of 88 patients with nonaneurysmal CAD, from 88 age- and sex-matched controls without dissection, and from 32 nonage-/sex-matched nonaneurysmal vertebral artery dissection control patients. We measured the nearest distance between the ICA and both the styloid and the hyoid bones, blinded to clinical information and radiological reports. RESULTS: Styloid-ICA and hyoid-ICA distances were significantly shorter on the side of the CAD as compared with nondissection control patients (P<0.0001 for the styloid-ICA distance; and P=0.0037 for the hyoid-ICA distance). Styloid-ICA distances, regardless of the side of the dissection, were shorter in CAD patients compared with the nondissection control group (right side, P=0.001; left side, P=0.0002) and the vertebral artery dissection control group (right side, P=0.0031; left side, P=0.0067). Direct mechanical contact of the styloid with the ICA was more common in CAD patients. CONCLUSIONS: Shorter distances between the styloid and ICA (and possibly also the hyoid and the ICA) are important risk factors for CAD. Further study is needed to determine whether dissections result from direct injury to the outer vessel wall of the carotid artery.

Cerebral Amyloid Angiopathy and Cerebral Amyloid Angiopathy-Related Inflammation: Comparison of Hemorrhagic and DWI MRI Features.

BACKGROUND: Cerebral amyloid angiopathy (CAA) can be associated with primary vasculitis of small/medium-sized leptomeningeal and cortical arteries, called CAA-related inflammation (CAA-ri). OBJECTIVE: To compare hemorrhagic and diffusion-weighted imaging (DWI) MRI features in CAA and CAA-ri. METHODS: We prospectively scored in a consecutive CAA and CAA-ri cohort: presence/number of chronic intracerebral hemorrhage (ICH), cerebral microbleeds (CMB), and cortical superficial siderosis (CSS) on initial T2*-weighted imaging, and DWI lesions on both initial and follow-up imaging. In a subgroup, ApoE, CSF, and 18F-florbetaben-positron emission tomography (FBB-PET) were also analyzed. RESULTS: In CAA-ri, CMB presence was more frequent (100% versus 40%, p < 0.001) and CMB numbers higher (mean 137 versus 8, p < 0.001). No difference was observed for chronic ICH or CSS. DWI lesions were more frequent in acute compared to chronic CAA-ri (p = 0.025), whereas no such difference was observed between acute and chronic CAA (p = 0.18). Both ApoE4 (genotyping available in 22 CAA-ri and 48 CAA patients) carriers and homozygosity were more frequent in CAA-ri (48% versus 19% [p = 0.014] and 32% versus 2% [p < 0.001] respectively). CSF biomarker analyses (performed in 20 CAA-ri and 45 CAA patients) showed lower Aß42 levels in CAA-ri compared to CAA (median 312 versus 422 pg/mL, p = 0.0032). FBB-PET (performed in 11 CAA-ri and 20 CAA patients) showed higher standardized uptake value ratios in CAA-ri compared with CAA, only significant when the pons was used as reference (p = 0.037). CONCLUSION: Compared to CAA, CAA-ri was associated with higher CMB numbers, more frequent ApoE4 carriers and homozygotes, lower CSF Aß42 levels, and more severe amyloid load on FBB-PET.

Cerebrospinal Fluid, MRI, and Florbetaben-PET in Cerebral Amyloid Angiopathy-Related Inflammation.

BACKGROUND: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is associated with a cerebrospinal fluid (CSF) biomarker profile similar to that observed in CAA. Few CAA-ri patients have been studied by fibrillar amyloid-ß (Aß) imaging (using 11C-Pittsburgh compound B and 18F-florbetapir, but not 18F-florbetaben). OBJECTIVE: To describe CSF biomarkers, magnetic resonance imaging (MRI), and 18F-florbetaben (FBB)-positron emission tomography (PET) changes in CAA-ri patients. METHODS: CSF levels of total tau, phosphorylated tau, Aß1-42, and Aß1-40, MRI (cerebral microbleeds count on susceptibility-weighted imaging and semi-quantitative analysis of fluid-attenuation inversion recovery white matter hyperintensities), and FBB-PET (using both cerebellar cortex and pons to calculate standardized uptake value ratios) were analyzed in nine consecutive CAA-ri patients. RESULTS: A median number of 769 cerebral microbleeds/patient were counted on MRI. When using the pons as reference region, amyloid load on FBB-PET was very strongly correlated to CSF Aß1-40 levels (rho = -0.83, p = 0.008) and moderately correlated to cerebral microbleed numbers in the occipital lobes (rho = 0.59, p = 0.001), while comparisons with other CSF biomarkers were not statistically significant (total tau, rho = -0.63, p = 0.076; phosphorylated tau, rho = -0.68, p = 0.05; Aß1-42, rho = -0.59, p = 0.09). All correlations were weaker, and not statistically significant, when using the cerebellum as reference region. A non-significant correlation (rho = -0.50, p = 0.18) was observed between CSF Aß1-40 levels and cerebral microbleed numbers. CONCLUSION: In CAA-ri, CSF Aß1-40 levels correlated well with amyloid load assessed by FBB-PET when the pons was used as reference, and to a lesser degree with cerebral microbleeds count on MRI. This confirms earlier data on CSF Aß1-40 as an in vivo marker for CAA and CAA-ri.

Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Cerebral Amyloid Angiopathy-Related Inflammation.

BACKGROUND: Decreased cerebrospinal fluid (CSF) amyloid-ß 1-40 (Aß40) and amyloid-ß 1-42 (Aß42) and increased total and phosphorylated tau (t-tau, p-tau) concentrations have been described in cerebral amyloid angiopathy (CAA). OBJECTIVE: Our aim was to analyze these biomarkers in patients with CAA-related inflammation (CAA-I). METHODS: We prospectively recruited nine patients with acute phase CAA-I fulfilling Chung criteria. CSF was analyzed for t-tau, p-tau, Aß42, and Aß40. Data were compared to controls (n = 14), patients with Alzheimer's disease (AD, n = 42), CAA (n = 10), and primary angiitis of the central nervous system (PACNS, n = 3). RESULTS: For the CAA-I group, statistically significant differences were: lower Aß42 (p = 0.00053) compared to the control group; lower t-tau (p = 0.018), p-tau (p <  0.001), and Aß40 (p <  0.001) compared to AD; lower Aß42 (p = 0.027) compared to CAA; lower Aß42 (p = 0.012) compared to PACNS. Nearly significantly lower Aß40 (p = 0.051) and higher t-tau (p = 0.051) were seen in CAA-I compared to controls. CONCLUSION: CSF biomarkers profile similar to that of CAA was observed in CAA-I (with even lower levels of Aß42 compared to CAA). Based on our findings, high p-tau seems more specific for AD, whereas low Aß42 differentiates CAA-I from CAA, PACNS, and controls, and low Aß40 differentiates CAA-I from AD.

Teaching NeuroImages: intermittent symptomatic occlusion of the vertebral artery caused by a cervical osteophyte.

A 77-year-old man presented with 2 episodes of waking up with symptoms of vertebrobasilar ischemia (figure, A and B) within 6 months. A CT angiogram showed narrowing of the right vertebral artery due to extrinsic compression by an osteophyte of the superior articular process of the fourth cervical vertebra, compromising the foramen transversarium (figure, C and D). Dynamic angiography demonstrated intermittent vascular occlusion associated with head turning (figure, E-G). After recurrence, surgical decompression of the vertebral artery was performed. Extrinsic compressions of the vertebral artery is rare.(1) The most frequent signs are those of vertebrobasilar insufficiency. Surgical treatment has been proposed when conservative management fails.(1).