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The article presents several studies related to Hemiplegic and Basilar-Type migraine. The study titled "Haploinsufficiency of ATP1A2 Encoding the Na+/K+ Pump Alpha2 Subunit Associated with Familial Hemiplegic Migraine Type 2" concludes that L764P and W887R are causative in the two Italian families. The study titled "Alterations in the Alpha2 Isoform of Na,K-AtPase Associated with Familial Hemiplegic Migraine Type 2" shows that spectrum of molecular phenotypes associated with FHM2 is broad.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary vascular disease that usually begins with migraine, followed by repeated strokes and progressive dementia. We describe an unusual clinical presentation of this condition in members of a Chilean family with an established NOTCH3 mutation. We report early clinical, neuropsychological, transcranial ultrasound, magnetic resonance imaging (MRI), cerebral blood flow, and skin biopsy findings on these patients. Of the patients, 2 presented with facial dystonia, 1 of whom had abnormal single photon emission computed tomography and transcranial ultrasound studies after normal brain MRI scans. Our report emphasizes that CADASIL must be considered in the study of patients with secondary dystonia. [ABSTRACT FROM AUTHOR]

Objective: Polygenic variation accounts for a substantial portion of the risk of Alzheimer's disease (AD), but its effect on the rate of fibrillar‐tau accumulation as a key driver of dementia symptoms is unclear. Methods: We combined the to‐date largest number of genetic risk variants of AD (n = 85 lead single‐nucleotide polymorphisms [SNPs]) from recent genome‐wide association studies (GWAS) to generate a polygenic score (PGS). We assessed longitudinal tau‐positron emission tomography (PET), amyloid‐PET, and cognition in 231 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Using the PGS, together with global amyloid‐PET, we predicted the rate of tau‐PET increases in Braak‐stage regions‐of‐interest and cognitive decline. We also assessed PGS‐risk enrichment effects on the required sample size in clinical trials targeting tau pathology. Results: We found that a higher PGS was associated with higher rates of tau‐PET accumulation, in particular at elevated amyloid‐PET levels. The tau‐PET increases mediated the association between PGS and faster cognitive decline. Risk enrichment through high PGS afforded sample size savings by 34%. Interpretation: Our results demonstrate that the PGS predicts faster tau progression and thus cognitive decline, showing utility to enhance statistical power in clinical trials. ANN NEUROL 2023;93:819–829 [ABSTRACT FROM AUTHOR]

Objective: Cerebral small vessel diseases (cSVDs) are a major cause of stroke and dementia. We used cutting‐edge 7T‐MRI techniques in patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), to establish which aspects of cerebral small vessel function are affected by this monogenic form of cSVD. Methods: We recruited 23 CADASIL patients (age 51.1 ± 10.1 years, 52% women) and 13 age‐ and sex‐matched controls (46.1 ± 12.6, 46% women). Small vessel function measures included: basal ganglia and centrum semiovale perforating artery blood flow velocity and pulsatility, vascular reactivity to a visual stimulus in the occipital cortex and reactivity to hypercapnia in the cortex, subcortical gray matter, white matter, and white matter hyperintensities. Results: Compared with controls, CADASIL patients showed lower blood flow velocity and higher pulsatility index within perforating arteries of the centrum semiovale (mean difference − 0.09 cm/s, p = 0.03 and 0.20, p = 0.009) and basal ganglia (mean difference − 0.98 cm/s, p = 0.003 and 0.17, p = 0.06). Small vessel reactivity to a short visual stimulus was decreased (blood‐oxygen‐level dependent [BOLD] mean difference −0.21%, p = 0.04) in patients, while reactivity to hypercapnia was preserved in the cortex, subcortical gray matter, and normal appearing white matter. Among patients, reactivity to hypercapnia was decreased in white matter hyperintensities compared to normal appearing white matter (BOLD mean difference −0.29%, p = 0.02). Interpretation: Multiple aspects of cerebral small vessel function on 7T‐MRI were abnormal in CADASIL patients, indicative of increased arteriolar stiffness and regional abnormalities in reactivity, locally also in relation to white matter injury. These observations provide novel markers of cSVD for mechanistic and intervention studies. ANN NEUROL 2023;93:29–39 [ABSTRACT FROM AUTHOR]

Objective: Ischemic stroke etiology remains undetermined in 30% of cases. We explored the genetic architecture of stroke classified as undetermined to test if mechanisms and risk factors underlying large‐artery atherosclerotic (LAAS), cardioembolic (CES), and small‐vessel stroke (SVS) contribute to its pathogenesis. Methods: We analyzed genome‐wide data from 16,851 ischemic stroke cases and 32,473 controls. Using polygenic risk scores for LAAS, CES, and SVS, we assessed the genetic overlap with stroke of undetermined source and used pairwise genomewide association study (GWAS‐PW) to search for shared loci. We then applied Mendelian randomization (MR) to identify potentially causal risk factors of stroke of undetermined source. Results: Genetic risk for LAS, CES, and SVS was associated with stroke of undetermined source pointing to overlap in their genetic architecture. Pairwise analyses revealed 19 shared loci with LAAS, 2 with CES, and 5 with SVS that have been implicated in atherosclerosis‐related phenotypes. Genetic liability to both carotid atherosclerosis and atrial fibrillation was associated with stroke of undetermined source, but the association with atrial fibrillation was attenuated after excluding cases with incomplete diagnostic workup. MR analyses showed effects of genetically determinants of blood pressure, diabetes, waist‐to‐hip ratio, inflammatory pathways (IL‐6 signaling, MCP‐1/CCL2 levels), and factor XI levels on stroke of undetermined source. Interpretation: Stroke of undetermined source shares genetic and vascular risk factors with other stroke subtypes, especially LAAS, thus highlighting the diagnostic limitations of current subtyping approaches. The potentially causal associations with carotid atherosclerosis and atherosclerotic risk factors might have implications for prevention strategies targeting these mechanisms. ANN NEUROL 2022;91:640–651 [ABSTRACT FROM AUTHOR]

Objective: Early discrimination of patients with ischemic stroke (IS) from stroke mimics (SMs) poses a diagnostic challenge. The circulating metabolome might reflect pathophysiological events related to acute IS. Here, we investigated the utility of early metabolic changes for differentiating IS from SM.Methods: We performed untargeted metabolomics on serum samples obtained from patients with IS (N = 508) and SM (N = 349; defined by absence of a diffusion weighted imaging [DWI] positive lesion on magnetic resonance imaging [MRI]) who presented to the hospital within 24 hours after symptom onset (median time from symptom onset to blood sampling = 3.3 hours; interquartile range [IQR] = 1.6-6.7 hours) and from neurologically normal controls (NCs; N = 112). We compared diagnostic groups in a discovery-validation approach by applying multivariable linear regression models, machine learning techniques, and propensity score matching. We further performed a targeted look-up of published metabolite sets.Results: Levels of 41 metabolites were significantly associated with IS compared to NCs. The top metabolites showing the highest value in separating IS from SMs were asymmetrical and symmetrical dimethylarginine, pregnenolone sulfate, and adenosine. Together, these 4 metabolites differentiated patients with IS from SMs with an area under the curve (AUC) of 0.90 in the replication sample, which was superior to multimodal cranial computed tomography (CT; AUC = 0.80) obtained for routine diagnostics. They were further superior to previously published metabolite sets detected in our samples. All 4 metabolites returned to control levels by day 90.Interpretation: A set of 4 metabolites with known biological effects relevant to stroke pathophysiology shows unprecedented utility to identify patients with IS upon hospital arrival, thus encouraging further investigation, including multicenter studies. ANN NEUROL 2020;88:736-746. [ABSTRACT FROM AUTHOR]

Objective: To systematically investigate causal relationships between obesity and cerebrovascular disease and the extent to which hypertension and hyperglycemia mediate the effect of obesity on cerebrovascular disease.Methods: We used summary statistics from genome-wide association studies for body mass index (BMI), waist-to-hip ratio (WHR), and multiple cerebrovascular disease phenotypes. We explored causal associations with 2-sample Mendelian randomization (MR) accounting for genetic covariation between BMI and WHR, and we assessed what proportion of the association between obesity and cerebrovascular disease was mediated by systolic blood pressure (SBP) and blood glucose levels, respectively.Results: Genetic predisposition to higher BMI did not increase the risk of cerebrovascular disease. In contrast, for each 10% increase in WHR there was a 75% increase (95% confidence interval [CI] = 44-113%) in risk for large artery ischemic stroke, a 57% (95% CI = 29-91%) increase in risk for small vessel ischemic stroke, a 197% increase (95% CI = 59-457%) in risk of intracerebral hemorrhage, and an increase in white matter hyperintensity volume (β = 0.11, 95% CI = 0.01-0.21). These WHR associations persisted after adjusting for genetic determinants of BMI. Approximately one-tenth of the observed effect of WHR was mediated by SBP for ischemic stroke (proportion mediated: 12%, 95% CI = 4-20%), but no evidence of mediation was found for average blood glucose.Interpretation: Abdominal adiposity may trigger causal pathological processes, partially independent from blood pressure and totally independent from glucose levels, that lead to cerebrovascular disease. Potential targets of these pathological processes could represent novel therapeutic opportunities for stroke. ANN NEUROL 2020;87:516-524. [ABSTRACT FROM AUTHOR]

Objective: To determine the contribution of acute infarcts, evidenced by diffusion-weighted imaging positive (DWI+) lesions, to progression of white matter hyperintensities (WMH) and other cerebral small vessel disease (SVD) markers.Methods: We performed monthly 3T magnetic resonance imaging (MRI) for 10 consecutive months in 54 elderly individuals with SVD. MRI included high-resolution multishell DWI, and 3-dimensional fluid-attenuated inversion recovery, T1, and susceptibility-weighted imaging. We determined DWI+ lesion evolution, WMH progression rate (ml/mo), and number of incident lacunes and microbleeds, and calculated for each marker the proportion of progression explained by DWI+ lesions.Results: We identified 39 DWI+ lesions on 21 of 472 DWI scans in 9 of 54 subjects. Of the 36 DWI+ lesions with follow-up MRI, 2 evolved into WMH, 4 evolved into a lacune (3 with cavity <3mm), 3 evolved into a microbleed, and 27 were not detectable on follow-up. WMH volume increased at a median rate of 0.027 ml/mo (interquartile range = 0.005-0.073), but was not significantly higher in subjects with DWI+ lesions compared to those without (p = 0.195). Of the 2 DWI+ lesions evolving into WMH on follow-up, one explained 23% of the total WMH volume increase in one subject, whereas the WMH regressed in the other subject. DWI+ lesions preceded 4 of 5 incident lacunes and 3 of 10 incident microbleeds.Interpretation: DWI+ lesions explain only a small proportion of the total WMH progression. Hence, WMH progression seems to be mostly driven by factors other than acute infarcts. DWI+ lesions explain the majority of incident lacunes and small cavities, and almost one-third of incident microbleeds, confirming that WMH, lacunes, and microbleeds, although heterogeneous on MRI, can have a common initial appearance on MRI. ANN NEUROL 2019;86:582-592. [ABSTRACT FROM AUTHOR]

We conducted a European‐only and transancestral genome‐wide association meta‐analysis in 72,147 stroke patients and 823,869 controls using data from UK Biobank (UKB) and the MEGASTROKE consortium. We identified an exonic polymorphism in NOS3 (rs1799983, p.Glu298Asp; p = 2.2E‐8, odds ratio [OR] = 1.05, 95% confidence interval [CI] = 1.04–1.07) and variants in an intron of COL4A1 (rs9521634; p = 3.8E‐8, OR = 1.04, 95% CI = 1.03–1.06) and near DYRK1A (rs720470; p = 6.1E‐9, OR = 1.05, 95% CI = 1.03–1.07) at genome‐wide significance for stroke. Effect sizes of known stroke loci were highly correlated between UKB and MEGASTROKE. Using Mendelian randomization, we further show that genetic variation in the nitric oxide synthase–nitric oxide pathway in part affects stroke risk via variation in blood pressure. Ann Neurol 2018;84:934–939 [ABSTRACT FROM AUTHOR]

Objective: To establish a fully automated, robust imaging marker for cerebral small vessel disease (SVD) and related cognitive impairment that is easy to implement, reflects disease burden, and is strongly associated with processing speed, the predominantly affected cognitive domain in SVD.Methods: We developed a novel magnetic resonance imaging marker based on diffusion tensor imaging, skeletonization of white matter tracts, and histogram analysis. The marker (peak width of skeletonized mean diffusivity [PSMD]) was assessed along with conventional SVD imaging markers. We first evaluated associations with processing speed in patients with genetically defined SVD (n = 113). Next, we validated our findings in independent samples of inherited SVD (n = 57), sporadic SVD (n = 444), and memory clinic patients with SVD (n = 105). The new marker was further applied to healthy controls (n = 241) and to patients with Alzheimer's disease (n = 153). We further conducted a longitudinal analysis and interscanner reproducibility study.Results: PSMD was associated with processing speed in all study samples with SVD (p-values between 2.8 × 10(-3) and 1.8 × 10(-10) ). PSMD explained most of the variance in processing speed (R(2) ranging from 8.8% to 46%) and consistently outperformed conventional imaging markers (white matter hyperintensity volume, lacune volume, and brain volume) in multiple regression analyses. Increases in PSMD were linked to vascular but not to neurodegenerative disease. In longitudinal analysis, PSMD captured SVD progression better than other imaging markers.Interpretation: PSMD is a new, fully automated, and robust imaging marker for SVD. PSMD can easily be applied to large samples and may be of great utility for both research studies and clinical use. Ann Neurol 2016;80:581-592. [ABSTRACT FROM AUTHOR]

Objective: Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and Ischaemic Stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases.Methods: Using genome wide association study (GWAS) data from METASTROKE+ (15,916 IS cases and 68,826 controls) and IGAP (17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype-level data (4,610 IS cases, 1,281 AD cases and 14,320 controls), we estimated the genome-wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, large vessel), using genome-wide SNP data. We then performed a meta-analysis and pathway analysis in the combined AD and small vessel stroke datasets to identify the SNPs and molecular pathways through which disease risk may be conferred.Results: We found evidence of a shared genetic contribution between AD and small vessel stroke (rG(SE)=0.37(0.17); p=0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall, or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta-analysis of AD IGAP and METASTROKE+ small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1), associated with both diseases (p=1.8x10-8 ). A pathway analysis identified four associated pathways, involving cholesterol transport and immune response.Interpretation: Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. This article is protected by copyright. All rights reserved. [ABSTRACT FROM AUTHOR]

Objective: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common inherited small-vessel disease, is associated with vascular aggregation of mutant Notch3 protein, dysfunction of cerebral vessels, and dementia. Pericytes, perivascular cells involved in microvascular function, express Notch3. Therefore, we hypothesize that these cells may play a role in the pathogenesis of CADASIL. Methods: Two-, 7-, and 12-month-old CADASIL mutant mice (TgNotch3(R169C) ) and wild-type controls were examined regarding Notch3 aggregation in pericytes, the coverage of cerebral vessels by pericytes, pericyte numbers, capillary density, blood-brain barrier (BBB) integrity, astrocytic end-feet, and the expression of astrocytic gap junction and endothelial adherens junction protein using immunostaining and Western blot analysis. In addition, we examined cerebrovascular CO2 reactivity using laser Doppler fluxmetry and in vivo microscopy. Results: With increasing age, mutated Notch3 aggregated around pericytes and smooth muscle cells. Notch3 aggregation caused significant reduction of pericyte number and coverage of capillaries by pericyte processes (p < 0.01). These changes were associated with detachment of astrocytic end-feet from cerebral microvessels, leakage of plasma proteins, reduction in expression of endothelial adherens junction protein, and reduced microvascular reactivity to CO2 . Smooth muscle cells were not affected by Notch3 accumulation. Interpretation: Our results show that pericytes are the first cells affected by Notch3 aggregation in CADASIL mice. Pericyte pathology causes opening of the BBB and microvascular dysfunction. Therefore, protecting pericytes may represent a novel therapeutic strategy for vascular dementia. [ABSTRACT FROM AUTHOR]

ABSTRACT OBJECTIVES Single case reports suggest that black blood MRI (T1-weighted fat and blood suppressed sequences with and without contrast injection; BB-MRI) may visualize intracranial vessel wall contrast enhancement (CE) in primary angiitis of the central nervous system (PACNS). In this single-center observational pilot study we prospectively investigated the value of BB-MRI in the diagnosis of large artery PACNS. METHODS Patients with suspected large artery PACNS received a standardized diagnostic program including BB-MRI. Vessel wall CE was graded (grade 0-2) by two experienced readers blinded to clinical data and correlated to the final diagnosis. RESULTS Four of 12 included patients received a final diagnosis of PACNS. All of them showed moderate (grade 1) to strong (grade 2) vessel wall CE at the sites of stenosis. A moderate (grade 1) vessel wall CE grade was also observed in 6 of the remaining 8 patients in whom alternative diagnoses were made: arteriosclerotic disease ( n= 4), intracranial dissection ( n= 1), and Moyamoya disease ( n= 1). CONCLUSIONS Our pilot study demonstrates that vessel wall CE is a frequent finding in PACNS and its mimics. Larger trials will be necessary to evaluate the utility of BB-MRI in the diagnostic workup of PACNS. [ABSTRACT FROM AUTHOR]

Objective Recent studies have identified a major locus for risk for coronary artery disease and myocardial infarction on chromosome 9p21.3. Stroke, in particular, ischemic stroke caused by atherosclerotic disease, shares common mechanisms with myocardial infarction. We investigated whether the 9p21 region contributes to ischemic stroke risk. Methods In an initial screen, 15 single nucleotide polymorphisms (SNPs) covering the critical genetic interval on 9p21 were genotyped in samples from Southern Germany (1,090 cases, 1,244 control subjects) and the United Kingdom (758 cases, 872 control subjects, 3 SNPs). SNPs significantly associated with ischemic stroke or individual stroke subtypes in either of the screening samples were subsequently genotyped in 2,528 additional cases and 2,189 additional control subjects from Europe and North America. Results Genotyping of the screening samples demonstrated associations between seven SNPs and atherosclerotic stroke (all p < 0.05). Analysis of the full sample confirmed associations between six SNPs and atherosclerotic stroke in multivariate analyses controlling for demographic variables, coronary artery disease, myocardial infarction, and vascular risk factors (all p < 0.05). The odds ratios for the lead SNP (rs1537378-C) were similar in the various subsamples with a pooled odds ratio of 1.21 (95% confidence interval, 1.07-1.37) under both fixed- and random-effects models ( p = 0.002). The point estimate for the population attributable risk is 20.1% for atherosclerotic stroke. Interpretation The chromosome 9p21.3 region represents a major risk locus for atherosclerotic stroke. The effect of this locus on stroke appears to be independent of its relation to coronary artery disease and other stroke risk factors. Our findings support a broad role of the 9p21 region in arterial disease. Ann Neurol 2009;65:531-539 [ABSTRACT FROM AUTHOR]

Transient ischemia has been shown to damage the basal lamina of the cerebral microvasculature. Other studies proved statins to be beneficial to non-cerebral microvessels. The aim of this study was to determine whether pravastatin pretreatment ameliorates microvascular basal lamina damage following transient ischemia. Using the suture model, we subjected 15 rats to focal ischemia (3 h) and reperfusion (24 h). Rats received pravastatin (20 mg/kg/day) or saline for 4 weeks prior to the experiment. The outcome was determined by a behavior test and the infarct size. Collagen type IV, a marker for an intact basal lamina, and hemoglobin extravasation were measured by Western blot analysis. A ratio (in percentage) between ischemic and contralateral hemispheres was calculated. Pravastatin pretreatment resulted in a significantly better neurological outcome and reduced infarct size (15 ± 0.5 and 59 ± 10 mm3, respectively) compared with controls (12.25 ± 0.4 and 167 ± 13 mm3, respectively, P < 0.01 for both). In controls, loss of collagen type IV was seen in the basal ganglia and in the cortex (43 ± 4 and 64 ± 5%, respectively). Pravastatin prevented significant collagen loss (basal ganglia: 106 ± 17%; cortex: 112 ± 14%, P < 0.01 for both) and significantly reduced the hemoglobin extravasation compared with controls in the basal ganglia (198 ± 49 vs. 553 ± 47%, P < 0.01). Pravastatin pretreatment resulted in a reduction of microvascular basal lamina damage and hemoglobin extravasation following transient ischemia. Pravastatin seems to protect the cerebral microvascular system. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article about familial carpal tunnel syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive adult-onset tremor/ataxia syndrome caused by premutations in the FMR1 gene. In cranial MRI, the most characteristic findings are bilateral T2 hyperintense lesions within the middle cerebellar peduncles. Here we present a sibpair of two affected brothers presenting with very different symptoms (typical FXTAS versus essential tremor-like), disease progression, and MRI findings, illustrating broad intrafamilial variability of FXTAS. Also, their family history suggests further evidence of possible manifestation of FXTAS in women. © 2005 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Focal cerebral ischemia leads to the gradual disruption of the extracellular matrix. A key role in the turnover of the extracellular matrix is played by the system of matrix metalloproteinases (MMPs). In this study we describe changes of the MMP inducer protein (EMMPRIN) following experimental cerebral ischemia (induced for 3 h and followed by 24 h reperfusion, suture model) in rats. Extracellular EMMPRIN was measured by Western blot of the ischemic and nonischemic basal ganglia and cortex separately. Compared with the contralateral nonischemic area, the ischemic hemisphere showed a significant increase in EMMPRIN: basal ganglia, 158% ± 4% ( P < 0.05); cortex, 128% ± 25% ( P < 0.05). Immunohistochemistry was used to localize EMMPRIN on cerebral microvessels. EMMPRIN-positive microvascular structures were quantified by automatic morphometric video-imaging analysis and a significant increase in the number of cerebral microvessels staining positive for EMMPRIN in the ischemic basal ganglia was shown. The significant loss of microvascular basal lamina antigen collagen type IV in ischemic cortex and basal ganglia was calculated by Western blot. Measured by gelatin zymography, we demonstrated an MMP-2 and MMP-9 increase in the ischemic brain regions ( P < 0.05). For the first time the MMP activation system EMMPRIN was shown to be relevant in cerebral ischemia. These results raise the possibility that the increased expression of EMMPRIN, the increase in MMPs and the damage of the basal lamina following cerebral ischemia are connected and part of a network of related changes. [ABSTRACT FROM AUTHOR]

We conducted a European-only and transancestral genome-wide association meta-analysis in 72,147 stroke patients and 823,869 controls using data from UK Biobank (UKB) and the MEGASTROKE consortium. We identified an exonic polymorphism in NOS3 (rs1799983, p.Glu298Asp; p = 2.2E-8, odds ratio [OR] = 1.05, 95% confidence interval [CI] = 1.04-1.07) and variants in an intron of COL4A1 (rs9521634; p = 3.8E-8, OR = 1.04, 95% CI = 1.03-1.06) and near DYRK1A (rs720470; p = 6.1E-9, OR = 1.05, 95% CI = 1.03-1.07) at genome-wide significance for stroke. Effect sizes of known stroke loci were highly correlated between UKB and MEGASTROKE. Using Mendelian randomization, we further show that genetic variation in the nitric oxide synthase-nitric oxide pathway in part affects stroke risk via variation in blood pressure. Ann Neurol 2018;84:934-939. [ABSTRACT FROM AUTHOR]