RNASEH2C c.194G>A is a Chinese-specific founder mutation in three unrelated patients with Aicardi-Goutières syndrome 3.

Biallelic pathogenic variants in RNASEH2C cause Aicardi-Goutières syndrome 3 (AGS3, MIM #610329), a rare early-onset encephalopathy characterized by intermittent unexplained fever, chilblains, irritability, progressive microcephaly, dystonia, spasticity, severe psychomotor retardation and abnormal brain imaging. Currently, approximately 50 individuals with AGS3 and 19 variants in RNASEH2C have been revealed. Here, we reported the novel clinical manifestations and genotypic information of three unrelated Chinese patients with AGS3 caused by pathogenic variants in RNASEH2C. In addition to three novel missense variants (c.101G>A, p.Cys34Tyr; c.401T>A, p.Leu134Gln and c.434G>T, p.Arg145Leu), one missense variant (c.194G>A, p.Gly65Asp) reoccurred in all patients but was completely absent in South Asian and other ethnicities. Our study expanded the variant spectrum of RNASEH2C and identified RNASEH2C c.194G>A as a Chinese-specific founder mutation. The novel phenotypes, including mouth ulcers, hip dysplasia, retarded dentition and hypogonadism, observed in our patients greatly enriched the clinical characteristics of AGS3.

Brain Aging in African-Americans: The Atherosclerosis Risk in Communities (ARIC) Experience.

Reported rates of dementia differ by race, although most studies have not focused on carefully measured outcomes, confounding by education or other demographic factors, nor have they studied other outcomes other than dementia. In this review we will discuss the experience in the Atherosclerosis Risk in Communities (ARIC) study evaluating racial disparities relating to stroke, subclinical brain infarction, leukoaraiosis, as well as cognitive change and dementia. ARIC is a biracial cohort of 15,792 participants from four U.S. communities, initially recruited in 1987-1989, and seen at a total of 5 in-person visits (most recently seen in 2011-2013) with annual follow-up phone calls. We will provide evidence from ARIC studies that disproportionate rates of vascular risk factors explain at least some of these observed disparities by race, but particular risk factors, including diabetes, may differentially affect the brain in African-American versus white participants. In addition, we will review some of the disparities by race in studies focusing on the genetics of stroke, small vessel disease, and dementia.

Global cortical atrophy (GCA) associates with worse performance in the Montreal Cognitive Assessment (MoCA). A population-based study in community-dwelling elders living in rural Ecuador.

BACKGROUND/OBJECTIVE: Increasing numbers of individuals with cognitive impairment are posing economic threads to the developing world. Proper assessment of this condition may be complicated by illiteracy and cross-cultural factors. We conducted a population-based study in elders living in rural Ecuador to evaluate whether the MoCA associated with structural brain damage in less-educated populations. METHODS: Atahualpa residents aged ≥60 years were identified during a door-to-door survey and invited to undergo MRI for grading GCA. Using a multivariate generalized linear model, we evaluated whether MoCA scores correlates with GCA, after adjusting for demographics, education, cardiovascular health (CVH) status, depression and edentulism. RESULTS: Out of 311 eligible persons, 241 (78%) were enrolled. Mean age was 69.2±7.5 years, 141 (59%) were women, 199 (83%) had primary school education, 175 (73%) had poor CVH status, 30 (12%) had symptoms of depression and 104 (43%) had edentulism. Average MoCA scores were 18.5±4.7 points. GCA was mild in 108, moderate in 95, and severe in 26 persons. Total and most domain-specific MoCA scores were significantly worse in persons with moderate to severe GCA. In the multivariate model, mean MoCA score was associated with GCA severity (ß=2.38, SE=1.07, p=0.027). CONCLUSIONS: MoCA scores associate with severity of GCA after adjusting for potential confounders, and may be used as reliable estimates of structural brain damage. However, a lower cut-off than that recommended for developed countries, would be better for recognizing cognitive impairment in less educated populations.

Cerebral structural changes in diabetic kidney disease: African American-Diabetes Heart Study MIND.

OBJECTIVE: Albuminuria and reduced kidney function are associated with cognitive impairment. Relationships between nephropathy and cerebral structural changes remain poorly defined, particularly in African Americans (AAs), a population at higher risk for both cognitive impairment and diabetes than European Americans. We examined the relationship between urine albumin:creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), and cerebral MRI volumes in 263 AAs with type 2 diabetes. RESEARCH DESIGN AND METHODS: Cross-sectional associations between renal parameters and white matter (WM), gray matter (GM), hippocampal, and WM lesion (WML) volumes were assessed using generalized linear models adjusted for age, education, sex, BMI, hemoglobin A1c (HbA1c) level, and hypertension. RESULTS: Participants had a mean (SD) age of 60.2 years (9.7 years), and 62.7% were female. Mean diabetes duration was 14.3 years (8.9 years), HbA1c level was 8.2% (2.2%; 66 mmol/mol), eGFR was 86.0 mL/min/1.73 m(2) (23.2 mL/min/1.73 m(2)), and UACR was 155.8 mg/g (542.1 mg/g; median 8.1 mg/g). Those with chronic kidney disease (CKD) (eGFR <60 mL/min/1.73 m(2) or UACR >30 mg/g) had smaller GM and higher WML volumes. Higher UACR was significantly associated with higher WML volume and greater atrophy (larger cerebrospinal fluid volumes), and smaller GM and hippocampal WM volumes. A higher eGFR was associated with larger hippocampal WM volumes. Consistent with higher WML volumes, participants with CKD had significantly poorer processing speed and working memory. These findings were independent of glycemic control. CONCLUSIONS: We found albuminuria to be a better marker of cerebral structural changes than eGFR in AAs with type 2 diabetes. Relationships between albuminuria and brain pathology may contribute to poorer cognitive performance in patients with mild CKD.

Estimating the prevalence and burden of major disorders of the brain in Nepal: methodology of a nationwide population-based study.

BACKGROUND: The major disorders of the brain (MDBs), in terms of their prevalence and the burdens of ill health, disability and financial cost that they impose on individuals and society, are headache, depression and anxiety. No population-based studies have been conducted in Nepal. AIM: Our purpose was to assess the prevalence and burden attributable to MDBs in Nepal in order to inform health policy. Here we report the methodology. METHODS: The unusual sociocultural diversity and extreme geographical variation of the country required adaptation of standard methodology. We ran pre-pilot and pilot studies before embarking on the main study. The study design was cross-sectional. The population of interest were adults aged 18-65 years who were Nepali speaking and living in Nepal. We selected, employed and trained groups of interviewers to visit randomly selected households by cold-calling. Households were selected from 15 representative districts out of 75 in the country through multistage cluster sampling. One participant was selected randomly from each household. We used structured questionnaires (the HARDSHIP questionnaire, Hospital Anxiety and Depression Scale, and Eysenck Personality Questionnaire -Neuroticism), culturally adapted and translated into Nepali. We recorded blood pressure, weight, height and waist circumference, and altitude of each household. We implemented various quality-assurances measures. RESULTS: We completed the survey in one month, prior to onset of the monsoon. Among 2,210 selected households, all were contacted, 2,109 were eligible for the study and, from these, 2,100 adults participated. The participation rate was 99.6%. CONCLUSION: Standard methodology was successfully applied in Nepal, with some adaptations. The sociocultural and extraordinary geographic diversity were challenging, but did not require us to compromise the scientific quality of the study.

Estimating prevalence and burden of major disorders of the brain in Nepal: cultural, geographic, logistic and philosophical issues of methodology.

BACKGROUND: Headache, anxiety and depression are major disorders of the brain in terms of their prevalence and the burdens and costs they impose on society. Nationwide population-based studies of these disorders are necessary to inform health policy but, in research-naïve and resource-poor countries such as Nepal, a host of methodological problems are encountered: cultural, geographic, logistic and philosophical. METHODS: Expert consensus was sought among researchers from different professional and cultural backgrounds in planning and conceptualizing an epidemiological study and adapting established methods to the special situation and circumstances of Nepal. RESULTS: The methodological problems were sorted into different themes: study design; climate; geography, access and transport; sociocultural issues; safety of interviewers. Each of these was dealt with separately, and their inter-relationships explored, in finding solutions that were sometimes pragmatic. A cross-sectional questionnaire-based study, with teams of interviewers visiting households across the three physiographic divisions (with extremes in altitude) in each of the five development regions of the country, would enable national sampling with sociocultural representativeness. However, the study instruments and interviews would be in Nepali only. Transport and access challenges were considerable, and their solutions combined travel by air, bus, river and foot, with allowances for rain-damaged roads, collapsed bridges and cancelled scheduled flights. The monsoon would render many routes impassable, and therefore set an absolute time limitation. Engaging participants willingly in the enquiry would be the key to success, and several tactics would be employed to enhance the success of this, most importantly enlisting the support of local community volunteers in each study site. CONCLUSION: Anticipating problems in advance of investing substantial resources in a large nationwide epidemiological study in Nepal was a sensible precaution. The difficulties could be resolved or circumvented without expected compromise in scientific quality. Expert consensus was an effective means of achieving this outcome.

Tremor-ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.3-10q23.31.

Leukodystrophies are a heterogeneous group of disorders associated with abnormal central nervous system white matter. The clinical features invariably include upper motor neuron signs and developmental regression with or without other neurological manifestations. The objective of this study was to characterize clinically and genetically a new form of childhood-onset leukodystrophy with ataxia and tremor. We recruited seven French-Canadian cases belonging to five families affected by an unknown form of childhood-onset leukodystrophy. Genome-wide scans (GWS) were performed using the Illumina Hap310 or Hap610 Bead Chip to identify regions of shared homozygosity that were further studied for linkage with STS markers. All cases presented between the ages of 1 and 5 years with spasticity along with other upper motor neuron signs, prominent postural tremor, and cerebellar signs. Though motor regression is a constant feature, cognitive functions are relatively preserved, even late in the course of the disease. The higher frequency of founder diseases in the French-Canadian population and the segregation in pedigrees are suggestive of a recessive mode of inheritance. By homozygosity mapping, we established linkage to a 12.6-Mb SNP-haplotyped region on chromosome 10q22.3-10q23.31 (maximum LOD score: 5.47). We describe an autosomal recessive childhood-onset leukodystrophy with ataxia and tremor mapping to a 12.6 Mb interval on chromosome 10q22.3-10q23.31. Identification of the mutated gene will allow precise diagnosis and genetic counseling and shed light on how its perturbed function leads to white matter abnormalities.

Towards construction of an ideal stereotactic brain atlas.

BACKGROUND: The role of the brain atlas is changing in many aspects with the advancements in stereotactic and functional neurosurgery. Therefore, there is a critical need to construct a new atlas. This paper addresses the definition and construction of an atlas, ideal (in our opinion) for stereotactic and functional neurosurgery. The essence of the new atlas is not only its population-based structural and functional content, but also its continuous "self-updatability" with the new clinical results obtained. METHOD: The ideal atlas defined here contains four major components: brain models, knowledge database, tools, and clinical results. Towards its creation, a multi-atlas is proposed. The construction of the initial version of the multi-atlas is detailed with the probabilistic functional atlas (PFA), interpolated Talairach-Tournoux atlas, and enhanced Schaltenbrand-Wahren atlas. These atlases are put in a spatial register by matching their AC-PC distances and heights of the thalamus; the Schaltenbrand coronal and sagittal microseries are scaled laterally to match the target structure centroids with the locations of the best targets of the PFA. FINDINGS: Construction of an initial version of the ideal stereotactic atlas is feasible at present from the available resources. To achieve that, our three atlases (PFA, Talairach and Schaltenbrand) are enhanced and combined together. A single lateral scaling factor per target structure is feasible to co-register the Schaltenbrand atlas with PFA in four situations (compensated against the third ventricle, non-compensated, bilateral, and non-bilateral). The STN has to be stretched by 18% more than the VIM on the Schaltenbrand coronal microseries, and the VIM has to be compressed by 13% less than the STN on the Schaltenbrand sagittal microseries. CONCLUSION: The new multi-atlas can potentially be more useful than the currently employed atlases and will facilitate further development of the ideal atlas for stereotactic and functional neurosurgery.

Arctic Peoples and Beyond: research opportunities in neuroscience and behaviour.

OBJECTIVES: Arctic and northern peoples are spread across Alaska, Canada, Russia and the Scandinavian countries. Inhabiting a variety of ecosystems, these 4 million residents include Indigenous populations who total about 10% of the population. Although Arctic peoples have very diverse cultural and social systems, they have health issues related to environmental impacts and knowledge/treatment disparities that are common to other minority and Indigenous peoples around the world. Research that explores the neuroscience and behavioural aspects of these health disparities offers challenges and significant opportunities. As the next generation of neuroscientists enter the field, it is imperative that they view their contributions in terms of translational medicine to address health disparities. STUDY DESIGN: A workshop was designed to bring neuroscientists together to report on the current directions of neuroscience research and how it could impact health disparities in the North. This workshop produced research recommendations for the growth of neuroscience in the North. METHODS: On May 31, 2006 the National Institute of Neurological Disorders and Stroke, the Burroughs Wellcome Foundation, the Arctic Division of AAAS and the University of Alaska co-sponsored a workshop entitled "Arctic Peoples and Beyond: Decreasing Health Disparities through Basic and Clinical Research." Also, the role and goals of the International Union for Circumpolar Health (IUCH) were presented at the meeting. RESULTS: A set of recommendations related to research opportunities in neuroscience and behaviour research and ways to facilitate national and international partnerships were developed. CONCLUSIONS: These recommendations should help guide the development of future health research in circumpolar neuroscience and behaviour. They provide ideas about research support and informational exchange that will address health challenges.

Clinical characteristics of corticobasal syndrome amongst Chinese in Taiwan.

This study reviewed the clinical characteristics of nine patients, the female-to-male ratio being 2 (6/3), with corticobasal syndrome (CBS) from 2001 to 2006. The mean age of onset was 60.33+/-5.20 years. The most popular symptom was rigidity (100%), followed by bradykinesia (88.89%), apraxia (88.89%) and dystonia (66.67%). The common presentations in neuropsychological assessment included frontal dysfunction (88.89%), disorientation (66.67%), memory impairments (66.67%) and visuospecial defects (66.67%). Single proton emission-computed tomography (CT) showed hypoperfusion at contralateral basal ganglia, thalamic, parietal or temporal region in eight of nine patients. This investigation suggests that functional neuroimages and neuropsychological tests are useful tools for the diagnosis of CBS.

Navajo neurohepatopathy is caused by a mutation in the MPV17 gene.

Navajo neurohepatopathy (NNH) is an autosomal recessive disease that is prevalent among Navajo children in the southwestern United States. The major clinical features are hepatopathy, peripheral neuropathy, corneal anesthesia and scarring, acral mutilation, cerebral leukoencephalopathy, failure to thrive, and recurrent metabolic acidosis with intercurrent infections. Infantile, childhood, and classic forms of NNH have been described. Mitochondrial DNA (mtDNA) depletion was detected in the livers of two patients, suggesting a primary defect in mtDNA maintenance. Homozygosity mapping of two families with NNH suggested linkage to chromosome 2p24. This locus includes the MPV17 gene, which, when mutated, causes a hepatocerebral form of mtDNA depletion. Sequencing of the MPV17 gene in six patients with NNH from five families revealed the homozygous R50Q mutation described elsewhere. Identification of a single missense mutation in patients with NNH confirms that the disease is probably due to a founder effect and extends the phenotypic spectrum associated with MPV17 mutations.

Gamma knife surgery for hypothalamic hamartomas accompanied by medically intractable epilepsy and precocious puberty: experience in Mexico.

OBJECT: Hypothalamic hamartoma is a nonneoplastic malformative mass of neurons and glia in the region of the hypothalamus. Because of its location, open surgery is associated with high morbidity and mortality rates. Gamma knife surgery (GKS) may be an efficient and safe treatment approach, which produces little morbidity. The authors describe the results of GKS in three patients with hypothalamic hamartomas. METHODS: All patients were male, aged 3, 12, and 15 years. The lesions were classified according to the Valdueza scale: one was Type IIb and two were Type IIa. The patients presented with gelastic seizures (15-20 per day), generalized epilepsy, behavioral abnormalities, and alterations of the sleep cycle. Precocious puberty was present in one patient. The Type IIb tumor had a volume of 1.8 cm3, and the Type IIa tumors were 597 mm3 and 530.1 mm3. The lesions received 12.5 Gy, 14 Gy, and 15 Gy, respectively, to the 50% isodose line. The patients were followed for 30 to 50 months. After 3 months, all patients showed improvement of their sleep, behavior, and epilepsy. At the present time, these patients are receiving low-dose antiepileptic agents and have achieved adequate social development and school integration. CONCLUSIONS: Gamma knife surgery appears to be a good, safe, and effective option for the treatment of selected hypothalamic hamartomas. No morbidity or mortality was associated with these three cases.

Lower prevalence of pre-morbid neurological illness in African-Caribbean than White psychotic patients in England.

BACKGROUND: It has been suggested that the increased incidence of psychosis in African-Caribbeans living in England may be due to illnesses in which social stress plays an important aetiological role. If this is the case, the prevalence of factors associated with psychosis that predate illness onset such as obstetric complications, pre-morbid neurological illness and poor childhood social adjustment may be expected to be lower in African-Caribbean than Whites psychotic patients. METHOD: Details of obstetric complications, pre-morbid neurological illness, and pre-morbid social adjustment were obtained for 337 psychotic patients by patient interview, interviews of mothers and chart review. The proportions of patients with each 'risk factor' in the African-Caribbean (N = 103) and White (N = 184) groups were compared using regression analysis; age, sex, social class, diagnosis and referral status were possible explanatory variables. RESULTS: African-Caribbean patients were less likely to have suffered a pre-morbid neurological disorder than their White counterparts (odds ratio 0.19, 95% CI 0.06-0.61). There was no significant difference in pre-morbid social adjustment or obstetric complications between the two groups, though fewer obstetric complications were reported in the African-Caribbean group (21.5%) than the White group (30.9%). CONCLUSIONS: African-Caribbean patients with psychosis have experienced less pre-morbid neurological illness.

Variability in midlife systolic blood pressure is related to late-life brain white matter lesions: the Honolulu-Asia Aging study.

BACKGROUND AND PURPOSE: Although white matter lesions (WMLs) on brain MRI in older persons are common, the mechanisms are unclear. Besides the associations with advanced age and high blood pressure (BP), variability in systolic BP (SBP) and the resulting changes in blood flow to the deep arteries of the brain may be contributing factors. METHODS: Japanese-American men in Hawaii have participated in a long-term study of cardiovascular disease, including midlife BP measurements at 3 clinical examinations in the period from 1965 to 1974. In the period from 1991 to 1993, dementia status was added to the fourth examination, and a brain MRI was completed in a fifth examination, which was from 1994 to 1996, on a subset of 575 men, who averaged 82 years. WMLs and ventricular atrophy were determined as the upper fifth in a standardized semiquantitative measure. Excess SBP variability was defined as greater than average increases in BP measurements from up to 3 examinations over 6 years. Logistic regression was used for the association of this variability with WMLs and atrophy, controlling for age, apolipoprotein E4 status, dementia diagnosis, and history of stroke. RESULTS: There were significant (2-fold) increased risks for WMLs among those with moderate and high SBP variability (third and fifth quintiles compared with the lowest quintile). Those in the highest SBP variability category (the fifth quintile) also had significantly more atrophy. CONCLUSIONS: These SBP variability-MRI relationships suggest that variation in SBP in midlife may be a contributing factor to the development of WMLs and ventricular atrophy in late life.

Vacuolating megalencephalic leukoencephalopathy in 12 Israeli patients.

Leukodystrophy with macrocephaly as the main features of infantile neurodegenerative disease are characteristics of Canavan's disease, L-2-hydroxyglutaric aciduria, type I glutaric aciduria, and Alexander's disease. Also occasionally described are occidental congenital muscular dystrophy, G(M)2-gangliosidosis, metachromatic leukodystrophy, Krabbe's disease, and mucopolysaccharidosis. Since 1995, over 60 patients with a new syndrome, vacuolating megalencephalic leukoencephalopathy, have been described. The syndrome is characterized by macrocephaly, a slowly progressive clinical course of ataxia, spastic paraparesis, and seizure disorder with relatively spared cognition. Unlike other leukodystrophies with macrocephaly (except Alexander's disease), no metabolic marker has been found. We describe a similar group of 12 patients from two different Jewish ethnic origins in whom consanguinity is prominent. These patients have neuroimaging features and magnetic resonance spectroscopy findings indicating that there is an initial increase in white-matter edema with subsequent cystic formation. Consistent with loss of tissue in these areas, brain metabolites are reduced. The familial incidence in this group of patients is suggestive of autosomal-recessive inheritance.

Dentatorubral and pallidoluysian atrophy (DRPLA). Clinical and neuropathological findings in genetically confirmed North American and European pedigrees.

Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant disorder that clinically overlaps with Huntington's disease (HD) and manifests combinations of chorea, myoclonus, seizures, ataxia, and dementia. DRPLA is caused by a CAG triplet repeat (CTG-B37) expansion coding for polyglutamine on chromosome 12 and exhibits the genetic phenomenon of anticipation. This neurodegenerative disease has only rarely been reported in non-Japanese pedigrees, and there are only a few neuropathological studies in genetically confirmed patients. We report 10 cases of DRPLA from two North American and two British pedigrees in which CTG-B37 expansions have been demonstrated within each kindred (54-83 repeats), individually in 8 of the 10 cases, and describe the neuropathological findings in 4 cases. Members of DRPLA kindreds have a wide range of clinical phenotypes and markedly variable ages at onset. The neuropathological spectrum is centered around the cerebellifugal and pallidofugal systems, but neurodegenerative changes can be found in many nuclei, tracts, and systems. Evidence of CTG-B37 triplet repeat expansion should be sought in HD-like cases that are negative for expanded triplet repeats within the HD IT15 gene or in autopsy cases with degeneration of the dentatorubral or pallidoluysian systems.

A dominant hereditary ataxia resembling Machado-Joseph disease in Arnhem Land, Australia.

A dominant ataxia among four families of the Arnhem Land Aboriginal people of Northern Australia has many clinical features in common with Machado-Joseph disease. Neuropathology on one case showed multiple system involvement, with sparing of the inferior olives and cerebellar cortex, consistent with Machado-Joseph disease. Portuguese ancestry is possible, although not proven.

[Adult cerebral malaria. Actual experience of the Infectious Diseases Intensive Care Department at the Claude Bernard Hospital]. / Accès pernicieux palustre de l'adulte. Expérience actuelle de la Clinique de Réanimation des maladies infectieuses de l'Hôpital Claude Bernard.

22 cases of adult cerebral malaria were observed between July 1987 and June 1989, either associated or not: parasitemia 5%, consciousness disorders, acute renal failure, thrombocytopenia. Two patients died (9%). Increased frequency of attacks is underlined. They are due to chloroquino-resistant parasite strains, even polychemoresistant, occurred in French speaking Tropical Africa since 1985. Therapeutic strategy is described. The necessity to use increased doses of quinine has been admitted, correlatively underlining importance of strict monitoring of the patients because, in first instance, the risk of hypoglycemia (eased by injecting too quickly high doses of quinine) and of acute pulmonary oedema (eased by too quick perfusions and/or transfusions).