OBJECTIVE: To follow the clinical course of patients with the mitochondrial DNA mutation 3243A>G for 3 years. METHODS: Thirty-three adult patients with the 3243A>G mutation entered a 3-year follow-up study. They were clinically evaluated annually, audiometry was performed, and samples were drawn for the analysis of blood chemistry and mutation heteroplasmy in leukocytes. Holter recording was performed three times during the follow-up and echocardiography, neuropsychological assessment, and quantitative EEG and brain imaging conducted at entry and after 3 years. RESULTS: The incidence of new neurologic events was low during the 3-year follow-up. Sensorineural hearing impairment (SNHI) progressed, left ventricular wall thickness increased, mean alpha frequency in the occipital and parietal regions decreased, and the severity of disease index (modified Rankin score) progressed significantly. The rate of SNHI progression correlated with mutation heteroplasmy in muscle. The increase in left ventricular wall thickness was seen almost exclusively in diabetic patients. Seven patients died during the follow-up, and they were generally more severely affected than those who survived. CONCLUSIONS: Significant changes in the severity of disease, sensorineural hearing impairment, left ventricular hypertrophy, and quantitative EEG were seen in adult patients with 3243A>G during the 3-year follow-up.
Comment In: Neurology. 2007 Jan 9;68(2):163-417210904
Our objectives are to facilitate autopsy consent, brain collection, and perform standardized neuropathologic assessments of all Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who come to autopsy at the 58 ADNI sites in the USA and Canada.
Building on the expertise and resources of the existing Alzheimer's Disease Research Center (ADRC) at Washington University School of Medicine, St. Louis, MO, a Neuropathology Core (NPC) to serve ADNI was established with one new highly motivated research coordinator. The ADNI-NPC coordinator provides training materials and protocols to assist clinicians at ADNI sites in obtaining voluntary consent for brain autopsy in ADNI participants. Secondly, the ADNI-NPC maintains a central laboratory to provide uniform neuropathologic assessments using the operational criteria for the classification of AD and other pathologies defined by the National Alzheimer Coordinating Center (NACC). Thirdly, the ADNI-NPC maintains a state-of-the-art brain bank of ADNI-derived brain tissue to promote biomarker and multi-disciplinary clinicopathologic studies.
During the initial year of funding of the ADNI Neuropathology Core, there was notable improvement in the autopsy rate to 44.4%. In the most recent year of funding (September 1(st), 2008 to August 31(st) 2009), our autopsy rate improved to 71.5%. Although the overall numbers to date are small, these data demonstrate that the Neuropathology Core has established the administrative organization with the participating sites to harvest brains from ADNI participants who come to autopsy.
Within two years of operation, the Neuropathology Core has: (1) implemented a protocol to solicit permission for brain autopsy in ADNI participants at all 58 sites who die and (2) to send appropriate brain tissue from the decedents to the Neuropathology Core for a standardized, uniform, and state-of-the-art neuropathologic assessment. The benefit to ADNI of the implementation of the NPC is very clear. Prior to the establishment of the NPC in September 2007, there were 6 deaths but no autopsies in ADNI participants. Subsequent to the establishment of the Core there have been 17 deaths of ADNI participants and 10 autopsies. Hence, the autopsy rate has gone from 0% to 59%. The third major accomplishment is the detection of co-existent pathologies with AD in the autopsied cases. It is possible that these co-morbidities may contribute to any variance in ADNI data.
BACKGROUND AND PURPOSE: Cerebral infarcts increase the risk for cognitive impairment. The relevance of location and number of infarcts with respect to cognitive function is less clear. METHODS: We studied the cross-sectional association between number and location of infarcts and cognitive performance in 4030 nondemented participants of the Age Gene/Environment Susceptibility-Reykjavik Study. Composite scores for memory, processing speed, and executive function were created from a neuropsychological battery. Subcortical, cortical, and cerebellar infarcts were identified on brain MRI. We performed linear regression analyses adjusted for demographic and vascular risk factors, depression, white matter lesions, and atrophy. RESULTS: Compared to participants with no infarcts, those with infarcts in multiple locations (n=287, 7%) had slower processing speed (beta=-0.19; P1 location is associated with poor performance in memory, processing speed, and executive function, independent of cardiovascular comorbidities, white matter lesions, and brain atrophy, suggesting that both the number and the distribution of infarcts jointly contribute to cognitive impairment.
We describe nine previously unreported individuals from six families who have homozygous mutations of HOXA1 and either the Bosley-Salih-Alorainy syndrome (BSAS) or the Athabascan brainstem dysgenesis syndrome (ABDS). Congenital heart disease was present in four BSAS patients, two of whom had neither deafness nor horizontal gaze restriction, thus raising the possibility that cardiovascular malformations might be a clinically isolated, or relatively isolated, manifestation of homozygous HOXA1 mutations. Two ABDS probands had relatively mild mental retardation. These individuals blur the clinical distinctions between the BSAS and ABDS HOXA1 variants and broaden the phenotype and genotype of the homozygous HOXA1 mutation clinical spectrum.
We performed a whole-genome expression study to clarify the nature of the biological processes mediating between inherited genetic variations and cognitive dysfunction in schizophrenia.
Gene expression was assayed from peripheral blood mononuclear cells using Illumina Human WG6 v3.0 chips in twins discordant for schizophrenia or bipolar disorder and control twins. After quality control, expression levels of 18,559 genes were screened for association with the California Verbal Learning Test (CVLT) performance, and any memory-related probes were then evaluated for variation by diagnostic status in the discovery sample (N = 190), and in an independent replication sample (N = 73). Heritability of gene expression using the twin design was also assessed.
After Bonferroni correction (p
Cites: Am J Hum Genet. 2000 Aug;67(2):369-8210880296
The estrogen receptor alpha (ESR1) gene has been implicated in the process of cognitive impairment in elderly women. In a paired case-control study, we tested whether two ESR1 gene polymorphisms (the XbaI and PvuII sites) are risk factors for cognitive impairment as measured by the six-item Orientation-Memory-Concentration test in postmenopausal Danish women. Hormone replacement therapy, age and executive cognitive ability were examined as covariates for ESR1 gene effects on cognitive impairment. The XbaI polymorphism showed a marginal effect on cognitive abilities (P=0.054) when adjusted for executive cognitive ability. Using a dominant genetic model for the X allele, we found an elevated risk (executive cognitive ability adjusted P=0.033) for cognitive impairment. Hormone replacement therapy also had a borderline effect on cognitive ability (P=0.049) and this effect was reflected in executive cognitive ability. These data support that the ESR1 gene variants affect cognitive functioning in postmenopausal women.
Neuropsychological findings of individuals with dyslexia (n=24) from a large, three-generation Finnish family are presented. We have previously performed whole genome linkage scanning in this family and found that dyslexia in this kindred segregates with a single locus in the pericentromeric area of chromosome 3. Those included in the analyses were carefully evaluated for general cognitive ability, reading and spelling skills, and reading-related neurocognitive skills. The neurocognitive type of dyslexia segregating in this family consisted of deficits in phonological awareness, verbal short-term memory, and rapid naming. Severe dyslexia also seemed to be connected with a general language difficulty and was most common in the eldest generation.
Despite its estimated high heritability, the genetic architecture leading to differences in cognitive performance remains poorly understood. Different cortical regions play important roles in normal cognitive functioning and impairment. Recently, we reported on sets of regionally enriched genes in three different cortical areas (frontomedial, temporal and occipital cortices) of the adult rat brain. It has been suggested that genes preferentially, or specifically, expressed in one region or organ reflect functional specialisation. Employing a gene-based approach to the analysis, we used the regionally enriched cortical genes to mine a genome-wide association study (GWAS) of the Norwegian Cognitive NeuroGenetics (NCNG) sample of healthy adults for association to nine psychometric tests measures. In addition, we explored GWAS data sets for the serious psychiatric disorders schizophrenia (SCZ) (n = 3 samples) and bipolar affective disorder (BP) (n = 3 samples), to which cognitive impairment is linked.
At the single gene level, the temporal cortex enriched gene RAR-related orphan receptor B (RORB) showed the strongest overall association, namely to a test of verbal intelligence (Vocabulary, P = 7.7E-04). We also applied gene set enrichment analysis (GSEA) to test the candidate genes, as gene sets, for enrichment of association signal in the NCNG GWAS and in GWASs of BP and of SCZ. We found that genes differentially expressed in the temporal cortex showed a significant enrichment of association signal in a test measure of non-verbal intelligence (Reasoning) in the NCNG sample.
Our gene-based approach suggests that RORB could be involved in verbal intelligence differences, while the genes enriched in the temporal cortex might be important to intellectual functions as measured by a test of reasoning in the healthy population. These findings warrant further replication in independent samples on cognitive traits.