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Biomedical subjects

Michael Hayden

Publications and source records attributed to Michael Hayden.

9 recordsLinked to original sources
PubMed2006

Brain-derived neurotrophic factor does not influence age at neurologic onset of Huntington's disease.

In Huntington's disease (HD), genetic factors in addition to the HD CAG repeat mutation play a significant role in determining age at neurologic onset. Brain-derived neurotrophic factor (BDNF), a survival factor for striatal neurons, has been implicated as a target of regulation by huntingtin and is an attractive candidate as a genetic modifier. We tested this hypothesis by genotyping a SNP known to alter BDNF function (rs6265, also termed Val66Met) and a SNP associated with Alzheimer disease (BDNF C270T), along with two BDNF intronic SNPs (rs7103411, rs11030104), in 228 cases with extreme young onset and 329 cases with extreme old onset of HD. No differences were seen between groups for allele frequencies or genotype frequencies for any SNP. Furthermore, no association to onset age was seen in GEE models controlling for HD repeat size or in haplotype analyses of these SNPs. These results indicate that BDNF does not influence significantly the mechanisms in HD pathogenesis that lead to neurologic onset.

Age of Onset↗
PubMed2006

Preparing for preventive clinical trials: the Predict-HD study.

BACKGROUND: The optimal design and outcome measures for preventive clinical trials in neurodegenerative diseases are unknown. OBJECTIVE: To examine measures that may be associated with disease in the largest cohort ever recruited of prediagnosed individuals carrying the gene expansion for Huntington disease (HD). DESIGN: The Predict-HD study is a multicenter observational research study in progress at 17 sites in the United States, 4 in Canada, and 3 in Australia. SETTING: Genetics and HD outpatient clinics. PARTICIPANTS: Five hundred five at-risk individuals who had previously undergone elective DNA analyses for the CAG expansion in the HD gene (predictive testing) and did not currently have a clinical diagnosis of HD. MAIN OUTCOME MEASURES: Basal ganglia volumes on magnetic resonance images, estimated probability of diagnosis (based on CAG repeat length), performances on 21 standardized cognitive tasks, total scores on 3 scales of psychiatric distress, and motor diagnosis based on the Unified Huntington's Disease Rating Scale. RESULTS: Several variables showed progressive decline as the diagnostic ratings advanced toward manifest disease. Estimated probability of diagnosis was associated with Unified Huntington's Disease Rating Scale prediagnostic stages and varied from 15% in persons with no motor abnormalities to nearly 40% in those with abnormalities suggestive of probable disease. Striatal volumes, cognitive performances, and even psychiatric ratings declined significantly with motor manifestations of disease. CONCLUSIONS: The documentation of biological and refined clinical markers suggests several clinical end points for preventive clinical trials. Longitudinal study is critical to further validate possible markers for prediagnosed HD.

Adult↗
PubMed2005

Effects of CAG repeat length, HTT protein length and protein context on cerebral metabolism measured using magnetic resonance spectroscopy in transgenic mouse models of Huntington's disease.

Huntington's disease is a neurodegenerative illness caused by expansion of CAG repeats at the N-terminal end of the protein huntingtin. We examined longitudinal changes in brain metabolite levels using in vivo magnetic resonance spectroscopy in five different mouse models. There was a large (>50%) exponential decrease in N-acetyl aspartate (NAA) with time in both striatum and cortex in mice with 150 CAG repeats (R6/2 strain). There was a linear decrease restricted to striatum in N171-82Q mice with 82 CAG repeats. Both the exponential and linear decreases of NAA were paralleled in time by decreases in neuronal area measured histologically. Yeast artificial chromosome transgenic mice with 72 CAG repeats, but low expression levels, had less striatal NAA loss than the N171-82Q mice (15% vs. 43%). We evaluated the effect of gene context in mice with an approximate 146 CAG repeat on the hypoxanthine phosphoribosyltransferase gene (HPRT). HPRT mice developed an obese phenotype in contrast to weight loss in the R6/2 and N171-82Q mice. These mice showed a small striatal NAA loss (21%), and a possible increase in brain lipids detectable by magnetic resonance (MR) spectroscopy and decreased brain water T1. Our results indicate profound metabolic defects that are strongly affected by CAG repeat length, as well as gene expression levels and protein context.

Animals↗
PubMed2004

Huntington's Disease-like 2 (HDL2) in North America and Japan.

Huntington's Disease-like 2 (HDL2) is a progressive, autosomal dominant, neurodegenerative disorder with marked clinical and pathological similarities to Huntington's disease (HD). The causal mutation is a CTG/CAG expansion mutation on chromosome 16q24.3, in a variably spliced exon of junctophilin-3. The frequency of HDL2 was determined in nine independent series of patients referred for HD testing or selected for the presence of an HD-like phenotype in North America or Japan. The repeat length, ancestry, and age of onset of all North American HDL2 cases were determined. The results show that HDL2 is very rare, with a frequency of 0 to 15% among patients in the nine case series with an HD-like presentation who do not have the HD mutation. HDL2 is predominantly, and perhaps exclusively, found in individuals of African ancestry. Repeat expansions ranged from 44 to 57 triplets, with length instability in maternal transmission detected in a repeat of r2=0.29, p=0.0098). The results further support the evidence that the repeat expansion at the chromosome 16q24.3 locus is the direct cause of HDL2 and provide preliminary guidelines for the genetic testing of patients with an HD-like phenotype.

Adult↗
PubMed2004

Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro.

Recent data in invertebrates demonstrated that huntingtin (htt) is essential for fast axonal trafficking. Here, we provide direct and functional evidence that htt is involved in fast axonal trafficking in mammals. Moreover, expression of full-length mutant htt (mhtt) impairs vesicular and mitochondrial trafficking in mammalian neurons in vitro and in whole animals in vivo. Particularly, mitochondria become progressively immobilized and stop more frequently in neurons from transgenic animals. These defects occurred early in development prior to the onset of measurable neurological or mitochondrial abnormalities. Consistent with a progressive loss of function, wild-type htt, trafficking motors, and mitochondrial components were selectively sequestered by mhtt in human Huntington's disease-affected brain. Data provide a model for how loss of htt function causes toxicity; mhtt-mediated aggregation sequesters htt and components of trafficking machinery leading to loss of mitochondrial motility and eventual mitochondrial dysfunction.

Aging↗
PubMed2003

CAG repeat polymorphisms in KCNN3 (HSKCa3) and PPP2R2B show no association or linkage to schizophrenia.

The purpose of this study was to determine whether genetic linkage or association could be observed between schizophrenia (SZ) and the CAG repeat polymorphisms within the genes KCNN3 (known previously as hSKCa3) and PPP2R2B (linked to Spino-Cerebellar Atrophy 12) in the Xhosa population in South Africa. Neither locus has been studied previously in African populations. The polymorphisms were genotyped in 589 individuals to form samples for Transmission Disequilibrium Test (TDT) analysis (176 unrelated probands, 145 with both parents and 30 with one parent genotyped), linkage analysis (49 families with 54 independent affected sib pairs [ASPs]), and case-control analyses (67 familial cases with a first-degree SZ relative, 101 sporadic cases with no affected first- or second-degree relative, and 90 control cases). No significant differences were found among familial cases, sporadic cases and controls in allele sizes (Kruskal-Wallis tests) or the numbers of alleles with sizes above and below the mean size for each polymorphism. Allele size was not correlated with age of onset (Spearman correlation). No significant evidence for association was observed using TDT analyses for all triads and separately for the familial triads. No significant evidence for linkage was observed for either locus with affected sib pair analysis using the possible triangle method or with Non-Parametric Linkage (NPL) analysis of the multiplex families. In conclusion, no significant evidence for linkage or association with SZ was observed for either polymorphism in this population.

Case-Control Studies↗
PubMed2003

Early success in using the relation between stimuli and rewards to deduce an abstract rule: perceived physical connection is key.

Are spatial proximity (0.10-12.5 cm), temporal proximity (0-, 2-, and 5-s gaps), and/or perceived connectedness of stimulus and reward key to infants' ability to deduce an abstract nonmatching rule from reward feedback? In this investigation, 3 conditions of the delayed nonmatching to sample task were administered to infants 9, 12, and 15 months old, and 5 more conditions were administered just to 12-month-olds. Results showed that connectedness is key. In its presence, neither close spatial or temporal proximity was needed. In the absence of the perception that stimulus and reward were components of a single thing, even close spatial and temporal proximity were insufficient for infants in the 1st year to grasp the rule-based association between stimuli and rewards.

Age Factors↗
PubMed2002

Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force.

BACKGROUND: The use of aspirin to prevent cardiovascular disease events in patients without a history of cardiovascular disease is controversial. PURPOSE: To examine the benefits and harms of aspirin chemoprevention. DATA SOURCES: MEDLINE (1966 to May 2001). STUDY SELECTION: 1) Randomized trials at least 1 year in duration that examined aspirin chemoprevention in patients without previously known cardiovascular disease and 2) systematic reviews, recent trials, and observational studies that examined rates of hemorrhagic strokes and gastrointestinal bleeding secondary to aspirin use. DATA EXTRACTION: One reviewer read and extracted data from each included article and constructed evidence tables. A second reviewer checked the accuracy of the data extraction. Discrepancies were resolved by consensus. DATA SYNTHESIS: Meta-analysis was performed, and the quantitative results of the review were then used to model the consequences of treating patients with different levels of baseline risk for coronary heart disease. Five trials examined the effect of aspirin on cardiovascular events in patients with no previous cardiovascular disease. For patients similar to those enrolled in the trials, aspirin reduces the risk for the combined end point of nonfatal myocardial infarction and fatal coronary heart disease (summary odds ratio, 0.72 [95% CI, 0.60 to 0.87]). Aspirin increased the risk for hemorrhagic strokes (summary odds ratio, 1.4 [CI, 0.9 to 2.0]) and major gastrointestinal bleeding (summary odds ratio, 1.7 [CI, 1.4 to 2.1]). All-cause mortality (summary odds ratio, 0.93 [CI, 0.84 to 1.02]) was not significantly affected. For 1000 patients with a 5% risk for coronary heart disease events over 5 years, aspirin would prevent 6 to 20 myocardial infarctions but would cause 0 to 2 hemorrhagic strokes and 2 to 4 major gastrointestinal bleeding events. For patients with a risk of 1% over 5 years, aspirin would prevent 1 to 4 myocardial infarctions but would cause 0 to 2 hemorrhagic strokes and 2 to 4 major gastrointestinal bleeding events. CONCLUSIONS: The net benefit of aspirin increases with increasing cardiovascular risk. In the decision to use aspirin chemoprevention, the patient's cardiovascular risk and relative utility for the different clinical outcomes prevented or caused by aspirin use must be considered.

Adult↗