J Hardy

..This mechanistic understanding is now leading to therapeutic strategies based on this new understanding. As yet, however, no mechanistic therapies are in use in the clinic...

..015 to <0.0001). These data suggest that genetic variation in DAPK1 modulates susceptibility to LOAD...

..In this article, we discuss the complexity of the problem and the pitfalls in the analytical methods that have been used and how we are approaching this problem...

..Cross-racial confounds (in addition to cultural confounds) make the interpretation of rates in different groups even more hazardous than seems to have been appreciated...

..Our aim is to investigate potential associations between hemostatic gene polymorphisms and ischemic stroke, with particular emphasis on detailed characterization of the phenotype...

..We have previously reported that in the Portuguese population the LRRK2 c.6055G > A; p.G2019S mutation has one of the highest frequencies in Europe...

..A new locus for amyotrophic lateral sclerosis--frontotemporal dementia (ALS-FTD) has recently been ascribed to chromosome 9p...

..Recently, a common LRRK2 variant Gly2385Arg was reported in ethnic Chinese PD population in Taiwan. We analyzed the frequency of this variant in our independent PD case-control population of Han Chinese from Taiwan...

..Several reports have tested the association of HFE variants with neurodegenerative diseases, such as AD and PD with conflicting results...

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..The progress toward effective mechanistic therapy is reviewed...

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..These developments are reviewed in the context of three known (synuclein, parkin, and DJ-1) and one suspected (ubiquitin hydrolase) genes for the disease...

..Here I recap the scientific and personal background of the delineation of the amyloid cascade hypothesis for Alzheimer's disease that I wrote with Gerry Higgins and the events leading to the writing of that influential review...

..In this article, I summarize the major pieces of evidence adduced to support the amyloid cascade hypothesis and point out their limitations...

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..Here I argue that while these diseases have separate and distinct etiologies, these initiate few pathogenic processes that lead to cell death...

..45000 to 18000 years ago and that the H2 haplotype has been under selection pressure since that time, possibly because of the role of this H1 haplotype in neurodegenerative disease...

..Using such a definition, there is only one certain and known cause: mutations in the alpha-synuclein gene. However, the phenotype of this one known cause is broader than PD and encompasses Lewy body dementia...

..In this review, I discuss the possibility that Abeta42 has a physiologic function in blood vessel homeostasis and the consequences that this might have for theories concerning the pathogenesis of Alzheimer's disease and for treatment...

..We suggest there has been selection at the prion locus, possibly mediated by Kuru-like diseases, which has influenced its allele frequency...

..We discuss the reason for this disequilibrium, its evolutionary history, and the role of genetic variability at MAPT in the etiology of tauopathies...

..Here we report that the same haplotype is associated with the risk of AD in two autopsy confirmed series of cases with ages at death >65 years...

..We discuss these findings both in terms of the problems facing the dissection of the etiologies of complex traits and the pathogenesis of the tauopathies...

..The authors did not identify any subjects with multiplication of SNCA and conclude this mutation is a rare cause of disease...

..This mutation sheds light on a novel mechanism by which over-expression of 4-repeat tau leads to disease. Based on our current findings, we propose a novel mechanism by which intronic mutations can lead to frontotemporal dementia...

..Several MAPT polymorphisms that define the tau H1 haplotype have been investigated for an association with PD with conflicting results; however, two meta-analyses support an association between haplotype H1 and PD...

..We did not find any such mutations...

..Our findings provide evidence for linkage to a novel susceptibility locus on chromosome 6p23. Analysis of additional ET-affected families is needed to confirm linkage and identify the underlying gene...

..As part of this analysis, we have assessed the NR1H2 gene on chromosome 19 and report here a modest association with the locus in sibpairs with late onset disease...

..All mutations were confirmed by independent gene dosage experiments. These data demonstrate the utility of this approach in the direct detection of mutations that underlie disease...

..The mutation was found only in Parkinson's disease patients or their relatives and not in those with other neurodegenerative disease...

..052-0.062). This research suggests a recessive component to the etiology of LOAD...

..We sought to identify genetic variants associated with an increased or decreased risk for developing ALS in a cohort of American sporadic cases...

..The range of mutations of PGRN that can result in the FTD phenotype and the clinical presentation of patients with PGRN mutations have yet to be determined...

..These data demonstrate a new locus for Lewy body parkinsonism and suggest that in some circumstances postural tremor can be an alternative phenotype of the samepathogenic mutation as Lewy body parkinsonism...

..Familial PD caused by mutation of the gene encoding alpha-synuclein or by alpha-synuclein gene triplication also features cardiac sympathetic denervation and baroreflex failure...

..Dystonia and parkinsonism may present as part of the same genetic disorder. Identification of the genetic mutations that underlie these diseases may help to shed light on the aetiological processes involved...

..The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Abeta production and Abeta clearance...

..Insulin-degrading enzyme (IDE) polymorphism is hypothesized to regulate insulin levels as well as processes involved in neuronal compromise found in dementia...

..We discuss this observation in terms of the origin of the H2 haplotype and the epidemiology of the tauopathies...

..The extreme rarity of the G2019S mutation in our population suggests the occurrence of this mutation resulted from a common European founder...

..Here we present the clinical and pathological features of a new case with this mutation and discuss whether the mutation is indeed pathogenic...

..Here, using a population-based sample of dystonia cases, we show an association with the torsin A haplotype and sporadic idiopathic dystonia...

..Reduced expression of the orphan nuclear receptor Nurr1 was also noted, suggesting that the co-ordinate regulation of dopamine synthesis is regulated through this transcription factor...

..This subject was diagnosed with probable PD at age 24 years with asymmetric onset and an excellent response to levodopa therapy. Our observations suggest that sequence alterations in DJ-1 are a rare cause of early-onset PD...

..This resource should facilitate genetic discoveries which we anticipate will ultimately provide a better understanding of the biological mechanisms of neurodegeneration in ALS...

..We show an apparent weak association of rs2230806 (p-value=0.01) with the disease in a sibpair series of Alzheimer's disease that had shown previously evidence for linkage to the chromosome 9 locus where ABCA1 maps...

..We discuss this observation in terms of the establishment of the haplotype structure and the possible impact of the tau haplotype on neurodegeneration in humans...

..Whereas major challenges undoubtedly remain, particularly regarding data handling and the functional classification of variants, we suggest that these will be largely practical and not conceptual...

..However, both wild type and mutant torsinA were affected to a similar extent, suggesting that this is not related to either disease state or the formation of ER-derived inclusions...

..Increased understanding of the cellular mechanisms for disposal of abnormal proteins and of the effects of toxic protein accumulation on neuronal survival may allow the development of rational, effective treatment for these disorders...

..005). We suggest that this polymorphism and others at the Apo(a) locus be further studied in relation to Alzheimer's disease...

..We find there is not and discuss this result in terms of the putative relationships between alpha-synuclein and parkin...

..Eight polymorphisms spanning the entire gene were examined using case control (CC) and family-based association methods. No association was observed by any method making it unlikely that variation in PLAU explains our linkage data...

..To describe a dementia case clinically diagnosed as Alzheimer disease with a PRNP genotype usually associated with familial fatal insomnia...

..In addition to demonstrating that disease in these families is not caused by a single founder mutation, these data show that there is no common fragile site between these mutational events...

..Recently, mutations in TARDBP have been linked to familial and sporadic ALS...

..We found sixteen different non-synonymous changes, eleven of which are novel variants...

..To determine the molecular genetic contribution to this disease we performed a mutation analysis of all type IV neuronal IF, SOD1 and NUDEL genes in cases of NIFID and unaffected control cases. We found no pathogenic variants...

..In fact, our analysis showed that all SCA2 mutations carriers had the same ataxin 2 haplotype: haplotype B, which accounts for only 15% of control haplotypes, implying that there is a common founder for all Taiwanese SCA2 patients...

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..We explore the utility, appropriateness, and possible implications of genetic testing for diagnostic and presymptomatic purposes...

..We also briefly discuss genetic testing for stroke risk and genetic analysis of treatment complications...

..This first genome-wide association study of bipolar disorder shows that several genes, each of modest effect, reproducibly influence disease risk. Bipolar disorder may be a polygenic disease...

..These results indicate that both parkinsonism and cardiac sympathetic denervation can result from an excess of normal synuclein...

..In some of these mutations, the pathologic consequence is uncertain and needs further investigation. To address this question we propose and use a systematic algorithm to classify the putative pathology of AD mutations...

..Clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and FTD prompted us to screen PGRN in patients with ALS and ALS-FTD...

..Our findings suggest that GAB2 modifies LOAD risk in APOE epsilon4 carriers and influences Alzheimer's neuropathology...

..Senile systemic amyloidosis (SSA) is characterized by deposition of wild-type transthyretin (TTR)-based amyloid in parenchymal organs in elderly individuals. Previously, no population-based studies have been performed on SSA...

..Where samples overlapped, the genotyping consistency was high, estimated to average at 97.3%. Our large-scale linkage analysis consolidates clear evidence for a susceptibility locus for LOAD on 10q21.2...

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..These results suggest for the first time that variation of alpha-synuclein modulates neurofibrillary tau pathology and support the recent observations of an interaction of alpha-synuclein and tau in neurodegeneration...

..Sequence analysis of 2p13 linked individuals affected with PD did not reveal any potentially pathogenic mutations within SFXN5, suggesting SFXN5 does not correspond to PARK3...

..There was no evidence of association between variants of ALOX5AP and ischemic stroke. These data suggest that common variants in PDE4D may contribute to the genetic risk for ischemic stroke in multiple populations...

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..Finally, minimum sample size calculations using parameters from the DLD locus suggest that sample sizes on the order of 1,000 total cases and controls are needed to detect association for a wide range of genetic model parameters...

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..Hsp70/CHIP may therefore play an important role in the pathogenesis of tauopathies and also represents a potential therapeutic target...

..None of these SNPs was associated with disease. Although an excellent candidate, we conclude that CTNNA3 is unlikely to account for the AD susceptibility locus on chromosome 10...

..Mutations in the DJ-1 gene are rare in EOPD in both sporadic and familial cases...

..To explore the importance of parkin in those of Turkish ancestry, we studied familial cases from that country, and identified a consanguineous family with early-onset Parkinson's disease due to a homozygous mutation in parkin...

..Our observations raise the possibility that GAPD genes are AD risk factors, a hypothesis that is consistent with the role of GAPD in neuronal apoptosis...

..Thus, LRRK2 mutations appear to be a common cause of typical Parkinson's disease and as such will alter clinical practice...

..43 [95% CI: 1.61-3.67]; OR(het)=2.15 [95% CI: 1.46-3.17]; P=0.00006) in the combined sample set. Our data raise the possibility that genetic variations in APBB2 may affect LOAD susceptibility...

..The absence of borderline mutations in the normal population, and the co-segregation of the expanded allele with neurological signs in one kindred suggest that SCA2 mutations may be responsible for a subset of familial parkinsonism...

..Characterization of the activity of a regulatory polymorphism of the APP gene points towards understanding mechanisms that likely underlie the majority of AD cases and may contribute to promoter-based drug design...

..Furthermore, mRNA analyses identified aberrantly spliced parkin transcripts, suggesting that unusual parkin protein isoforms may be expressed in the brain and retain some function...

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..No significant difference has emerged from the comparison of either genotype or allele frequencies (P>0.5). We conclude that the catalase gene -262C-->T polymorphism does not confer a protective effect with respect to AD...

..Therefore, parkin and alpha-synuclein are linked by common effects on a pathway associated with selective cell death in catecholaminergic neurons...