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John Hardy

Publications and source records attributed to John Hardy.

At least 55 records · Page 3Linked to original sources
PubMed2006

Has the amyloid cascade hypothesis for Alzheimer's disease been proved?

After much initial debate for and against the role of amyloid in Alzheimer's disease (AD), mutations on the amyloid precursor protein (APP) and processing pathways that increase levels of the amyloid b peptide of 42 residues (Abeta42) have established that faulty function or processing of these proteins are responsible for AD pathogenesis. Given the neurotoxicity of aggregates of Ab42, the central role of this peptide in AD pathogenesis is self evident. In this article, I summarize the major pieces of evidence adduced to support the amyloid cascade hypothesis and point out their limitations.

Alzheimer Disease↗
PubMed2006

European multi-center evaluation of the Abbott Cell-Dyn sapphire hematology analyzer.

This study presents the results of performance evaluations of the Cell-Dyn Sapphire (CD-Sapphire) undertaken by 3 study sites in Europe. These studies focused on the routine blood count analyses with specific consideration of precision and imprecision, linearity, inter-instrument correlations, and white blood cell differential and flagging efficiencies. The CD-Sapphire was compared to the Cell-Dyn CD4000, Bayer Advia 120, Beckman Coulter GenS, and reference microscopy.

Europe↗
PubMed2005

The dardarin G 2019 S mutation is a common cause of Parkinson's disease but not other neurodegenerative diseases.

Mutations in the leucine-rich kinase 2 gene (LRRK 2) encoding dardarin, on chromosome 12, are a common cause of familial and sporadic Parkinson's disease. The most common mutation, a heterozygous 6055 G>A transition (G 2019 S) accounts for approximately 3--10% of familial Parkinson's disease and 1--8% sporadic Parkinson's disease in several European-derived populations. Some families with disease caused by LRRK 2 mutations have been reported to include patients with highly variable clinical and pathological features. We screened for the most common LRRK 2 mutation in a series of patients with Parkinson's Disease, Alzheimer's disease, Progressive Supranuclear Palsy, Multiple System Atrophy and frontotemporal dementia, as well as in neurologically normal controls. The mutation was found only in Parkinson's disease patients or their relatives and not in those with other neurodegenerative disease.

Aged↗
PubMed2005

A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.

Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10-specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P < .05). Five of these markers replicated at P < .05 in the validation sample sets. One marker, rs498055, located in a gene homologous to RPS3A (LOC439999), was significantly associated with Alzheimer disease in four of six case-control series, with an allelic P value of .0001 for a meta-analysis of all six samples. One of the case-control samples with significant association to rs498055 was derived from the linkage sample (P = .0165). These results indicate that variants in the RPS3A homologue are associated with LOAD and implicate this gene, adjacent genes, or other functional variants (e.g., noncoding RNAs) in the pathogenesis of this disorder.

Alleles↗
PubMed2005

Analysis of the PINK1 gene in a cohort of patients with sporadic early-onset parkinsonism in Taiwan.

Mutations in the PINK1 gene have been shown to cause autosomal recessive Parkinson's disease (PD) and/or early onset sporadic PD in Italy, Spain, North America, Ireland, and Asia. However, there are limited data on PINK1 mutations in sporadic early onset Asian PD patients. To determine the prevalence of PINK1 mutation in Taiwanese population, we conducted genetic analysis of PINK1 mutation in 73 early onset sporadic PD and 94 normal control subjects. We only identified a novel single heterozygous mutation R 407Q mutation in exon 6 of this gene in one patient at the age onset of 54. Overall, these data indicate that PINK1 mutations are rare in our population. Based on our results, unless common mutational hotspots are identified, routine testing for this mutation at least in our population may not be cost-effective.

Adult↗
PubMed2005

Estrogen selectively promotes the differentiation of dendritic cells with characteristics of Langerhans cells.

The steroid hormone estrogen regulates the differentiation, survival, or function of diverse immune cells. Previously, we found that physiological amounts of 17beta-estradiol act via estrogen receptors (ER) to promote the GM-CSF-mediated differentiation of dendritic cells (DC) from murine bone marrow progenitors in ex vivo cultures. Of the two major subsets of CD11c(+) DC that develop in these cultures, estrogen is preferentially required for the differentiation of a CD11b(int)Ly6C(-) population, although it also promotes increased numbers of a CD11b(high)Ly6C(+) population. Although both DC subsets express ERalpha, only the CD11b(high)Ly6C(+) DC express ERbeta, perhaps providing a foundation for the differential regulation of these two DC types by estrogen. The two DC populations exhibit distinct phenotypes in terms of capacity for costimulatory molecule and MHC expression, and Ag internalization, which predict functional differences. The CD11b(int)Ly6C(-) population shows the greatest increase in MHC and CD86 expression after LPS activation. Most notably, the estrogen-dependent CD11b(int)Ly6C(-) DC express langerin (CD207) and contain Birbeck granules characteristic of Langerhans cells. These data show that estrogen promotes a DC population with the unique features of epidermal Langerhans cells and suggest that differentiation of Langerhans cells in vivo will be dependent upon local estrogen levels and ER-mediated signaling events in skin.

Animals↗
PubMed2005

Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by deposition of beta-amyloid (Abeta) peptides as senile plaques in the brain. Recent studies suggest that green tea flavonoids may be used for the prevention and treatment of a variety of neurodegenerative diseases. Here, we report that (-)-epigallocatechin-3-gallate (EGCG), the main polyphenolic constituent of green tea, reduces Abeta generation in both murine neuron-like cells (N2a) transfected with the human "Swedish" mutant amyloid precursor protein (APP) and in primary neurons derived from Swedish mutant APP-overexpressing mice (Tg APPsw line 2576). In concert with these observations, we find that EGCG markedly promotes cleavage of the alpha-C-terminal fragment of APP and elevates the N-terminal APP cleavage product, soluble APP-alpha. These cleavage events are associated with elevated alpha-secretase activity and enhanced hydrolysis of tumor necrosis factor alpha-converting enzyme, a primary candidate alpha-secretase. As a validation of these findings in vivo, we treated Tg APPsw transgenic mice overproducing Abeta with EGCG and found decreased Abeta levels and plaques associated with promotion of the nonamyloidogenic alpha-secretase proteolytic pathway. These data raise the possibility that EGCG dietary supplementation may provide effective prophylaxis for AD.

Alzheimer Disease↗
PubMed2005

Chromosome 21 BACE2 haplotype associates with Alzheimer's disease: a two-stage study.

Genetic linkage studies have provided evidence for a late-onset Alzheimer's disease (AD) susceptibility locus on chromosome 21q. We have tested, in a two-stage association study, whether allelic or haplotype variation of the beta-amyloid cleaving enzyme-2 (BACE2) locus on chromosome 21q affects the risk of late-onset AD. In stage-1, an unselected population-based sample of Finns aged 85 years or over (n=515) was analysed. Neuropathologic examination including beta-amyloid load quantification was possible in over 50% (n=264) of these subjects. AD patients (n=100) and controls (n=48) were defined by modified neuropathological NIA-RI criteria. Positive associations were taken as a hypothesis, and tested in stage-2 using 483 AD families from the USA. Four single nucleotide polymorphisms (SNPs) of BACE2 gene were tested in stage-1. A SNP close to exon-6 was associated with neuropathologically verified AD (p=0.02) and also with beta-amyloid load in non-selected autopsied subjects after conditioning with APOE genotype (p=0.001). In haplotype analysis a specific, relatively common haplotype (H5) was found to associate with AD (p=0.004) and a second haplotype (H7) showed a weaker association with protection against AD (p=0.04). In stage-2, the SNP association was not replicated, whereas the haplotype H5 association was replicated (p=0.004) and a trend to association was found with the putative protective haplotype H7 (two-sided p=0.08). BACE2 haplotype association with AD in two independent datasets provides further evidence for an AD susceptibility locus on chromosome 21q within or close to BACE2.

Aged↗
PubMed2005

Mutations in neurofilament genes are not a significant primary cause of non-SOD1-mediated amyotrophic lateral sclerosis.

While 1 to 2% of amyotrophic lateral sclerosis (ALS) is caused by mutations in the SOD1 gene, the basis of the remaining instances of inherited disease is unknown. Neuropathology, mouse modeling, and human genetics have implicated neurofilaments in the pathogenesis of motor neuron diseases such as ALS and Charcot-Marie-Tooth disease (CMT). A systematic analysis of the coding region and intron-exon boundaries of all three neurofilament genes is now reported from DNA samples derived from more than 200 non-SOD1 linked familial and sporadic ALS patients, along with >400 non-disease control individuals. Rare variants within each of the three neurofilament subunits that are predicted to affect neurofilament assembly properties were identified at higher frequency in non-SOD1 mutant ALS samples. However, none could be unambiguously linked to dominantly inherited disease. Thus, mutations in neurofilaments are possible risk factors that may contribute to pathogenesis in ALS in conjunction with one or more additional genetic or environmental factors, but are not significant primary causes of ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Abeta42 is essential for parenchymal and vascular amyloid deposition in mice.

Considerable circumstantial evidence suggests that Abeta42 is the initiating molecule in Alzheimer's disease (AD) pathogenesis. However, the absolute requirement for Abeta42 for amyloid deposition has never been demonstrated in vivo. We have addressed this by developing transgenic models that express Abeta1-40 or Abeta1-42 in the absence of human amyloid beta protein precursor (APP) overexpression. Mice expressing high levels of Abeta1-40 do not develop overt amyloid pathology. In contrast, mice expressing lower levels of Abeta1-42 accumulate insoluble Abeta1-42 and develop compact amyloid plaques, congophilic amyloid angiopathy (CAA), and diffuse Abeta deposits. When mice expressing Abeta1-42 are crossed with mutant APP (Tg2576) mice, there is also a massive increase in amyloid deposition. These data establish that Abeta1-42 is essential for amyloid deposition in the parenchyma and also in vessels.

Age Factors↗
PubMed2005

Mutation analysis of patients with neuronal intermediate filament inclusion disease (NIFID).

Abnormal neuronal aggregates of alpha-internexin and the three neurofilament (NF) subunits, NFL, NFM, and NFH have recently been identified as the signature lesions of neuronal intermediate filament (IF) inclusion disease (NIFID), a novel neurological disease of early onset with a variable clinical phenotype including frontotemporal dementia, pyramidal and extrapyramidal signs. In other neurodegenerative diseases in which protein aggregates contribute to disease pathogenesis, mutations in the encoding protein cause the hereditary variant of the disease. 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.

Adult↗
PubMed2005

Association studies between risk for late-onset Alzheimer's disease and variants in insulin degrading enzyme.

Linkage studies have suggested there is a susceptibility gene for late onset Alzheimer's disease (LOAD) in a broad region of chromosome 10. A strong positional and biological candidate is the gene encoding the insulin-degrading enzyme (IDE), a protease involved in the catabolism of Abeta. However, previous association studies have produced inconsistent results. To systematically evaluate the role of variation in IDE in the risk for LOAD, we genotyped 18 SNPs spanning a 276 kb region in and around IDE, including three "tagging" SNPs identified in an earlier study. We used four case-control series with a total of 1,217 cases and 1,257 controls. One SNP (IDE_7) showed association in two samples (P-value = 0.0066, and P = 0.026, respectively), but this result was not replicated in the other two series. None of the other SNPs showed association with LOAD in any of the tested samples. Haplotypes, constructed from the three tagging SNPs, showed no globally significant association. In the UK2 series, the CTA haplotype was over-represented in cases (P = 0.046), and in the combined data set, the CCG haplotype was more frequent in controls (P = 0.015). However, these weak associations observed in our series were in the opposite direction to the results in previous studies. Although our results are not universally negative, we were unable to replicate the results of previous studies and conclude that common variants or haplotypes of these variants in IDE are not major risk factors for LOAD.

Alleles↗
PubMed2005

Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism.

Patients with Alzheimer's disease (AD) have abnormally low positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose (CMRgl) in regions of the precuneus and the posterior cingulate, parietotemporal, and frontal cortex. Apolipoprotein E (APOE) epsilon4 gene dose (i.e., the number of epsilon4 alleles in a person's APOE genotype) is associated with a higher risk of AD and a younger age at dementia onset. We previously found that cognitively normal late-middle-aged APOE epsilon4 carriers have abnormally low CMRgl in the same brain regions as patients with probable Alzheimer's dementia. In a PET study of 160 cognitively normal subjects 47-68 years of age, including 36 epsilon4 homozygotes, 46 heterozygotes, and 78 epsilon4 noncarriers who were individually matched for their gender, age, and educational level, we now find that epsilon4 gene dose is correlated with lower CMRgl in each of these brain regions. This study raises the possibility of using PET as a quantitative presymptomatic endophenotype to help evaluate the individual and aggregate effects of putative genetic and nongenetic modifiers of AD risk.

Age of Onset↗
PubMed2005

Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer's disease.

We performed an affected sib-pair (ASP) linkage analysis to test for the effects of age at onset (AAO), rate of decline (ROD), and Apolipoprotein E (APOE) genotype on linkage to late-onset Alzheimer's disease (AD) in a sample comprising 428 sib-pairs. We observed linkage of mean AAO to chromosome 21 in the whole sample (max LOD = 2.57). This came entirely from the NIMH sample (max LOD = 3.62), and was strongest in pairs with high mean AAO (>80). A similar effect was observed on chromosome 2q in the NIMH sample (max LOD = 2.73); this region was not typed in the IADC/UK sample. Suggestive evidence was observed in the combined sample of linkage of AAO difference to chromosome 19q (max LOD = 2.33) in the vicinity of APOE and 12p (max LOD = 2.22), with linkage strongest in sib-pairs with similar AAO. Mean ROD showed suggestive evidence of linkage to chromosome 9q in the whole sample (max LOD = 2.29), with the effect strongest in the NIMH sample (max LOD = 3.58), and in pairs with high mean ROD. Additional suggestive evidence was also observed in the NIMH sample with AAO difference on chromosome 6p (max LOD = 2.44) and 15p (max LOD = 1.87), with linkage strongest in pairs with similar AAO, and in the UK sample with mean ROD on chromosome 1p (max LOD = 2.73, linkage strongest in pairs with high mean ROD). We also observed suggestive evidence of increased identical by descent (IBD) in APOE epsilon4 homozygotes on chromosome 1 (max LOD = 3.08) and chromosome 9 (max LOD = 3.34). The previously reported genome-wide linkage of AD to chromosome 10 was not influenced by any of the covariates studied.

Age of Onset↗
PubMed2005

Defining the ends of Parkin exon 4 deletions in two different families with Parkinson's disease.

Autosomal recessive juvenile parkinsonism (AR-JP, PARK2) is characterized by an early onset parkinsonism, often presenting with dystonia as an early feature. Mutations in Parkin are a relatively common cause of AR-JP and are estimated to be present in approximately 30% of familial young onset Parkinson disease (PD) [Abbas et al. (1999); Hum Mol Genet 8:567-574]. These mutations include exon rearrangements (deletions and duplications), point mutations, and small deletions. Similar genomic mutations have been described in unrelated patients, thereby indicating independent mutational events or ancient founder effects. We have identified homozygous deletion mutations of exon 4 in Parkin in two unrelated families, one from Brazil and the other from Turkey [Dogu et al. (2004); Mov Dis 9:812-816; Khan et al., Mov Dis, in press]. We have performed molecular analysis of the deletion breakpoints and this data indicates these mutations originated independently. We present here data demonstrating that the mutation responsible for disease in the Brazilian kindred consists of two separate deletions (1,069 and 1,750 bp) surrounding and including exon 4. The deletion removing parkin exon 4 identified in the Turkish family extended 156,203 bp. 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.

Base Sequence↗