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Biomedical subjects

J Hardy

Publications and source records attributed to J Hardy.

At least 91 records · Page 5Linked to original sources
PubMed2001

Genetic dissection of primary neurodegenerative diseases.

Neurodegenerative diseases have traditionally been defined as clinico-pathological entities. The clinician observes characteristic clusters of symptoms that relate to the anatomical distribution of the lesion. Typically, these symptoms progress in a characteristic sequence allowing the clinician to make a provisional diagnosis. At autopsy, the pathologist examines the nature and distribution of the lesions, reads the clinical report and makes a definitive diagnosis. This structure is so deeply embedded in our concepts of neurodegenerative disease that we are hardly aware of it. It has become deeply embedded because it has been a useful construct that allows grouping of patients for research, especially in treatment trials. However this success has served to hide its limitations and molecular genetic analysis has clearly shown that there are other ways of thinking about neurodegenerative disease. In this review, I will summarize the limitations of the clinicopathological approach, and discuss how molecular genetics offers an alternative way of thinking about neurodegeneration. My intention is not to suggest that we should replace the clinicopathological approach (Newtonian physics is a perfectly good way of thinking about the world on a day-to-day basis even though we know it is only an approximation to the truth) but rather, to suggest that future treatments for these most devastating diseases may come from a deeper understanding of their related pathogenesis.

Alzheimer Disease↗
PubMed2001

Patients with pulmonary and cardiac disease show an elevated proportion of immature reticulocytes.

The value of reticulocyte analysis has been largely confined to classification of anaemia. In the present study, we have investigated the value of undertaking automated fluorescent reticulocyte analysis (Abbott Cell-Dyn 4000) in patients with pulmonary or cardiac diseases. A control group of nonanaemic (n = 367) and anaemic patients (n = 57) was established and thereafter compared with a group of patients with pulmonary disease (172 without anaemia, 92 with anaemia) and another group with cardiac disease (520 without anaemia, 254 with anaemia). The Hb level and reticulocyte RNA content (as measured by the immature reticulocyte fraction, IRF) of the study subjects were inversely correlated (r = -0.41). The mean IRF of nonanaemic patients with pulmonary (mean = 0.331, SD=0.124) and cardiac disease (mean = 0.266, SD = 0.079) were both significantly higher (P < 0.05) than in control subjects (mean = 0.220, SD = 0.062). Nonanaemic and anaemic patients with cardiac disease both showed significantly higher (P < 0.05) reticulocyte percentage counts than the equivalent anaemic and nonanaemic controls. Each of these phenomena can all be attributed to hypoxia mediated EPO production. Our observation that 35% of patients with pulmonary disease have elevated levels of IRF, may prove useful in screening for tissue hypoxia in nonanaemic patients. Furthermore, serial monitoring of the IRF may prove valuable in observing the efficacy of therapy in these patients.

Adult↗
PubMed2001

Identification and characterization of the human parkin gene promoter.

Compound mutations and homozygous loss of function of the parkin gene causes juvenile and early onset, autosomal recessive parkinsonism. Pathologically, the disease is associated with loss of dopaminergic neurons in the substantia nigra pars compacta and locus ceruleus, usually without Lewy body pathology. Hemizygous families have been described that may harbor mutations outside of the open reading frame. The parkin gene promoter has yet to be characterized, and therein, mutations in hemizygous families may plausibly be identified. To identify the promoter of the parkin gene, the transcription start site was defined by a combination of primer extension and 5' RACE. Five kilobases of DNA 5' to the parkin start codon were directly sequenced from a BAC containing parkin exon 1 and evaluated for promoter motifs. The parkin promoter lacks TATA or CAAT boxes and appears to share homology to the alpha-synuclein promoter. Deletion constructs demonstrated core promoter activity and tissue specific enhancing regions in HEK-293T and SH-SY5Y cells.

5' Untranslated Regions↗
PubMed2001

Healthcare utilization and costs in managed care patients with Alzheimer's disease during the last few years of life.

OBJECTIVES: To learn whether managed care patients with Alzheimer's disease (AD) are more or less costly to care for than patients with other forms of dementia or patients without dementia during the last few years of life. DESIGN: Case control study. SETTING: A health maintenance organization base population. PARTICIPANTS: Three groups of subjects (mean age 85) who were deceased members of a dementia registry obtained from a health maintenance organization base population: 263 subjects with clinically diagnosed probable AD, 133 subjects with other forms of dementia, and 100 cognitively intact controls. MEASUREMENTS: Utilization records were examined for the 3 years preceding death. RESULTS: In all subcategories and in aggregate, utilization and costs of care were either similar or lower for patients with AD than for the other groups, even after controlling for age, gender, and comorbidity. CONCLUSIONS: Persons with AD do not incur higher costs than persons with other types of dementia or age-matched persons without dementia in a mature health maintenance organization during the last few years of life, when utilization is likely to be highest.

Aged↗
PubMed2001

Exploring self-talk and affective states in sport.

In this study, we examined (1) the relationship between self-talk and affect and (2) the nature of motivating self-talk. Ninety high-school athletes completed the Affect Grid and the Self-Talk Grid before practice and competition. Significant positive second-order partial correlations of low to moderate strength offered support for a relationship between self-talk and affect. In addition, significant positive second-order partial correlations of moderate strength were found for a relationship between negative-positive self-talk and demotivating-motivating self-talk. An examination of scatter plots indicated that some athletes rated their self-talk as negative as well as being motivational. These findings lend support to the suggestion that negative self-talk may motivate some athletes.

Adolescent↗
PubMed2001

Number of Abeta inoculations in APP+PS1 transgenic mice influences antibody titers, microglial activation, and congophilic plaque levels.

There have been several reports on the use of beta-amyloid (Abeta ) vaccination in different mouse models of Alzheimer's disease (AD) and its effects on pathology and cognitive function. In this report, the histopathologic findings in the APP+PS1 doubly transgenic mouse were compared after three, five, or nine Abeta inoculations. The number of inoculations influenced the effects of vaccination on Congo red levels, microglia activation, and anti-Abeta antibody titers. After three inoculations, the antibody titer of transgenic mice was substantially lower than that found in nontransgenic animals. However, after nine inoculations, the levels were considerably higher in both genotypes and no longer distinguishable statistically. The number of inoculations influenced CD45 expression, an indicator of microglial activation. There was an initial upregulation, which was significant after five inoculations, but by nine inoculations, the extent of microglial activation was equivalent to that in mice given control vaccinations. Along with this increased CD45 expression, there was a correlative reduction in staining by Congo red, which stains compact plaques. When data from the mice from all groups were combined, there was a significant correlation between activation of microglia and Congo red levels, suggesting that microglia play a role in the clearance of compact plaque.

Alzheimer Disease↗
PubMed2001

A clinical and pathological study of motor neurone disease on Guam.

Despite over 40 years of intensive study, the cause of the high incidence of motor neurone disease (MND) on Guam, and the relationship between this disease and MND seen in the rest of the world are still uncertain. We present a series of 45 cases of Guamanian MND, which reaffirm the clinical similarity between this disease and MND seen in other countries. However, the occurrence of MND among the indigenous Chamorros of Guam is distinguished by four factors: (i) high prevalence; (ii) frequent familial occurrence; (iii) co-occurrence with the parkinsonism-dementia complex (PDC); and (iv) association with an unusual and distinctive linear retinopathy termed Guam retinal pigment epitheliopathy (GRPE). These distinguishing factors were not present in four non-Chamorros who resided on Guam when their MND symptoms occurred. Pathologically, the classical features of MND were seen in Guamanian Chamorro cases including ubiquitin inclusions. Neurofibrillary tangles were frequently seen. The neurofibrillary tangles appeared in the same distribution as described in the PDC but, unlike classical PDC, they were not usually associated with cell loss and occurred less frequently. While neurofibrillary tangle formation and the clinicopathological syndrome of MND may occur in parallel, observations from this series suggest that pathologically classical MND on Guam may occur independently of neurofibrillary degeneration and the clinical features of PDC.

Adult↗
PubMed2001

Cotton wool plaques in non-familial late-onset Alzheimer disease.

Cotton wool plaques (CWP) are large, ball-like plaques lacking dense amyloid cores that displace adjacent structures. They were first described in a Finnish kindred with early-onset Alzheimer disease (AD) with spastic paraparesis due to a presenilin-1 delta9 mutation. We describe a case of sporadic late-onset AD with numerous neocortical CWP as well as severe amyloid angiopathy and marked leukoencephalopathy, compared with 16 cases of late-onset AD with similar degrees of amyloid angiopathy and leukoencephalopathy. The cases were studied with histologic methods and with single and double immunostaining for beta-amyloid (Abeta), paired helical filaments-tau (PHF-tau), neurofilament (NF), glial fibrillary acidic protein (GFAP), HLA-DR, and amyloid precursor protein (APP). We found that CWP were well-circumscribed amyloid deposits infiltrated by ramified microglia and surrounded by dystrophic neurites that were immunopositive for APP, but only weakly for NF and PHF-tau. Abeta1-12 was diffuse throughout the CWP, while Abeta37-42 was peripherally located and Abeta20-40 more centrally located. Two of the 16 late-onset AD cases also had CWP, but they were also admixed with diffuse plaques and plaques with dense amyloid cores. Pyramidal tract degeneration was not a consistent finding or a prominent feature in any case. The results suggest that CWP are not specific for early-onset familial AD with spastic paraparesis.

Age of Onset↗
PubMed2001

Variant Alzheimer disease with spastic paraparesis: neuropathological phenotype.

Variant Alzheimer disease (varAD) is clinically characterized by the combination of presenile dementia with spastic paraparesis and is caused by certain mutations of the presenilin 1 (PS-1) gene. We now present the unusual neuropathological phenotype of varAD as seen in 5 affected members of the original Finnish family with a genomic deletion encompassing exon 9 of the PS-1 gene. Their primary and association cortices and hippocampus showed a profusion of eosinophilic, roundish structures with distinct borders termed "cotton wool" plaques (CWPs). The CWPs were immunoreactive for Abeta42/43 but weakly or not at all for Abeta40 isoforms of the amyloid beta peptide (Abeta). They were devoid of a congophilic core, and fibrillar amyloid could not be identified within them by electron microscopy. Confocal microscopy showed reduced density of axons within individual CWPs and only few CWP-related PHF-tau-positive dystrophic neurites. CWPs were particularly numerous in the medial motor cortex representing the lower extremities, and degeneration of the lateral corticospinal tracts was observed at the level of the medulla oblongata and the spinal cord. In addition to the predominant CWPs, variable numbers of diffuse and cored plaques were found in the cerebral cortex. Diffuse and non-neuritic cored amyloid plaques but no CWPs occurred in the cerebellum. In conclusion, varAD in this Finnish family is distinct from classic AD because of the degeneration of lateral corticospinal tracts, predominance of CWPs devoid of fibrillar amyloid cores in the cerebral cortex, and presence of non-neuritic amyloid plaques in the cerebellum.

Alzheimer Disease↗
PubMed2001

Effects of anti-inflammatory drugs on lipopolysaccharide-challenged and -unchallenged equine synovial explants.

OBJECTIVE: To evaluate the effects of anti-inflammatory drugs on lipopolysaccharide (LPS)-challenged and -unchallenged equine synovial membrane in terms of production of prostaglandin E2 (PGE2) and hyaluronan, viability, and histomorphologic characteristics. SAMPLE POPULATION: Synovial membranes were collected from the carpal, tarsocrural, and femoropatellar joints of 6 adult horses. PROCEDURE: Synovial membranes from each horse were minced and pooled and explants were treated with one of the following: no drug (control), drug, LPS alone, or LPS and drug. Treatment drugs were phenylbutazone (PBZ), flunixin meglumine (FNX), ketoprofen (KET), carprofen (CRP), meloxicam (MEL), low-concentration methylprednisolone (METH), high-concentration METH, dimethyl sulfoxide (DMSO), or an experimental COX-2 inhibitor (dissolved in DMSO). Following 48 hours of culture, medium was assayed for PGE2 and hyaluronan concentration. Synovial explants were assessed for viability and histomorphologic characteristics. RESULTS: For the LPS-challenged explants, PBZ, FNX, KTP CRF MEL, and low-concentration METH suppressed PGE2 production, compared with LPS challenge alone. Only MEL suppressed PGE2 production from LPS-challenged explants, compared with unchallenged explants. Synovial explants maintained > 90% viability and there was no significant difference in viability or hyaluronan production among explants. Histomorphologic scores were significantly decreased for explants treated with low-concentration METH or DMSO. CONCLUSIONS AND CLINICAL RELEVANCE: PBZ, FNX, KTP, CRFP MEL, and low-concentration METH suppressed PGE2 production in LPS-challenged explants. Meloxicam appeared to have more selective suppression of COX-2 activity. Histomorphologic scores suggest detrimental effects of METH, DMSO, and the experimental COX-2 inhibitor. Commonly used nonsteroidal anti-inflammatory drugs suppress induced synovial membrane PGE2 production without detrimental effects on synovial membrane viability and function.

Animals↗
PubMed2001

Association of lipoprotein lipase Ser447Ter polymorphism with brain infarction: a population-based neuropathological study.

BACKGROUND: Variants of the lipoprotein lipase (LPL) gene have been shown to influence serum lipid levels, risk of coronary heart disease and, as found recently, risk of clinical ischaemic cerebrovascular disease. Here we tested for an association between brain infarction and two common polymorphisms of the LPL gene, Ser447Ter and Asn291 Ser. METHOD: To avoid ascertainment and selection bias involved in many association studies, we compared the distribution of these polymorphisms in neuropathologically verified patients (n = 119) vs controls (n = 133) derived from a prospective, population-based study (the Vantaa 85+ study). RESULTS: The LPL Ter447 variant was negatively associated with neuropathologically verified brain infarcts (P = 0.006), and even more strongly with small brain infarcts (P = 0.004). In addition, we found that the Ter447 variant was associated with higher serum HDL chblesterol (P = 0.004) and lower triglyceride levels (P= 0.003), and that it was negatively associated with pathologically verified severe coronary artery disease (P=0.001) in the Vantaa 85+ study sample. The Asn291Ser polymorphism was not significantly associated with brain infarction. CONCLUSION: The Ter447 variant of LPL is associated with decreased risk of brain infarction and coronary artery disease in our very elderly population.

Aged↗
PubMed2000

Susceptibility locus for Alzheimer's disease on chromosome 10.

The apolipoprotein E (APOE) gene is the only genetic risk factor that has so far been linked to risk for late-onset Alzheimer's disease (LOAD). However, 50 percent of Alzheimer's disease cases do not carry an APOE4 allele, suggesting that other risk factors must exist. We performed a two-stage genome-wide screen in sibling pairs with LOAD to detect other susceptibility loci. Here we report evidence for an Alzheimer's disease locus on chromosome 10. Our stage one multipoint lod score (logarithm of the odds ratio for linkage/no linkage) of 2.48 (266 sibling pairs) increased to 3.83 in stage 2 (429 sibling pairs) close to D10S1225 (79 centimorgans). This locus modifies risk for Alzheimer's disease independent of APOE genotype.

Age of Onset↗
PubMed2000

A pathogenic presenilin-1 deletion causes abberrant Abeta 42 production in the absence of congophilic amyloid plaques.

Familial Alzheimer's disease (FAD) is frequently associated with mutations in the presenilin-1 (PS1) gene. Almost all PS1-associated FAD mutations reported so far are exchanges of single conserved amino acids and cause the increased production of the highly amyloidogenic 42-residue amyloid beta-peptide Abeta42. Here we report the identification and pathological function of an unusual FAD-associated PS1 deletion (PS1 DeltaI83/DeltaM84). This FAD mutation is associated with spastic paraparesis clinically and causes accumulation of noncongophilic Abeta-positive "cotton wool" plaques in brain parenchyma. Cerebral amyloid angiopathy due to Abeta deposition was widespread as were neurofibrillary tangles and neuropil threads, although tau-positive neurites were sparse. Although significant deposition of Abeta42 was observed, no neuritic pathology was associated with these unusual lesions. Overexpressing PS1 DeltaI83/DeltaM84 in cultured cells results in a significantly elevated level of the highly amyloidogenic 42-amino acid amyloid beta-peptide Abeta42. Moreover, functional analysis in Caenorhabditis elegans reveals reduced activity of PS1 DeltaI83/DeltaM84 in Notch signaling. Our data therefore demonstrate that a small deletion of PS proteins can pathologically affect PS function in endoproteolysis of beta-amyloid precursor protein and in Notch signaling. Therefore, the PS1 DeltaI83/DeltaM84 deletion shows a very similar biochemical/functional phenotype like all other FAD-associated PS1 or PS2 point mutations. Since increased Abeta42 production is not associated with classical senile plaque formation, these data demonstrate that amyloid plaque formation is not a prerequisite for dementia and neurodegeneration.

Alzheimer Disease↗
PubMed2000

The presenilin 1 C92S mutation increases abeta 42 production.

Although wild-type human presenilin 1 (PS1) rescues the C. elegans egg-laying (egl) phenotype that is caused by a loss of function mutation in the C. elegans presenilin homologue sel12, most familial Alzheimer's disease (FAD)-linked PS1 mutants only partially rescue this phenotype. To investigate the effects of the loss of function sel12 mutation on Abeta production in mammalian cells, we analyzed Abeta production in transfected H4 neuroglioma cells expressing the PS1 homologue of the sel12 C60S mutant, PS1 C92S. This analysis revealed that PS1 C92S increased Abeta42 levels in a similar fashion to other pathogenic Alzheimer's disease (AD) PS1 mutations. Significantly, the PS1 C92S mutation has recently been identified as the pathogenic mutation in an Italian family with FAD. Thus, placing a mutation that results in loss of function in C. elegans into a context whereby its effect on mammalian cells can be evaluated suggests that all FAD-linked PS1 mutants result in increased Abeta42 production through a partial loss of function mechanism.

Alzheimer Disease↗
PubMed2000

Cardiovascular risk factors and Alzheimer's disease: a genetic association study in a population aged 85 or over.

Increasing evidence suggests a relation between vascular disorders and late-onset Alzheimer's disease (AD). We performed an association analysis of low-density lipoprotein receptor-related protein (LRP), lipoprotein lipase (LPL), and angiotensin converting enzyme (ACE) genes, known to be involved in vascular disorders, and AD. Genotyping was carried out in 113 patients with clinically defined Alzheimer's disease (NINCDS-ADRDA criteria) and 203 non-demented controls in a prospective, population-based study of people aged 85 years or over (Vantaa 85+ Study). Corresponding analysis was performed on 121 neuropathologically verified AD patients (CERAD criteria) and 75 controls derived from the same study population. We did not find significant associations between the polymorphisms studied and AD. However, analysis of the LPL polymorphism showed a weak trend (uncorrected P-value 0.095) towards protection against neuropathologically defined AD. Our study is based on very elderly Finns. Therefore, further studies are warranted in other populations.

Aged↗
PubMed2000

Spinocerebellar ataxia type 2 with parkinsonism in ethnic Chinese.

OBJECTIVE: To describe the clinical and molecular genetic analysis of a large family of northern Chinese descent with a mutation at the SCA2 locus causing carbidopa-levodopa-responsive parkinsonism. BACKGROUND: Most causes of parkinsonism remain unknown. However, molecular genetic analysis of families with parkinsonism has recently identified five distinct loci and pathogenic mutations in four of those. Additionally, some of the spinocerebellar ataxia syndromes (SCA), particularly Machado-Joseph syndrome (SCA3), are known to cause parkinsonism. Spinocerebellar ataxia type 2 (SCA2) has not previously been described as causing a typical dopamine-responsive asymmetric PD phenotype. METHODS: A large family was evaluated clinically and molecularly for apparent autosomal dominant parkinsonism. RESULTS: The phenotype includes presentation consistent with typical dopamine-responsive parkinsonism. Other presentations in this family include a parkinsonism/ataxia phenotype, which is classic for SCA2 and parkinsonism, resembling progressive supranuclear palsy. CONCLUSIONS: Patients presenting with a family history of parkinsonism, including familial progressive supranuclear palsy and PD, should be tested for the spinocerebellar ataxia type 2 expansion.

Adult↗