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M Rossor

Publications and source records attributed to M Rossor.

At least 37 records · Page 2Linked to original sources
PubMed1999

Molecular genetic characterisation of frontotemporal dementia on chromosome 3.

We have previously localized a locus causing familial nonspecific dementia to the centromeric region of chromosome 3 in a pedigree from the Jutland area of Denmark. This pedigree shows anticipation. Here we present further analysis of these anticipation data which are suggestive of trinucleotide repeat expansion involvement. We also outline our strategies to clone the mutant gene via its putative associated trinucleotide repeat sequence.

Adult↗
PubMed1998

ApoE genotype is a risk factor in nonpresenilin early-onset Alzheimer's disease families.

The apolipoprotein E (ApoE) genotype is a significant risk factor and modulator of age of onset of Alzheimer's disease (AD). We analyzed the effect of the ApoE genotype in two distinct early-onset familial AD groups: families with a mutation in the presenilin-1 gene (PS-1) on chromosome 14, and families without a mutation detectable in the PS-1, presenilin-2 (PS-2), and the amyloid precursor protein (APP) gene (non-PS early-onset familial AD). The ApoE genotype is clearly shown not to modulate age of onset in families with a mutation in the PS-1 gene and families with no lesion detectable in either the presenilin or APP gene. The effects of a double dose of ApoE4 on age of onset were not assessed in the PS-1 AD families due to the lack of any affected ApoE4 homozygotes in the sample set; this insufficiency will need to be assessed in further studies. There was no association between the ApoE4 allele and AD in the PS-1 families. Non-PS early-onset AD families were shown to have a significantly higher frequency of ApoE4 compared to controls and the PS-1 AD group. These observations are important and suggest that 1) other genetic and environmental factors modify the AD phenotype in PS-1 and non-PS early-onset families; and 2) the ApoE4 allele is a significant risk factor in the etiology of non-PS early-onset AD and will be a useful adjunct in the diagnosis of unaffected family members.

Alleles↗
PubMed1998

Clinical trial designs for demonstrating disease-course-altering effects in dementia.

Advances in our understanding of the pathogenesis of Alzheimer disease (AD) and vascular dementia (VaD) now permit responsible discussion of therapies that may go beyond relief of cognitive and behavioral symptoms and actually slow progression of disease. The mechanisms of neuronal death and the pathologic role of glia are being elucidated, and epidemiologic studies have suggested potential protective value for anti-inflammatory drugs, estrogen, and free-radical scavengers. However, demonstrating disease-modifying drug effects for progressive conditions such as dementia can be a daunting task, fraught with clinical, statistical, and ethical dilemmas. To evaluate trial designs for demonstrating such effects, the International Working Group on Harmonization of Dementia Drug Guidelines (IWG) conducted a symposium at the Sixth International Congress on Alzheimer's Disease and Related Disorders, held July 1998 in Amsterdam. The presentations at the IWG symposium covered the two basic designs currently being used in clinical trials, survival analysis and staggered-start/withdrawal, in addition to clinical data generated from the National Institute on Aging Alzheimer's Disease Cooperative Study vitamin E/selegiline trial in patients with AD and the phase III clinical studies of propentofylline in patients with AD and VaD. It is hoped that this article will open a dialogue among investigators and regulatory authorities regarding appropriate trial designs to support a regulatory claim for disease-modifying effects.

Aged↗
PubMed1997

Diagnosis of Alzheimer's disease. Report of an International Psychogeriatric Association Special Meeting Work Group under the cosponsorship of Alzheimer's Disease International, the European Federation of Neurological Societies, the World Health Organization, and the World Psychiatric Association.

Current knowledge with respect to the diagnosis of Alzheimer's disease (AD) is reviewed. There is agreement that AD is a characteristic clinicopathologic entity that is amenable to diagnosis. The diagnosis of AD should no longer be considered one of exclusion. Rather, the diagnostic process is one of recognition of the characteristic features of AD and of conditions that can have an impact on presentation or mimic aspects of the clinicopathologic picture. The present availability of improved prognosis, management, and treatment strategies makes the proper, and state-of-the-art, diagnosis of AD a clinical imperative in all medical settings. Concurrently, information regarding the relevance and applicability of current diagnostic procedures in diverse cultural settings must continue to accrue.

Aged↗
PubMed1996

Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease.

The presenilin 1 gene has recently been identified as the locus on chromosome 14 which is responsible for a large proportion of early onset, autosomal dominantly inherited Alzheimer's disease (AD). We have elucidated the intron/exon structure of the gene and designed intronic primers to enable direct sequencing of the entire coding region (10 exons) of the presenilin gene in a large number of families. This strategy has enabled us to find a further two novel mutations in the gene. We discuss the distribution of mutations and the proportions of autosomal dominant AD with a mean age of onset below 60 years caused by mutations in this gene.

Alzheimer Disease↗
PubMed1996

A multicenter double-blind study of controlled-release physostigmine for the treatment of symptoms secondary to Alzheimer's disease. Physostigmine Study Group.

OBJECTIVE: A multicenter trial to evaluate the efficacy of controlled-release physostigmine salicylate, a cholinesterase inhibitor, was conducted in 1,111 mild-to-moderate Alzheimer's disease (AD) subjects. DESIGN: During dose titration, subjects received 18, 24, or 30 mg of physostigmine or placebo daily. After a 2-week washout period, 366 subjects with putative improvement were randomized to receive either placebo or their best dose of physostigmine in a 6-week double-blind trial. Nonresponding patients (439) were randomized to receive in a separate double-blind trial either placebo or their highest tolerated dose of physostigmine. The primary efficacy measures included the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS) and a Clinical Global Impression of Change (CGIC). Secondary measures included the Mini-Mental State Examination and two activities-of-daily-living scales. RESULTS: At the end of the 6-week double-blind phase, physostigmine-treated patients scored 1.75 points higher than placebo-treated patients on the ADAS (p = 0.003) and 0.26 points higher on the CGIC (p = 0.012) in the intent-to-treat analysis. There was no significant improvement on the secondary outcome measures. Patients failing to respond to physostigmine during the dose titration phase failed to respond on any of the outcome measures during the double-blind period of re-exposure. Common adverse events included nausea, vomiting, diarrhea, and anorexia. There were no significant changes in liver function tests. CONCLUSION: This study demonstrated statistically significant differences between physostigmine and placebo on both a performance-based cognitive functioning instrument and a clinician's global evaluation. The magnitude of the effect size was small and occurred only in the subset of patients who responded in the initial dose titration study period. Nevertheless, the results suggest that in a subset of patients, physostigmine can induce a degree of cognitive improvement over 6 weeks of treatment.

Aged↗
PubMed1995

Evidence that the APOE locus influences rate of disease progression in late onset familial Alzheimer's Disease but is not causative.

An association has been observed in several independent data sets between late onset Alzheimer's Disease (AD) and the APOE locus on chromosome 19. We have examined the genotype in family history positive (FHP) and family history negative (FHN) cases and find a distortion of the APOE allele frequencies in accord with previous studies. However, when we examined the allele distribution of the at-risk siblings of the FHP group we found an excess of the epsilon 4 allele which also differs significantly from historic controls but not from the affected siblings. The age distribution of the affected and unaffected siblings was similar, suggesting that the allelic frequency distortion in the unaffected siblings was not due to their being below the mean age of onset. Lod score linkage analysis, with age dependent onset and non-stringent specification of the genetic parameters, did not suggest linkage to the APOE locus. Furthermore, an analysis of variance of the age of disease free survival suggested that APOE genotype contributes a small fraction of the total variance indicating that the APOE locus is a poor predictor of disease free survival age within late onset families. One explanation for the age dependent association reported by other groups, and our results, is that the APOE locus enhances the rate of progression of the disease process in otherwise predisposed individuals and that variation at this locus is not able in and of itself to cause the disease. We suggest this hypothesis is compatible with the current literature regarding APOE and AD.

Age Factors↗
PubMed1995

Familial non-specific dementia maps to chromosome 3.

A significant minority of degenerative dementias lack distinctive inclusion bodies, plagues or tangles on pathological examination. Half of these cases have a positive family history of dementia. We have studied the largest published family with such a dementia and mapped the disease locus to a 12 cM region of chromosome 3 spanning the centromere. Haplotype analysis demonstrates a common region shared between all affected individuals between the markers D3S1284 and D3S1603. Like a number of other late onset neurodegenerative diseases, the disease presents at an earlier age when paternally inherited.

Chromosome Mapping↗
PubMed1995

Microsatellite D21S210 (GT-12) allele frequencies in sporadic Alzheimer's disease.

Four disease-causing mutations have so far been described in the amyloid precursor protein gene on chromosome 21 in familial early-onset Alzheimer's disease. Linkage analysis with a fourteen-allele microsatellite at D21S210 named GT-12 has proven useful in the elucidation of amyloid precursor protein gene involvement in Alzheimer's disease families, as it is closely linked to the gene. Most cases of Alzheimer's disease are thought to be sporadic and not familial. However, evidence from earlier studies suggests an important genetic contribution also in sporadic cases, where gene-environment interaction may contribute to the disease. We have determined frequencies of the GT-12 alleles in 78 Swedish and 49 British sporadic Alzheimer's disease cases and 104 healthy elderly control subjects, to investigate if the disease associates with a particular genotype in GT-12. However, no differences in allele frequencies were observed between any of the groups.

Aged↗
PubMed1994

Confirmation that familial clustering and age of onset in late onset Alzheimer's disease are determined at the apolipoprotein E locus.

We confirm that familial clustering in late onset Alzheimer's disease is associated with the zeta 4 allele of apolipoprotein E. This allele occurs in the great majority (82%) of late onset familial Alzheimer cases. Together with previously published data, it is suggested that the effect of a single zeta 4 allele is to increase the risk of developing AD by an amount equivalent to 5 years and that the effect of zeta 4 homozygosity is to increase the risk of developing AD by an amount equivalent to 10 years of age.

Age of Onset↗
PubMed1994

The genetics of Alzheimer's disease.

The discovery of pathogenic mutations in the amyloid precursor protein gene in families with Alzheimer's disease is a major advance in the understanding of the pathogenesis of Alzheimer's disease. In certain families at least, beta-amyloid metabolism plays a central role in the disease process. It is tempting to speculate that beta-amyloid is common to the majority of Alzheimer cases. In the immediate future the discovery of the mutations responsible for the condition in those families that show linkage to chromosomes 14 and 19 will enable it to be established whether beta-amyloid is involved in these pedigrees as well. If amyloid metabolism is involved in APP and chromosomes 14 and 19 families, it suggests that Alzheimer's disease is a single disease with a common metabolic pathway. However, if other mechanisms are implicated, evidence is provided that Alzheimer's disease is a heterogeneous disorder that shares common clinicopathological features.

Alzheimer Disease↗
PubMed1993

Age of onset in familial early onset Alzheimer's disease correlates with genetic aetiology.

Age of onset is the most robust clinical feature demarcating aetiologic subtypes of familial Alzheimer's disease. It has previously been noted that early onset disease (arbitrarily below the age of 65 years) conforms to an autosomal dominant pattern of transmission. Late onset disease is generally thought to have a more complex aetiology. We present data here suggesting that early onset disease can be subdivided by genetic aetiology with which age of onset correlates. In general, those pedigrees showing linkage to the chromosome 14 locus have a mean age of onset in the forties whereas those pedigrees with an APP mutation have an age of onset in the fifties.

Adult↗