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Biomedical subjects

D G Munoz

Publications and source records attributed to D G Munoz.

At least 19 recordsLinked to original sources
PubMed2005

Rate of progression of cognitive decline in Alzheimer's disease: effect of butyrylcholinesterase K gene variation.

OBJECTIVE: To determine whether individuals with Alzheimer's disease (AD) and the K variant allele of butyrylcholinesterase have a slower rate of cognitive decline than those without the K variant allele of butyrylcholinesterase. METHOD: The cognitive status of 339 community based subjects with AD was assessed with the Mini Mental State Examination at baseline and yearly over a three year follow up period. The rates of cognitive decline of subjects with and without the K variant allele were compared. RESULT: Presence of the K allele was associated with a slower average rate of cognitive decline in subjects with severe AD. CONCLUSIONS: This finding is consistent with the suggestion that the K variant of butyrylcholinesterase has an important role in disease progression in AD, and this may have implications for treatment.

Aged↗
PubMed2001

Cognitive impairment in sporadic ALS: a pathologic continuum underlying a multisystem disorder.

BACKGROUND: Traditionally considered a motor neuron-selective disorder, the clinical manifestations of ALS can include a frontotemporal dementia. Although the pathologic substrate of cognitive impairment remains to be defined, the presence of ubiquitin-immunoreactive (Ub+) intraneuronal inclusions in cortical regions has been suggested to constitute a pathologic marker of this process. METHODS: The authors compared the neuropathological features of four cognitively impaired patients with ALS, four cognitively intact patients with ALS, and four neurologically normal patients. The extent and load of Ub+ neuronal inclusions, Ub+ dystrophic neurites, and superficial linear spongiosis (SLS) was determined among a number of cortical, hippocampal, and subcortical regions. RESULTS: Although Ub+, alpha-synuclein-negative, and tau-negative neuronal inclusions were observed in both cognitively impaired and cognitively intact patients with ALS, their density and extent was greater among the former, with the difference greatest in the cingulate gyrus. Ub+ neurites were observed in a similar distribution. Only the presence of SLS, affecting the first and second cortical layers, reliably distinguished between the cognitively impaired and cognitively intact ALS subpopulations. In three of four cognitively impaired patients with ALS, SLS was associated with transcortical microglial activation, in the absence of detectable differences in astrocytosis, density of calbindin or parvalbumin neurons, or optical density of synaptophysin and SNAP-25. CONCLUSIONS: Although intraneuronal Ub+ inclusions and dystrophic neurites are observed in both ALS subpopulations, the presence of cognitive impairment was associated with a greater distribution and load of both neuropathologic features, suggesting a disease continuum. Moreover, cognitive impairment was uniformly associated with superficial linear spongiosis, a pathologic feature common to several forms of frontotemporal dementia.

Adult↗
PubMed2001

Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype.

OBJECTIVE: To analyze the association of polymorphisms in the tau gene with pathologically confirmed corticobasal degeneration (CBD). BACKGROUND: The authors previously described an extended tau haplotype (H1) that covers the human tau gene and is associated with the development of progressive supranuclear palsy (PSP). The authors now extend this analysis to CBD, a neurodegenerative condition with clinical and neuropathologic similarities to PSP. Like PSP, CBD is associated with accumulation of aggregates containing the 4-repeat isoforms of tau. Because of difficulty in diagnosis of CBD, the authors only analyzed cases with pathologically confirmed CBD. METHODS: The authors collected 57 unrelated, neuropathologically confirmed cases of CBD. Tau sequencing in these cases failed to show the presence of pathogenic mutations. Polymorphisms that spanned the tau gene were analyzed in all CBD cases and controls. RESULTS: Analyzing tau polymorphisms in CBD cases showed that the frequency of H1 and H1/H1 was significantly increased when analyzing all cases and when separating by country of origin. H1 frequency in all CBD cases was 0.921, compared with a control frequency of 0.766 (X(2) = 9.1, p = 0.00255 [1df], OR 3.56 [8.43 > CI 95% > 1.53]). The H1/H1 frequency was also significantly higher at 0.842 compared with 0.596 in age-matched controls (X(2) = 17.42, p = 0.00016, 2df), OR 3.61 [7.05 > CI 95% > 1.85]). CONCLUSIONS: The CBD tau association described here suggests that PSP and CBD share a similar cause, although the pathogenic mechanism behind the two diseases leads to a different clinical and pathologic phenotype.

Genotype↗
PubMed2001

Frontotemporal dementia with ubiquitinated cytoplasmic and intranuclear inclusions.

Dementia of motor neuron disease type (DMND) is a variety of frontotemporal dementia (FTD) which is pathologically defined by characteristic neuronal ubiquitinated, tau- and synuclein-negative intracytoplasmic inclusions. Many cases with this pathology, however, do not have motor neuron disease. In the present study, we document the presence of ubiquitinated neuronal intranuclear inclusions in a sub-population of cases of neuropathologically verified DMND. Immunohistochemical localization of ubiquitin was performed on sections of post-mortem brain from 12 patients with DMND as well as from cases with other neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, and multiple system atrophy. All of the cases of DMND showed ubiquitinated, tau-negative intracytoplasmic inclusions in dentate granule cells and cortical neurons. Of these 12 cases of DMND, 3 also showed neuronal ubiquitinated intranuclear inclusions. In 1 of these cases, CAG repeat expansions in the genes known to harbor these mutations were excluded. Cases with intranuclear inclusions displayed striatal atrophy and reduced brain weight relative to non-inclusion-bearing cases. In addition, patients with intranuclear inclusions tended to have a younger age of onset, a prolonged duration of disease, absence of motor neuron symptoms, and a family history of dementia. Intranuclear inclusions were not identified in the control cases with other neurodegenerative diseases. Ubiquitinated neuronal intranuclear inclusions have not been reported previously in DMND. The presence of ubiquitinated intranuclear inclusions along with striatal atrophy in a subset of cases of DMND may signify the existence of a neuropathologically distinct subset of this unique form of FTD.

Brain↗
PubMed2000

The corticobasal degeneration syndrome overlaps progressive aphasia and frontotemporal dementia.

OBJECTIVE: To provide evidence for the hypothesis that the corticobasal degeneration syndrome (CBDs) overlaps significantly with primary progressive aphasia and frontotemporal dementia, and that CBDs is part of the Pick complex. BACKGROUND: Corticobasal degeneration has been mainly described as a movement disorder, but cognitive impairment is also increasingly noted. METHODS: Thirty-five cases of clinically diagnosed CBDs were followed-up with clinical, neuropsychological, and neuroimaging investigations. Twenty-nine patients were seen prospectively in movement disorder and cognitive neurology clinics; five of these came to autopsy. Six other autopsied cases that fulfilled the clinical criteria of CBDs were added with retrospective review of records. RESULTS: All 15 patients presenting with movement disorders developed behavioral, cognitive, or language deficits shortly after onset or after several years. Patients presenting with cognitive problems (n = 20), progressive aphasia (n = 13), or frontotemporal dementia (n = 7) developed the movement disorder subsequently. Eleven cases with autopsy had CBD or other forms of the Pick complex. CONCLUSIONS: There is a clinical overlap between CBD, frontotemporal dementia, and primary progressive aphasia. There is also a pathologic overlap between these clinical syndromes. The recognition of this overlap will facilitate the diagnosis and avoid consideration of CBD as "heterogenous."

Aphasia↗
PubMed2000

Familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions.

OBJECTIVE: To describe the clinical features, neuropathology, and genetic studies in a family with autosomal dominant frontotemporal dementia (FTD). BACKGROUND: Clinical Pick's disease, or FTD with parkinsonism, has been described in several families linked to chromosome 17 (FTDP-17). Most of these have shown tau protein mutations. The clinical and pathologic variations in these families resemble the spectrum of sporadic FTD or "Pick complex." METHODS: Clinical and behavioral analysis of the affected members with extensive histochemical and neuropathologic description of three cases, genetic analysis of three clinically affected members and seven at risk members to assess linkage to chromosome 17, and sequencing of the tau gene in two patients were performed. RESULTS: The clinical pattern shows a highly stereotypic disinhibition dementia with late extrapyramidal features, progressive mutism, and terminal dysphagia in three generations of affected individuals. Neuropathology showed frontotemporal atrophy, and microscopically tau- and synuclein-negative and ubiquitin-positive neuronal inclusions, in the background of superficial cortical spongiosis, neuronal loss, and gliosis. Tau expression was restricted to oligodendroglia. All exons and surrounding introns of the tau gene were sequenced, and no mutation or disease-related polymorphisms were detected in either of two affected pedigree members. CONCLUSION: This family with autosomal dominant frontotemporal dementia (FTD) shows no tau expression in neurons. The ubiquitin-positive, tau-negative inclusions have been described before in FTD with and without motor neuron disease, but not in a familial form. The clinical and some pathologic features are similar to those of several of the families included in descriptions of FTD with parkinsonism linked to chromosome 17, but the linkage to tau has been excluded. The defect in this family, however, could be functionally related to tau mutations.

Adult↗
PubMed2000

Causes of Alzheimer's disease.

It is now understood that genetic factors play a crucial role in the risk of developing Alzheimer's disease (AD). Rare mutations in at least 3 genes are responsible for early-onset familial AD. A common polymorphism in the apolipoprotein E gene is the major determinant of risk in families with late-onset AD, as well as in the general population. Advanced age, however, remains the major established risk factor for AD, although environmental variables may also have some role in disease expression. Some pathogenic factors directly associated with aging include oxidative damage and mutations in messenger RNA. Other factors unrelated to the aging process may, in the future, be amenable to therapeutic intervention by way of estrogen replacement therapy for postmenopausal women, anti-inflammatory drug therapy and reducing vascular risk factors. Older theories, such as aluminum playing a role in the pathogenesis of AD, have been mostly discarded as our understanding of pathogenic mechanisms of AD has advanced.

Aged↗
PubMed2000

Educational attainment and socioeconomic status of patients with autopsy-confirmed Alzheimer disease.

OBJECTIVE: To determine whether patients with autopsy-confirmed Alzheimer disease (AD) have different educational attainment and socioeconomic status than subjects without neurodegenerative disease. DESIGN: Comparison of 2 groups of autopsied patients. Information on education and occupation was obtained by telephone interview of relatives conducted post mortem. PATIENTS: One hundred fifteen patients enrolled in the University of Western Ontario Dementia Study with dementia and fulfilling diagnostic criteria of AD at autopsy were compared with 142 patients 65 years or older without dementia who died in the hospital and in whom autopsy did not show neurodegenerative disease. MAIN OUTCOME MEASURES: Highest education level attained, years of education, occupation, and socioeconomic and income levels. All results were adjusted for sex, age at time of death, and year of birth. RESULTS: There were no statistically significant differences in education, occupation, or socioeconomic and income levels between the groups. CONCLUSIONS: There is no evidence that educational attainment is different in patients with AD than in subjects who die in the hospital from other diseases. These results indicate that education does not protect against advanced AD.

Aged↗
PubMed2000

Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy.

Corticobasal degeneration is a sporadic form of tauopathy, involving the cerebral cortex and extrapyramidal motor system. A series of affected subjects was genotyped for a set of genetic markers along the tau protein gene. A specific haplotype is significantly overrepresented in patients versus controls. This haplotype is the same already reported in association with progressive supranuclear palsy. These data show that corticobasal degeneration and progressive supranuclear palsy, in addition to several clinical, pathological, and molecular features, may have the same genetic background.

Aged↗
PubMed1999

An autopsy-verified study of the effect of education on degenerative dementia.

A longitudinal study of the relationship between education and age of onset, rate of progression and cerebral lesion burden in a series of autopsy-confirmed demented patients with clinical and 6-monthly psychometric follow-up and autopsy was carried out. The study was conducted at the London Health Sciences Centre University Campus of the University of Western Ontario on 87 patients with pathologically confirmed Alzheimer's disease (60), dementia with Lewy bodies (11) or dementia with Lewy bodies plus Alzheimer's disease (16). Their educational attainment was classified as below high school, high school or above high school, and was similar to that of the age-adjusted general Ontario population. The age of onset of dementia, age at death, progression of cognitive decline, amount of neurodegenerative changes (senile plaques, neurofibrillary tangles and Lewy bodies) and cerebrovascular lesions (infarcts, lacunar state and white matter rarefaction) were assessed. Less educated patients became demented later and died later, but cognitive function declined at the same rate in all educational groups and there was no difference in the burden of neurodegenerative lesions between them. However, the less educated patients had more cerebrovascular lesions. It can be concluded that higher education does not modify the course of Alzheimer's disease, but lower education relates to the occurrence of cerebral infarcts. Our results suggest that a 'brain battering' model related to the higher prevalence of small vascular lesions in less educated individuals may explain their increased risk of dementia described by epidemiological studies better than the prevalent 'brain reserve' hypothesis.

Age Factors↗
PubMed1999

Meningioangiomatosis. A comprehensive analysis of clinical and laboratory features.

Meningioangiomatosis (MA) is a rare, benign, focal lesion of the leptomeninges and underlying cerebral cortex characterized by leptomeningeal and meningovascular proliferation. It may occur sporadically or in association with neurofibromatosis type 2. Previous reports have emphasized histological and imaging features. Data on the management of these patients are sparse, and electrophysiological features of MA lesions have not been published. We assessed the clinical, electrophysiological, histopathological and imaging features as well as the surgical outcome in MA, and compared MA with and without neurofibromatosis. Seven patients with MA at our centre were investigated and their outcome was assessed. A review of the literature is included. MA exhibits a wide range of clinical, imaging, histopathological and electrophysiological features, making the diagnosis difficult. Sporadic MA cases are not associated with neurofibromatosis and the two disorders are genetically distinct. Medically refractory, localization-related epilepsy is the commonest presentation in sporadic cases, but atypical presentations also occur. Unlike sporadic cases, MA with neurofibromatosis is often found incidentally, does not produce seizures, occurs less frequently (ratio of 1:4), and is multifocal. MRI findings in MA correspond to the histological picture. However, the appearance on imaging is non-specific and may suggest cystic atrophy, angioma and tumours. Several abnormalities have been found in close proximity to MA lesions, i.e. meningioma, oligodendroglioma, arteriovenous malformation, encephalocoel and orbital erosion. In spite of histopathological diversity, MA lesions are either predominantly cellular or vascular. Immunohistochemical results are inconsistent among cases, add little to the diagnosis, and do not support a meningeal origin. Electrocorticographic recordings from the surface and within MA lesions revealed a spectrum of electrophysiological expressions. Intrinsic epileptogenicity of MA lesions was documented in some cases. Epileptogenicity was confined to the perilesional cortex in some patients and it was complex (extralesional, multifocal, generalized) in others. Only 43% of our patients became seizure-free postoperatively compared with 68% previously reported, and >70% of our patients and those in the literature continued to require antiepileptic drugs. This is in keeping with the diverse electrophysiology of MA and suggests a less optimistic postoperative outcome than previously recognized.

Adolescent↗
PubMed1999

Clinical and pathological overlap between frontotemporal dementia, primary progressive aphasia and corticobasal degeneration: the Pick complex.

A substantive overlap between the clinical syndromes of frontal lobe dementia (FLD), frontotemporal dementia (FTD), or primary progressive aphasia (PPA), and corticobasal degeneration syndrome (CBDS) has been demonstrated in a population of 55 patients followed for more than 3 years in a cognitive neurology clinic. Patients presenting with the personality behavior disorder (FLD) often develop progressive aphasia (PA) and vice versa. CBDS is often associated with FLD and PA, and the extrapyramidal-apractic syndrome of CBDS often appears in FLD and PPA. The histopathological variations do not predict the clinical phenotype. The term Pick complex is suggested to indicate that these clinical and pathological variations are related and they were first described by Pick as clinical manifestations of fronotemporal atrophy. This term will avoid the confusion of using FLD or FTD or for the whole complex and also for the personality behavioral presentation. The relationship of the various clinical presentations has been strengthened by the discovery of chromosome 17 linkage in families manifesting them.

Aphasia, Primary Progressive↗
PubMed1999

Stains for the differential diagnosis of degenerative dementias.

Our understanding of the structural substrates underlying the dementia syndrome has been transformed by the introduction of the Gallyas silver stain and the application of immunostains for tau, ubiquitin, and alpha-synuclein. Visualization of sequential changes in Alzheimer's disease and the recognition of a new substrate for dementia and dementia with argyrophilic grains, are two of the advances related to the application of the Gallyas method. The specificity of alpha-synuclein for recognizing Lewy bodies enables the unequivocal diagnosis of dementia with Lewy bodies. The diverse entities that constitute the Pick complex can be identified by applying immunostains for tau and ubiquitin in addition to the Gallyas silver stain.

Alzheimer Disease↗