Michael Gold

Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank

Alzheimer disease (AD) is the most common dementing illness in the elderly, but there is equivocal evidence regarding the frequency of other disorders such as Lewy body disease (LBD), vascular dementia (VaD), frontotemporal dementia (FTD), and hippocampal sclerosis (HS). This ambiguity may be related to factors such as the age and gender of subjects with dementia. Therefore, the objective of this study was to calculate the relative frequencies of AD, LBD, VaD, FTD, and HS among 382 subjects with dementia from the State of Florida Brain Bank and to study the effect of age and gender on these frequencies. AD was the most frequent pathologic finding (77%), followed by LBD (26%), VaD (18%), HS (13%), and FTD (5%). Mixed pathology was common: Concomitant AD was present in 66% of LBD patients, 77% of VaD patients, and 66% of HS patients. The relative frequency of VaD increased with age, whereas the relative frequencies of FTD and LBD declined with age. Males were overrepresented among those with LBD, whereas females were overrepresented among AD subjects with onset age over 70 years. These estimates of the a priori probabilities of dementing disorders have implications for clinicians and researchers.

Current Issues in Depression in Parkinson's Disease

Depression affects 40%-50% of Parkinsons disease (PD) patients. The authors, by use of a Mednet and manual search of pertinent literature, summarize current issues in the treatment of depression in PD. Open-label studies suggest that antidepressants may be effective for treating depression in PD. Although case reports indicate that selective serotonin reuptake inhibitors (SSRIs) can potentially worsen the motor symptoms of PD, this effect has not been confirmed in the small number of open-label studies that have been performed to date. The occurrence of the serotonin syndrome resulting from a combination of selegiline and an SSRI appears to be rare. Double-blind prospective studies are needed to evaluate the safety and efficacy of antidepressants in PD and their effect on motor function.

The −491A/T apolipoprotein E promoter polymorphism association with Alzheimer's disease: independent risk and linkage disequilibrium with the known APOE polymorphism

The epsilon4 allele of the apolipoprotein E gene (APOE) has repeatedly been associated with increased risk for Alzheimers disease (AD). Bullido and colleagues recently identified a polymorphism in the promoter region of the APOE gene (-491A/T) and found that -491A homozygosity predicted AD independently of APOE epsilon4. Since the -491A/T polymorphism and the known APOE polymorphism must be in tight linkage disequilibrium, and the later polymorphism is know to be associated with the disease, we wished to determine to what extent this linkage disequilibrium explained the -491A/T polymorphism association with Alzheimers disease. We genotyped a community-based control sample (n = 132) and a clinic-based Alzheimers disease sample (n = 190) for the known APOE and -491A/T polymorphisms, and find that, while the -491A/T polymorphism confers some independent risk for AD, linkage disequilibrium between the known APOE and -491A/T polymorphic sites explains most of the -491A association. Furthermore, when considering the known APOE and -491A/T polymorphisms alone, APOE epsilon4 status is the best predictor of the disease.

An open-label trial of bromocriptine in nonfluent aphasia: a qualitative analysis of word storage and retrieval.

Anomia is a commonly found in aphasia and has been attributed to a loss of representations (storage deficit) or to a loss of access to these representations (retrieval deficit). Bromocriptine, a dopamine agonist, was tested on four patients, two men and two women, with nonfluent aphasia. The patients were tested in an open-label ABBA design using a stochastic model that measured the degree of storage and retrieval deficits. All patients showed significant improvements in word retrieval. Bromocriptine may be a useful adjunct in the treatment of selected patients with a nonfluent aphasia in which retrieval deficits play a major role.

The butyrylcholinesterase gene is neither independently nor synergistically associated with late-onset AD in clinic-and community-based populations

The K variant of the butyrylcholinesterase gene (BChE) was recently found to occur at an increased frequency in a late onset Alzheimers disease (AD) population, specifically in individuals carrying the epsilon4 allele of the apolipoprotein E (APOE) gene. This suggested synergy between these two genes resulting in an increased risk of late-onset AD. We have genotyped 62 community-based and 329 clinic-based AD cases, and 201 community-based controls at BChE and APOE and find no independent association between BChE and AD nor interaction with APOE in risk for AD in either our clinic or community-based samples.

Plasma Thiamine Deficiency Associated with Alzheimer's Disease but Not Parkinson's Disease

In this study we compared plasma and erythrocyte thiamine levels in a group of patients with idiopathic Parkinsons Disease (iPD) to a group of patients with probable Alzheimers Disease (pAD). pAD patients had significantly lower plasma thiamine levels (raw and z-score) than iPD patients. A significantly higher number of pAD patients had plasma thiamine deficiencies than iPD patients. The demographics of our patient groups were similar to those reported by other investigators, making age, sex and nutritional status unlikely explanations for our findings. These results suggest that plasma thiamine deficiency is associated with pAD but not with iPD.

Non-Mendelian mitochondrial inheritance as a cause of progressive genetic sensorineural hearing loss

Awareness of non-Mendelian mitochondrial inheritance and of its role as an agent of genetic sensorineural hearing loss (SNHL) is recent. Mitochondria are passed on exclusively from the ovum to all the offspring of both sexes, a novel pattern of inheritance. Owing to the critical role of mitochondria in cellular energy metabolism, deletions or point mutations of the mitochondrial DNA often cause progressive SNHL and a variety of disorders in other organ systems (mitochondrial cytopathies). The clinical expression of mitochondrial diseases varies and depends on the proportion of mutated mitochondria in various body tissues, as well as the nature of the mutation or deletion. In order to determine how often SNHL occurs in mitochondrial diseases and what is its presenting symptom, and also whether SNHL is a marker for particular phenotypes, we carried out a review of published case reports of patients with an established diagnosis of mitochondrial disease. The review indicates that SNHL occurs at all ages and in virtually all variants of mitochondrial diseases. It is not clear whether SNHL is a marker for a more severe and more rapid course of disease; the lower prevalence of SNHL in descriptions of live patients than of those who had died may be an artifact of case selection reported in the literature. Mitochondrial disease needs to be considered in progressive hearing loss and better longitudinal audiometric study of established cases will be required to answer these questions.

Treatment of pancreatic pseudoaneurysm with percutaneous transabdominal thrombin injection.

Severe acute pancreatitis is associated with significant morbidity and mortality. Although rare, pancreatic pseudoaneurysm is a serious and often fatal complication of acute pancreatitis. This case report describes an alcoholic male patient with a psuedoaneurysm that was successfully treated with percutaneous transabdominal thrombin injection.

No association between the intronic presenilin-1 polymorphism and Alzheimer's disease in clinic and population-based samples.

Mutations in the Presenilin 1 (PS1) gene on chromosome 14 cause most early-onset familial Alzheimers disease (AD). An intronic polymorphism in the PS1 gene was recently identified and reported to be associated with late-onset AD [Wragg et al., Lancet 347: 509-512, 1996]. The authors found an excess of homozygotes for the more common allele (allele 1) in AD cases, associated with an approximate doubling of risk. In the present study, we report the PS1 polymorphism distributions in clinic and population-based samples. We were not able to replicate the findings of Wragg et al. [1996]. Our results are consistent with those of other researchers and do not support the conclusion that the PS1 polymorphism is associated with late-onset AD.

No association between the very low density lipoprotein receptor gene and late-onset Alzheimer's disease nor interaction with the apolipoprotein E gene in population-based and clinic samples

It is now commonly known that possession of one of the three common alleles of the apolipoprotein E (APOE) gene (allele ϵ4) confers an increased risk for both familial and sporadic Alzheimers disease (AD), and that this risk is dose‐dependent. Other genes that may play a role in AD, either through independent association with the disease or through modification of the existing APOE risk, are under investigation. One such gene, the very low density lipoprotein receptor (VLDL‐R) gene, was reported by Okuizumi et al. to be independently associated with AD in a Japanese population, but not interactive with the APOE4 conferred risk. Their clinic‐based data set demonstrated a 2‐fold increased risk conferred by the 5‐repeat allele of a polymorphism in VLDL‐R. As recruitment from a clinic rather than a population‐based sample may result in a distortion of allele frequencies, as has been shown with APOE allele frequencies, it is important to investigate this association in a population‐based study. We have genotyped both population and clinic‐based AD data sets at this VLDL‐R polymorphism, and we find no independent association between the VLDL‐R gene and the occurrence of AD in either sample. Further, despite the biochemical relationship between the VLDL‐R and APOE proteins, we find no significant statistical interaction between the alleles at these loci. Genet. Epidemiol. 14:299–305,1997.