ABSTRACT
BACKGROUND: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU). METHODS: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants' clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials. RESULTS: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial's demographic distribution. Participants' decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome. CONCLUSION: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden.
Subject(s)
Alzheimer Disease , Antibodies, Monoclonal, Humanized , Patient Satisfaction , Humans , Alzheimer Disease/drug therapy , Alzheimer Disease/psychology , Male , Female , Middle Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Double-Blind Method , Adult , Surveys and Questionnaires , Clinical Trials as TopicABSTRACT
The objective of this study was to compare ruminal starch disappearance rates of hull-less barley, hulled barley, and corn grains. Five different genotypes were used for each of the 2 barley types. In addition, each of these genotypes was grown in 2 different locations and years, resulting 10 independent barley samples for each of the 2 barley grain types. Five different genotypes of corn grain were obtained from a commercial seed company. After being ground to pass through a 4-mm screen of a cutter mill, 3.6 g of each grain was placed into a porous bag, which was then incubated in the rumen of 2 ruminally cannulated cows for 0, 4, 8, 12, 24, and 48 h. Corn grains had greater instant ruminal starch disappearances than barley grains (22.4 and 8.2%, respectively). Instant ruminal starch disappearances did not differ between hulled and hull-less barley grains. Ruminal starch fractional disappearance rates were greatest for hulled barley grains, moderate for hull-less barley grains, and lowest for corn grains (15.3, 13.9, and 7.1%/h, respectively). Ruminal starch half-life was shortest for hulled and hull-less barley grains (4.4 h) and longest for corn grains (6.6 h). Ruminal starch half-life did not differ between hulled barley and hull-less barley grains. In conclusion, using a holistic experimental design and statistical analysis, this study showed that starch from hull-less barley grains has a ruminal half-life similar to that of hulled barley grains and shorter than that of corn grains.
Subject(s)
Cattle/metabolism , Hordeum , Rumen/metabolism , Starch/metabolism , Zea mays , Animal Feed , Animals , Diet , Digestion , Female , KineticsABSTRACT
The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer's disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer's disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/therapy , Biomedical Research/methods , Clinical Trials as Topic/methods , Genes, Dominant , Home Care Services , Humans , Magnetic Resonance Imaging , Medication Systems, Hospital , Monitoring, Physiologic/methods , Patient Selection , Research DesignABSTRACT
Barley leaf rust, caused by Puccinia hordei Otth., has been problematic in United States barley (Hordeum vulgare L.) production in the Mid-Atlantic coast region and California. During the early 1990s, P. hordei pathotypes with virulence to resistance gene Rph7 caused average yield losses from 6 to 16% (3). 'Doyce' barley was released in 2003 and was described as being resistant to leaf rust (2). Initially in April 2010 and subsequently in spring 2011 and 2012, high severities and infection responses were observed on experimental plots of 'Doyce' in Warsaw and Blacksburg, Virginia. Three single uredinial isolates of P. hordei were derived from collections made from 'Doyce' barley. The isolates were characterized for virulence to barley leaf rust resistance genes by inoculating at least two replicates of a barley leaf rust differential set including 12 Rph genes (1). Previous methods used for inoculation, incubation, and pathotyping were followed (1). Infection types were scored on a 0 to 4 scale where 2 and below indicated resistance and 3 and above indicated susceptibility (4). The three isolates collected from Doyce barley displayed large pustules with infection types 3,3+ to cultivars Estate (Rph3) and Cebada Capa (Rph7). Avirulent isolates of P. hordei displayed infection types 0; to 0;1c to Estate and ;n to 0;1n to Cebada Capa (1). The data indicated that all three isolates were virulent to both barley leaf rust resistance genes Rph3 and Rph7. Though combined Rph3 and Rph7 virulence has been reported in the Mediterranean region, this is the first report of Rph3 virulence in North America. These isolates of P. hordei are virulent to important sources of resistance to barley leaf rust and threaten barley production in environments conducive for disease development in North America. References: (1) W. S. Brooks et al. Phytopathology 90:1131, 2000. (2) W. S. Brooks et al. Crop Sci. 45:792, 2005. (3) C. A. Griffey et al. Plant Dis. 78:256, 1994. (4) M. N. Levine and W. J. Cherewick. U.S. Dept. Agric. Tech. Bull. 1056, 1952.
ABSTRACT
A putative ubiquitin conjugating enzyme known as UBE2Q2 was previously identified in a microarray screen for mitotic regulatory proteins. UBE2Q2 is very similar to another human protein, UBE2Q1 and orthologs from other higher eukaryotic species. In these studies, we demonstrate that UBE2Q2 can covalently bind ubiquitin on the active site cysteine in vitro and show that inhibition of this protein in vivo causes an early mitotic arrest and increased cytotoxicity when cells are treated with microtubule inhibiting agents (MIAs). Changes in cell cycle progression and viability are not observed in the absence of MIA treatment, indicating that UBE2Q2 is involved in the response to MIAs rather than performing a more general function in mitosis. Inhibition of the UBE2Q2 protein causes cells to undergo a prolonged prophase arrest suggesting that UBE2Q2 normally functions to antagonize an early mitotic checkpoint. Furthermore, UBE2Q2 inhibition sensitizes cells to the cytotoxic effects of MIAs through caspase-mediated apoptosis that is correlated with PARP-1 cleavage. These data provide insights into the cellular response to MIAs and demonstrate that inhibition of UBE2Q2 protein function may be useful in the treatment of malignancies.
Subject(s)
Apoptosis/drug effects , Cytoskeletal Proteins/physiology , Prophase/drug effects , Tubulin Modulators/pharmacology , Ubiquitin-Conjugating Enzymes/physiology , Binding Sites , Cell Cycle , Cytoskeletal Proteins/antagonists & inhibitors , HeLa Cells , Humans , Mitosis/drug effects , Poly (ADP-Ribose) Polymerase-1 , Poly(ADP-ribose) Polymerases/metabolism , Ubiquitin/metabolism , Ubiquitin-Conjugating Enzymes/antagonists & inhibitors , Vincristine/pharmacologyABSTRACT
BACKGROUND: Most mutations in the amyloid precursor protein (APP) gene have been associated with familial Alzheimer disease (AD); however, some mutations within the Abeta-coding sequence have been described in families with recurrent cerebral hemorrhage. The APPAla692Gly (Flemish) mutation was reported in a family in which affected members developed hemorrhagic stroke, progressive dementia, or both. OBJECTIVE: To describe clinical, neuropathologic, and genetic features of a family of British origin with the Flemish APP mutation. METHODS: Clinical features of the proband and two affected relatives were obtained by history, examination, and medical record review. Some information on deceased affected relatives was obtained by informant interview. Neuropathologic examination was carried out on one case. DNA studies were carried out on three affected and three unaffected individuals. RESULTS: Presenile dementia was present in a pattern consistent with dominant inheritance, with the APP692 mutation being found in all affecteds and no unaffecteds. The proband also had a cerebral hemorrhage, but was the only one of five affecteds to have this complication. Neuropathologic examination confirmed AD, congophilic angiopathy, and hemorrhagic infarction. CONCLUSIONS: This expands the number of families reported with mutations in the coding region of the amyloid precursor protein gene. Cerebral hemorrhage appears to be less frequent in this family than in the previously reported Flemish pedigree with the same mutation.
Subject(s)
Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Cerebral Hemorrhage/genetics , Mutation , Alzheimer Disease/diagnosis , Alzheimer Disease/pathology , Brain/pathology , Cerebral Hemorrhage/diagnostic imaging , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Pedigree , Tomography, X-Ray Computed , White People/geneticsABSTRACT
BACKGROUND: It is unclear whether there are early clinical features that can distinguish between patients with familial and non-familial frontotemporal dementia (FTD). OBJECTIVE: To compare the clinical features of FTD cases who have tau gene mutations with those of cases with a family history of FTD but no tau gene mutation, and with sporadic cases with neither feature. METHODS AND RESULTS: Comparisons of the behavioural, cognitive, and motor features in 32 FTD patients (five positive for tau gene mutations, nine familial but tau negative, and 18 tau negative sporadic) showed that age of onset and duration to diagnosis did not differ between the groups. Apathy was not observed in tau mutation positive cases, and dysexecutive signs were more frequent in familial tau mutation negative cases. Memory deficits and behavioural changes were common in all groups. CONCLUSIONS: In comparison with other neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, neither tau gene mutations nor strong familial associations confer earlier disease susceptibility.
Subject(s)
Dementia/genetics , Dementia/pathology , Genetic Predisposition to Disease , tau Proteins/genetics , Adult , Age of Onset , Aged , Case-Control Studies , Cognition Disorders/etiology , DNA Mutational Analysis , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Motor Skills Disorders/etiology , Pedigree , Retrospective StudiesABSTRACT
HLA genotype and anti-inflammatory drug use have independently been associated with a lower risk of Alzheimer's disease (AD). We recently reported a negative association between aspirin use and AD. To investigate this further, we performed a cross-sectional study to investigate cognitive performance in 151 non-demented individuals in relation to HLA-DRB1 genotype and aspirin use. Aspirin and HLA-DRB1*01 were positive predictors of performance on logical memory (aspirin, p=0.04) and verbal fluency tests (HLA-DRB1*01, p=0.018), respectively. HLA-DRB1*05 had a negative impact on the Boston naming test (p=0.002). Our results suggest that aspirin use and inflammatory genotype may influence cognition in non-demented subjects.
Subject(s)
Aspirin/pharmacology , Cognition/drug effects , HLA Antigens/genetics , Aged , Aged, 80 and over , Alleles , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cross-Sectional Studies , Genotype , HLA Antigens/physiology , HLA-DR Antigens/genetics , HLA-DRB1 Chains , Humans , Male , Mental Status Schedule , Neuropsychological Tests , Prospective Studies , Psychomotor Performance , Wechsler ScalesABSTRACT
Mutations in the presenilin-1 (PS-1) gene on chromosome 14 account for the majority of early-onset familial Alzheimer's disease (FAD) cases. To date, more than 90 mutations have been identified and, while most of these mutations are completely penetrant, the Glu318Gly mutation has been suggested to be partially penetrant. These findings indicate that it may play a similar role to apolipoprotein E (APOE)-epsilon4 by acting as a genetic risk factor for AD. In the current study, a total of 682 subjects were tested to assess the frequency of the Glu318Gly mutation in AD in the Australian population. The Glu318Gly mutation was identified in six sporadic late-onset AD patients, four FAD patients (unrelated) and in nine control subjects. The frequency of this mutation was highest in the familial AD group (8.7%) and lowest in control subjects (2.2%). When the mutation frequencies were compared, we found a statistically significant difference between the latter two groups (Fisher's exact test, P < 0.05). The genotype frequency of the Glu318Gly mutation in all AD cases and controls in the Australian population was 2.8%. This frequency is comparable to that observed for the Dutch population (3.2%), but not for the Finnish population (6.8% and 6.0%) or the Spanish population (5.3%). These findings show that the frequency of the Glu318Gly mutation is increased in FAD patients, suggesting a potential role as a genetic risk factor contributing to the pathogenesis of familial AD.
Subject(s)
Alzheimer Disease/genetics , Membrane Proteins/genetics , Point Mutation , Adult , Age of Onset , Aged , Alzheimer Disease/epidemiology , Australia , Family Health , Female , Genetic Predisposition to Disease/epidemiology , Humans , Male , Middle Aged , Presenilin-1 , Risk FactorsABSTRACT
A variant form of Alzheimer's disease (AD), in which spastic paraparesis (SP) precedes dementia, is characterised by large, noncored, weakly neuritic Abeta-amyloid plaques resembling cotton wool balls and is caused by genomic deletion of presenilin 1 exon 9. A pedigree with a 5.9 kb exon 9 deletion shows a phenotypic spectrum including subjects with typical AD or with SP and numerous cotton wool plaques. In SP subjects, dementia onset is delayed and modified. This phenotypic variation suggests that modifying factors are associated with exon 9 deletions.
Subject(s)
Alzheimer Disease/genetics , Paraparesis, Spastic/genetics , Adult , Alzheimer Disease/complications , Female , Humans , Male , Middle Aged , Paraparesis, Spastic/complications , Pedigree , PhenotypeABSTRACT
CONTEXT: Anti-inflammatory medications have an inverse association with Alzheimer disease (AD). OBJECTIVES: To examine at what doses this anti-inflammatory drug effect occurs and whether other medications and/or International Classification of Diseases, Ninth Revision, Clinical Modification diagnoses affect the association. DESIGN: Subjects 75 years and older from a random population sample were classified by consensus using International Classification of Diseases, Ninth Revision, Clinical Modification diagnoses. Drug associations with different types of dementia with and without the International Classification of Diseases, Ninth Revision, Clinical Modification diagnoses as well as dosage data were analyzed. SETTING: The Centre for Education and Research on Aging, Concord Hospital, Concord, Australia. PATIENTS: The Sydney Older Persons Study recruited 647 subjects (average age, 81 years). A total of 163 patients were given diagnoses placing them in different dementia categories and were compared with 373 control subjects. Of the patients with dementia, 78 had AD without vascular dementia, 45 had vascular dementia (permissive of other dementia diagnoses), and 40 had other dementia diagnoses (without AD or vascular dementia). MAIN OUTCOME MEASURES: Fifty drugs or drug groups were subjected to a 2 (drug used vs drug not used) x 4 (dementia and control groups) chi(2) analysis. Drugs with inverse associations were identified and potential confounders (logistic regression) and dosage data (exact small sample 1-tailed tests) analyzed. RESULTS: As expected, there was an inverse association between nonsteroidal anti-inflammatory drugs and aspirin (and unexpectedly angiotensin-converting enzyme inhibitors) and AD. This association was not observed with vascular dementia or any other diagnoses. Analysis showed no evidence for a dosage effect, ie, responses were equivalent for low and high doses. CONCLUSIONS: This study does not support a high-dose anti-inflammatory action of nonsteroidal anti-inflammatory drugs or aspirin in AD. Potential mechanisms for the beneficial effects of these medications are discussed.
Subject(s)
Alzheimer Disease/prevention & control , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Aged , Aged, 80 and over , Case-Control Studies , Dose-Response Relationship, Drug , Female , Humans , Logistic Models , MaleABSTRACT
Genetic mutations in the tau gene on chromosome 17 are known to cause frontotemporal dementias. We have identified a novel silent mutation (S305S) in the tau gene in a subject without significant atrophy or cellular degeneration of the frontal and temporal cortices. Rather the cellular pathology was characteristic of progressive supranuclear palsy, with neurofibrillary tangles concentrating within the subcortical regions of the basal ganglia. Two affected family members presented with symptoms of dementia and later developed neurological deficits including abnormality of vertical gaze and extrapyramidal signs. The third presented with dystonia of the left arm and dysarthria, and later developed a supranuclear gaze palsy and falls. The mutation is located in exon 10 of the tau gene and forms part of a stem-loop structure at the 5' splice donor site. Although the mutation does not give rise to an amino acid change in the tau protein, functional exon-trapping experiments show that it results in a significant 4.8-fold increase in the splicing of exon 10, resulting in the presence of tau containing four microtubule-binding repeats. This study provides direct molecular evidence for a functional mutation that causes progressive supranuclear palsy pathology and demonstrates that mutations in the tau gene are pleiotropic.
Subject(s)
Brain/pathology , Mutation , Polymorphism, Genetic , Supranuclear Palsy, Progressive/genetics , Supranuclear Palsy, Progressive/pathology , tau Proteins/genetics , Aged , Aged, 80 and over , Atrophy , Basal Ganglia/pathology , Base Sequence , Brain/diagnostic imaging , Child , Chromosomes, Human, Pair 17 , Dinucleotide Repeats , Exons , Female , Fluorodeoxyglucose F18 , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neurofibrillary Tangles/pathology , Pedigree , Phenotype , Radiopharmaceuticals , Tomography, Emission-ComputedABSTRACT
ABSTRACT Leaf rust, caused by Puccinia hordei, is an important disease of barley in many parts of the world. In the eastern United States, this disease was effectively controlled for over 20 years through the deployment of cultivars carrying the resistance gene Rph7. Isolates of P. hordei with virulence for Rph7 appeared in this region in the early 1990s rendering barley cultivars with this gene vulnerable to leaf rust infection. From a preliminary evaluation test, 13 accessions from diverse geographic locations possessed resistance to P. hordei isolate VA90-34, which has virulence for genes Rph1, 2, 4, 6, 7, 8, and 11. Each of these 13 accessions was crossed with susceptible cvs. Moore or Larker to characterize gene number and gene action for resistance to P. hordei. Additionally, the 13 accessions were intercrossed and crossed to host differential lines possessing genes Rph3, Rph5, and Rph9 to determine allelic relationships of resistance genes. Seedlings of F(1), F(2), and BC(1)F(1) populations were evaluated in the greenhouse for their reaction to P. hordei isolate VA90-34. Leaf rust resistance in six of the accessions including Collo sib, CR270.3.2, Deir Alla 105, Giza 119, Gloria, and Lenka is governed by a single dominant gene located at or near the Rph3 locus. All accessions for which the gene Rph3 was postulated to govern leaf rust resistance, except for Deir Alla 105, likely possess an allele different than Rph3.c found in Estate based on the differential reaction to isolates of P. hordei. The resistance gene in Grit and Donan is located at or near the Rph9 locus. Alleles at both the Rph3 and Rph9 loci confer resistance in Femina and Dorina. In addition to Rph3, Caroline and CR366.13.2 likely possess a second unknown recessive gene for leaf rust resistance. Resistance in Carre 180 is governed by a recessive gene that is different from all other genes considered in this study. Identification of both known and unique genes conferring leaf rust resistance in the barley germplasm included in this study provides breeding programs with the knowledge and opportunity to assess currently used sources of leaf rust resistance and to incorporate new sources of resistance into their programs.
ABSTRACT
The present investigation aimed to examine associations of anaemia with dementia. Analysis of community-dwelling, elderly subjects characterized for different dementias failed to confirm a previously reported association of anaemia with Alzheimer's disease (AD) but revealed instead a significant association with vascular dementia (VAD). Nearly 45% of VAD subjects were anaemic, compared with 17% of controls. Close to one-third of all subjects with haemoglobin levels > 0.5 g/dl below reference anaemia levels had VAD. Co-existing VAD may explain previous links between AD and anaemia. The association was independent of age, dementia severity and a range of other factors including vitamin B 12 and folate levels. Anaemia can exacerbate focal cerebral ischaemia and could precipitate or amplify VAD symptoms in elderly subjects with vasculopathy.
Subject(s)
Anemia/complications , Dementia, Vascular/complications , Aged , Aged, 80 and over , Alzheimer Disease/complications , Alzheimer Disease/psychology , Anemia/blood , Dementia, Vascular/psychology , Female , Hemoglobins/analysis , Humans , Male , Psychiatric Status Rating Scales , Retrospective StudiesABSTRACT
Recent evidence suggests that a polymorphism in the regulatory region of the apolipoprotein E gene (APOE) is associated with an increased risk for developing Alzheimer's disease (AD) independent of that conveyed by the epsilon4 allele of APOE. Previous work by our group indicated that plasma apolipoprotein E (apoE) levels were elevated in AD, raising the possibility that the -491 genotype might modify AD risk by increasing expression of the APOE gene. In a total of 638 individuals the -491AA genotype was significantly associated with AD (P < 0.005) while the TT genotype was associated with controls (P < 0.005). In 138 individuals the AA genotype showed significantly higher plasma apoE levels, independent of epsilon4 and AD status (P < 0.01) as well as within control and AD groups (P < 0.05). Within the AD group the AA genotype showed increased apoE levels when compared to AA controls (P < 0.0001). These results suggest that the -491 AA genotype is associated with increased plasma apoE levels, providing a potential basis for elucidating how that genotype increases the risk for developing AD.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Apolipoproteins E/blood , Apolipoproteins E/genetics , Apolipoprotein E4 , DNA/genetics , Genotype , Humans , Polymorphism, Genetic/genetics , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Mutations in the presenilin-1 (PS-1) gene account for the majority of early onset autosomal-dominant familial Alzheimer's disease (FAD) cases. We identified three missense mutations in the coding sequence of the PS-1 gene in three early onset (EO), FAD pedigrees. Alzheimer's disease was confirmed in one pedigree by autopsy. Mutation analysis of PCR products amplified from genomic DNA templates of affected individuals showed two novel mutations resulting in Ser169Leu and Pro436Gln and one known mutation resulting in Glu318Gly. The two new mutations are located within predicted transmembrane domains three (TM-3) and seven (TM-7), and are associated with a very early age of onset which is consistent with a marked loss of function of the protein. The age of onset in the pedigree with Glu318Gly mutation was similar to that reported previously in a separate pedigree with this mutation.
Subject(s)
Alzheimer Disease/genetics , Membrane Proteins/genetics , Point Mutation , Adult , Age of Onset , Alleles , DNA Mutational Analysis , Family Health , Fatal Outcome , Female , Genotype , Humans , Male , Middle Aged , Pedigree , Presenilin-1ABSTRACT
We screened 703 Australian subjects for an intronic polymorphism in the presenilin-1 (PS-1) gene. PS-1 intronic allele 1 homozygosity was not associated with individuals with early- or late-onset sporadic Alzheimer's disease (EOAD or LOAD). Carriers for the PS-1 intronic allele 1 were also not associated with significantly increased risk for AD regardless of gender. Our results for the Australian population are consistent with those of recent reports for other populations and do not support the conclusion that the PS-1 intronic polymorphism is associated with AD.
Subject(s)
Alzheimer Disease/genetics , Introns/genetics , Membrane Proteins/genetics , Polymorphism, Genetic , Adult , Aged , Aged, 80 and over , Alleles , Apolipoprotein E4 , Apolipoproteins E/genetics , Australia , DNA/analysis , DNA Mutational Analysis/statistics & numerical data , Female , Gene Frequency , Genetic Linkage , Genetic Testing , Genotype , Humans , Leukocytes/chemistry , Logistic Models , Male , Middle Aged , Presenilin-1ABSTRACT
Cortical atrophy and cell loss in the cholinergic nucleus basalis is a well-established characteristic of Alzheimer's disease; however, previous studies not have analysed cholinergic cell loss and cortical atrophy in concert. In autopsy brains from eight patients with Alzheimer's disease and 12 control subjects, the numbers of nucleus basalis neurons were determined from 50-microm serial Nissl-stained sections. Volumes of the cerebrum, cortical gray matter (total, lobar and subregional), white matter and deep gray structures were computed by point counting on black and white photographs of gapless 3-mm coronal slices of formalin-fixed brains. Cell loss in the nucleus basalis was found to range between 89% and 42% in Alzheimer's disease compared with controls. White matter volume was unchanged in absolute terms in Alzheimer's disease patients compared with controls, while cortical volume was significantly reduced. Gray matter atrophy was most prominent in temporal and frontal cortices. A highly significant linear relationship was found between cortical volume and nucleus basalis cell number in controls and Alzheimer's disease patients, with values for both groups on a single regression line. Whole brain and cerebral volumes were also highly correlated to nucleus basalis cell numbers in both groups. A quantitative analysis of plaque and tangle burden in cortical target areas of the nucleus basalis was performed. In contrast to the relationship with cortical volume, nucleus basalis cell number and neurofibrillary tangle number were not significantly correlated to the density of cortical histopathology. These results suggest that the volume of cortical gray matter is coupled to the number of nucleus basalis neurons. Compromised viability of nucleus basalis neurons may precede cortical volume loss as large numbers of neurofibrillary tangles, detected with nickel peroxidase staining, were found in this nucleus in all Alzheimer's disease cases, including those with minimal cell loss.
Subject(s)
Alzheimer Disease/pathology , Basal Ganglia/pathology , Cerebral Cortex/pathology , Parasympathetic Nervous System/pathology , Adult , Aged , Aged, 80 and over , Atrophy/pathology , Cell Count , Female , Humans , Immunohistochemistry , Male , Middle Aged , Neurofibrillary Tangles/pathology , Organ SizeABSTRACT
Eleven early-onset dementia families, all with affected individuals who have either presented clinical symptoms of early onset familial Alzheimer's disease (EOFAD) or have been confirmed to have EOFAD by autopsy, and two early onset cases with biopsy-confirmed AD pathology, were screened for missense mutations in the entire coding region of presenilin-1 (PS-1) and -2 (PS-2) genes. Missense mutations were detected by direct sequence analysis of PCR products amplified from genomic DNA templates of affected individuals. Three pedigrees were attributable to known mutations in the PS-1 gene: P264L, E280A and the splice acceptor site (G to T) mutation, which results in the deletion of residues 290-319 of PS-1 (PS-1 delta 290-319). In a fourth pedigree, a novel PS-1 mutation was identified in exon 7 (M233T), which is homologous to a pathogenic PS-2 mutation (M239V), and is characterized by a very early average age of onset (before the age of 35). In one early onset case, another novel PS-1 mutation was identified in exon 8 (R278T). Of the five remaining families and the other early onset case, none have missense mutations in the PS-1 or PS-2 genes, or in exon 16 and 17 of the APP gene. Moreover, two of the PS-1 mutations, PS-1 delta 290-319 and R278T, are associated with the co-presentation of familial spastic paraparesis (FSP) in some of the affected family members. Our data raise the possibility that the phenotypic spectrum associated with PS-1 mutations may extend beyond typical FAD to include FSP, a disease heretofore unsuspected to bear any relationship to FAD. In addition, our data suggest that other novel EOFAD loci, in addition to APP and the presenilin genes, are involved in the aetiology of up to 50% of EOFAD cases.
Subject(s)
Alzheimer Disease/genetics , Genetic Testing/methods , Membrane Proteins/genetics , Point Mutation , Adult , Age of Onset , Female , Humans , Male , Middle Aged , Pedigree , Phenotype , Presenilin-1ABSTRACT
BACKGROUND: Several previous studies have reported an increased frequency of the E4 allele of the gene for Apolipoprotein (APOE4) in both familial and sporadic Alzheimer's disease (AD). We report the results of a study of this association in an Australian clinic-base sample. AIM: To investigate the relationship between APOE4 frequency and AD in an Australian clinic-based sample and compare the results with previous studies. METHODS: Subject DNA was PCR amplified, enzymatically digested with Hha1 and the resulting fragments electrophoretically separated. The genotypes were ascertained according to the resulting fragment sizes and the resulting allele frequencies analysed by calculating a z-statistic for comparison of two proportions. RESULTS: The frequency of the APOE4 allele was 53% in the AD group and 11% in the control group. This difference is statistically significant. There was no significant difference in E4 allele frequencies between AD subjects with a family history and those without. At least one E4 allele was found in 26/30 (87%) of AD patients and 10/50 (20%) of controls. The allele frequencies of the control subjects used in this study were found to be consistent with those of several previous studies. CONCLUSION: The frequency of the APOE4 allele was significantly higher in AD subjects than in unaffected controls. This provides further evidence of an association between APOE4 and both familial and sporadic AD.