Variant Alzheimer Research Articles

Progressive topographical disorientation: a case of focal Alzheimer's disease

We describe a follow-up study of a patient with a selective, progressive impairment of topographical orientation. The patient's topographical difficulties were evident only in unfamiliar surroundings at the beginning of the observation period but later on they were observed even at home. Serial neuropsychological tests demonstrated a progressive impairment of visuospatial abilities with sparing of the other cognitive domains; only at the last assessment, about six years after early disturbances and three years after the first evaluation, the patient developed the typical cognitive impairments of Alzheimer's disease (AD). This case represents a focal variant of AD not previously described and suggests that the neuronal pathways underlying spatial orientation may be selectively damaged by the degenerative process.

Absence of β-Amyloid Deposits After Immunization in Alzheimer Disease With Lewy Body Dementia

To describe the neuropathological and biochemical findings of the brain examination of a patient enrolled in the AN-1792(QS-21) trial with an initial clinical diagnosis of Alzheimer disease (AD), in whom Lewy body variant was thereafter clinically diagnosed. A case report. University memory clinic. Patient A 74-year-old woman with clinical features of probable AD. Intervention The patient received 2 injections of 225 mug of AN-1792 (beta-amyloid [Abeta]) plus 50 mug of the adjuvant QS-21 at an interval of 4 weeks. The patient was an antibody responder with an IgG anti-AN-1792 antibody titer exceeding 10 000 and an IgM titer exceeding 3500. Maximum serum anti-Abeta titers were reached in 4.7 months. During the 3 following years, while the Mini-Mental State Examination score remained globally stable despite several confusional episodes, she developed clinical features of dementia with Lewy bodies. The patient died 34 months postimmunization. An autopsy was performed. Neuropathological and biochemical examination of the brain using standardized evaluation for tau, beta-amyloid, and synuclein deposits. Neither neuropathological nor biochemical examinations showed amyloid deposit in the brain of this immunized patient. For tau deposition, Braak stage was IV/VI, and the Western blot analysis score was 9c/10. The neuropathological semiquantitative score for alpha-synuclein aggregation was 4. There was no inflammation. These results were compared with those of an age-matched patient with AD and a control devoid of any neurological disease. In this Lewy body variant case, with globally stable functional and cognitive features, Abeta immunization resulted in a significant clearance of amyloid deposits, with remaining tau and synuclein pathological features in the brain. Patients with a Lewy body variant of AD should not be excluded from enrollment in Abeta-immunization trials.

Parkin and synphilin-1 isoform expression changes in Lewy body diseases

Alternative splicing gives rise to at least seven parkin and eight synphilin-1 isoforms. Since both parkin and synphilin-1 have been involved in Lewy body (LB) formation, we decided to explore whether their isoforms are differentially expressed in LB diseases. With this aim, we studied relative mRNA expression levels of parkin and synphilin-1 isoforms in the frontal cortices of patients with dementia with LBs, the LB variant of Alzheimer's disease and Parkinson's disease and compared the findings with those obtained from Alzheimer's disease patients and control individuals. Duplex real-time PCR reactions, with beta-actin as internal standard, were carried out in a LightCycler. mRNA expression levels of parkin and synphilin-1 isoforms were seen to be specifically altered in each of the LB diseases studied. These findings suggest that parkin and synphilin-1 isoform expression changes play a significant role in the pathogenesis of LB diseases.

The Woman Who Needed a Pet

A 72-year-old woman developed difficulty reading, driving, and playing dominoes. Ophthalmologic examination revealed a homonymous hemianopia, but brain MRI showed no abnormality to explain the visual field defect. Neuropsychiatric testing demonstrated severely impaired visual processing (simultagnosia, visual agnosia, visuospatial difficulty). Positron emission tomography revealed hypometabolism of both parietal and occipital lobes consistent with posterior cortical atrophy or the visual variant of Alzheimer disease. Functional neuroimaging should be considered in the setting of a normal MRI among patients with signs and symptoms of the visual variant Alzheimer disease.

Convergence of Heat Shock Protein 90 with Ubiquitin in Filamentous α-Synuclein Inclusions of α-Synucleinopathies

Convergence of Heat Shock Protein 90 with Ubiquitin in Filamentous α-Synuclein Inclusions of α-Synucleinopathies

Low mRNA levels of RGS4 splice variants in Alzheimer's disease: Association between a rare haplotype and decreased mRNA expression

Regulator of G-protein signaling 4 (RGS4) showed decreased mRNA levels in Alzheimer's disease in a large collection of human brain autopsies from prefrontal cortex. The expression levels of three RGS4 splice variants were examined in the same samples, and the association between RGS4 gene expression and/or the disease with single nucleotide polymorphisms located in this gene was explored. We show that all splice variants are down-regulated in patients. We also demonstrate that one rare haplotype (ATAG) is associated with decreased mRNA levels in both cases and controls. Our results suggest that an altered regulation in transcription initiation may be an important mechanism for low RGS4 protein levels in Alzeimer's disease.

The pathophysiology and treatment of dementia with Lewy bodies: An overview

Kosaka in Japan first identified dementia with Lewy bodies as a distinct form of dementia in 1990. It has been known by a variety of names such as diffuse Lewy body disease, Lewy body dementia, Lewy body variant of Alzheimer's disease and senile dementia of the Lewy body type. It is now thought by many to be the second most common form of dementia affecting those over 65 years of age, although it shares many features with other forms of dementia and is sometimes difficult to differentiate clinically or diagnostically. This paper is an overview of the pathophysiology of the disease and diagnostic criteria. Current treatment options are identified and the case of James, a 65-year-old man who presented with the disease, is reviewed.

“Frontal variant Alzheimer's disease”: A reappraisal

Two cases of clinically diagnosed sporadic Alzheimer's disease with early and prominent behavioural features (social disinhibition, emotional blunting, stereotyped verbal utterances) sufficient to prompt an initial diagnosis of frontotemporal dementia are presented. It is suggested that the term “frontal variant AD” be used for this clinically defined phenotype, which has also been described in cases of inherited AD associated with certain presenilin-1 gene mutations. This differs from previous usage of the term “frontal variant AD” to describe AD with predominant frontal lobe neuropathological change (although the clinical phenotype may reflect regional distribution of pathology), but parallels the clinical definition of visual agnosic, aphasic and apraxic presentations of AD. The proposed usage would also emphasise differential diagnosis.

Reversible Inhibition of α-Synuclein Fibrillization by Dopaminochrome-mediated Conformational Alterations

Previous studies demonstrated that alpha-synuclein (alpha-syn) fibrillization is inhibited by dopamine, and studies to understand the molecular basis of this process were conducted (Conway, K. A., Rochet, J. C., Bieganski, R. M., and Lansbury, P. T., Jr. (2001) Science 294, 1346-1349). Dopamine inhibition of alpha-syn fibrillization generated exclusively spherical oligomers that depended on dopamine autoxidation but not alpha-syn oxidation, because mutagenesis of Met, His, and Tyr residues in alpha-syn did not abrogate this inhibition. However, truncation of alpha-syn at residue 125 restored the ability of alpha-syn to fibrillize in the presence of dopamine. Mutagenesis and competition studies with specific synthetic peptides identified alpha-syn residues 125-129 (i.e. YEMPS) as an important region in the dopamine-induced inhibition of alpha-syn fibrillization. Significantly, the dopamine oxidation product dopaminochrome was identified as a specific inhibitor of alpha-syn fibrillization. Dopaminochrome promotes the formation of spherical oligomers by inducing conformational changes, as these oligomers regained the ability to fibrillize by simple denaturation/renaturation. Taken together, these data indicate that dopamine inhibits alpha-syn fibrillization by inducing structural changes in alpha-syn that can occur through the interaction of dopaminochrome with the 125YEMPS129 motif of alpha-syn. These results suggest that the dopamine autoxidation can prevent alpha-syn fibrillization in dopaminergic neurons through a novel mechanism. Thus, decreased dopamine levels in substantia nigra neurons might promote alpha-syn aggregation in Parkinson's disease.

Variabilidad y variantesde la enfermedad de Alzheimer

The heterogeneity and variants of Alzheimer disease (AD) are reviewed. There are cases with a slow or fast evolution and with early or late onset. Most cases are sporadic but there are also hereditary forms. About 50% of patients show neuropsychiatric disorders (depression and psychoses). Some cases have a greater deficit of right or left hemispheric functions. Among the variants, there are forms that start as pure aphasias, predominantly prefrontal cases and posterior cortical forms. Occasionally AD may simulate other disorders such as supranuclear palsy, corticobasal ganglionar degeneration and Jacob-Creutzfeldt disease. Finally, there are mixed forms, in which AD is associated with cerebrovascular disease (very commonly) and with other diseases such as dementia with Lewy bodies. We conclude that AD is a heterogeneous disorder and, therefore, clinical diagnosis may be insufficient. Biological markers and specific imaging studies are needed for a correct clinical diagnosis.

A mutant PSEN1 causes dementia with lewy bodies and variant Alzheimer's disease

We report early-onset parkinsonism and dementia of 18 years' duration in a 52-year-old man whose grandfather and father had suffered from a similar neurological disease. In this patient, we found neuronal loss in various brain regions including the substantia nigra and cerebral cortex, Lewy bodies, cotton wool plaques, corticospinal tract degeneration, cerebral amyloid angiopathy, and a novel three-base pair deletion in exon 12 of the presenilin-1 (PSEN1) gene. We considered that the mutant PSEN1 might play an important role in the pathogenetic process of both aggregation of alpha-synuclein into Lewy bodies and deposition of beta-amyloid into cotton wool plaques.

Genetic association between the APOE * 4 allele and Lewy bodies in Alzheimer disease

To explore the association between APOE*4 and pathologically confirmed cases of the Lewy body (LB) variant of Alzheimer disease (AD). With use of alpha-synuclein (AS) immunohistochemistry, LBs were detected in 74 of 131 (56.5%) of the AD + LB cases; the remaining 57 cases (43.5%) did not have LBs. There were no differences in gender or age between Caucasian subjects with AD + LB or AD alone or control subjects. The APOE*4 allele frequency was highest in the AD + LB group (47.3%; 95% CI = 37.8 to 57.0%), intermediate in the AD-alone group (35.1%; 95% CI = 25.3 to 46.3%), and lowest in the control group (14.2%; 95% CI = 10.5 to 18.9%). With use of logistic regression analysis, the odds of having AD + LB vs AD alone were 2.1-fold (95% CI = 1.0 to 4.5, p = 0.055) greater in persons with an APOE*4 allele than in those without an APOE*4 allele. The APOE*4 allele is associated with the presence of concomitant Lewy bodies in Alzheimer disease.

Differential expression of N-methyl-D-aspartate receptor NR2 isoforms in Alzheimer's disease.

We have previously shown that the expression of NMDA receptor NR1 subunit mRNA splice variants in Alzheimer's disease (AD) brain varies according to regional susceptibility to pathological damage. Here we investigated the expression of the modulatory NR2 subunits of the NMDA receptor using quantitative RT-PCR to assay all NR2 isoforms. Significantly lower expression of NR2A and NR2B transcripts was found in susceptible regions of AD brain, whereas expression of NR2C and NR2D transcripts did not differ from that in controls. Western blot analysis confirmed a lower expression of the NR2A and NR2B isoforms at the protein level. The results suggest that NR2 subunit composition may modulate NMDA receptor-mediated excitotoxicity. NMDA receptor dysfunction might give rise to the regionally selective pattern of neuronal loss that is characteristic of AD.

P3-367 Posterior cortical atrophy — variant of Alzheimer's disease?

P3-367 Posterior cortical atrophy — variant of Alzheimer's disease?

O2-03-07 Biochemical analysis of Aβ amyloid deposits in the Iowa variant of Alzheimer's disease

O2-03-07 Biochemical analysis of Aβ amyloid deposits in the Iowa variant of Alzheimer's disease

Genetic variation in CTNNA3 encoding alpha-3 catenin and Alzheimer's disease

Linkage studies have implicated a broad region on chromosome 10q in Alzheimer's disease (AD). A recent genetic association study has provided evidence that polymorphism in the gene encoding alpha-3 catenin ( CTNNA3, referred to previously as VR22 and also known as alpha-T catenin) may underlie linkage signals. Here, to investigate this finding, markers that previously exhibited maximum evidence of association have been tested in Swedish and Scottish AD case-control samples. Across models of disease risk and in relation to multiple quantitative indices of AD pathology (CSF Aβ42 and tau levels, age-at-onset, MMSE scores, and measures of senile plaque density) no evidence was found supporting a role for these particular variants in AD. More detailed studies of regional linkage disequilibrium structure around CTNNA3 will likely be required to determine whether sequence variation in this region impacts AD.

Neuro-ophthalmic findings in the visual variant of Alzheimer's disease

Purpose To describe the clinical features of a visual variant Alzheimer's disease, a disorder that might be seen by the ophthalmologist with visual symptoms and signs. Design Retrospective case series. Participants Eight patients with Alzheimer's disease presenting with predominantly visual complaints. Methods A retrospective review of patients at a tertiary care academic center seen by the authors from 1999 to 2001 with Alzheimer's disease and predominantly visual complaints. Results Eight patients with the visual variant of Alzheimer's disease were reviewed. All had seen eye care providers before referral to the neuro-ophthalmology clinic for visual complaints but without a diagnosis. Four patients had homonymous visual field loss, and two had presumed cortical visual impairment. Neuroimaging showed either normal brain (1 patient) or atrophy of the parietal or occipital areas but no structural lesions (7 patients). Fluoro-18-deoxyglucose positron emission tomography scans were performed in five of the cases, and all showed hypoperfusion in the parietooccipital areas. Neuropsychologic testing revealed visuospatial deficits in all 5 patients tested. Conclusions Visual symptoms might be the presenting (or rarely only) manifestation of Alzheimer's disease. Clinicians should be aware of the visual variant of Alzheimer's disease. Neuropsychological testing and magnetic resonance imaging (MRI) provide supporting evidence for the diagnosis. Positron emission tomography scans might be helpful in selected cases, especially those with a normal MRI.

Genetic association studies in Alzheimer's disease research: challenges and opportunities.

Genetic association studies have identified important risk factors for Alzheimer's disease and other diseases. However, the ease with which these methods can be applied and the shear number of polymorphisms in the human genome has led to a well-characterized multiple comparison problem-given the number of genetic variants being tested, it is likely that many of the positive findings reported in the literature to date will prove to be false positive findings explained simply by random fluctuation in data and type I error. The disparity of findings in initial positive reports versus subsequent negative replication studies observed in the Alzheimer's disease literature underscores this problem. The problem of a high false positive rate can be addressed in part by using statistical correction for multiple comparisons in larger and statistically more powerful samples and in meta-analyses of smaller samples. National initiatives are now being considered to address this problem by encouraging sharing of genetic material. Of equal concern in planning future initiatives are methodological issues that are the domain of the epidemiologist. In fact, it is possible that disparate findings across case-control studies reported to date may be explained in part by problems in the design, analysis and interpretation of these studies. The involvement of epidemiologists may improve the situation in this regard. For example, population stratification bias, control selection bias and prevalent case bias can be minimized by careful study design and by appropriate statistical analysis. Regarding interpretation of case-control studies, a more careful consideration of the strength of evidence for a given genetic variant may help to temper enthusiasm for, or appropriately qualify, positive findings. Epidemiologists have well-developed causal criteria for this purpose. This paper reviews the current state of case-control studies of genetic variants in Alzheimer's disease from the epidemiological perspective. The problem of multiple comparisons and a high false positive rate is reviewed. The potential for bias in case-control studies of Alzheimer's disease is reviewed by way of example. Future initiatives to promote case-control studies of genetic variants in Alzheimer's disease can only benefit from increased awareness the tools of epidemiology.

Neuropsychological functions in variant Alzheimer's disease with spastic paraparesis

Few data exist on the effects of specific Alzheimer's disease (AD)-related mutations on cognitive function. We present neuropsychological test results in eight members of a large kindred with variant Alzheimer's disease (VarAD) due to a deletion of the presenilin 1 ( PS-1) gene, encompassing exon 9. The disease was neuropathologically characterized by the presence of large, unusual, “cotton wool” plaques (CWP). Four surviving patients were prospectively tested, and retrospective neuropsychological data were collected from additional four deceased patients. The neuropsychological evaluation was based on tests of verbal and visual memory, abstract thinking, and visuoconstructive and spatial functions. In addition, psychiatric symptoms were evaluated. In four patients, brain glucose metabolism was examined by positron emission tomography (PET). PET showed temporoparietal hypometabolism typical of AD. In addition, variable patterns of hypometabolism (hemispherical asymmetry and occipital accentuation) were related to individual deficits of cognitive performance. However, all these early-onset patients (age range 43–63 years) with a deletion mutation of PS-1 gene showed prominent memory impairment and deficits in visuoconstructive and intellectual functions.

Cerebral Amyloid Angiopathies: A Pathologic, Biochemical, and Genetic View

Amyloid deposition can take place in the walls of arteries, arterioles, and, less often, capillaries and veins of the central nervous system, a phenomenon known as cerebral amyloid angiopathy (CAA). The major clinicopathological manifestations of CAA include cerebral hemorrhage, ischemic lesions, and dementia. CAA may be classified according to the amyloid protein deposited. In the most common form, sporadic CAA, and in CAA related to sporadic Alzheimer disease (AD). A beta deposition is characteristic. CAA can also be severe in variants of familial AD caused by mutations of the amyloid-beta precursor protein or presenilin-1 genes in which deposition of A beta variants and/or wild-type A beta occurs. Other amyloid proteins involved in familial CAAs include 1) the mutant cystatin C (ACys) in hereditary cerebral hemorrhage with amyloidosis of Icelandic type, 2) variant transthyretins (ATTR) in meningo-vascular amyloidoses, 3) mutated gelsolin (AGel) in familial amyloidosis of Finnish type, 4) disease-associated prion protein (PrP(Sc)) in a variant of the Gerstmann-Sträussler-Scheinker syndrome, and 5) ABri and ADan in CAAs observed in the recently described BRI2 gene-related dementias, familial British dementia and familial Danish dementia, respectively. This review addresses issues related to the correlation between morphology, biochemistry, and genetics, and briefly discusses both the pathogenesis and animal models of CAAs.