The Arctic AβPP mutation leads to Alzheimer's disease pathology with highly variable topographic deposition of differentially truncated Aβ.

Background: The Arctic mutation (p.E693G/p.E22G)fs within the β-amyloid (Aβ) region of the β-amyloid precursor protein gene causes an autosomal dominant disease with clinical picture of typical Alzheimer's disease.

Inclusion-body myositis associated with Alzheimer's disease.

Sporadic inclusion-body myositis (s-IBM) is a myopathy that is characterized by progressive weakness and muscle pathology demonstrating inflammation and rimmed vacuoles. In addition, similar to the pathology observed in the brains of patients with Alzheimer's disease, the deposition of beta-amyloid and phosphorylated tau proteins in muscle fibers has been reported. These shared pathologic features have prompted hypotheses suggesting a shared etiology of these two conditions.

Phenotype-genotype analysis of dystrophinopathy caused by duplication mutation in Dystrophin gene in an African patient.

Background: The dystrophinopathies, duchenne muscular dystrophy (DMD) and Becker muscular dystrophy are common X-linked genetic myopathies resulting from mutations in the dystrophin gene. Duplication is an uncommon mechanism of mutation occurring in about 5% of DMD cases. The global prevalence of DMD is reported as 1/18,000 males.

Familial prion disease with Alzheimer disease-like tau pathology and clinical phenotype.

Objective: To describe the Alzheimer disease (AD)-like clinical and pathological features, including marked neurofibrillary tangle (NFT) pathology, of a familial prion disease due to a rare nonsense mutation of the prion gene (PRNP).

Methods: Longitudinal clinical assessments were available for the proband and her mother. After death, both underwent neuropathological evaluation.

Kikuchi-fujimoto disease associated with myasthenia gravis: a case report.

Kikuchi-Fujimoto disease is a self-limited benign condition of unknown etiology characterized by cervical lymphadenopathy, fever, and leucopenia. An autoimmune hypothesis has been suggested and an association with systemic lupus erythematosus, Sjogren's disease, and antiphospholipid syndrome has been noted. We report a 27-year-old male who presented for evaluation of weakness and he was diagnosed with seropositive generalized myasthenia gravis and underwent a thymectomy.

De novo formation of large arteriovenous shunting and a vascular nidus mimicking an arteriovenous malformation within an anaplastic oligodendroglioma: treatment with embolization and resection.

The authors report the de novo occurrence and treatment of an arteriovenous lesion within an anaplastic oligodendroglioma in a patient with previously unremarkable brain imaging. Intracranial arteriovenous malformations (AVMs) are believed to be congenitally acquired lesions, and their association with brain neoplasms is extremely rare. Diagnostic imaging revealed a mass lesion with large arteriovenous shunts and a vascular nidus mimicking a true AVM.

Rosai-Dorfman disease manifesting as intracranial and intraorbital lesion.

Rosai-Dorfman disease is a rare benign idiopathic histioproliferative disorder usually manifesting as massive painless adenopathy. Extranodal involvement of the Central Nervous System (CNS) mimicking a skull base meningioma is rare. A 42-year-old male presented with painless, progressive left visual loss of 4 months duration.

Clinical and neuropathological features of the arctic APP gene mutation causing early-onset Alzheimer disease.

Background: A majority of mutations within the beta-amyloid region of the amyloid precursor protein (APP) gene cause inherited forms of intracerebral hemorrhage. Most of these mutations may also cause cognitive impairment, but the Arctic APP mutation is the only known intra-beta-amyloid mutation to date causing the more typical clinical picture of Alzheimer disease.

Objective: To describe features of 1 Swedish and 1 American family with the previously reported Arctic APP mutation.

Clinicopathological concordance and discordance in three monozygotic twin pairs with familial Alzheimer's disease.

Aim: Neuropathological examination of both individuals in a monozygotic (MZ) twin pair with Alzheimer's disease (AD) is rare, especially in the molecular genetic era. We had the opportunity to assess the concordance and discordance of clinical presentation and neuropathology in three MZ twin pairs with AD.

Methods: The MZ twins were identified and characterised by the University of Washington Alzheimer's Disease Research Center.

Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype.

Background: The origin and significance of Lewy bodies and neurites (Lewy body pathology [LBP]) in Alzheimer disease (AD) are poorly understood.

Objective: To examine LBP in the brainstem, limbic cortex, and neocortex of a large number of familial AD cases with mutations in 2 presenilin (PSEN) genes.

Methods: Twenty-five familial AD cases with 9 known PSEN 1 mutations and 14 familial AD cases with a single PSEN 2 mutation (N141I) were examined for LBP using alpha-synuclein immunohistochemistry and sampling of multiple brainstem and cortical regions.

Evaluation of selection bias in an incident-based dementia autopsy case series.

Neuropathological (np) relative frequency estimates of dementia may be biased if the autopsied subjects are not representative of all dementia subjects within a target population. We identified characteristics that differed between autopsied and non-autopsied subjects from an incident-based dementia case series and compared autopsy-based estimates of the relative frequency of np diagnoses before and after adjusting for potential selection bias. Clinically demented subjects who were autopsied (n = 206), had died but were not autopsied (n = 271), were still alive (n = 71), or had dropped out of the study (n = 82) were included.

APOE and other loci affect age-at-onset in Alzheimer's disease families with PS2 mutation.

Several kindreds of Volga German (VG) ancestry have a single PS2 mutation that causes an autosomal dominant form of Alzheimer's disease (AD). These families show a wide range in age-at-onset, which suggests the existence of modifying factors other than the PS2 mutation. To examine evidence for a genetic basis of variation in onset age, we performed a Bayesian oligogenic segregation and linkage analysis on nine VG families confirmed to have at least one affected PS2 carrier.

Effect of vascular lesions on cognition in Alzheimer's disease: a community-based study.

Objectives: To investigate whether clinical and neuropathological differences exist between Alzheimer's disease (AD) cases with and without vascular lesions neuropathologically diagnosed using Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria.

Design: Descriptive observational study.

Setting: A community-based registry that identified incident dementia cases.

Evidence for a novel late-onset Alzheimer disease locus on chromosome 19p13.2.

Late-onset familial Alzheimer disease (LOFAD) is a genetically heterogeneous and complex disease for which only one locus, APOE, has been definitively identified. Difficulties in identifying additional loci are likely to stem from inadequate linkage analysis methods. Nonparametric methods suffer from low power because of limited use of the data, and traditional parametric methods suffer from limitations in the complexity of the genetic model that can be feasibly used in analysis.

Missense mutations in the regulatory domain of PKC gamma: a new mechanism for dominant nonepisodic cerebellar ataxia.

We report a nonepisodic autosomal dominant (AD) spinocerebellar ataxia (SCA) not caused by a nucleotide repeat expansion that is, to our knowledge, the first such SCA. The AD SCAs currently comprise a group of > or =16 genetically distinct neurodegenerative conditions, all characterized by progressive incoordination of gait and limbs and by speech and eye-movement disturbances. Six of the nine SCAs for which the genes are known result from CAG expansions that encode polyglutamine tracts.

Constitutive Wee1 activity in adult brain neurons with M phase-type alterations in Alzheimer neurodegeneration.

The cdc2/cyclin B1 kinase is absent from neurons that are terminally differentiated. However, unscheduled activation of Cdc2/cyclin B and accumulation of mitotic phosphoepitopes have been described in degenerating neurons of Alzheimer's disease (AD), and their appearance precedes hallmark lesion formation. In cycling cells the timing of cdc2 activation and onset of mitosis are determined by the Wee1 tyrosine kinase.

A new dominant spinocerebellar ataxia linked to chromosome 19q13.4-qter.

Background: The autosomal dominant spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders. Although molecular genetic studies have so far implicated 16 loci in the etiology of these diseases, approximately 30% of families with SCAs remain unlinked.

Objectives: To report the location of a gene causing a "pure" autosomal dominant cerebellar ataxia in one family and to describe the clinical phenotype.

Clinical and neuropathological characteristics of hippocampal sclerosis: a community-based study.

Background: Hippocampal sclerosis (HS) is a neuropathologic finding characterized by neuronal loss and gliosis in the CA-1 and subiculum of the hippocampus. Previous studies of HS have shown that this is a common postmortem finding in elderly subjects with dementia. However, these studies were from selected samples and therefore are not necessarily representative of patients seen in the general medical community.

Hyperphosphorylation of RNA polymerase II and reduced neuronal RNA levels precede neurofibrillary tangles in Alzheimer disease.

Affected neurons of Alzheimer disease (AD) brain are distinguished by the presence of the cell cycle cdc2 kinase and mitotic phosphoepitopes. A significant body of previous data has documented a decrease in neuronal RNA levels and nucleolar volume in AD brain. Here we present evidence that integrates these seemingly distinct findings and offers an explanation for the degenerative outcome of the disease.

Constitutive Cdc25B tyrosine phosphatase activity in adult brain neurons with M phase-type alterations in Alzheimer's disease.

The Cdc2/cyclin B kinase is a critical regulator of mitosis that is normally absent from terminally differentiated neurons of adult brain. However, unscheduled expression and activation of Cdc2/cyclin B has been seen in neurons undergoing degeneration in Alzheimer's disease. The presence of this mitotic kinase correlates with accumulation of mitotic phosphoepitopes in protein components of the hallmark neurofibrillary tangles.

Prion proteins with different conformations accumulate in Gerstmann-Sträussler-Scheinker disease caused by A117V and F198S mutations.

Gerstmann-Sträussler-Scheinker disease (GSS) is characterized by the accumulation of proteinase K (PK)-resistant prion protein fragments (PrP(sc)) of approximately 7 to 15 kd in the brain. Purified GSS amyloid is composed primarily of approximately 7-kd PrP peptides, whose N terminus corresponds to residues W(81) and G(88) to G(90) in patients with the A117V mutation and to residue W(81) in patients with the F198S mutation. The aim of this study was to characterize PrP in brain extracts, microsomal preparations, and purified fractions from A117V patients and to determine the N terminus of PrP(sc) species in both GSS A117V and F198S.

Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia.

Background: Mutations in the tau gene have been reported in families with frontotemporal dementia (FTD) linked to chromosome 17. It remains uncertain how commonly such mutations are found in patients with FTD or non-Alzheimer dementia with or without a positive family history.

Objective: To determine the frequency of tau mutations in patients with non-Alzheimer dementia.

Brain expression of presenilins in sporadic and early-onset, familial Alzheimer's disease.

Background: Mutations in the presenilin proteins cause early-onset, familial Alzheimer's disease (FAD).

Materials And Methods: We characterized the cellular localization and endoproteolysis of presenilin 2 (PS2) and presenilin 1 (PS1) in brains from 25 individuals with presenilin-mutations causing FAD, as well as neurologically normal individuals and individuals with sporadic Alzheimer's disease (AD).

Results: Amino-terminal antibodies to both presenilins predominantly decorated large neurons.

Mitotic activation: a convergent mechanism for a cohort of neurodegenerative diseases.

Previous evidence from our lab and others has implicated the mitotic cdc2/cyclin B1 kinase in the neurofibrillary degeneration of Alzheimer's disease. To examine the specificity of this relationship, and define conditions leading to atypical activation of mitotic kinase in postmitotic neurons, we have applied antibodies specific for the cdc2 kinase, its activator, cyclin B1, and three cdc2 produced phosphoepitopes: the TG-3 phosphoepitope in tau and nucleolin, the MPM-2 phosphoepitope in a variety of substrates, and the H5 phosphoepitope in RNA polymerase II, to affected brain regions from a spectrum of neurodegenerative disorders. Our results demonstrate that neurons containing characteristic lesions in a subset of diseases including Down Syndrome (DS), Frontotemporal Dementia linked to chromosome 17 (FTD-17), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Parkinson-Amyotrophic Lateral Sclerosis of Guam (GP-ALS), Niemann Pick disease type C (NPDC), and Pick's disease, display mitotic indices, implicating diverse etiologies in mitotic activation.

The cell cycle Cdc25A tyrosine phosphatase is activated in degenerating postmitotic neurons in Alzheimer's disease.

The Cdc25 phosphatases play key roles in cell-cycle progression by activating cyclin-dependent kinases. The latter are absent from neurons that are terminally differentiated in adult brain. However, accumulation of mitotic phosphoepitopes, and re-expression and activation of the M phase regulator, Cdc2/cyclin B, have been described in neurons undergoing degeneration in Alzheimer's disease (AD).