Validation of the new consensus criteria for the diagnosis of corticobasal degeneration.

BACKGROUND: Corticobasal degeneration (CBD) is a complex neurodegenerative disorder. Accurate diagnosis is increasingly important, with the advent of clinical trials of drugs aimed at modifying the underlying tau pathology. CBD often presents with a 'corticobasal syndrome' including impairments of movement and cognition. However, patients with similar corticobasal syndromes can have neurodegenerative pathologies that are not CBD. In addition, patients with CBD may present with aphasia or behavioural change. The clinical diversity of CBD and mimicry by non-CBD pathologies hinders accurate diagnosis. METHODS: We applied the new consensus criteria of Armstrong and colleagues et al 1 to a cohort of patients with detailed longitudinal clinical evaluation and neuropathology. RESULTS: In patients with pathologically confirmed CBD, accuracy of diagnosis was similar under the new and previous criteria: 9/19 (47%) met criteria for probable CBD at presentation, 13/19 (68%) at last clinical assessment. Patients with a corticobasal syndrome but without CBD pathology all (14/14) met the new diagnostic criteria of probable or possible CBD, demonstrating that the new criteria lacks the necessary specificity for an accurate ante mortem clinical diagnosis of CBD. None of the clinical features used in the new criteria were more common in the patients with CBD pathology (n=19) than without (n=14). CONCLUSIONS: The Armstrong criteria usefully broadens the recognised clinical phenotype of CBD but does not sufficiently improve the specificity of diagnosis to increase the power of clinical trials or targeted applications of tau-based disease-modifying therapies. Further work is required to show whether biomarkers could be more effective than clinical signs in the diagnosis of CBD.

Clinical phenotypes in autopsy-confirmed Pick disease.

BACKGROUND: Neuropathology of frontotemporal lobar degeneration is variable and relationship between the pathology and the clinical presentation remains uncertain. Abnormal deposits of hyperphosphorylated and ubiquitinated tau protein are present in 30% of cases, which include the classic presentation of Pick disease with argyrophilic, intraneuronal inclusions known as Pick bodies. This study aimed to improve sensitivity of clinicopathologic relations in cases with neuropathologically confirmed Pick disease and to identify clinical symptoms and signs predictive of disease progression. METHODS: This was a retrospective analysis of 21 cases with a pathologic diagnosis of Pick disease and sufficient clinical information to establish early presenting clinical features from 2 specialist centers, representing 70% of all cases of Pick disease identified between 1998 and 2007 in these centers. RESULTS: At presentation, 13/21 cases (62%) were clinically diagnosed with behavioral variant frontotemporal dementia (bvFTD) and 8/21 (38%) with language variant frontotemporal dementia (lvFTD) including 2 with mixed syndromes. Patients with bvFTD died on average 5 years earlier than those with lvFTD (7 years vs 12 years after disease onset). Pathologically, fewer Pick bodies were present in the frontal and inferior temporal cortices of bvFTD than lvFTD cases. In contrast, both groups showed decreased neuronal density in the dentate gyrus with increasing disease duration. CONCLUSIONS: The pathologic course of the disease in FTLD cases with Pick bodies is not uniform and disease duration can be estimated based on early clinical features. These findings have relevance as treatment options, which are likely to be pathology specific, are developed.

Atrophy patterns in histologic vs clinical groupings of frontotemporal lobar degeneration.

OBJECTIVE: Predictable patterns of atrophy are associated with the clinical subtypes of frontotemporal dementia (FTD): behavioral variant (bvFTD), semantic dementia (SEMD), and progressive nonfluent aphasia (PNFA). Some studies of pathologic subtypes have also suggested specific atrophy patterns; however, results are inconsistent. Our aim was to test the hypothesis that clinical, but not pathologic, classification (FTD with ubiquitin inclusions [FTD-U] and FTD with tau inclusions [FTD-T]) is associated with predictable patterns of regional atrophy. METHODS: Magnetic resonance scans of nine FTD-U and six FTD-T patients (histologically confirmed) were compared with 25 controls using voxel-based morphometry (VBM). Analyses were conducted with the patient group classified according to histologic or clinical variant. Additionally, three Alzheimer pathology patients who had the syndrome of SEMD in life (FTD-A) were analyzed. RESULTS: The VBM studies in clinical variants confirmed established patterns of atrophy (SEMD, rostral temporal; bvFTD, mesial frontal; PNFA, left insula). FTD-U and FTD-T VBM results were very similar, showing severe atrophy in the temporal poles, mesial frontal lobe, and insulae. A conjunction analysis confirmed this similarity. Subgroup analysis found that SEMD associated with either FTD-T or FTD-U was associated with similar rostral temporal atrophy; however, FTD-A had a qualitatively different pattern of left hippocampal atrophy. CONCLUSIONS: While there is predictable atrophy for clinical variants of frontotemporal dementia (FTD), histologic FTD variants show no noticeable differences. Reports of specific atrophy profiles are likely the result of idiosyncrasies in small groups. Semantic dementia associated with Alzheimer pathology, however, presented a distinct atrophy pattern.

Sporadic malignant nerve sheath tumour of the oculomotor nerve.

Malignant peripheral nerve sheath tumours (MPNST) are exceedingly rare in an intracranial location. In this report clinical and pathological evidence for the diagnosis of a MPNST arising from of the oclumotor nerve is presented. To our knowledge this is the first such case reported in the medical literature.

Ubiquitin-positive inclusions and progression of pathology in frontotemporal dementia and motor neurone disease identifies a group with mainly early pathology.

Frontotemporal lobar degeneration (FTLD) with tau-negative, ubiquitin-positive inclusions has been a topic of major interest in recent years, with this group now accounting for the majority of tau-negative cases of frontotemporal degeneration. The severity of neurodegeneration in FTLD is dependent on the stage of disease and is substantial even in the earliest stages. Elucidating the pathogenesis of FTLD requires evaluation of changes during the earliest possible stage of disease. However, the long survival of most frontotemporal dementia cases means that cases with early neuropathology are not frequently encountered. Cases of FTLD with the shortest survival are those with coexisting motor neurone disease (FTLD + MND), making these the ideal group for studying early FTLD pathology. It is not clear, however, what the pathological contribution of MND is in these cases. This study evaluates the pathology of 20 cases of FTLD (11 with no clinical signs of MND and nine with FTLD + MND) as well as 10 cases of MND without dementia. Our findings indicate that the deposition of ubiquitin does not play a key role in the neurodegenerative process in FTLD, and that the severity of neurodegeneration in FTLD is similar in cases with and without clinical MND.

Cerebral neutrophil recruitment, histology, and outcome in acute ischemic stroke: an imaging-based study.

BACKGROUND AND PURPOSE: Evidence now exists for a pathogenic role for neutrophils in acute cerebral ischemia. We have studied the patterns and temporal profile of cerebral neutrophil recruitment to areas of acute ischemic stroke (IS) and have attempted to correlate this with neurological status and outcome. METHODS: Patients with cortical middle cerebral artery (MCA) IS were recruited within 24 hours of clinical onset. Neutrophil recruitment was studied using indium-111 (111In) troponolate-labeled neutrophils, planar imaging, and single-photon emission computed tomography (SPECT). Volume of brain infarction was calculated from concurrent computed tomography (CT). Hematoxylin and eosin sections were obtained postmortem (n=2). Outcome was measured using Barthel, Rankin, and National Institute of Health Stroke (NIHSS) scales. RESULTS: Fifteen patients were studied. Significant 111In-neutrophil recruitment to ipsilateral hemisphere, as measured by asymmetry index (AI), was demonstrated within 24 hours of onset in 9 patients; this response was heterogenous between patients and on repeated measurement attenuated over time. Histologically, recruitment was confirmed within intravascular, intramural, and intraparenchymal compartments. Interindividual heterogeneity in neutrophil response did not correlate with infarct volume or outcome. In an exploratory analysis, neutrophil accumulation appeared to correlate significantly with infarct expansion (Spearman rho=0.66; P=0.03, n=12). CONCLUSIONS: Neutrophils recruit to areas of ischemic brain within 24 hours of symptom onset. This recruitment attenuates over time and is confirmed histologically. While neutrophil accumulation may be associated with either the magnitude or the rate of infarct growth, these results require confirmation in future studies.

Rapidly reversible dementia in cerebral amyloid inflammatory vasculopathy.

This report discusses a biopsy proven case of cerebral amyloid angiopathy, with additional prominent vascular inflammatory features, characterized by a rapidly progressive dementia and leukoencephalopathy, where the clinical and radiological abnormalities resolved rapidly with minimal therapeutic intervention. We propose the term cerebral amyloid inflammatory vasculopathy (CAIV) to describe this condition.

Identification and characterization of the promoter region of the GRM3 gene.

We have recently described the genomic organisation of the human metabotropic glutamate receptor 3 (GRM3) gene. The putative promoter region is characterised by the presence of a CCAAT and Sp1 site and the absence of a TATA box. Using a reporter gene assay, now we describe the functional activity of GRM3 promoter by transient transfection in both human neuroblastoma and astroglioma cell lines. Deletion of the CCAAT box and Sp1 site resulted in a pronounced reduction of reporter gene expression in both cell types, which indicates that these elements to correspond to the core promoter region. Moreover, we found that the genomic sequence 140 bp upstream of the first transcription initiation site appears to contain regulatory promoter elements for a preferential transcription of the gene in neuroblastoma cells. We also provide evidence that the genomic sequence spanning exon I, corresponding to the GRM3 5'-untranslated region, contains a negative regulatory element that represses gene transcription.

Selective impairment of verb processing associated with pathological changes in Brodmann areas 44 and 45 in the motor neurone disease-dementia-aphasia syndrome.

We report six patients with clinically diagnosed and electrophysiologically confirmed motor neurone disease (MND), in whom communication problems were an early and dominant feature. All patients developed a progressive non-fluent aphasia culminating in some cases in complete mutism. In five cases, formal testing revealed deficits in syntactic comprehension. Comprehension and production of verbs were consistently more affected those that of nouns and this effect remained stable upon subsequent testing, despite overall deterioration. The classical signs of MND, including wasting, fasciculations and severe bulbar symptoms, occurred over the following 6-12 months. The behavioural symptoms ranged from mild anosognosia to personality change implicating frontal-lobe dementia. In three cases, post-mortem examination has confirmed the clinical diagnosis of MND-dementia. In addition to the typical involvement of motor and premotor cortex, particularly pronounced pathological changes were observed in the Brodmann areas 44 (Broca's area) and 45. The finding of a selective impairment of verb/action processing in association with the dementia/aphasia syndrome of MND suggests that the neural substrate underlying verb representation is strongly connected to anterior cortical motor systems.

Pathology of early-onset Alzheimer's disease cases bearing the Thr113-114ins presenilin-1 mutation.

Most cases of familial presenile Alzheimer's disease are caused by mutations in the presenilin-1 (PSEN-1) gene, most of these mutations being missense mutations. A mutation in the splice donor site of intron 4 of PSEN-1 has been described recently which results in aberrant splicing of PSEN-1 mRNA, causing insertion of an additional amino acid, Thr113-114ins, into the protein. We studied the neuropathology of four cases bearing this mutation in an attempt to clarify the pathology of this hereditary form of Alzheimer's disease and to determine whether it differs from other familial forms of the disease. The disease presented as a progressive cognitive decline, myoclonus and seizures developing later in the disease, a feature common to PSEN-1-linked Alzheimer's disease. The course of the disease was relatively rapid, death occurring approximately 6 years after onset. Pathology in the intron 4 cases demonstrated a severe Alzheimer's disease pathology with abundant deposition of ss-amyloid (Ass) 1-42 senile plaques and the formation of neurofibrillary tangles. Amyloid angiopathy was present in these cases and was readily demonstrated by Ass 1-40 staining, particularly in the cerebellum. Cases with the intron 4 mutation appear clinically and pathologically similar to other cases of early-onset Alzheimer's disease bearing PSEN-1 mutations.

Tau gene mutation K257T causes a tauopathy similar to Pick's disease.

Exonic and intronic mutations in Tau cause neurodegenerative syndromes characterized by frontotemporal dementia and filamentous tau protein deposits. Here we describe a K257T missense mutation in exon 9 of Tau. The proband, a 47-yr-old male, presented with severe personality changes followed by semantic memory loss. A diagnosis of Pick's disease was made. The symptoms progressed until death at age 51. The proband's brain showed a marked frontotemporal atrophy that was most pronounced in the temporal lobes. Numerous tau-immunoreactive Pick bodies were present in the neocortex and the hippocampal formation, as well as in some subcortical brain regions. Their appearance and staining characteristics were indistinguishable from those of sporadic Pick's disease. Diffuse staining for hyperphosphorylated tau was also observed in some nerve cell bodies. Immunoblot analysis of sarkosyl-insoluble tau showed 2 major bands of 60 and 64 kDa and 2 very minor bands of 68 and 72 kDa. Upon dephosphorylation, these bands resolved into 6 bands consisting of 3-repeat and 4-repeat tau isoforms, with an overall preponderance of 3-repeat tau. Isolated tau filaments were narrow, irregularly twisted ribbons. Biochemically, recombinant tau proteins with the K257T mutation showed a reduced ability to promote microtubule assembly, suggesting that this may be the primary effect of the mutation. In addition, the K257T mutation was found to stimulate heparin-induced assembly of 3-repeat tau into filaments. Taken together, the present findings indicate that the K257T mutation in Tau can cause a dementing condition similar to Pick's disease.

Staging of cytoskeletal and beta-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer's disease.

We have examined the relationships between dementia, loss of synaptic proteins, changes in the cytoskeleton, and deposition of beta-amyloid plaques in the neocortex in a clinicopathologically staged epidemiological cohort using a combination of biochemical and morphometric techniques. We report that loss of synaptic proteins is a late-stage phenomenon, occurring only at Braak stages 5 and 6, or at moderate to severe clinical grades of dementia. Loss of synaptic proteins was seen only after the emergence of the full spectrum of tau and beta-amyloid pathology in the neocortex at stage 4, but not in the presence of beta-amyloid plaques alone. Contrary to previous studies, we report increases in the levels of synaptophysin, syntaxin, and SNAP-25 at stage 3 and of alpha-synuclein and MAP2 at stage 4. Minimal and mild clinical grades of dementia were associated with either unchanged or elevated levels of synaptic proteins in the neocortex. Progressive aggregation of paired helical filament (PHF)-tau protein could be detected biochemically from stage 2 onwards, and this was earliest change relative to the normal aging background defined by Braak stage 1 that we were able to detect in the neocortex. These results are consistent with the possibility that failure of axonal transport associated with early aggregation of tau protein elicits a transient adaptive synaptic response to partial de-afferentation that may be mediated by trophic factors. This early abnormality in cytoskeletal function may contribute directly to the earliest clinically detectable stages of dementia.

Neuropathological findings in the very old. Results from the first 101 brains of a population-based longitudinal study of dementing disorders.

We report a unique longitudinal epidemiological study of cognitive decline in the elderly population of the city of Cambridge, UK. A population sample of people aged 75 and over was surveyed between 1984-1996 (n = 2,616) and followed 2.4, 6, and 9 years later. CAMDEX diagnostic criteria were used for clinical assessment, and the neuropathological protocol (in 101 cases) was based on the CERAD method, with additional features to allow Braak staging of neurofibrillary pathology. The main findings are of the heterogeneity of lesions to be found in very old populations, and the existence of considerable overlap in the pathologies found in the demented and nondemented. It seems that white matter (ischemic) pallor an amyloid angiopathy, as well as neuritic plaques, neurofibrillary tangles and Lewy body formation are all lesions that increase the likelihood of dementia.

Corticobasal ganglionic degeneration and/or frontotemporal dementia? A report of two overlap cases and review of literature.

OBJECTIVE: According to the existing viewpoint, Corticobasal degeneration (CBD) is thought of as a predominantly extrapyramidal motor disorder that is distinct and unrelated to frontotemporal dementia (FTD), the most common form of non-Alzheimer dementias. A lack of understanding of the aetiopathogenesis, and poor correlation between the pathology and the clinical syndromes, has resulted in a disparity in the classification of cases of non-Alzheimer dementias. This report intends to highlight the overlap between FTD and CBD in the light of the evolution of these terms, and to discuss the implications of these findings on the nosology of CBD and the classification of non-Alzheimer dementias. METHODS AND RESULTS: Two cases who presented with cognitive dysfunction, which, on comprehensive neuropsychological testing warranted an antemortem diagnosis of FTD are reported. A detailed necropsy study of their brains, however, favoured a pathological diagnosis of CBD. The literature on the overlap between CBD and FTD is also reviewed. CONCLUSIONS: Firstly, evidence is emerging to suggest that the clear distinction drawn between FTD and CBD by the existing viewpoint, needs revision. Secondly, until such time that a comprehensive classification of non-Alzheimer dementias is evolved, it may be better to distinguish between the clinical and pathological levels of description and to classify cases, in vivo, on the basis of the clinical phenotype.

Atypical and typical presentations of Alzheimer's disease: a clinical, neuropsychological, neuroimaging and pathological study of 13 cases.

There has been increasing awareness that some slowly progressive focal cortical syndromes can be the presenting features of Alzheimer's disease, but pathological evidence has been sparse. This clinico-pathological series presents our experience with pathologically proven atypical as well as typical Alzheimer's disease presentations. We report and compare four patterns of presentation: a typical pattern with initial amnesic syndrome (n = 4 cases), progressive visual dysfunction (n = 1), progressive biparietal syndrome (n = 2) and progressive aphasia (n = 6). The aphasic presentations include both fluent and non-fluent aphasic syndromes. The neuropsychological profiles and neuroimaging clearly reflect the presenting clinical features, and show a close relationship to the distribution of pathology in these cases. Of note was the sparing of medial temporal structures (hippocampus and/or entorhinal cortex) in several aphasic cases and the severe occipito-parietal involvement in those with prominent visuospatial disorders at presentation. Our data demonstrate the wide spectrum of Alzheimer's disease presentations. The recognition of atypical presentations of Alzheimer's disease is important when attempting to make an early accurate pre-morbid diagnosis of neurodegenerative disease.

Genomic organization of the human metabotropic glutamate receptor subtype 3.

In this study, the genomic organization of the human metabotropic glutamate receptor subtype 3 (mGluR3) gene has been determined. We have identified two transcription initiation sites and the polyadenylation signal by using 5'-rapid amplification of cDNA ends (RACE) and 3'-RACE, respectively. The exon/intron organization of the human mGluR3 gene revealed the presence of 6 exons separated by 5 introns. The size of introns varied from 10.4 to 120 kbp that contained consensus sequences for repetitive elements such as Alu and long interspersed elements. A putative promoter region flanking the 5' sequence of exon 1 was identified by computer-aided analysis. The putative promoter region was characterized by the presence of a CAAT and GC box, and the absence of a TATA box or CpG islands. Several putative binding sites for transcription factors were also identified. In addition, we have isolated, from a mouse genomic library, part of the mouse mGluR3 gene and found it to correspond to exon 2 in the human mGluR3 gene. The mouse mGluR3 gene was then mapped by fluorescent in situ hybridization analysis to chromosome 5qA2.

Membrane instability, plasmalogen content, and Alzheimer's disease.

The normal stability of the cell membrane bilayer depends on its lipid composition being appropriate to the ambient (physiological) temperature, Tp. Membrane lipid composition may be altered by disease such that the bilayer is only stable at a new critical temperature, T*, which may differ from Tp. In Alzheimer's disease (AD) temporal cortex, a defect of lipid composition has previously been identified, namely, a decrease in the ratio of plasmalogen to nonplasmalogen ethanolamine glycerophospholipids. Furthermore, for AD temporal cortex neural membranes, T* << Tp, a finding confirmed in the present study in a larger series than previously, using a new method for obtaining T*. This inequality between T* and Tp has been proposed as a putative contributory pathogenetic mechanism leading to membrane destabilisation in AD brain. The plasmalogen deficiency could account for the change in T* in AD, as shown by experiments where T* was measured for artificial lipid mixtures simulating brain membranes with varying plasmalogen/nonplasmalogen ratios. The critical temperature was found to be very sensitive to small alterations in plasmalogen content.

Somatic neurofibromatosis type 2 gene mutations and growth characteristics in vestibular schwannoma.

BACKGROUND: The growth of hereditary and sporadic vestibular schwannomas shows wide variation, but what determines this is poorly understood. HYPOTHESIS: In neurofibromatosis type 2 (NF2), there is some correlation between the nature of the germline NF2 gene mutation and phenotype. Somatic mutations in the NF2 gene occur in sporadic tumors, but their relation to tumor behavior is unknown. METHODS: This study has investigated the molecular pathogenesis of vestibular schwannoma by looking for NF2 gene mutations. The authors have screened 17 exons of the NF2 gene in 91 sporadic vestibular schwannomas, 2 NF2, and 1 vagal schwannoma. These data have been correlated with a clinical growth index and a tumor cell proliferation index, determined using a monoclonal antibody to the proliferating cell nuclear antigen. RESULTS: Of the 94 tumors studied, 40 somatic gene mutations (38%) have been sequenced in 36 tumors. The mutations included 36 protein truncating mutations, 1 in-frame deletion, 2 splice site mutations, and 1 missense mutation. Regression analysis showed no correlation between the nature of the NF2 gene mutation and either the clinical (R2 = 0.006) or the proliferative index (R2 = 4 x 10(-8). CONCLUSION: The results of this study show no association between the nature of the intragenic NF2 gene mutation and tumor behavior. It is likely therefore that NF2 gene inactivation is not the only determinant of tumor behavior in vestibular schwannoma.

A molecular, clinical, and immunohistochemical study of vestibular schwannoma.

The molecular pathogenesis of vestibular schwannoma has been investigated by determining the extent of chromosome 22 loss of heterozygosity in 77 tumors and relating these findings to clinical and immunohistochemical indexes of tumor behavior. Loss of heterozygosity was looked for at eight chromosome 22q loci. Clinical details were obtained in all 77 cases, and a clinical growth index was calculated for each tumor. The proliferative index was estimated in all tumors by using a monoclonal antibody to the proliferating cell nuclear antigen and by calculating the labeling index. Forty percent (31 of 77) of the tumors showed allele loss, and in each case this loss involved the region of the neurofibromatosis type 2 gene. No evidence was found that the presence of chromosome 22 allele loss was associated with the clinical growth index. On the log scale, however, an association was seen between the clinical growth index and the proliferating cell nuclear antigen labeling index p = 0.001). These results suggest that chromsome 22 allele loss is a frequent event in vestibular schwannoma. Tumor behavior, however, appears to be independent of the chromosome 22 mutation. It is proposed that chromosome 22 allele loss and neurofibromatosis type 2 gene inactivation is an early event, possibly involved in the initiation of tumorigenesis in vestibular schwannoma. Tumor growth appears to be independent of this mutation and is likely to be determined by other as yet undefined factors.