Peripheral inflammation in behavioural variant frontotemporal dementia: associations with central degeneration and clinical measures.

BACKGROUND: Neuroinflammation plays a significant role in the progression of frontotemporal dementia (FTD). However, the association between peripheral inflammatory factors and brain neurodegeneration is poorly understood. We aimed to examine changes in peripheral inflammatory markers in patients with behavioural variant FTD (bvFTD) and explore the potential association between peripheral inflammation and brain structure, metabolism, and clinical parameters. METHODS: Thirty-nine bvFTD patients and 40 healthy controls were enrolled and underwent assessment of plasma inflammatory factors, positron emission tomography/magnetic resonance imaging, and neuropsychological assessments. Group differences were tested using Student's t test, Mann‒Whitney U test, or ANOVA. Partial correlation analysis and multivariable regression analysis were implemented using age and sex as covariates to explore the association between peripheral inflammatory markers, neuroimaging, and clinical measures. The false discovery rate was used to correct for the multiple correlation test. RESULTS: Plasma levels of six factors, including interleukin (IL)-2, IL-12p70, IL-17A, tumour necrosis superfamily member 13B (TNFSF/BAFF), TNFSF12 (TWEAK), and TNFRSF8 (sCD30), were increased in the bvFTD group. Five factors were significantly associated with central degeneration, including IL-2, IL-12p70, IL-17A, sCD30/TNFRSF8, and tumour necrosis factor (TNF)-α; the association between inflammation and brain atrophy was mainly distributed in frontal-limbic-striatal brain regions, whereas the association with brain metabolism was mainly in the frontal-temporal-limbic-striatal regions. BAFF/TNFSF13B, IL-4, IL-6, IL-17A and TNF-α were found to correlate with clinical measures. CONCLUSION: Peripheral inflammation disturbance in patients with bvFTD participates in disease-specific pathophysiological mechanisms, which could be a promising target for diagnosis, treatment, and monitoring therapeutic efficacy.

Psychiatric symptoms of frontotemporal dementia and subcortical (co-)pathology burden: new insights.

Three subtypes of distinct pathological proteins accumulate throughout multiple brain regions and shape the heterogeneous clinical presentation of frontotemporal lobar degeneration (FTLD). Besides the main pathological subtypes, co-occurring pathologies are common in FTLD brain donors. The objective of this study was to investigate how the location and burden of (co-)pathology correlate to early psychiatric and behavioural symptoms of FTLD. Eighty-seven brain donors from The Netherlands Brain Bank cohort (2008-2017) diagnosed with FTLD were included: 46 FTLD-TAR DNA-binding protein 43 (FTLD-TDP), 34 FTLD-tau, and seven FTLD-fused-in-sarcoma (FTLD-FUS). Post-mortem brain tissue was dissected into 20 standard regions and stained for phosphorylated TDP-43, phosphorylated tau, FUS, amyloid-ß, and α-synuclein. The burden of each pathological protein in each brain region was assessed with a semi-quantitative score. Clinical records were reviewed for early psychiatric and behavioural symptoms. Whole-brain clinico-pathological partial correlations were calculated (local false discovery rate threshold = 0.01). Elaborating on the results, we validated one finding using a quantitative assessment of TDP-43 pathology in the granular layer of the hippocampus in FTLD-TDP brain donors with (n = 15) and without (n = 15) hallucinations. In subcortical regions, the presence of psychiatric symptoms showed positive correlations with increased hippocampal pathology burden: hallucinations with TDP-43 in the granular layer (R = 0.33), mania with TDP-43 in CA1 (R = 0.35), depression with TDP-43 in CA3 and with parahippocampal tau (R = 0.30 and R = 0.23), and delusions with CA3 tau (R = 0.26) and subicular amyloid-ß (R = 0.25). Behavioural disinhibition showed positive correlations with tau burden in the thalamus (R = 0.29) and with both TDP-43 and amyloid-ß burden in the subthalamus (R = 0.23 and R = 0.24). In the brainstem, the presence of α-synuclein co-pathology in the substantia nigra correlated with disinhibition (R = 0.24), tau pathology in the substantia nigra correlated with depression (R = 0.25) and in the locus coeruleus with both depression and perseverative/compulsive behaviour (R = 0.26 and R = 0.32). The quantitative assessment of TDP-43 in the granular layer validated the higher burden of TDP-43 pathology in brain donors with hallucinations compared to those without hallucinations (P = 0.007). Our results show that psychiatric symptoms of FTLD are linked to subcortical pathology burden in the hippocampus, and hallucinations are linked to a higher burden of TDP-43 in the granular layer. Co-occurring non-FTLD pathologies in subcortical regions could contribute to configuring the clinical phenotype of FTLD.

Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions.

The medial temporal lobe (MTL) is a nidus for neurodegenerative pathologies and therefore an important region in which to study polypathology. We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyloid-ß and α-synuclein pathology were rated on a scale of 0 (absent)-3 (severe) in the hippocampus and entorhinal cortex (ERC) of 58 individuals with and without neurodegenerative diseases (median age 75.0 years, 60.3% male). Thickness measurements in ERC, Brodmann Area (BA) 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare (SRLM) were derived from 0.2 × 0.2 × 0.2 mm3 post-mortem MRI scans of excised MTL specimens from the contralateral hemisphere using a semi-automated approach. Spearman's rank correlations were performed between neurodegenerative pathologies and thickness, correcting for age, sex and hemisphere, including all four proteinopathies in the model. We found significant associations of (1) TDP-43 with thickness in all subregions (r = - 0.27 to r = - 0.46), and (2) tau with BA35 (r = - 0.31) and SRLM thickness (r = - 0.33). In amyloid-ß and TDP-43 negative cases, we found strong significant associations of tau with ERC (r = - 0.40), BA35 (r = - 0.55), subiculum (r = - 0.42) and CA1 thickness (r = - 0.47). This unique dataset shows widespread MTL atrophy in relation to TDP-43 pathology and atrophy in regions affected early in Braak stageing and tau pathology. Moreover, the strong association of tau with thickness in early Braak regions in the absence of amyloid-ß suggests a role of Primary Age-Related Tauopathy in neurodegeneration.

Clinical features of the behavioural variant of frontotemporal dementia that are useful for predicting underlying pathological subtypes of frontotemporal lobar degeneration.

BACKGROUND: The behavioural variant of frontotemporal dementia (bvFTD) is the most common phenotype of frontotemporal lobar degeneration (FTLD). FTLD is divided into three main pathological subtypes: tau-positive FTLD (FTLD-tau), FTLD-TAR DNA-binding protein (TDP), and FTLD-Fused in sarcoma (FUS). At present, it is difficult to predict the underlying pathological subtypes of sporadic bvFTD before a patient's death. METHODS: We retrospectively investigated the clinical features of 34 Japanese patients with sporadic bvFTD, with or without motor neuron disease (MND), who had been pathologically diagnosed with FTLD. We examined whether, and how, the clinical features differed among Pick's disease, FTLD-TDP, and FTLD-FUS patients. RESULTS: Six of the 34 patients developed MND during the course of bvFTD. These six bvFTD-MND patients were all pathologically diagnosed with FTLD-TDP. The other 28 patients were composed of 12 FTLD-tau patients including 11 Pick's disease patients, 8 FTLD-TDP patients, and 8 FTLD-FUS patients. A comparison of the clinical features of the three pathological subtypes of the 33 patients demonstrated that the age at onset was significantly younger in FTLD-FUS patients than in Pick's disease or FTLD-TDP patients. Furthermore, while hyperorality and dietary changes in the early stage of the disease were present in approximately 40% of Pick's disease and FTLD-FUS patients, they were absent in FTLD-TDP patients. CONCLUSION: The comorbidity of MND, a younger age at onset, and hyperorality and dietary changes in the early stage may be useful clinical features for predicting underlying pathological subtypes of sporadic bvFTD. The results of our study should be confirmed by prospective studies employing a larger number of cases.

Selective targeting of 3 repeat Tau with brain penetrating single chain antibodies for the treatment of neurodegenerative disorders.

Alzheimer's disease (AD) is the most common form of dementia in the elderly affecting more than 5 million people in the U.S. AD is characterized by the accumulation of ß-amyloid (Aß) and Tau in the brain, and is manifested by severe impairments in memory and cognition. Therefore, removing tau pathology has become one of the main therapeutic goals for the treatment of AD. Tau (tubulin-associated unit) is a major neuronal cytoskeletal protein found in the CNS encoded by the gene MAPT. Alternative splicing generates two major isoforms of tau containing either 3 or 4 repeat (R) segments. These 3R or 4RTau species are differentially expressed in neurodegenerative diseases. Previous studies have been focused on reducing Tau accumulation with antibodies against total Tau, 4RTau or phosphorylated isoforms. Here, we developed a brain penetrating, single chain antibody that specifically recognizes a pathogenic 3RTau. This single chain antibody was modified by the addition of a fragment of the apoB protein to facilitate trafficking into the brain, once in the CNS these antibody fragments reduced the accumulation of 3RTau and related deficits in a transgenic mouse model of tauopathy. NMR studies showed that the single chain antibody recognized an epitope at aa 40-62 of 3RTau. This single chain antibody reduced 3RTau transmission and facilitated the clearance of Tau via the endosomal-lysosomal pathway. Together, these results suggest that targeting 3RTau with highly specific, brain penetrating, single chain antibodies might be of potential value for the treatment of tauopathies such as Pick's Disease.

Neuroprotective effects of Cerebrolysin in triple repeat Tau transgenic model of Pick's disease and fronto-temporal tauopathies.

BACKGROUND: Tauopathies are a group of neurodegenerative disorders with accumulation of three-repeat (3R) or four-repeat (4R) Tau. While 3R tau is found in Pick's disease and Alzheimer's disease (AD), 4R tau is more abundant in corticobasal degeneration, progressive supranuclear palsy, and AD. We have previously shown that Cerebrolysin™ (CBL), a neuropeptide mixture with neurotrophic effects, ameliorates the pathology in amyloid precursor protein transgenic (tg) mouse model of AD and 4R tau, however it is unclear if CBL ameliorates the deficits and neuropathology in the mouse model of Pick's disease over expressing 3R tau. RESULTS: Mice expressing 3R tau (L266V and G272V mutations) under the mThy-1 promoter were treated with CBL in two separate groups, the first was 3 months old (treated for 3 months, IP) and the second was 6 months old (treated for 3 months, IP) at the start of the treatment. We found that although the levels of total 3R tau were unchanged, CBL reduced the levels of hyper-phosphorylated tau in both groups of mice. This was accompanied by reduced neurodegenerative pathology in the neocortex and hippocampus in both groups and by improvements in the behavioral deficits in the nest-building test and water maze in the 3-6 month group. CONCLUSION: Taken together these results support the notion that CBL may be beneficial in other taupathy models by reducing the levels of aberrantly phosphorylated tau.

An autopsy case of incipient Pick's disease: immunohistochemical profile of early-stage Pick body formation.

There is little immunohistochemical information about the early stage of Pick body formation, due to the extremely limited opportunities of studying Pick's disease at the incipient or subclinical stage. We report a 62-year-old man without any clinical manifestations of Pick's disease, who died of B-cell lymphoma of the brainstem. Post mortem examination revealed many Pick bodies without obvious neuronal loss mainly in the left frontal and temporal lobes. Three brains of patients with typical Pick's disease (disease duration: 7, 11 and 16 years) were also examined. Pick bodies were immunopositive for phosphorylated tau and 3-repeat tau, and less consistently for p62 in both incipient and typical cases. In the incipient case, borderline positivity for ubiquitin was evident in only a few Pick bodies, whereas in the typical cases many Pick bodies showed obvious positivity for ubiquitin. These findings suggest that Pick bodies are rarely ubiquitinated in the early stage of Pick body formation.

ALS-associated protein FIG4 is localized in Pick and Lewy bodies, and also neuronal nuclear inclusions, in polyglutamine and intranuclear inclusion body diseases.

FIG4 is a phosphatase that regulates intracellular vesicle trafficking along the endosomal-lysosomal pathway. Mutations of FIG4 lead to the development of Charcot-Marie-Tooth disease type 4J and amyotrophic lateral sclerosis (ALS). Moreover, ALS-associated proteins (transactivation response DNA protein 43 (TDP-43), fused in sarcoma (FUS), optineurin, ubiquilin-2, charged mutivesicular body protein 2b (CHMP2B) and valosin-containing protein) are involved in inclusion body formation in several neurodegenerative diseases. Using immunohistochemistry, we examined the brains and spinal cords of patients with various neurodegenerative diseases, including sporadic TDP-43 proteinopathy (ALS and frontotemporal lobar degeneration). TDP-43 proteinopathy demonstrated no FIG4 immunoreactivity in neuronal inclusions. However, FIG4 immunoreactivity was present in Pick bodies in Pick's disease, Lewy bodies in Parkinson's disease and dementia with Lewy bodies, neuronal nuclear inclusions in polyglutamine and intranuclear inclusion body diseases, and Marinesco and Hirano bodies in aged control subjects. These findings suggest that FIG4 is not incorporated in TDP-43 inclusions and that it may have a common role in the formation or degradation of neuronal cytoplasmic and nuclear inclusions in several neurodegenerative diseases.

Nonfluent/agrammatic PPA with in-vivo cortical amyloidosis and Pick's disease pathology.

The role of biomarkers in predicting pathological findings in the frontotemporal dementia (FTD) clinical spectrum disorders is still being explored. We present comprehensive, prospective longitudinal data for a 66 year old, right-handed female who met current criteria for the nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA). She first presented with a 3-year history of progressive speech and language impairment mainly characterized by severe apraxia of speech. Neuropsychological and general motor functions remained relatively spared throughout the clinical course. Voxel-based morphometry (VBM) showed selective cortical atrophy of the left posterior inferior frontal gyrus (IFG) and underlying insula that worsened over time, extending along the left premotor strip. Five years after her first evaluation, she developed mild memory impairment and underwent PET-FDG and PiB scans that showed left frontal hypometabolism and cortical amyloidosis. Three years later (11 years from first symptom), post-mortem histopathological evaluation revealed Pick's disease, with severe degeneration of left IFG, mid-insula, and precentral gyrus. Alzheimer's disease (AD) (CERAD frequent/Braak Stage V) was also detected. This patient demonstrates that biomarkers indicating brain amyloidosis should not be considered conclusive evidence that AD pathology accounts for a typical FTD clinical/anatomical syndrome.

Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration.

Relating clinical symptoms to neuroanatomical profiles of brain damage and ultimately to tissue pathology is a key challenge in the field of neurodegenerative disease and particularly relevant to the heterogeneous disorders that comprise the frontotemporal lobar degeneration spectrum. Here we present a retrospective analysis of clinical, neuropsychological and neuroimaging (volumetric and voxel-based morphometric) features in a pathologically ascertained cohort of 95 cases of frontotemporal lobar degeneration classified according to contemporary neuropathological criteria. Forty-eight cases (51%) had TDP-43 pathology, 42 (44%) had tau pathology and five (5%) had fused-in-sarcoma pathology. Certain relatively specific clinicopathological associations were identified. Semantic dementia was predominantly associated with TDP-43 type C pathology; frontotemporal dementia and motoneuron disease with TDP-43 type B pathology; young-onset behavioural variant frontotemporal dementia with FUS pathology; and the progressive supranuclear palsy syndrome with progressive supranuclear palsy pathology. Progressive non-fluent aphasia was most commonly associated with tau pathology. However, the most common clinical syndrome (behavioural variant frontotemporal dementia) was pathologically heterogeneous; while pathologically proven Pick's disease and corticobasal degeneration were clinically heterogeneous, and TDP-43 type A pathology was associated with similar clinical features in cases with and without progranulin mutations. Volumetric magnetic resonance imaging, voxel-based morphometry and cluster analyses of the pathological groups here suggested a neuroanatomical framework underpinning this clinical and pathological diversity. Frontotemporal lobar degeneration-associated pathologies segregated based on their cerebral atrophy profiles, according to the following scheme: asymmetric, relatively localized (predominantly temporal lobe) atrophy (TDP-43 type C); relatively symmetric, relatively localized (predominantly temporal lobe) atrophy (microtubule-associated protein tau mutations); strongly asymmetric, distributed atrophy (Pick's disease); relatively symmetric, predominantly extratemporal atrophy (corticobasal degeneration, fused-in-sarcoma pathology). TDP-43 type A pathology was associated with substantial individual variation; however, within this group progranulin mutations were associated with strongly asymmetric, distributed hemispheric atrophy. We interpret the findings in terms of emerging network models of neurodegenerative disease: the neuroanatomical specificity of particular frontotemporal lobar degeneration pathologies may depend on an interaction of disease-specific and network-specific factors.

In vivo positron emission tomographic imaging of glial responses to amyloid-beta and tau pathologies in mouse models of Alzheimer's disease and related disorders.

Core pathologies of Alzheimer's disease (AD) are aggregated amyloid-ß peptides (Aß) and tau, and the latter is also characteristic of diverse neurodegenerative tauopathies. These amyloid lesions provoke microglial activation, and recent neuroimaging technologies have enabled visualization of this response in living brains using radioligands for the peripheral benzodiazepine receptor also known as the 18 kDa translocator protein (TSPO). Here, we elucidated contributions of Aß and tau deposits to in vivo TSPO signals in pursuit of mechanistic and diagnostic significance of TSPO imaging in AD and other tauopathies. A new antibody to human TSPO revealed induction of TSPO-positive microgliosis by tau fibrils in tauopathy brains. Emergence of TSPO signals before occurrence of brain atrophy and thioflavin-S-positive tau amyloidosis was also demonstrated in living mice transgenic for mutant tau by positron emission tomography (PET) with two classes of TSPO radioligands, [(11)C]AC-5216 and [(18)F]fluoroethoxy-DAA1106. Meanwhile, only modest TSPO elevation was observed in aged mice modeling Aß plaque deposition, despite the notably enhanced in vivo binding of amyloid radiotracer, [(11)C]Pittsburgh Compound-B, to plaques. In these animals, [(11)C]AC-5216 yielded better TSPO contrasts than [(18)F]fluoroethoxy-DAA1106, supporting the possibility of capturing early neurotoxicity with high-performance TSPO probes. Furthermore, an additional line of mice modeling intraneuronal Aß accumulation displayed elevated TSPO signals following noticeable neuronal loss, unlike TSPO upregulation heralding massive neuronal death in tauopathy model mice. Our data corroborate the utility of TSPO-PET imaging as a biomarker for tau-triggered toxicity, and as a complement to amyloid scans for diagnostic assessment of tauopathies with and without Aß pathologies.

[The complexes of degenerative dementias: an evolution from disease to spectrum]. / Los complejos de las demencias degenerativas: una evolución de la enfermedad al espectro.

INTRODUCTION: Everyone has a particular combination of risk polymorphisms and occasionally determinant mutations, related to molecular items which are pathogenetic in degenerative dementias. If we add other epigenetic factors to this, we can generate a very heterogeneous base, which explains why these diseases manifest through varied clinical and neuropathological phenotypes, distributed in <> (groups of entities with symptomatic, neurochemical, histopathologic and proteinopathic affinities). METHOD: A review of the current knowledge about phenotype variants of degenerative dementias has been carried out, detecting overlapping and divergent aspects between them and generating groups (complexes) which are more operative to work with, instead of using the current independent entities (diseases). RESULTS: Besides the known Pick complex, there are sufficient data to propose the recognition of the Lewy complex, Alzheimer complex, multisystemic atrophy complex, and polyglutamine complex. Each one of them contains phenotypic variants that overlap with other complex variants, creating links between all the complexes and forming a spectrum in which almost all degenerative dementias can be included. CONCLUSIONS: The progression of medical knowledge has made it more appropriate to locate each patient at a specific point in a complex, in the degenerative dementia spectrum, instead of diagnosing a generic disease. This change makes it recommendable to adjust the diagnostic criteria, and the therapeutic decisions should be designed individually according to their specific location in a complex. Researchers should also take into account this diversity when establishing both the criteria for selecting participants and the objectives of their therapeutic trials.

[Rivastigmine in a case of autopsy proved frontotemporal dementia (Pick's disease)]. / Rivastigmina en un caso de demencia frontotemporal, enfermedad de Pick verificada por autopsia.

INTRODUCTION: Cholinesterase inhibitors are useful in the treatment of behavioural and psychological symptoms in Alzheimer's disease. Their effectiveness in frontotemporal dementia has not been proved, since such a claim has only been backed by the publication of one open-label trial in which the behavioural and psychological symptoms of the patients treated with rivastigmine over a 12-month period improved significantly with respect to those belonging to a group that were given a placebo. We report a case of frontotemporal dementia, Pick's disease, which improved with rivastigmine treatment. CASE REPORT: A 61-year-old male who presented a progressive clinical picture of behavioural disorders and executive-cognitive impairment that had begun two years earlier. Magnetic resonance imaging of the head revealed severe frontotemporal atrophy. Neuropsychological Inventory (NPI). Overall score 36/144 (6/12: anxiety, disinhibition and aberrant motor behaviour, 4/12: agitation, irritability and apathy; 3/12: sleep and eating disorders. After three months' treatment with rivastigmine, the overall score on the NPI was 10/144. This improvement remained stable over the months that followed. The patient died eight months later after developing liver cancer with metastasis. The microscopic study of the brain showed tau-positive neuronal inclusions, gliosis and neuronal loss. The inclusions were well-circumscribed Pick bodies, which were present in the frontal and temporal cortices and in the dentate gyrus of the hippocampus. CONCLUSIONS: This case confirms the idea that treatment with cholinesterase inhibitors can be effective in the behavioural and psychological symptoms of frontotemporal dementia.

Three-repeat Tau 69 is a major tau isoform in laser-microdissected Pick bodies.

By utilizing a novel combinatorial method of a Laser Microdissection System and Western blot analysis, we demonstrate that a distinct isoform of abnormally phosphorylated tau (69 kDa, Tau 69) predominantly aggregated in laser-microdissected Pick bodies (PBs) in sporadic Pick's disease. By contrast, tau migrated as two major bands of 60 and 64 kDa (Tau 60 and 64) in total brain homogenates as previously reported. Comparative immunohistochemical analysis with anti-4-repeat antibody revealed that a major component of the abnormally phosphorylated tau in these PBs was 3-repeat tau (3R-tau). Whether 29 amino acid repeat encoded by exons 2 and 3 in the Tau 69 might accelerate the formation of PBs remains to be further investigated. Such a combination of morphological and biochemical techniques significantly complements the existing histopathological methods.

Expression of transcription factors c-Fos, c-Jun, CREB-1 and ATF-2, and caspase-3 in relation with abnormal tau deposits in Pick's disease.

Hyper-phosphorylated tau deposition in Pick bodies and neuron loss are major hallmarks of Pick's disease (PiD). However, there is no regional correlation between neuron loss and Pick bodies, as illustrated in dentate gyrus, where Pick bodies are present in almost every neuron, whereas cell death, if present, is not a major event. In order to better understand the possible role of selected transcription factors and members of the caspase family in cell death and cell survival, immunohistochemistry to c-Fos, c-Jun, CREB-1, ATF-2; c-Fos(P), c-Jun(P) and CREB-1(P); and procaspase-8, procaspase-3 and active (cleaved) caspase-3 immunohistochemistry was carried out in the frontal cortex and hippocampus. Increased expression of c-Fos, c-Jun, CREB-1 and ATF-2 was observed in PiD cases. Increased c-Fos(P), c-Jun(P) and CREB-1(P) was also found in the nuclei of neurons in diseased brains. Interestingly, c-Fos but not c-Fos(P) co-localized in many Pick bodies, as observed by double labelling-immunofluorescence and confocal microscopy. Pro-caspase-8 and pro-caspase-3 were increased in PiD. Moreover, granular active caspase-3 was observed in the nuclei as was aggregated active caspase-3 in the cytoplasm of neurons in PiD. Finally, double-labelling immunofluorescence and confocal microscopy disclosed co-localization of cytoplasmic active caspase-3 only in neurons with Pick bodies. Together, these findings show an increased expression of selected transcription factors and active (phosphorylated) forms in PiD, c-Fos sequestration in Pick bodies, and increased active caspase-3 expression in relation with Pick bodies. Since all these findings were observed equally in neurons of both vulnerable regions (frontal cortex) and resistant regions (dentate gyrus), it may be suggested that transcription factors are only barely related with cell death. Active caspase-3 is associated with tau deposition in Pick bodies, but it is not a marker of cell death in the dentate gyrus in PiD. The present findings are in line with the previous studies showing tau products cleaved by caspase-3, as recognized by specific tau-cleaved antibodies, in Alzheimer's disease and other tauopathies.

Autosomal dominant inclusion body myopathy, Paget disease of bone, and frontotemporal dementia.

Autosomal dominant proximal limb girdle or inclusion body myopathy, associated with Paget disease of bone and frontotemporal dementia (IBMPFD) is a recently described disorder that maps to chromosome 9p21.1-p12. We refined the critical locus and identified the gene as the Valosin Containing Protein (VCP) gene, a member of the AAA-ATPase superfamily using a candidate gene approach. Six missense mutations were found to co-segregate with affected individuals only, two of these representing mutation hot spots. We report the clinical and molecular findings in 99 individuals in 13 families. VCP is associated with a variety of cellular activities, including the control of cell cycle, membrane fusion, and the ubiquitin-proteasome degradation pathway. Previous studies have associated VCP mutants in cell lines with vacuole formation and aggregate formation. Identification of VCP as the gene causing IBMPFD has important implications for understanding the pathogenesis of neurodegenerative disorders.

Brain biopsy in dementia.

Brain biopsy has an uncertain role in the diagnosis of dementia. Here we report a retrospective analysis of 90 consecutive cerebral biopsies undertaken for the investigation of dementia in adults at a tertiary referral centre between 1989 and 2003. In most cases (90%), biopsy consisted of a right frontal full thickness resection of cortex, white matter and overlying leptomeninges. Fifty-seven per cent of biopsies were diagnostic: the most frequent diagnoses were Alzheimer's disease (18%), Creutzfeldt-Jakob disease (12%) and inflammatory disorders (9%). Other diagnoses in individual patients included Pick's disease, corticobasal degeneration and other tauopathies, Lewy body dementia, multiple sclerosis, Whipple's disease, progressive multifocal leucoencephalopathy, cerebral autosomal dominant arteriopathy with subcortical ischaemic leucoencephalopathy, vasculopathies and paraneoplastic encephalopathy. The most frequent biopsy finding in the non-diagnostic group and for the series as a whole (37%) was non-specific gliosis variably affecting both cortex and white matter. Complications (11%) included seizures, intracranial and wound infections, and intracranial haemorrhage; there were no deaths or lasting neurological sequelae attributable to the procedure. No trends in diagnostic yield or complication rate over the course of the series were identified. Information obtained at biopsy determined treatment in 11%. A raised cerebrospinal fluid cell count was the only robust predictor of a potentially treatable (inflammatory) process at biopsy. The constellation of behavioural change, raised CSF protein and matched oligoclonal bands in CSF and serum was associated with non-specific gliosis at biopsy. This series underlines the value of cerebral biopsy in the diagnosis of dementia, and suggests that certain clinical and laboratory features may be useful in guiding the decision to proceed to brain biopsy where a treatable disease cannot be excluded by other means.

Pathological properties of the Parkinson's disease-associated protein DJ-1 in alpha-synucleinopathies and tauopathies: relevance for multiple system atrophy and Pick's disease.

Mutations in the PARK7 gene DJ-1 are associated with recessive hereditary Parkinson's disease (PD). Fibrillar inclusions of alpha-synuclein comprise the neuropathological hallmarks of PD and related Lewy body diseases as well as multiple system atrophy (MSA). Moreover, neuronal and glial inclusions containing tau have been observed in alpha-synucleinopathy patients. Using a collection of antibodies against DJ-1, we have performed a comprehensive investigation of DJ-1 in alpha-synucleinopathies and tauopathies. DJ-1 was abundantly expressed in reactive astrocytes of patients with neurodegenerative diseases. Likewise, DJ-1 antiserum immunostained reactive astrocytes that became abundant with disease progression in the brain stem of transgenic mice expressing mutant [A30P]alpha-synuclein. Human Lewy bodies as well as Lewy body-like inclusions in the alpha-synuclein transgenic mice were DJ-1 negative. Neuronal tau inclusions were DJ-1 immunopositive in Pick's disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimer's disease. In addition, we found DJ-1-immunopositive glial inclusions in CBD, PSP and MSA. Biochemical extraction experiments revealed the specific presence of insoluble, modified DJ-1 in PiD and MSA. Our results suggest that DJ-1 is up-regulated in reactive astrocytes as well as in neuronal and glial cells with specific alpha-synucleinopathy and tauopathy.