The role of tau in the pathological process and clinical expression of Huntington's disease.

Huntington's disease is a neurodegenerative disorder caused by an abnormal CAG repeat expansion within exon 1 of the huntingtin gene HTT. While several genetic modifiers, distinct from the Huntington's disease locus itself, have been identified as being linked to the clinical expression and progression of Huntington's disease, the exact molecular mechanisms driving its pathogenic cascade and clinical features, especially the dementia, are not fully understood. Recently the microtubule associated protein tau, MAPT, which is associated with several neurodegenerative disorders, has been implicated in Huntington's disease. We explored this association in more detail at the neuropathological, genetic and clinical level. We first investigated tau pathology by looking for the presence of hyperphosphorylated tau aggregates, co-localization of tau with mutant HTT and its oligomeric intermediates in post-mortem brain samples from patients with Huntington's disease (n = 16) compared to cases with a known tauopathy and healthy controls. Next, we undertook a genotype-phenotype analysis of a large cohort of patients with Huntington's disease (n = 960) with a particular focus on cognitive decline. We report not only on the tau pathology in the Huntington's disease brain but also the association between genetic variation in tau gene and the clinical expression and progression of the disease. We found extensive pathological inclusions containing abnormally phosphorylated tau protein that co-localized in some instances with mutant HTT. We confirmed this related to the disease process rather than age, by showing it is also present in two patients with young-onset Huntington's disease (26 and 40 years old at death). In addition we demonstrate that tau oligomers (suggested to be the most likely neurotoxic tau entity) are present in the Huntington's disease brains. Finally we highlight the clinical significance of this pathology by demonstrating that the MAPT haplotypes affect the rate of cognitive decline in a large cohort of patients with Huntington's disease. Our findings therefore highlight a novel important role of tau in the pathogenic process and clinical expression of Huntington's disease, which in turn opens up new therapeutic avenues for this incurable condition.The authors thank the EHDN REGISTRY Study Group investigators (listed in the Supplementary material) for collecting the data and all participating REGISTRY patients for their time and efforts, the Cambridge Brain Bank for the post-mortem tissue which is supported by a grant to the NIHR Cambridge Biomedical Research Centre and in particular to J. Wilson and Dr D. O’ Donovan. We are grateful to S. Sawcer and M. Ban in the Neurology Unit at the University of Cambridge, for their help with the genotyping, C.H. Williams-Gray at the John van Geest Centre for Brain Repair, University of Cambridge, for her help with the statistical analyses, J. Hardy, J.L. Holton, and T. Revesz at the UCL Institute of Neurology for their helpful discussions as well as K. Strand, F. Javad and A. Posada Bórbon, at the UCL Institute of Neurology, for their support with the experimental work, R. Kayed at the University of Texas Medical Branch, Galveston, for providing the TOMA and T22 antibodies. Finally, P. Tyers, R. Raha-Chowdhury, A. Tolkovsky, B. Ossola and J. Simpson for their support and encouragement throughout this work.This is the final version of the article. It was first available from Oxford University Press viahttp://dx.doi.org/10.1093/brain/awv10

Late-onset Parkinsonism in NFκB/c-Rel-deficient mice

Activation of the nuclear factor κB/c-Rel can increase neuronal resilience to pathological noxae by regulating the expression of pro-survival manganese superoxide dismutase (MnSOD, now known as SOD2) and Bcl-xL genes. We show here that c-Rel-deficient (c-rel(-/-)) mice developed a Parkinson's disease-like neuropathology with ageing. At 18 months of age, c-rel(-/-) mice exhibited a significant loss of dopaminergic neurons in the substantia nigra pars compacta, as assessed by tyrosine hydroxylase-immunoreactivity and Nissl staining. Nigral degeneration was accompanied by a significant loss of dopaminergic terminals and a significant reduction of dopamine and homovanillic acid levels in the striatum. Mice deficient of the c-Rel factor exhibited a marked immunoreactivity for fibrillary α-synuclein in the substantia nigra pars compacta as well as increased expression of divalent metal transporter 1 (DMT1) and iron staining in both the substantia nigra pars compacta and striatum. Aged c-rel(-/-) mouse brain were characterized by increased microglial reactivity in the basal ganglia, but no astrocytic reaction. In addition, c-rel(-/-) mice showed age-dependent deficits in locomotor and total activity and various gait-related deficits during a catwalk analysis that were reminiscent of bradykinesia and muscle rigidity. Both locomotor and gait-related deficits recovered in c-rel(-/-) mice treated with l-3,4-dihydroxyphenylalanine. These data suggest that c-Rel may act as a regulator of the substantia nigra pars compacta resilience to ageing and that aged c-rel(-/-) mice may be a suitable model of Parkinson's disease

Locus coeruleus pathology in progressive supranuclear palsy, and its relation to disease severity

Abstract: The locus coeruleus is the major source of noradrenaline to the brain and contributes to a wide range of physiological and cognitive functions including arousal, attention, autonomic control, and adaptive behaviour. Neurodegeneration and pathological aggregation of tau protein in the locus coeruleus are early features of progressive supranuclear palsy (PSP). This pathology is proposed to contribute to the clinical expression of disease, including the PSP Richardson’s syndrome. We test the hypothesis that tau pathology and neuronal loss are associated with clinical heterogeneity and severity in PSP. We used immunohistochemistry in post mortem tissues from 31 patients with a clinical diagnosis of PSP (22 with Richardson’s syndrome) and 6 control cases. We quantified the presence of hyperphosphorylated tau, the number of pigmented cells indicative of noradrenergic neurons, and the percentage of pigmented neurons with tau-positive inclusions. Ante mortem assessment of clinical severity using the PSP rating scale was available within 1.8 (±0.9) years for 23 patients. We found an average 49% reduction of pigmented neurons in PSP patients relative to controls. The loss of pigmented neurons correlated with disease severity, even after adjusting for disease duration and the interval between clinical assessment and death. The degree of neuronal loss was negatively associated with tau-positive inclusions, with an average of 44% of pigmented neurons displaying tau-inclusions. Degeneration and tau pathology in the locus coeruleus are related to clinical heterogeneity of PSP. The noradrenergic deficit in the locus coeruleus is a candidate target for pharmacological treatment. Recent developments in ultra-high field magnetic resonance imaging to quantify in vivo structural integrity of the locus coeruleus may provide biomarkers for noradrenergic experimental medicines studies in PSP

The tauopathy associated with mutation +3 in intron 10 of Tau: characterization of the MSTD family

Multiple system tauopathy with presenile dementia (MSTD) is an inherited disease caused by a (g) to (a) transition at position +3 in intron 10 of Tau. It belongs to the spectrum of frontotemporal dementia and parkinsonism linked to chromosome 17 with mutations in Tau (FTDP-17T). Here we present the longitudinal clinical, neuropsychological, neuroimaging, neuropathological, biochemical and genetic characterization of the MSTD family. Presenting signs were consistent with the behavioural variant of frontotemporal dementia in 17 of 21 patients. Two individuals presented with an atypical form of progressive supranuclear palsy and two others with either severe postural imbalance or an isolated short-term memory deficit. Memory impairment was present at the onset in 15 patients, with word finding difficulties and stereotyped speech also being common. Parkinsonism was first noted 3 years after the onset of symptoms. Neuroimaging showed the most extensive grey matter loss in the hippocampus, parahippocampal gyrus and frontal operculum/insular cortex of the right hemisphere and, to a lesser extent, in the anterior cingulate gyrus, head of the caudate nucleus and the posterolateral orbitofrontal cortex and insular cortex bilaterally. Neuropathologically, progressive nerve cell loss, gliosis and coexistent neuronal and/or glial deposits consisting mostly of 4-repeat tau were present in frontal, cingulate, temporal and insular cortices, white matter, hippocampus, parahippocampus, basal ganglia, selected brainstem nuclei and spinal cord. Tau haplotyping indicated that specific haplotypes of the wild-type allele may act as modifiers of disease presentation. Quantitative neuroimaging has been used to analyse the progression of atrophy in affected individuals and for predicting disease onset in an asymptomatic mutation carrier. This multidisciplinary study provides a comprehensive description of the natural history of disease in one of the largest known families with FTDP-17T

Silicon calorimeter for cosmic antimatter search

Abstract The silicon sampling calorimeter presented is conceived as a fine grained imaging device to carry out studies of the anti-matter component in the primary cosmic radiation; it will be used in balloon payload program starting in 1993. The first sampling layer (48×48 cm2) of this silicon calorimeter has been completed and successfully tested. We report the first results form studies performed at the CERN PS t7 beam. The complete calorimeter contains 20 xy sampling layers (strip pitch 3.6 mm) interleaved with 19 showering material planes (tungsten 0.5 X0). This allows to picture the transverse distributions of the shower in both coordinates at each sampling. The outstanding imaging capabilities reflects in high particle identification power. Preliminary results from beam tests performed with antiprotons at 3.5 GeV on a tower prototype of the calorimeter are reported

A silicon imaging calorimeter prototype for antimatter search in space: experimental results

Abstract This report presents the results obtained with a prototype silicon-tungsten (Si-W) electromagnetic calorimeter, conceived as a fine-grained imaging device to carry out studies of the antimatter component in primary cosmic radiation. The calorimeter prototype contains 20 x , y sampling layers interleaved with 19 showering material planes. One sensitive layer is obtained with two silicon strip detectors (Si-D) (60 × 60) mm 2 , each divided into 16 strips, 3.6 mm wide; the two detectors are assembled back to back with perpendicular strips. This allows the transverse distributions of the shower in both coordinates at each sampling (0.5 X 0 ) to be pictured. The basic characteristics of the design and the experimental results obtained on a test beam at the CERN proton synchrotron (PS) for electrons and pions are reported. The main results presented are the response of the calorimeter to the electron at various energies (1–7 GeV), and the transverse shower profiles at different calorimeter depths as well as the patterns of the electromagnetic shower and those of the interacting and non-interacting pions. The capability of the calorimeter in measuring the direction of the incoming electromagnetic particle from the pattern of the shower has been evaluated at different energies. These results are encouraging in view of the possible use of this detector to search for high-energy γ sources in space

CALOCUBE: An approach to high-granularity and homogenous calorimetry for space based detectors

Future space experiments dedicated to the observation of high-energy gamma and cosmic rays will increasingly rely on a highly performing calorimetry apparatus, and their physics performance will be primarily determined by the geometrical dimensions and the energy resolution of the calorimeter deployed. Thus it is extremely important to optimize its geometrical acceptance, the granularity, and its absorption depth for the measurement of the particle energy with respect to the total mass of the apparatus which is the most important constraint for a space launch. The proposed design tries to satisfy these criteria while staying within a total mass budget of about 1.6 tons. Calocube is a homogeneous calorimeter instrumented with Cesium iodide (CsI) crystals, whose geometry is cubic and isotropic, so as to detect particles arriving from every direction in space, thus maximizing the acceptance; granularity is obtained by filling the cubic volume with small cubic CsI crystals. The total radiation length in any direction is more than adequate for optimal electromagnetic particle identification and energy measurement, whilst the interaction length is at least sufficient to allow a precise reconstruction of hadronic showers. Optimal values for the size of the crystals and spacing among them have been studied. The design forms the basis of a three-year R&D activity which has been approved and financed by INFN. An overall description of the system, as well as results from preliminary tests on particle beams will be described