Motor neurone disease/amyotrophic lateral sclerosis associated with intermediate-length CAG repeat expansions in Ataxin-2 does not have 1C2-positive polyglutamine inclusions.

BACKGROUND: Intermediate-length cytosine-adenine-guanine repeat expansions in the ATXN2 gene (which encodes for Ataxin-2 protein) have been linked to increased risk for motor neurone disease/amyotrophic lateral sclerosis (ALS). We screened DNA from cases for which we had post-mortem brain tissue to enable characterization of the neuropathology associated with this mutation. METHODS: Polymerase chain reaction and sequencing of DNA from frozen brain tissue on a cohort of 178 amyotrophic lateral sclerosis (ALS) autopsy cases from the north of England and 159 controls was performed. This was followed by tinctorial staining and immunohistochemistry (including for Ataxin-2) on selected blocks from ALS cases with intermediate-length expansions (ATXN2-ALS), sporadic ALS cases and neurologically healthy controls. RESULTS: Four ALS cases with intermediate-length CAG repeat expansions within ATXN2 were identified. One such case also had a mutation of the C9ORF72 gene. All had lower motor neurone depletion, and three out of four cases had transactive response DNA binding protein 43 (TDP-43)-positive neuronal cytoplasmic inclusions (predominantly skein-like). No inclusions of aggregated polyglutamine proteins were identified. Ataxin-2 protein expression was largely granular and cytoplasmic with the most prominent staining observed in larger neurones. Ataxin-2 staining was variable both within and between cases, but no staining pattern that was specific for cases with ATXN2 mutations was seen. CONCLUSIONS: Intermediate expansions of the CAG repeat in ATXN2 are associated with ALS. They are mostly associated with TDP-43 proteinopathy, but not with 1C2-positive polyglutamine inclusions. In the nervous system, Ataxin-2 protein expression is predominantly seen in large neurones. There is no consistent histopathological hallmark that is unique to ATXN2-ALS.

Gamma-synuclein pathology in amyotrophic lateral sclerosis.

OBJECTIVE: The prominent histopathological feature of the amyotrophic lateral sclerosis (ALS) is the presence of intracellular inclusions in degenerating neurons and their axons. The appearance and localization of these pathological structures depend on an aggregated protein that forms their scaffold. We investigated if γ-synuclein, an aggregation-prone protein highly expressed in healthy motor neurons, and predominantly localized in their axons and synaptic terminals is involved in ALS pathology. METHODS: Immunostaining of histological sections and sequential protein extraction from postmortem neural samples followed by immunoblotting. RESULTS: Immunohistochemical screening revealed a subset of sporadic (9 of 31) and familial (8 of 23) ALS cases with a novel type of pathology characterized by the accumulation of γ-synuclein in distinct profiles within the dorsolateral column. Sequential fractionation of proteins from the spinal cord tissues revealed detergent-insoluble γ-synuclein species specifically in the dorsolateral corticospinal tracts of a ALS patient with γ-synuclein-positive profiles in this region. These profiles are negative for protein markers commonly found in pathological inclusions in the spinal cord of ALS patients and most probably represent degenerated axons of upper motor neurons that have lost their neurofilaments. A subset of these profiles was found in association with phagocytic cells positive for Mac-2/Galectin-3. A smaller subset of studied ALS cases (4 of 54) contained large cytoplasmic inclusions in the cell body of remaining spinal motor neurons. INTERPRETATION: Our observations suggest that pathological aggregation of γ-synuclein might contribute to the pathogenesis of ALS.

Antibody-negative neuromyelitis optica with heavy B-cell infiltration.

There are several distinct clinical phenotypes of inflammatory demyelinating diseases of the central nervous system. In classical multiple sclerosis (MS) there are varied pathological patterns, possibly with differences in pathogenesis. Neuromyelitis optica (NMO) is often associated with a specific antibody, suggesting a distinct pathogenesis. We report a case of a young Caucasian male who presented with right hemiparesis secondary to a left fronto-parietal inflammatory brain lesion, which improved over years leaving minimal deficit. Seventeen years later he re-presented with a progressive tetraparesis secondary to cervical myelitis that did not respond to treatment. The NMO antibody was not detected and neuropathological examination was unusual with evidence of a persistent B-cell inflammatory response in the cord. Although having some of the clinical features of NMO, this case presented novel clinico-pathological features that do not easily fit into current MS subtypes.

Sulcal variability, stereological measurement and asymmetry of Broca's area on MR images.

Leftward volume asymmetry of the pars opercularis and pars triangularis may exist in the human brain, frequently referred to as Broca's area, given the functional asymmetries observed in this region with regard to language expression. However, post-mortem and magnetic resonance imaging (MRI) studies have failed to consistently identify such a volumetric asymmetry. In the present study, an analysis of the asymmetry of sulco-gyral anatomy and volume of this anterior speech region was performed in combination with an analysis of the morphology and volume asymmetry of the planum temporale, located within the posterior speech region, in 50 healthy subjects using MRI. Variations in sulcal anatomy were documented according to strict classification schemes and volume estimation of the grey matter within the brain structures was performed using the Cavalieri method of stereology. Results indicated great variation in the morphology of and connectivity between the inferior frontal, inferior precentral and diagonal sulci. There were significant inter-hemispheric differences in the presence of (1) the diagonal sulcus within the pars opercularis, and (2) horizontal termination of the posterior Sylvian fissure (relative to upward oblique termination), both with an increased leftward incidence. Double parallel inferior precentral sulci and absent anterior rami of the Sylvian fissure prevented stereological measurements in five subjects. Therefore volumes were obtained from 45 subjects. There was a significant leftward volume asymmetry of the pars opercularis (P = 0.02), which was significantly related to the asymmetrical presence of the diagonal sulcus (P < 0.01). Group-wise pars opercularis volume asymmetry did not exist when a diagonal sulcus was present in both or neither hemispheres. There was no significant volume asymmetry of the pars triangularis. There was a significant leftward volume asymmetry of the planum temporale (P < 0.001), which was significantly associated with the shape of the posterior Sylvian fissure as a unilateral right or left upward oblique termination was always associated with leftward or rightward volume asymmetry respectively (P < 0.01). There was no relationship between volume asymmetries of the anterior and posterior speech regions. Our findings illustrate the extent of morphological variability of the anterior speech region and demonstrate the difficulties encountered when determining volumetric asymmetries of the inferior frontal gyrus, particularly when sulci are discontinuous, absent or bifid. When the intrasulcal grey matter of this region is exhaustively sampled according to strict anatomical landmarks, the volume of the pars opercularis is leftward asymmetrical. This manuscript illustrates the importance of simultaneous consideration of brain morphology and morphometry in studies of cerebral asymmetry.