Simple and clear differentiation of spinocerebellar degenerations: Overview of macroscopic and low-power view findings.

Spinocerebellar degenerations (SCDs) are a diverse group of rare and slowly progressive neurological diseases that include spinocerebellar ataxia type 1 (SCA1), SCA2, SCA3, SCA6, SCA7, dentatorubral-pallidoluysian atrophy (DRPLA) and multiple system atrophy (MSA). They are often inherited, and affect the cerebellum and related pathways. The combination of clinical findings and lesion distribution has been the gold-standard for classifying SCDs. This conventional approach has not been very successful in providing a solid framework shared among researchers because their points of views have been quite variable. After identification of genetic abnormalities, classification was overwhelmed by genotyping, replacing the conventional approach far behind. In this review, we describe a stepwise operational approach that we constructed based only on macroscopic findings without microscopy to classify SCDs into three major groups: pure cerebellar type for SCA6 and SCA31; olivopontocerebellar (OPC) type for SCA1, SCA2, SCA7 and MSA; and dentatorubral-pallidoluysian (DRPL) type for SCA1, SCA3, DRPLA and progressive supranuclear palsy (PSP). Spinocerebellar tract involvement distinguishes SCA1 and SCA3 from DRPLA. Degeneration of the internal segment of the pallidum is accentuated in SCA3 and PSP, while degeneration of the external segment is accentuated in SCA1 and DRPLA. These contrasts are helpful in subdividing OPC and DRPL types to predict their genotypes. Lesion distribution represents disease-specific selective vulnerability, which is readily differentiated macroscopically using our stepwise operational approach. Precise prediction of the major genotypes will provide a basis to understand how genetic abnormalities lead to corresponding phenotypes through disease-specific selective vulnerabilities.

Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration.

Hereditary spastic paraplegias (HSP) are neurodegenerative diseases mainly characterized by lower limb spasticity associated, in complicated forms, with additional neurological signs. We have analysed a large series of index patients (n = 76) with this condition, either from families with an autosomal recessive inheritance (n = 43) or isolated patients (n = 33), for mutations in the recently identified SPG11 gene. We found 22 truncating mutations, including the first four splice-site mutations, segregating in seven isolated cases and 13 families. Nineteen mutations were novel. Two recurrent mutations were found in Portuguese and North-African patients indicating founder effects in these populations. The mutation frequency varied according to the phenotype, from 41%, in HSP patients presenting with a thin corpus callosum (TCC) visualized by MRI, to 4.5%, in patients with mental impairment without a TCC. Disease onset occurred during the first to the third decade mainly by problems with gait and/or mental retardation. After a mean disease duration of 14.9 +/- 6.6 years, the phenotype of 38 SPG11 patients was severe with 53% of patients wheelchair bound or bedridden. In addition to mental retardation, 80% of the patients showed cognitive decline with executive dysfunction. Interestingly, the phenotype also frequently included lower motor neuron degeneration (81%) with wasting (53%). Slight ocular cerebellar signs were also noted in patients with long disease durations. In addition to a TCC (95%), brain MRI revealed white matter alterations (69%) and cortical atrophy (81%), which worsened with disease duration. In conclusion, our study reveals the high frequency of SPG11 mutations in patients with HSP, a TCC and cognitive impairment, including in isolated patients, and extends the associated phenotype.

Was the ataxia of Pierre Marie Machado-Joseph disease?: A reappraisal based on the last autopsy case from la Salpêtrière Hospital.

Nosological placement of l'hérédo-ataxie cérébelleuse de Pierre Marie (HAC) has never been established even after several autopsy cases from the original Haudebourg family had been reported. To reappraise the clinical and pathological features of HAC in the current framework of hereditary ataxias, we screened the autopsy records of la Salpêtrière hospital and identified a patient with a diagnosis of HAC who underwent an autopsy in 1943. Clinical features included heredity compatible with autosomal dominant inheritance, spasticity, increased tendon reflexes, mask-like face, visual impairment, nuclear ophthalmoparesis, and exophthalmos in addition to progressive ataxia. Pathological lesions included the spinal cord (spinocerebellar tracts, anterolateral fascicles, and posterior column), cerebellar dentate nucleus, pontine nucleus, pallidum, motor neurons including the oculomotor nucleus, and substantia nigra. The cerebellar cortex and inferior olives were preserved. These clinical and pathological features, similar to those described in patients from the Haudebourg family, a core prototype of HAC, are indistinguishable from those of Machado-Joseph disease. It would then be possible to conclude that some of the patients historically considered to have HAC would today be classified as having Machado-Joseph disease.

PML nuclear bodies and neuronal intranuclear inclusion in polyglutamine diseases.

In polyglutamine diseases, accumulation in the nucleus of mutant proteins induces the formation of neuronal intranuclear inclusions (NIIs). The nucleus is compartmentalized into structural and functional domains, which are involved in NII formation. Promyelocytic leukemia protein (PML), a major component of nuclear bodies, and mSin3A, a component of the transcription co-repressor complex, were used to investigate how the intranuclear domains/sites relate to NII formation in SCA2, SCA3, SCA7, SCA17 and DRPLA brains. We demonstrate that the size of PML-positive intranuclear structures was larger in pathological brains than in control ones and that these structures contained mutant proteins. PML colocalized only with small NIIs, which maintained the ring-like structure of normal nuclear bodies. Enlarged ring-like PML-positive structures, devoid of mutant proteins, were also found and might represent structures where mutant polyglutamine proteins have been successfully processed. These data suggest that NIIs originate from nuclear bodies, where mutant proteins accumulate for degradation.

Reversible conformational change of tau2 epitope on exposure to detergent in glial cytoplasmic inclusions of multiple system atrophy.

Tau-like immunoreactivity (IR) on glial cytoplasmic inclusions (GCIs) of multiple system atrophy (MSA) was investigated with a panel of anti-tau antibodies and we found that tau2, one of the phosphorylation-independent antibodies, preferentially immunolabeled GCIs. Co-presence (0.03%) of polyethyleneglycol- p-isooctylphenyl ether (Triton X-100, TX) with tau2, however, abolished this IR on GCIs, but did not abolish tau2 IR on neurofibrillary tangles (NFTs). Tau2-immunoreactive bands on immunoblot of brain homogenates from MSA brains were retrieved mainly in a TRIS-saline-soluble fraction, as reported in normal brains. This was in contrast to SDS-soluble fractions from brain with Down's syndrome, which contained tau2-immunoreactive bands of higher molecular weight. It indicates that the appearance of tau2 IR on GCIs is not related to hyperphosphorylation of tau. These tau2-immunoreactive bands, except those from bovine brain, were similarly abolished in the presence of TX (0.06%), and repeated washing after exposure to TX restored the tau2 IR on immunohistochemistry and on immunoblot. These findings can be explained if the modified tau2 epitope undergoes a reversible conformational change on exposure to TX, which is reversible after washing. Because the conformation centered at Ser101 of bovine tau is crucial for its affinity to tau2, the Ser-like conformation mimicked by its human counterpart Pro may represent pathological modification of tau shared by GCIs and NFTs. The relative resistance of tau2 epitope on NFTs on exposure to TX suggests that tau woven into NFTs confers additional stability to the pathological conformation of tau2 epitope. The conformation of the tau2 epitope in GCIs is not as stable as in NFTs, suggesting that tau proteins are not the principal constituents of the fibrillary structures of GCIs, even though they were immunodecorated with tau2. The difference in the susceptibility of the tau2 epitope to TX may distinguish its conformational states, which are variously represented according to disease conditions.

Attenuated nuclear shrinkage in neurons with nuclear aggregates--a morphometric study on pontine neurons of Machado-Joseph disease brains.

Nuclear aggregates (NAs) and neurodegeneration in brains from patients with Machado-Joseph disease (MJD) are both triggered by pathological expansion of CAG/polyglutamine repeat in ataxin-3, but it remains to be clarified whether NA formation is associated with accelerated neurodegeneration. In an attempt to clarify a possible influence of NAs on neurons in human brains, we quantified the size and deformity of neuronal nuclei (those with or without NAs, separately) cross-sectioned on pontine preparations of autopsied brains from four patients with MJD and five controls. Nuclear shrinkage and deformity were more marked in MJD brains than in controls, and these changes were attenuated in neurons harboring NAs. NAs of MJD are presumably linked to a mechanism that attenuates rather than accelerates nuclear shrinkage and deformity. This finding leads us to consider that NAs are not necessarily toxic to neurons in diseased human brains.