G. Lennox

A filamentous inclusion body within anterior horn neurones in motor neurone disease defined by immunocytochemical localisation of ubiquitin

Using an immunocytochemical method to localise antibodies to ubiquitin, filamentous inclusion bodies were seen in spinal anterior horn neurones in cases of motor neurone disease (MND) but not in any control cases. These inclusion bodies appeared to be closely associated with classical Bunina bodies and immuno-electron microscopy suggested that they were based on arrays of straight 10-15 nm filaments together with some granular material. These observations link the protein ubiquitin with a chronic neurodegenerative disease and extend previous observations of a close association between filamentous inclusion bodies and ubiquitin. Ubiquitin-filament inclusions should be regarded as a new hallmark in the histological diagnosis of MND.

Ballooned neurons in several neurodegenerative diseases and stroke contain αB crystallin

αB crystallin is a protein which has homology with the small cell stress proteins. A characterized antibody to residues 1–10 of αB crystallin was used to immunostain tissues containing ballooned (chromatolytic, achromasic) neurons. The tissues included two cases of classical Picks disease, one case of dementia with swollen achromasic neurons in the cortex, two cases of Alzheimers disease with large numbers of ballooned neurons, two cases of motor neuron disease, four cases of cortico‐basal degeneration, and four cases with areas of brain showing swollen neurons adjacent to recent cerebral infarcts. The anti‐αB crystallin showed strong diffuse cytoplasmic immunoreac‐tivity of swollen cortical neurons in all the diseases. Astrocytes and oligodendroglial cells were also stained in normal tissues as previously described. Weak diffuse immunoreactivity with an antibody to ubiquitin‐conjugates was also seen in the swollen neurons from cases of neurodegenerative disease but not following infarction. Ballooned neurons have been shown to contain phosphorylated neurofilament epitopes not normally present in the perikaryonal region. The presence of αB crystallin in ballooned neurons, together with previous data which also indicate its close association with intermediate filaments, suggest that αB crystallin may be involved in aggregation and remodelling of neurofilaments in disease. The presence of αB crystallin in neurons at the edge of areas of cerebral infarction is likely to reflect cells which are regenerating following damage; its detection may therefore be a marker for such cells. On a practical level, the antibody greatly facilitates the localization of such abnormal neurons in diagnostic histology.

The cortical neuritic pathology of Huntington's disease

We have studied the brains of 10 patients with clinically and pathologically defined Huntingtons disease and graded the degree of striatal pathology according to the Vonsattel grading system. Sections from nine cerebral cortical areas (Brodmann areas 8. 10, 24, 33, 28, 38, 7, 39, 18), the cerebellum, hypothalamus, medulla and caudate nucleus were stained with antibodies to ubiquitin and ubiquitin C‐terminal hydrolase (PGP 9.5). Dystrophic neurites. immunoreactive with ubiquitin and PGP 9.5 were detected in all cortical areas. in layers 3, 5 and 6, of all brains studied. No dystrophic neurites were found in subcortical areas or cerebellum. Sections from cortical areas 8 and 24 from the two brains with the most and least ubiquitin‐immunoreactive neurites were stained with antibodies to β‐amyloid precursor protein, tau, glial fibrillary acidic protein, neurofilament protein, αB crystallin, GABA, cholecystokinin and somatostatin. The dystrophic neurites were found to also react with β‐amyloid precursor protein. Electron microscopy showed the abnormal neurites to contain granulo‐filamentous material. Granular deposits with a diameter of 40–100 nm were interspersed between randomly orientated ‘fuzzy’ or coated, straight or slightlv curved filaments measuring 10–15 nm in diameter. These structures have not been seen in control brain and differ from age‐related neuritic degeneration and neurites associated with amyloid. Immunohistochemically these structures most resemble CA 2/3 neurites seen in Lewy body disease, and, ultrastructurally, the intraneuronal filamentous inclusions in motor neuron disease. The areal density of these neurites was quantified in 20 microscopic fields in the superior frontal and anterior cingulate sections (Brodmann areas 8 and 24) and did not correlate with the Vonsattel grade, suggesting that they are an independent and possibly primary cortical pathology in Huntingtons disease.

Ubiquitin is a component of neurofibrillary tangles in a variety of neurodegenerative diseases

Ubiquitin has been shown to be a component of neurofibrillary tangles in Alzheimers disease. We now show immunocytochemically that it is also a component of neurofibrillary tangles in several other neurodegenerative diseases of diverse aetiology, including Downs syndrome, dementia pugilistica and postencephalitic parkinsonism, and in normal ageing. Ubiquitin immunoreactivity is not, however, generally found in the neurofibrillary tangles of progressive supranuclear palsy. These findings show that while associated ubiquitin is not a feature unique to the tangles of Alzheimers disease, it is not simply a non-specific response to the presence of an inclusion body within the cell. The observations suggest that ubiquitin may have an important role in the formation of neurofibrillary tangles in a variety of neurodegenerative diseases.

The Effects of Cognitive Abilities on Driving in People with Parkinson's Disease

Objective: The aim was to develop a cognitive screening procedure, which could be used to identify cognitive problems in patients with Parkinsons disease, which might affect their safety to drive. Design: Two group comparison of those found safe to drive and those found unsafe. Setting: People living in the community who were attending an outpatient Movement Disorders clinic or who had been referred to a Regional Mobility Centre. Participants: Fifty-one people with Parkinsons disease who were driving or who wished to resume driving. The 41 men and 10 women were aged 44 – 85 years (mean 64.4 SD 9.1). Main measures: Websters Rating Scale, Unified Parkinsons Disease Rating Scale motor examination, Stroke Drivers Screening Assessment, Adult Memory and Information Processing Battery, Stroop, Paced Auditory Serial Addition Task and a Tapping task. Results: The unsafe drivers were significantly more disabled, as assessed on Websters Scale, than those who were found safe to drive. There were no significant differences in the cognitive abilities of safe and unsafe drivers. The most common faults, which caused drivers to be judged unsafe, were lack of observations to the side at junctions, poor positioning on the road and poor driving on roundabouts. There were significant correlations (p < 0.05) between driving ability and performance on the SDSA Dot Cancellation task and the AMIPB Story Recall and Information Processing A. Conclusions: Cognitive abilities were not found to be associated with fitness to drive in people with Parkinsons disease. Websters Rating Scale differentiated between safe and unsafe drivers. This could be used to determine who to refer to a mobility centre for advice on fitness to drive.

Inclusion bodies in motor cortex and brainstem of patients with motor neurone disease are detected by immunocytochemical localisation of ubiquitin.

Histological sections of cerebral motor cortex, brainstem, and spinal cord from 10 cases of clinically diagnosed motor neurone disease (MND) and 10 control cases were examined by conventional histology and immunocytochemical methods to localise ubiquitin. Intracytoplasmic inclusion bodies were identified in motor neurones of hypoglossal nuclei and appeared specific for MND. Similar inclusions were found in both large pyramidal cells and small neurones in the motor cortex, and were restricted to 4 cases having the amyotrophic lateral sclerosis form of MND with severe degeneration of corticospinal tracts. As reported in earlier studies, cellular inclusion bodies were identified in motor neurones of spinal cord from cases of MND but not in control material. Ubiquitin inclusions in motor neurones appear to be markers for the degenerative process causing neuronal loss in MND and there appears to be a close association between the anatomical location of inclusions and clinical manifestations of disease.

Protein processing in lysosomes : the new therapeutic target in neurodegenerative disease

A little recognised feature of neurons is their large complement of lysosomes. Studies of the accumulation of the abnormal isoform of the prion protein (PrPSC) in the prion encephalopathies and the formation of beta/A4 protein from its precursor in Alzheimers disease suggest that generation of these key proteins takes place in lysosome-related organelles. The release of hydrolytic enzymes from lysosomes may be a primary cause of neuronal damage. Although molecular genetic approaches have identified protein mutations central to the main neurodegenerative disease, cell biological observations are now beginning to unravel the intracellular pathways involved in the molecular pathogenesis of neurodegeneration: as a result, it is now appropriate to consider therapeutic manipulation of the lysosomal system as an approach to treatment.

Migraine Angiitis Precipitated by Sex Headache and Leading to Watershed Infarction

Vasospasm is a rare cause of cerebrovascular disease except following subarachnoid haemorrhage. We describe a woman who developed an explosive-type sex headache, followed by a series of severe migrainous headaches associated with fully reversible segmental cerebral arterial narrowing and dilatation, resulting in widespread infarction in cerebral arterial border zones. This led to transient loss of consciousness and multiple focal cortical deficits including blindness. She had a past history of migraine and a family history of both migraine and sex headaches. Similar cases have been reported in the literature under a variety of rubrics. We suggest that this newly recognized clinico-radiological syndrome is a migraine variant.

Ubiquitin gene expression in brain and spinal cord in motor neurone disease

A restriction fragment of the coding region of a human ubiquitin gene has been used in Northern analyses of RNA prepared from human motor cortex and anterior horn region of cervical spinal cord. The analyses show that there is a substantial increase (approximately two-fold) in the expression of a polyubiquitin gene in motor cortex and spinal cord from patients with motor neurone disease compared to these tissues from control cases. Polyubiquitin gene expression in other organisms is associated with physical or chemical cell stresses. The data indicate that the primary stresses which result in the generation of ubiquitinated filamentous inclusion bodies in neurones in motor neurone disease also result in increased transcription of a gene coding for a polyprotein of ubiquitin.

Rosenthal fibres are based on the ubiquitination of glial filaments.

Rosenthal fibres are based on the ubiquitination of glial filaments