Clinico-pathological evidence that axonal loss underlies disability in progressive multiple sclerosis.

Growing evidence suggests that axonal degeneration rather than demyelination is the pathological substrate underlying chronic, irreversible disability in multiple sclerosis. However, direct evidence linking clinical disability measured in vivo with corresponding post-mortem measures of axonal pathology is lacking. Our objective in this study was to investigate the relationship between motor disability accumulated by patients with multiple sclerosis during life and the degree of axonal loss observed in their descending motor tracts after death. Human spinal cord derived at autopsy from 45 patients with multiple sclerosis was investigated. The medical records of each patient were reviewed by a multiple sclerosis neurologist to determine the degree of motor disability reached before death. Spinal cord sections were stained immunohistochemically. The degree of demyelination and the number of surviving corticospinal tract axons were measured in each patient. Patients who had accumulated higher levels of motor disability prior to death demonstrated fewer surviving corticospinal axons. Motor disability did not correlate with degree of demyelination. This study provides for the first time, direct clinico-pathological evidence that axonal loss is the pathological substrate of established disability in multiple sclerosis.

Patients with a novel neurofilamentopathy: dementia with neurofilament inclusions.

We report a new disease, dementia with neurofilament inclusions, characterized clinically by early-onset dementia with frontal lobe signs, focal atrophy of the frontal and temporal lobes, and microscopically by the presence in many brain regions of intraneuronal, cytoplasmic, neurofilament inclusions. The neuronal inclusions are immunoreactive to all three molecular weight neurofilament subunits: heavy (NF-H), light, and medium subunits, including the phosphorylated and non-phosphorylated forms of NF-H. Prion protein and beta-amyloid deposits were absent. The inclusions do not contain tau or alpha-synuclein protein aggregates known to characterize many neurodegenerative disorders. In addition to delineating a new disease entity, the identification of intraneuronal, cytoplasmic, neurofilament inclusions extends the molecular classification of neurodegenerative diseases and implicates new mechanisms of neurodegeneration in diseases affecting the human brain.

Atypical progressive multifocal leukoencephalopathy associated with an unusual JC polyomavirus mutation.

OBJECTIVE: To report the clinical and radiologic features in a patient with myelofibrosis who developed atypical progressive multifocal leukoencephalopathy. DESIGN: Case report. SETTING: Tertiary referral center. Patient A 72-year-old man with myelofibrosis and mild leukopenia experienced progressive limb weakness and dysarthria. RESULTS: Imaging revealed almost complete sparing of the white matter with isolated involvement of the brainstem and deep gray matter. Postmortem examination led to definitive diagnosis of progressive multifocal leukoencephalopathy and demonstrated an unusual miliary pattern of disease rather than the typical confluent involvement. Genetic analysis revealed a mutation in the transcription control region of the JC polyomavirus, prompting speculation about the pathogenesis of progressive multifocal leukoencephalopathy. CONCLUSIONS: Leukopenia may render patients effectively immunosuppressed. The differential diagnosis should include progressive multifocal leukoencephalopathy even in patients with atypical clinical and radiologic features.

The ubiquitin-binding protein p62 identifies argyrophilic grain pathology with greater sensitivity than conventional silver stains.

The routine diagnosis of argyrophilic grain disease is fraught by the lack of availability of an easily applied reproducible stain that can highlight the grain pathology with sensitivity and with minimal background. The Gallyas silver iodide technique is not widely used and, even in experienced hands, is difficult to perform due to inconsistencies inherent in silver-based techniques on thin sections. Grain pathology can be detected using immunohistochemistry for phosphorylated tau protein, but the grain pathology is most often masked by background tau-positive material; leading to problems with interpretation, especially for practitioners seeing small numbers of cases. There is a need for a reliable immunohistochemical stain that can detect grain pathology and provide a clear contrast between grains and other tau-positive neurodegenerative pathologies. We have investigated the novel ubiquitin-binding protein p62 as a potential biomarker for grain pathology in argyrophilic grain disease. Four cases of argyrophilic grain disease, in which the pathology was determined using the Gallyas silver iodide technique, were re-assessed using paraffin-embedded sections immunostained with antibodies specific for p62. We found that the detection of grain pathology was more sensitive than with silver-based techniques and that the resolution of the pathology was significantly improved. We suggest that p62 could be used to replace the Gallyas technique in the routine diagnosis of argyrophilic grain disease.

Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration.

The aim of this study was to improve the neuropathologic recognition and provide criteria for the pathological diagnosis in the neurodegenerative diseases grouped as frontotemporal lobar degeneration (FTLD); revised criteria are proposed. Recent advances in molecular genetics, biochemistry, and neuropathology of FTLD prompted the Midwest Consortium for Frontotemporal Lobar Degeneration and experts at other centers to review and revise the existing neuropathologic diagnostic criteria for FTLD. The proposed criteria for FTLD are based on existing criteria, which include the tauopathies [FTLD with Pick bodies, corticobasal degeneration, progressive supranuclear palsy, sporadic multiple system tauopathy with dementia, argyrophilic grain disease, neurofibrillary tangle dementia, and FTD with microtubule-associated tau (MAPT) gene mutation, also called FTD with parkinsonism linked to chromosome 17 (FTDP-17)]. The proposed criteria take into account new disease entities and include the novel molecular pathology, TDP-43 proteinopathy, now recognized to be the most frequent histological finding in FTLD. TDP-43 is a major component of the pathologic inclusions of most sporadic and familial cases of FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Molecular genetic studies of familial cases of FTLD-U have shown that mutations in the progranulin (PGRN) gene are a major genetic cause of FTLD-U. Mutations in valosin-containing protein (VCP) gene are present in rare familial forms of FTD, and some families with FTD and/or MND have been linked to chromosome 9p, and both are types of FTLD-U. Thus, familial TDP-43 proteinopathy is associated with defects in multiple genes, and molecular genetics is required in these cases to correctly identify the causative gene defect. In addition to genetic heterogeneity amongst the TDP-43 proteinopathies, there is also neuropathologic heterogeneity and there is a close relationship between genotype and FTLD-U subtype. In addition to these recent significant advances in the neuropathology of FTLD-U, novel FTLD entities have been further characterized, including neuronal intermediate filament inclusion disease. The proposed criteria incorporate up-to-date neuropathology of FTLD in the light of recent immunohistochemical, biochemical, and genetic advances. These criteria will be of value to the practicing neuropathologist and provide a foundation for clinical, clinico-pathologic, mechanistic studies and in vivo models of pathogenesis of FTLD.