Neurofilament inclusion body disease: a new proteinopathy?

Abstract

We describe four cases of a new clinicopathological entity presenting with either a frontotemporal dementia or corticobasal degeneration syndrome with a mean age of onset of 45 years (range 41-50) characterized pathologically by deposition of neurofilament proteins. All four patients had a rapidly progressive course and have become mute and non-ambulatory, and three have died after mean illness duration of only 3 years (range 2 1/2 -4). Both structural (MRI) and functional (PET and SPECT) imaging demonstrated frontal and temporal lobe and basal ganglia involvement. Gross neuropathological examination in the three deceased patients (the fourth patient, still alive, was diagnosed by brain biopsy) revealed changes affecting predominantly the frontal and temporal cortices, basal ganglia and brainstem. There was superficial linear spongiosis affecting the frontal lobes in all three autopsied patients, and severe caudate atrophy was noted in two of them and demonstrated on MRI in the living patient. On routine staining, there were numerous intracytoplasmic inclusions, which ranged from eosinophilic to basophilic. Some had a clearly defined basophilic margin, while others were granular with a hyaline core. With modified Bielschowsky silver technique, a small number of the inclusions were intensely stained. Inclusions were not labelled with other silver stains. Immuno histochemistry revealed that the inclusions were immunoreactive with antibodies to neurofilament heavy and light chain subunits and to ubiquitin, but not with antibodies to tau and alpha-synuclein. These neurofilament- and ubiquitin-positive inclusions were widespread, specific to neurons and occasionally intranuclear. The frequency and distribution of the inclusions and the silver and immunohistochemical profiles in these four cases is novel and has not been described in detail before. We propose the term neurofilament inclusion body disease for this entity.

The cytoskeleton in neurodegenerative diseases

“…α-Internexin has recently been identified as a major component of the pathological inclusions of the frontotemporal dementia, neuronal intermediate filament inclusion disease (NIFID) (Figure 2). The signature lesion of this disease is the neuronal cytoplasmic inclusion, which is tau-and α-synuclein negative, variably ubiquitinated, and contains epitopes of all type IV IF proteins [59][60][61]. In addition to NFs in swollen axons and spheroids in ALS, peripherin has also been demonstrated by immunohistochemistry (IHC) in the ubiquitinated inclusions of ALS [62].…”

?-Internexin aggregates are abundant in neuronal intermediate filament inclusion disease (NIFID) but rare in other neurodegenerative diseases

“…Neuronal intermediate filament (IF) inclusion disease (NIFID) is a novel neurological disease with a clinically heterogeneous phenotype including progressive early-onset dementia, pyramidal and extrapyramidal signs. Grossly, there is focal atrophy of the frontal lobes, and to a lesser degree the temporal and parietal lobes, and, microscopically, there are intraneuronal, cytoplasmic, neuronal IF inclusions which contain neither tau nor α-synuclein [2,4,12,15,21,38]. The inclusions are present in neocortex, where clusters of inclusions have been reported [3], subcortical nuclei and spinal cord.…”

The molecular basis of frontotemporal dementia

“…Although previous reports failed to detect abnormal protein deposits in brains of patients with FTD-3, a recent study demonstrated the presence of granular NCIs that were immunoreactive for ubiquitin and p62, but negative for TDP-43 and tau, predominantly in the dentate granule cells of the hippocampus (Fig. 4e) The neuropathological findings in NIFID are heterogeneous, but have a number of consistent features (Refs 148,150,151,152,153,154,155,156,157). Chronic degenerative changes may affect a variety of cortical and subcortical regions, with the frontal and temporal lobes and caudate nucleus most consistently and severely involved.…”