Neuronal Intermediate Filament Inclusion Disease Research Articles

Mutation analysis of patients with neuronal intermediate filament inclusion disease (NIFID)

Abnormal neuronal aggregates of α-internexin and the three neurofilament (NF) subunits, NFL, NFM, and NFH have recently been identified as the signature lesions of neuronal intermediate filament (IF) inclusion disease (NIFID), a novel neurological disease of early onset with a variable clinical phenotype including frontotemporal dementia, pyramidal and extrapyramidal signs. In other neurodegenerative diseases in which protein aggregates contribute to disease pathogenesis, mutations in the encoding protein cause the hereditary variant of the disease. To determine the molecular genetic contribution to this disease we performed a mutation analysis of all type IV neuronal IF, SOD1 and NUDEL genes in cases of NIFID and unaffected control cases. We found no pathogenic variants.

Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease

Recently described neuronal intermediate filament inclusion disease (NIFID) shows considerable clinical heterogeneity. To assess the spectrum of the clinical and neuropathological features in 10 NIFID cases. Retrospective chart and comprehensive neuropathological review of these NIFID cases was conducted. The mean age at onset was 40.8 (range 23 to 56) years, mean disease duration was 4.5 (range 2.7 to 13) years, and mean age at death was 45.3 (range 28 to 61) years. The most common presenting symptoms were behavioral and personality changes in 7 of 10 cases and, less often, memory loss, cognitive impairment, language deficits, and motor weakness. Extrapyramidal features were present in 8 of 10 patients. Language impairment, perseveration, executive dysfunction, hyperreflexia, and primitive reflexes were frequent signs, whereas a minority had buccofacial apraxia, supranuclear ophthalmoplegia, upper motor neuron disease (MND), and limb dystonia. Frontotemporal and caudate atrophy were common. Histologic changes were extensive in many cortical areas, deep gray matter, cerebellum, and spinal cord. The hallmark lesions of NIFID were unique neuronal IF inclusions detected most robustly by antibodies to neurofilament triplet proteins and alpha-internexin. NIFID is a neuropathologically distinct, clinically heterogeneous variant of frontotemporal dementia (FTD) that may include parkinsonism or MND. Neuronal IF inclusions are the neuropathological signatures of NIFID that distinguish it from all other FTD variants including FTD with MND and FTD tauopathies.

October 26 Highlights

Cairns et al. describe the clinical and neuropathologic features of 10 patients with neuronal intermediate filament inclusion disease (NIFID). Their cases have features of both frontotemporal dementia and motor neuron disease. Age at onset ranged from 23 to 56 years (mean 40.8) with a mean duration until death of 4.5 years. ⇓ Neuronal IF inclusions in the temporal lobe. Subiculum (A) and pyramidal neurons (B, arrows) and swollen axons and spheroids (B, arrowheads). see page 1376 The accompanying editorial by DeKosky and Ikonomovic notes that this article adds to the evidence that the most common mechanism of chronic neurodegenerative disorders involves abnormal protein production, processing, or misfolding, and subsequent accumulation in the brain. Specific neurons manifest selective vulnerability to specific protein processing abnormalities, for example, altered tau metabolism is associated with FTD AD, corticobasal degeneration, and progressive supranuclear palsy. In NIFID light, medium, and heavy (molecular weight) NF triplet proteins (NF-L, NF-M, …

Spatial correlations between the neuronal inclusions, swollen achromatic neurons, and glial cells in neuronal intermediate filament inclusion disease (NIFID).

Neuronal intermediate filament (IF) inclusion disease (NIFID) is characterized by neuronal loss, neuronal cytoplasmic IF-positive inclusions (NI), swollen neurons (SN), and a glial cell reaction. We studied the spatial correlations between the clusters of NI, SN, and glial cells in four gyri of the temporal lobe (superior temporal gyrus, inferior temporal gyrus, lateral occipitotemporal gyrus, and parahippocampal gyrus) in four cases of NIFID. The densities of histological features (per 50 x 250 microm sample field) were as follows: NI (mean = 0.41, range 0.28-0.68), SN (mean = 1.41, range 0.47-2.65), glial cell nuclei (mean = 5.21, range 3.63-8.17). The NI and the SN were positively correlated in half of the brain regions examined, the correlations being present at the smallest field size (50 x 250 microm). The NI were also positively or negatively correlated with the glial cell nuclei in different areas, the negative correlations being present at the smallest field size. Glial cell nuclei were positively or negatively correlated with the SN in different brain areas, mainly at the larger field sizes (400 x 250 and 800 x 250 microm). The spatial correlation between the clusters of NI and SN in the cortex suggests their development within the same columns of cells. At first, the glial cell reaction is also confined to these columns but later becomes more generally distributed across the cortex.

O4-06-01 α-Internexin is present in the hallmark lesions of neuronal intermediate filament inclusion disease

O4-06-01 α-Internexin is present in the hallmark lesions of neuronal intermediate filament inclusion disease

α-Internexin Is Present in the Pathological Inclusions of Neuronal Intermediate Filament Inclusion Disease

Neuronal intermediate filament (IF) inclusion disease (NIFID) is a novel neurological disease of early onset with a variable clinical phenotype including frontotemporal dementia, pyramidal, and extrapyramidal signs. Pathologically, in affected areas, there is neuronal loss, astrocytosis, and neuronal intracytoplasmic aggregates of abnormal neuronal IFs that contain neither tau nor alpha-synuclein. Thus, to characterize the neuronal IF protein profile of inclusions in NIFID, immunohistochemistry (IHC) was performed on 10 cases of NIFID, four normal aged controls (NL), and two cases of Alzheimer's disease (AD) using a panel of anti-neuronal IF proteins. Immunoelectron microscopy was performed on selected cases and frozen tissue from the frontal lobe of four cases was used for biochemical studies including sequential extractions and Western blotting. Based on these studies, we report here for the first time that alpha-internexin, a neuronal IF protein, is present within the inclusions of NIFID as are all three neurofilament subunits: heavy, medium, and light. Thus, all class IV neuronal IF proteins are present within the pathological inclusions of this disease. Biochemistry revealed that IF aggregates were soluble in sodium dodecyl sulfate (SDS) and no post-translational modification was detected when compared with Alzheimer's disease or aged control brains. Hence, we conclude that NIFID is characterized by the pathological cytoplasmic aggregation of all class IV neuronal IF proteins in brain. The discovery of alpha-internexin in the cytoplasmic inclusions implicates novel mechanisms of pathogenesis in NIFID and other neurological diseases with pathological accumulations of IFs.