Background

Steroid-responsive encephalopathies can considered vasculitic or nonvasculitic. Clinicopathological studies of nonvasculitic steroid-responsive encephalopathy are unusual, but can explain the range of diagnoses consistent with a steroid responsive presentation in life.

Objective

To extend the range of clinical features and pathological findings consistent with steroid-responsive encephalopathy.

Design, Methods, and Patients

A clinicopathological case series of four patients (ages 54–71 years, 2 women) with steroid-responsive encephalopathy followed at this institution until the time of death.

Results

Clinical features were suggestive of Creutzfeld-Jakob disease, dementia with Lewy Bodies, and parkinsonism, but pathological examination revealed only Alzheimer’s Disease-related findings without evidence of Lewy bodies or prion disease in all cases. All patients demonstrated marked, sustained improvement following steroid treatment, based on clinical, magnetic resonance imaging, and/or electroencephalogram studiesAlzheimer’s Disease was not diagnosed in life due to a lack of hippocampal atrophy on brain imaging and a dramatic symptomatic response to steroids.

Conclusions

Steroid-responsive encephalopathy is the clinical presentation of some patients with Alzheimer’s Disease related pathology at autopsy, and can be consistent with the clinical diagnoses of parkisonism, dementia with Lewy Bodies, or Creutzfeld-Jakob Disease in life.

Objective

There are no Food and Drug Administration (FDA)-approved medications indicated for the treatment of frontotemporal dementia (FTD). We sought to determine the most commonly used drugs used to treat behavioral variant FTD (bvFTD) in specialized dementia clinics.

Methods

Medication and demographic data from the Alzheimer’s Disease Research Centers of California (ARCC) and a multicenter FTD natural history study (NHS) data set were compared in bvFTD and Alzheimer’s disease (AD), and effects of demographic variables were assessed using logistic regression.

Results

Overall, the percentage of patients taking one or more FDA-approved AD or psychiatric medications was similar in bvFTD and AD; however, after controlling for demographic variables, acetylcholinesterase inhibitor (AChI) use was less common in bvFTD, whereas memantine use remained similar in the 2 groups.

Conclusions

Despite lack of evidence for efficacy, the use of AChIs and memantine is common in bvFTD. Clinical trials should be pursued to determine the optimal therapeutic interventions for bvFTD.

To design clinical trials for the frontotemporal lobar degenerations (FTLD), knowledge about measurement of disease progression is needed to estimate power and enable the choice of optimal outcome measures. The aim here was to conduct a multicentre, 1 year replica of a clinical trial in patients with one of four FTLD syndromes, behavioural variant frontotemporal dementia (bvFTD), progressive nonfluent aphasia (PNFA), progressive logopenic aphasia (PLA) and semantic dementia (SMD). Patients with one of the four FTLD syndromes were recruited from five academic medical centres over a 2 year period. Standard operationalized diagnostic criteria were used. In addition to clinical inclusion and exclusion criteria, patients were required to exhibit focal frontal, temporal or insular brain atrophy or dysfunction by neuroimaging. Patients underwent neuropsychological, functional, behavioural, neurological and MR imaging assessment at baseline and approximately 12 months later. Potential outcome measures were examined for their rates of floor and ceiling values at baseline and end of study, their mean changes and variances. The neuropsychological tests were combined into two cognitive composites—one for language functions and the other for executive functions. There were 107 patients who underwent baseline assessment and 78 who completed a follow-up assessment within 10–16 months. Two global measures, the FTLD-modified Clinical Dementia Rating (FTLD-modified CDR) and the Clinical Global Impression of Change (CGIC) demonstrated decline in the majority of patients. Several cognitive measures showed negligible floor or ceiling scores either at baseline or follow-up. Scores declined at follow-up in the majority of patients. The cognitive, executive and combined composites were shown to be sensitive to change across all FTLD syndromes. Patients improved at follow-up on the behavioural scales—the Frontal Behavioural Inventory (22%) and the Neuropsychiatric Inventory (28%)—suggesting that these instruments may not be ideal for clinical trial use. It was feasible to recruit FTLD patients in a simulated multi-centre trial. There are several candidate outcome measures—including the FTLD-CDR and the cognitive composites— that could be used in clinical trials across the spectrum of FTLD.

The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43–positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the ∼25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis.

Author Summary

The abnormal accumulation of disease proteins in neuronal cells of the brain is a characteristic feature of many neurodegenerative diseases. Rare mutations in the genes that encode the accumulating proteins have been identified in these disorders and are crucial for the development of cell and animal models used to study neurodegeneration. Recently, the TAR DNA-binding protein 43 (TDP-43) was identified as the disease accumulating protein in patients with frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) and in amyotrophic lateral sclerosis (ALS). TDP-43 was also found in the brains of 20–30% of patients with Alzheimer's disease (AD). Here, we evaluated whether mutations in TDP-43 cause disease in a cohort of 296 patients presenting with FTLD, ALS or AD. We identified three missense mutations in three out of 92 familial ALS patients (3.3%), and no mutations in AD or FTLD patients. All the identified mutations clustered in exon 6, which codes for a highly conserved region in the C-terminal part of the TDP-43 protein, which is known to be involved in the interaction of TDP-43 with other proteins. We conclude that mutations in TDP-43 are a rare cause of familial ALS, but so far are not found in other neurodegenerative diseases.

Loss-of-function mutations in progranulin (GRN) cause ubiquitin- and TAR DNA-binding protein 43 (TDP-43)-positive frontotemporal dementia (FTLD-U), a progressive neurodegenerative disease affecting ∼10% of early-onset dementia patients. Here we expand the role of GRN in FTLD-U and demonstrate that a common genetic variant (rs5848), located in the 3′-untranslated region (UTR) of GRN in a binding-site for miR-659, is a major susceptibility factor for FTLD-U. In a series of pathologically confirmed FTLD-U patients without GRN mutations, we show that carriers homozygous for the T-allele of rs5848 have a 3.2-fold increased risk to develop FTLD-U compared with homozygous C-allele carriers (95% CI: 1.50–6.73). We further demonstrate that miR-659 can regulate GRN expression in vitro, with miR-659 binding more efficiently to the high risk T-allele of rs5848 resulting in augmented translational inhibition of GRN. A significant reduction in GRN protein was observed in homozygous T-allele carriers in vivo, through biochemical and immunohistochemical methods, mimicking the effect of heterozygous loss-of-function GRN mutations. In support of these findings, the neuropathology of homozygous rs5848 T-allele carriers frequently resembled the pathological FTLD-U subtype of GRN mutation carriers. We suggest that the expression of GRN is regulated by miRNAs and that common genetic variability in a miRNA binding-site can significantly increase the risk for FTLD-U. Translational regulation by miRNAs may represent a common mechanism underlying complex neurodegenerative disorders.