No abstract

Hippocampal sclerosis (HpScl) is frequent in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), but it also occurs in dementia of the elderly with or without accompanying Alzheimer type pathology. HpScl has been hypothesized to be a neurodegenerative process given its association with TDP-43 pathology, but this is still controversial. TDP-43 pathology is found in Lewy body disease (LBD), but no study has focused on the pathologic and genetic characteristics of HpScl in LBD. We found HpScl in 5.2% of 669 LBD cases (289 transitional and 380 diffuse). Older age, higher Braak neurofibrillary tangle (NFT) stage, and presence of TDP-43 pathology were associated with HpScl. There was no difference in the frequency of HpScl between transitional and diffuse LBD, suggesting that Lewy related pathology appears to have no direct association with HpScl. All HpScl cases had TDP-43 pathology consistent with Type A pattern. HpScl cases harbored genetic variation in TMEM106B that has been previously associated with FTLD-TDP. Interestingly, the severity of TDP-43-positive fine neurites in CA1 sector, a possible pathologic precursor of HpScl, was associated with the TMEM106B variant. These results demonstrate HpScl in LBD is a TDP-43 proteinopathy and is similar to FTLD-TDP Type A. Furthermore, a subset of LBD cases without HpScl (“pre-HpScl”) had similar pathologic and genetic characteristics to typical HpScl, suggesting that the spectrum of HpScl pathology may be wider than previously thought. Some cases with many extracellular NFTs also had a similar profile. We suggest that HpScl is “masked” in these cases.

Although the clinical presentation of PLA2G6-associated neurodegeneration was reported to be homogeneous, our findings suggest patients with PLA2G6 mutation could show heterogeneous phenotype such as dystonia-parkinsonism, dementia, frontotemporal atrophy/hypoperfusion, with or without brain iron accumulation. Based on the clinical heterogeneity, the functional roles of PLA2G6 and the roles of PLA2G6 variants including single heterozygous mutations should be further elucidated in patients with atypical parkinsonism, dementia, or Parkinson disease. PLA2G6 mutations should be considered in patients with early-onset l-dopa-responsive parkinsonism and dementia with frontotemporal lobar atrophy.

See Gandhi and Plun-Favreau (doi:) for a scientific commentary on this article.Heterozygous mutations in recessive Parkinson’s disease genes have been postulated to increase disease risk. Puschmann et al. report a genetic association between heterozygous PINK1 p.G411S and Parkinson’s disease. They provide structural and functional explanations for a partial dominant-negative effect of the mutant protein, which impairs wild-type PINK1 activity through hetero-dimerization.

The incidence of neurodegenerative diseases has shown an increasing trend. These conditions typically cause progressive functional disability. Identification of robust biomarkers of neurodegenerative diseases is a key imperative to facilitate early identification of the pathological features and to foster a better understanding of the pathogenetic mechanisms of individual diseases. Diffusion tensor imaging (DTI) is the most widely used diffusion MRI technique for assessment of neurodegenerative diseases. The DTI parameters are promising biomarkers for evaluation of microstructural changes; however, some limitations of DTI restrict its wider clinical use. New diffusion MRI techniques, such as diffusion kurtosis imaging (DKI), bi-tensor DTI, and neurite orientation density and dispersion imaging (NODDI) have been demonstrated to provide value addition to DTI for evaluation of neurodegenerative diseases. In this review article, we summarize the key technical aspects and provide an overview of the current state of knowledge regarding the role of DKI, bi-tensor DTI, and NODDI as biomarkers of microstructural changes in representative neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Level of Evidence: 5 Technical Efficacy Stage: 2