Citations

BackgroundRecently, a novel mutation in exon 24 of DNAJC13 gene (p.Asn855Ser, rs387907571) has been reported to cause autosomal dominant Parkinson's disease (PD) in a multi‐incident Mennonite family.MethodsIn the present study the mutation containing exon of the DNAJC13 gene has been sequenced in a Caucasian series consisting of 1938 patients with clinical PD and 838 with pathologically diagnosed Lewy body disease (LBD).ResultsOur sequence analysis did not identify any coding variants in exon 24 of DNAJC13. Two previously described variants in intron 23 (rs200204728 and rs2369796) were observed.ConclusionOur results indicate that the region surrounding the DNAJC13 p.Asn855Ser substitution is highly conserved and mutations in this exon are not a common cause of PD or LBD among Caucasian populations.

ObjectiveAn extensive analysis of white matter plaques in a large sample of multiple sclerosis (MS) autopsies provides insights into the dynamic nature of MS pathology.MethodsOne hundred twenty MS cases (1,220 tissue blocks) were included. Plaque types were classified according to demyelinating activity based on stringent criteria. Early active, late active, smoldering, inactive, and shadow plaques were distinguished. A total of 2,476 MS white matter plaques were identified. Plaque type distribution was analyzed in relation to clinical data.ResultsActive plaques were most often found in early disease, whereas at later stages, smoldering, inactive, and shadow plaques predominated. The presence of early active plaques rapidly declined with disease duration. Plaque type distribution differed significantly by clinical course. The majority of plaques in acute monophasic and relapsing–remitting MS (RRMS) were active. Among secondary progressive MS (SPMS) cases with attacks, all plaque types could be distinguished including active plaques, in contrast to SPMS without attacks, in which inactive plaques predominated. Smoldering plaques were frequently and almost exclusively found in progressive MS. At 47 years of age, an equilibrium was observed between active and inactive plaques, whereas smoldering plaques began to peak. Men displayed a higher proportion of smoldering plaques.InterpretationDisease duration, clinical course, age, and gender contribute to the dynamic nature of white matter MS pathology. Active MS plaques predominate in acute and early RRMS and are the likely substrate of clinical attacks. Progressive MS transitions to an accumulation of smoldering plaques characterized by microglial activation and slow expansion of pre‐existing plaques. Whether current MS therapeutics impact this pathological driver of disease progression remains uncertain. Ann Neurol 2015;78:Ann Neurol 2015;78:679–696

ObjectiveThe aim of this study was to determine whether the frequency of TAR DNA‐binding protein 43 (TDP‐43) deposition in Alzheimer's disease (AD) differs across pathologically defined AD subtypes (hippocampal sparing [HpSp]; typical and limbic) and further examine the relationship between TDP‐43, pathological subtype, and clinical features in AD.MethodsWe identified all cases with pathologically confirmed AD (NIA‐Reagan intermediate‐high probability, Braak stage IV–VI) independent of cognitive status (n = 188). Neurofibrillary tangle counts were performed using thioflavin‐S microscopy in hippocampus and three neocortical regions, and all cases were subtyped: HpSp AD pathology (n = 19); typical AD pathology (n = 136); and limbic AD pathology (n = 33). TDP‐43 immunoreactivity was performed in multiple brain regions to assess for the presence of TDP‐43 and TDP‐43 stage. All cases were clinically subclassified at presentation as amnestic AD dementia versus atypical AD dementia. Statistical analysis was performed using linear and penalized logistic regression to assess associations with pathological subtype, and the effects of TDP‐43, accounting for possible interactions between pathological subtype and TDP‐43.ResultsTDP‐43 deposition was frequent in typical (59%) and limbic AD pathologies (67%), but not HpSp AD pathology (21%; p = 0.003). The observed associations of TDP‐43 with greater memory loss, naming and functional decline, and smaller hippocampal volumes, closest to death, did not differ across AD pathological subtype. Clinical presentation was associated with pathological subtype (p = 0.01), but not TDP‐43 (p = 0.69).InterpretationAlthough the frequency of TDP‐43 deposition in AD varies by pathological subtype, the observed effects of TDP‐43 on clinical/magnetic resonance imaging features are consistent across pathological subtypes. Clinical presentation in AD is driven by pathological subtype, not by TDP‐43. Ann Neurol 2015;78:Ann Neurol 2015;78:679–696

AbstractBackgroundHistaminergic neurons of the tuberomammillary nucleus are critical for maintenance of wakefulness and participate in basal ganglia modulation and sympathoexcitation. All of these functions are affected in multiple system atrophy and dementia with Lewy bodies.ObjectivesTo determine the involvement of histaminergic neurons in these synucleinopathies.MethodsImmunocytochemical staining for histidine decarboxylase and stereological cell counts in the posterolateral hypothalamus from six cases with multiple system atrophy, six with dementia with Lewy bodies, and five healthy controls.ResultsCompared with healthy controls, significant reduction of histaminergic neurons was found both in multiple system atrophy (total estimated cell count, 94,677 ± 5,521 vs. 169,579 ± 12,443; P < 0.001) and in dementia with Lewy bodies (91,110 ± 13,021 vs. 169,579 ± 12,443; P < 0.001).ConclusionsLoss of tuberomammillary histaminergic neurons could potentially contribute to motor, sleep, and autonomic manifestations of both multiple system atrophy and dementia with Lewy bodies. © 2015 International Parkinson and Movement Disorder Society

BackgroundThere are no effective treatments that slow the progression of neurodegenerative diseases. A major challenge of treatment in neurodegenerative diseases is appropriate delivery of pharmaceuticals into the cerebrospinal fluid (CSF) of affected individuals. Mesenchymal stromal cells (MSCs—either naïve or modified) are a promising therapy in neurodegenerative diseases and may be delivered directly into the CSF where they can reside for months. In this preclinical study, we evaluated the safety of intrathecal autologous MSCs in a rabbit model.Study Design and MethodsAutologous adipose‐derived MSCs (or artificial CSF) were delivered intrathecally, either with single or with repeated injections into the foramen magnum of healthy rabbits and monitored for 4 and 12 weeks, respectively.ResultsRabbits tolerated injections well and no definitive MSC‐related side effects were observed apart from three rabbits that had delayed death secondary to traumatic foramen magnum puncture. Functional assessments and body weights were equivalent between groups. Gross pathology and histology did not reveal any abnormalities or tumor growth. Complete blood count data were normal and there were no differences in CSF interleukin‐6 levels in all groups tested.ConclusionOur data suggest that intrathecal delivery of autologous MSCs is safe in a rabbit model. Data from this study have supported two successful investigational new drug applications to the Food and Drug Administration, resulting in the initiation of two clinical trials using autologous MSCs in amyotrophic lateral sclerosis and multiple system atrophy.