Clinical and pathological characteristics of patients with Leucine‐rich repeat kinase‐2 mutations

Mutations in LRRK2 are the single most common known cause of Parkinson's disease (PD). Two new PD patients with LRRK2 mutation were identified from a cohort with extensive postmortem assessment. One of these patients harbors the R793M mutation and presented with the typical clinical and pathological features of PD. A novel L1165P mutation was identified in a second patient. This patient had the classical and pathological features of PD, but additionally developed severe neuropsychological symptoms and dementia associated with abundant neurofibrillary tangles in the hippocampal formation; features consistent with a secondary diagnosis of tangle‐predominant dementia. α‐Synuclein‐containing pathological inclusions in these patients also were highly phosphorylated at Ser‐129, similar to other patients with idiopathic PD. These two PD patients also were characterized by the presence of occasional cytoplasmic TDP‐43 inclusions in the temporal cortex, a finding that was not observed in three other patients with the G2019S mutation in LRRK2. These findings extend the clinical and pathological features that may be associated with LRRK2 mutations. © 2008 Movement Disorder Society     

Selective coexpression of synaptic proteins, α‐synuclein,cysteine string protein‐α, synaptophysin,synaptotagmin‐1, and synaptobrevin‐2 in vesicular acetylcholine transporter‐immunoreactive axons in the guinea pig ileum

Parkinson's disease is a neurodegenerative disorder characterized by Lewy bodies and neurites composed mainly of the presynaptic protein α‐synuclein. Frequently, Lewy bodies and neurites are identified in the gut of Parkinson's disease patients and may underlie associated gastrointestinal dysfunctions. We recently reported selective expression of α‐synuclein in the axons of cholinergic neurons in the guinea pig and human distal gut; however, it is not clear whether α‐synuclein expression varies along the gut, nor how closely expression is associated with other synaptic proteins. We used multiple‐labeling immunohistochemistry to quantify which neurons in the guinea pig ileum expressed α‐synuclein, cysteine string protein‐α (CSPα), synaptophysin, synaptotagmin‐1, or synaptobrevin‐2 in their axons. Among the 10 neurochemically defined axonal populations, a significantly greater proportion of vesicular acetylcholine transporter‐immunoreactive (VAChT‐IR) varicosities (80% ± 1.7%, n = 4, P < 0.001) contained α‐synuclein immunoreactivity, and a significantly greater proportion of α‐synuclein‐IR axons also contained VAChT immunoreactivity (78% ± 1.3%, n = 4) compared with any of the other nine populations (P < 0.001). Among synaptophysin‐, synaptotagmin‐1‐, synaptobrevin‐2‐, and CSPα‐IR varicosities, 98% ± 0.7%, 96% ± 0.7%, 88% ± 1.6%, and 85% ± 2.9% (n = 4) contained α‐synuclein immunoreactivity, respectively. Among α‐synuclein‐IR varicosities, 96% ± 0.9%, 99% ± 0.6%, 83% ± 1.9%, and 87% ± 2.3% (n = 4) contained synaptophysin‐, synaptotagmin‐1‐, synaptobrevin‐2‐, and CSPα immunoreactivity, respectively. We report a close association between the expression of α‐synuclein and the expression of other synaptic proteins in cholinergic axons in the guinea pig ileum. Selective expression of α‐synuclein may relate to the neurotransmitter system utilized and predispose cholinergic enteric neurons to degeneration in Parkinson's disease. J. Comp. Neurol. 521:2523–2537, 2013. © 2013 Wiley Periodicals, Inc.     

Uncovering novel actors in astrocyte–neuron crosstalk in Parkinson's disease: the Wnt/β‐catenin signaling cascade as the common final pathway for neuroprotection and self‐repair

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive loss of dopaminergic (DAergic) neuronal cell bodies in the substantia nigra pars compacta and gliosis. The cause and mechanisms underlying the demise of nigrostriatal DAergic neurons are ill‐defined, but interactions between genes and environmental factors are recognized to play a critical role in modulating the vulnerability to PD. Current evidence points to reactive glia as a pivotal factor in PD pathophysiology, playing both protective and destructive roles. Here, the contribution of reactive astrocytes and their ability to modulate DAergic neurodegeneration, neuroprotection and neurorepair in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) rodent model of PD will be discussed in the light of novel emerging evidence implicating wingless‐type mouse mammary tumor virus integration site (Wnt)/β‐catenin signaling as a strong candidate in MPTP‐induced nigrostriatal DAergic plasticity. In this work, we highlight an intrinsic Wnt1/frizzled‐1/β‐catenin tone that critically contributes to the survival and protection of adult midbrain DAergic neurons, with potential implications for drug design or drug action in PD. The dynamic interplay between astrocyte‐derived factors and neurogenic signals in MPTP‐induced nigrostriatal DAergic neurotoxicity and repair will be summarized, together with recent findings showing a critical role of glia–neural stem/progenitor cell (NPC) interactions aimed at overcoming neurodegeneration and inducing neurorestoration. Understanding the intrinsic plasticity of nigrostriatal DAergic neurons and deciphering the signals facilitating the crosstalk between astrocytes, microglia, DAergic neurons and NPCs may have major implications for the role of stem cell technology in PD, and for identifying potential therapeutic targets to induce endogenous neurorepair.     

Epidural premotor cortical stimulation in primary focal dystonia: Clinical and 18F‐fluoro deoxyglucose positron emission tomography open study

The aim of this study was to evaluate the efficacy and safety of epidural premotor stimulation in patients with primary focal dystonia. Seven patients were selected: 6 had cervical dystonia and 1 had right upper limb dystonia. In 2 patients, sustained muscle contractions led to a prevalently fixed head posture. Patients with cervical dystonia received a bilateral implant, whereas the patient with hand dystonia received a unilateral implant. Neurological and neuropsychological evaluations were performed before surgery (baseline), and 1, 3, 6, and 12 months afterward. The Burke‐Fahn‐Marsden scale (BFMS) and the Toronto Western spasmodic torticollis rating scale (TWSTRS) were administered at the same time points. Patients underwent resting ¹⁸F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) scans, before and 12 months after surgery. No adverse events occurred. An overall improvement was observed on the BFMS and TWSTRS after surgery. Patients with prevalently fixed cervical dystonia had a reduced benefit. Presurgical neuroimaging revealed a significant bilateral metabolic increase in the sensorimotor areas, which was reduced after surgery. © 2012 Movement Disorder Society     

Assessment of idiopathic rapid‐eye‐movement sleep behavior disorder by transcranial sonography,olfactory function test,and FP‐CIT‐SPECT

Idiopathic rapid‐eye‐movement (REM) sleep behavior disorder (iRBD) has been suggested to be a risk factor for subsequent development of neurodegenerative disorders, especially Parkinson's disease (PD) and other α‐synucleinopathies. At present, it is not possible to predict whether or not an iRBD patient will eventually develop PD. Here, we report 5 iRBD patients who underwent a test battery comprising a neurological examination (including UPDRS rating), mini mental state examination testing, transcranial sonography, olfactory function testing, and presynaptic dopamine transporter imaging with FP‐CIT‐SPECT. Our preliminary data show the diverse pattern of individual combinations of pathological findings when a multimodal assessment approach is applied in this patient group. Large‐size longitudinal studies in iRBD patients are required to evaluate the usefulness of diagnostic tests to identify the subgroup of iRBD patients that is prone to develop PD. © 2007 Movement Disorder Society     

Somatic alpha‐synuclein mutations in Parkinson's disease: Hypothesis and preliminary data

Alpha‐synuclein (SNCA) is crucial in the pathogenesis of Parkinson's disease (PD), yet mutations in the SNCA gene are rare. Evidence for somatic genetic variation in normal humans, also involving the brain, is increasing, but its role in disease is unknown. Somatic SNCA mutations, arising in early development and leading to mosaicism, could contribute to PD pathogenesis and yet be absent or undetectable in DNA derived from peripheral lymphocytes. Such mutations could underlie the widespread pathology in PD, with the precise clinical outcome dependent on their type and the timing and location of their occurrence. We recently reported a novel SNCA mutation (c.150T>G, p.H50Q) in PD brain‐derived DNA. To determine if there was mosaicism for this, a PCR and cloning strategy was used to take advantage of a nearby heterozygous intronic polymorphism. No evidence of mosaicism was found. High‐resolution melting curve analysis of SNCA coding exons, which was shown to be sensitive enough to detect low proportions of 2 known mutations, did not reveal any further mutations in DNA from 28 PD brain‐derived samples. We outline the grounds that make the somatic SNCA mutation hypothesis consistent with genetic, embryological, and pathological data. Further studies of brain‐derived DNA are warranted and should include DNA from multiple regions and methods for detecting other types of genomic variation. © 2013 The Authors. International Parkinson and Movement Disorder Society published by Wiley Periodicals, Inc.     

β‐amyloid in lewy body disease is related to Alzheimer's disease‐like atrophy

The aim of this study was to investigate whether amyloid deposition is associated with Alzheimer's disease (AD)‐like cortical atrophy in Lewy body (LB) disease (LBD). Participants included 15 LBD with dementia patients (8 with dementia with Lewy bodies [DLB] and 7 with Parkinson's disease [PD] with dementia [PDD]), 13 AD patients, and 17 healthy controls. Age, gender, and Mini–Mental State Examination scores were matched between patient groups. All subjects underwent PET scans with [¹¹C]Pittsburgh Compound B to measure brain amyloid deposition as well as three‐dimensional T1‐weighted MRI. Gray‐matter volumes (GMVs) were estimated by voxel‐based morphometry. Volumes‐of‐interest analyses were also performed. Forty percent of the 15 DLB/PDD patients were amyloid positive, whereas all AD patients and none of the healthy controls were amyloid positive. Amyloid‐positive DLB/PDD and AD patients showed very similar patterns of cortical atrophy in the parahippocampal area and lateral temporal and parietal cortices, with 95.2% of cortical atrophy distribution being overlapped. In contrast, amyloid‐negative DLB/PDD patients had no significant cortical atrophy. Compared to healthy controls, parahippocampal GMVs were reduced by 26% in both the amyloid‐positive DLB/PDD and AD groups and by 10% in the amyloid‐negative DLB/PDD group. The results suggest that amyloid deposition is associated with AD‐like atrophy in DLB/PDD patients. Early intervention against amyloid may prevent or delay AD‐like atrophy in DLB/PDD patients with amyloid deposition. © 2012 Movement Disorder Society     

Coexistence of TDP‐43 and tau pathology in neurodegeneration with brain iron accumulation type 1 (NBIA‐1, formerly Hallervorden‐Spatz syndrome)

We report here an autopsy case of sporadic adult‐onset Hallervorden‐Spatz syndrome, also known as neurodegeneration with brain iron accumulation type 1 (NBIA1), without hereditary burden. A 49‐year‐old woman died after a 27‐year disease course. At the age of 22, she suffered from akinesia, resting tremor, and rigidity. At the age of 28, she was admitted to our hospital because of worsening parkinsonism and dementia. Within several years, she developed akinetic mutism. At the age of 49, she died of bleeding from a tracheostomy. Autopsy revealed a severely atrophic brain weighing 460 g. Histologically, there were iron deposits in the globus pallidus and substantia nigra pars reticulata, and numerous axonal spheroids in the subthalamic nuclei. Neurofibrillary tangles were abundant in the hippocampus, cerebral neocortex, basal ganglia, and brain stem. Neuritic plaques and amyloid deposits were absent. Lewy bodies and Lewy neurites, which are immunolabeled by anti‐α‐synuclein, were absent. We also observed the presence of TDP‐43‐positive neuronal perinuclear cytoplasmic inclusions, with variable frequency in the dentate gyrus granular cells, frontal and temporal cortices, and basal ganglia. TDP‐43‐positive glial cytoplasmic inclusions were also found with variable frequency in the frontal and temporal lobes and basal ganglia. The present case was diagnosed with adult‐onset NBIA‐1 with typical histological findings in the basal ganglia and brainstem. However, in this case, tau and TDP‐43 pathology was exceedingly more abundant than α‐synuclein pathology. This case contributes to the increasing evidence for the heterogeneity of NBIA‐1.