Cerebrospinal fluid lysosomal enzymes and alpha‐synuclein in Parkinson's disease

To assess the discriminating power of multiple cerebrospinal fluid (CSF) biomarkers for Parkinson's disease (PD), we measured several proteins playing an important role in the disease pathogenesis. The activities of β‐glucocerebrosidase and other lysosomal enzymes, together with total and oligomeric α‐synuclein, and total and phosphorylated tau, were thus assessed in CSF of 71 PD patients and compared to 45 neurological controls. Activities of β‐glucocerebrosidase, β‐mannosidase, β‐hexosaminidase, and β‐galactosidase were measured with established enzymatic assays, while α‐synuclein and tau biomarkers were evaluated with immunoassays. A subset of PD patients (n = 44) was also screened for mutations in the β‐glucocerebrosidase‐encoding gene (GBA1). In the PD group, β‐glucocerebrosidase activity was reduced (P < 0.05) and patients at earlier stages showed lower enzymatic activity (P < 0.05); conversely, β‐hexosaminidase activity was significantly increased (P < 0.05). Eight PD patients (18%) presented GBA1 sequence variations; 3 of them were heterozygous for the N370S mutation. Levels of total α‐synuclein were significantly reduced (P < 0.05) in PD, in contrast to increased levels of α‐synuclein oligomers, with a higher oligomeric/total α‐synuclein ratio in PD patients when compared with controls (P < 0.001). A combination of β‐glucocerebrosidase activity, oligomeric/total α‐synuclein ratio, and age gave the best performance in discriminating PD from neurological controls (sensitivity 82%; specificity 71%, area under the receiver operating characteristic curve = 0.87). These results demonstrate the possibility of detecting lysosomal dysfunction in CSF and further support the need to combine different biomarkers for improving the diagnostic accuracy of PD. © 2014 International Parkinson and Movement Disorder Society     

High‐frequency oscillations in Parkinson's disease: Spatial distribution and clinical relevance

The pathophysiology of Parkinson's disease (PD) has been related to excessive beta band oscillations in the basal ganglia. Recent recordings from the subthalamic nucleus of PD patients showed that beta oscillations show strong cross‐frequency coupling with high‐frequency oscillations (>200 Hz). However, little is known about the characteristics and functional properties of these oscillations. We studied the spatial distribution of high‐frequency oscillations and their relation to PD motor symptoms. We included 10 PD patients in medication OFF who underwent implantation of deep brain stimulation (DBS) electrodes. Intraoperative five‐channel microelectrode recordings were performed at 9 to 10 recording sites within the subthalamic nucleus and its immediate surroundings. We found a focal spatial distribution of high‐frequency oscillations with highest power 2 mm below the dorsolateral border of the subthalamic nucleus. Within the subthalamic nucleus, power peaked slightly anterior to the DBS target site. In addition, contralateral akinesia/rigidity scores were negatively correlated with high‐frequency oscillation power. Our results demonstrate a focal origin of high‐frequency oscillations within the subthalamic nucleus and provide further evidence for their functional association with motor state. © 2014 International Parkinson and Movement Disorder Society     

Parkinson's disease,cortical dysfunction,and alpha‐synuclein

The ability to understand how Parkinson's disease neurodegeneration leads to cortical dysfunction will be critical for developing therapeutic advances in Parkinson's disease dementia. The overall purpose of this project was to study the small‐amplitude cortical myoclonus in Parkinson's disease as an in vivo model of focal cortical dysfunction secondary to Parkinson's disease neurodegeneration. The objectives were to test the hypothesis that cortical myoclonus in Parkinson's disease is linked to abnormal levels of α‐synuclein in the primary motor cortex and to define its relationship to various biochemical, clinical, and pathological measures. The primary motor cortex was evaluated for 11 Parkinson's disease subjects with and 8 without electrophysiologically confirmed cortical myoclonus (the Parkinson's disease + myoclonus group and the Parkinson's disease group, respectively) who had premortem movement and cognitive testing. Similarly assessed 9 controls were used for comparison. Measurements for α‐synuclein, Aβ‐42 peptide, and other biochemical measures were made in the primary motor cortex. A 36% increase in α‐synuclein was found in the motor cortex of Parkinson's disease + myoclonus cases when compared with Parkinson's disease without myoclonus. This occurred without significant differences in insoluble α‐synuclein, phosphorylated to total α‐synuclein ratio, or Aβ‐42 peptide levels. Higher total motor cortex α‐synuclein levels significantly correlated with the presence of cortical myoclonus but did not correlate with multiple clinical or pathological findings. These results suggest an association between elevated α‐synuclein and the dysfunctional physiology arising from the motor cortex in Parkinson's disease + myoclonus cases. Alzheimer's disease pathology was not associated with cortical myoclonus in Parkinson's disease. Cortical myoclonus arising from the motor cortex is a model to study cortical dysfunction in Parkinson's disease. © 2011 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.     

Role of low‐ and high‐frequency oscillations in the human hippocampus for encoding environmental novelty during a spatial navigation task

The hippocampus plays a key role in the encoding and retrieval of information related to novel environments during spatial navigation. However, the neural basis for these processes in the human hippocampus remains unknown because it is difficult to directly measure neural signals in the human hippocampus. This study investigated hippocampal neural oscillations involved in encoding novel environments during spatial navigation in a virtual environment. Seven epileptic patients with implanted intracranial hippocampal depth electrodes performed three sessions of virtual environment navigation. Each session consisted of a navigation task and a location‐recall task. The navigation task consisted of eight blocks, and in each block, the participant navigated to the location of four different objects and was instructed to remember the location of the objects. After the eight blocks were completed, a location‐recall task was performed for each of the four objects. Intracranial electroencephalography data were monitored during the navigation tasks. Theta (5–8 Hz) and delta (1–4 Hz) oscillations were lower in the first block (novel environment) than in the eighth block (familiar environment) of the navigation task, and significantly increased from block one to block eight. By contrast, low‐gamma (31–50 Hz) oscillations were higher in the first block than in the eighth block of the navigation task, and significantly decreased from block one to block eight. Comparison of sessions with high recall performance (low error between identified and actual object location) and low recall performance revealed that high‐gamma (51–100 Hz) oscillations significantly decreased from block one to block eight only in sessions with high recall performance. These findings suggest that delta, theta, and low‐gamma oscillations were associated with encoding of environmental novelty and high‐gamma oscillations were important for the successful encoding of environmental novelty. © 2014 Wiley Periodicals, Inc.     

Spinal cord stimulation improves forelimb use in an alpha-synuclein animal model of Parkinson's disease

Neuromodulation by spinal cord stimulation has been proposed as a symptomatic treatment for Parkinson's disease. We tested the chronic effects of spinal cord stimulation in a progressive model of Parkinson's based on overexpression of alpha-synuclein in the substantia nigra. Adult Sprague Dawley rats received unilateral injections of adeno-associated virus serotype 6 (AAV6) in the substantia nigra to express alpha-synuclein. Locomotion and forepaw use of the rats were evaluated during the next 10 weeks. Starting on week 6, a group of AAV6-injected rats received spinal cord stimulation once a week. At the end of the experiment, tyrosine hydroxylase and alpha-synuclein immunostaining were performed. Rats with unilateral alpha-synuclein expression showed a significant decrease in the use of the contralateral forepaw, which was mildly but significantly reverted by spinal cord stimulation applied once a week from the 6th to the 10th week after the AAV6 injection. Long-term spinal cord stimulation proved to be effective to suppress or delay motor symptoms in a sustained and progressive model of Parkinson's and might become an alternative, less invasive neuromodulation option to treat this disease.     

A sporadic case of Creutzfeldt–Jakob disease with beta‐amyloid deposits and alpha‐synuclein inclusions

Neurodegenerative disorders are characterized by the correlation of clinical symptoms and neuropathological changes in the brain. However, overlaps between distinct entities are becoming more and more evident. We report the coexistence of Alzheimer pathology and alpha‐synuclein inclusions in a sporadic, methionine/valine type 1, Creutzfeldt–Jakob disease (CJD) case. There were neurofibrillary changes in the neocortex and beta amyloid cerebral angiopathy was marked. Several Lewy bodies were present in the substantia nigra, locus ceruleus and the dorsal motor nucleus of the vagus, and alpha‐synuclein cytoplasmic inclusions were also found in cortical neurons. These findings raise the debated relationship between Parkinson’s disease with dementia, dementia with Lewy bodies and a Lewy body variant of Alzheimer disease. Among the factors that may have contributed to this considerable morphological overlap are the patient’s age (79 years at autopsy) and the over 2‐year duration of the disease. As the average disease duration in sporadic methionine/valine type 1 CJD is less than 6 months, it seems legitimate to speculate that the initial symptoms resulted from Alzheimer and alpha‐synuclein related pathologies. This observation shows that CJD can be present in elderly patients who are suspected of having other neurodegenerative diseases, which could underline the importance of neuropathology‐based surveillance systems.     

Progression of intestinal permeability changes and alpha‐synuclein expression in a mouse model of Parkinson's disease

Parkinson's disease (PD) is a multifocal degenerative disorder for which there is no cure. The majority of cases are sporadic with unknown etiology. Recent data indicate that untreated patients with de novo PD have increased colonic permeability and that both de novo and premotor patients have pathological expression of α‐synuclein (α‐syn) in their colon. Both endpoints potentially can serve as disease biomarkers and even may initiate PD events through gut‐derived, lipopolysaccharide (LPS)‐induced neuronal injury. Animal models could be ideal for interrogating the potential role of the intestines in the pathogenesis of PD; however, few current animal models of PD encompass these nonmotor features. We sought to establish a progressive model of PD that includes the gastrointestinal (GI) dysfunction present in human patients. C57/BL6 mice were systemically administered one dose of either LPS (2.5 mg/kg) or saline and were sacrificed in monthly intervals (n = 5 mice for 5 months) to create a time‐course. Small and large intestinal permeability was assessed by analyzing the urinary output of orally ingested sugar probes through capillary column gas chromatography. α‐Syn expression was assessed by counting the number of mildly, moderately, and severely affected myenteric ganglia neurons throughout the GI tract, and the counts were validated by quantitative optical density measurements. Nigrostriatal integrity was assessed by tyrosine hydroxylase immunohistochemistry stereology and densitometry. LPS caused an immediate and progressive increase in α‐syn expression in the large intestine but not in the small intestine. Intestinal permeability of the whole gut (large and small intestines) progressively increased between months 2 and 4 after LPS administration but returned to baseline levels at month 5. Selective measurements demonstrated that intestinal permeability in the small intestine remained largely intact, suggesting that gut leakiness was predominately in the large intestine. Phosphorylated serine 129‐α‐syn was identified in a subset of colonic myenteric neurons at months 4 and 5. Although these changes were observed in the absence of nigrostriatal degeneration, an abrupt but insignificant increase in brainstem α‐syn was observed that paralleled the restoration of permeability. No changes were observed over time in controls. LPS, an endotoxin used to model PD, causes sequential increases in α‐syn immunoreactivity, intestinal permeability, and pathological α‐syn accumulation in the colon in a manner similar to that observed in patients with PD. These features are observed without nigrostriatal degeneration and incorporate PD features before the motor syndrome. This allows for the potential use of this model in testing neuroprotective and disease‐modifying therapies, including intestinal‐directed therapies to fortify intestinal barrier integrity. © 2013 International Parkinson and Movement Disorder Society     

Numerical working memory alters alpha‐beta oscillations and connectivity in the parietal cortices

Although the neural bases of numerical processing and memory have been extensively studied, much remains to be elucidated concerning the spectral and temporal dynamics surrounding these important cognitive processes. To further this understanding, we employed a novel numerical working memory paradigm in 28 young, healthy adults who underwent magnetoencephalography (MEG). The resulting data were examined in the time‐frequency domain prior to image reconstruction using a beamformer. Whole‐brain, spectrally‐constrained coherence was also employed to determine network connectivity. In response to the numerical task, participants exhibited robust alpha/beta oscillations in the bilateral parietal cortices. Whole‐brain statistical comparisons examining the effect of numerical manipulation during memory‐item maintenance revealed a difference centered in the right superior parietal cortex, such that oscillatory responses during numerical manipulation were significantly stronger than when no manipulation was necessary. Additionally, there was significantly reduced cortico‐cortical coherence between the right and left superior parietal regions during the manipulation compared to the maintenance trials, indicating that these regions were functioning more independently when the numerical information had to be actively processed. In sum, these results support previous studies that have implicated the importance of parietal regions in numerical processing, but also provide new knowledge on the spectral, temporal, and network dynamics that serve this critical cognitive function during active working memory maintenance.     

Alpha‐synuclein polymorphisms are associated with Parkinson's disease in a Saskatchewan population

Alpha‐synuclein gene (SNCA) mutations cause familial Parkinsonism but the role of SNCA variability in idiopathic Parkinson's disease (PD) remains incompletely defined. We report a study of SNCA genetic variation in 452 idiopathic PD cases and 245 controls. SNCA copy number mutations were not associated with early‐onset disease in this population. The minor allele “G” at rs356165 was associated with increased odds of PD (P = 0.013) and genetic variation in D4S3481 (Rep1) was associated with age of disease onset (P = 0.007). There was a trend toward association between variation at rs2583988 and rapid PD progression. © 2009 Movement Disorder Society