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1.  α-Synuclein Pathology and Axonal Degeneration of the Peripheral Motor Nerves Innervating Pharyngeal Muscles in Parkinson’s Disease 
Parkinson’s disease (PD) is a neurodegenerative disease primarily characterized by cardinal motor symptoms and central nervous system pathology. As current drug therapies can often stabilize these cardinal motor symptoms attention has shifted to the other motor and non-motor symptoms of PD which are resistant to drug therapy. Dysphagia in PD is perhaps the most important drug resistant symptom as it leads to aspiration and pneumonia, the leading cause of death. Here, we present direct evidence for degeneration of the pharyngeal motor nerves in PD. In this study, we examined the cervical vagal (X) nerve, pharyngeal branch of the X nerve (Ph-X), and pharyngeal plexus innervating the pharyngeal muscles in 14 postmortem specimens, 10 subjects with PD and 4 age-matched control subjects. Synucleinopathy in the pharyngeal nerves was detected using an immunohistochemical method for phosphorylated α-synuclein. α-Synuclein aggregates were revealed in the X nerve and Ph-X and immunoreactive intramuscular nerve twigs and axon terminals within the neuromuscular junctions were identified in all the PD subjects and in none of the controls. These findings indicate that the motor nervous system of the pharynx is involved in the pathological process of PD. Notably, PD subjects with dysphagia had a higher density of α-synuclein aggregates in the pharyngeal nerves as compared with those without dysphagia. Motor involvement of the pharynx in PD appears to be one of the factors leading to oropharyngeal dysphagia commonly seen in PD patients.
doi:10.1097/NEN.0b013e3182801cde
PMCID: PMC3552335  PMID: 23334595
α-Synuclein aggregates; Dysphagia; Immunohistochemistry; Intramuscular nerve twigs; Lewy bodies; Lewy neurites; Motor nerve; Nerve degeneration; Parkinson’s disease; Peripheral nervous system; Pharyngeal constrictor muscles; Pharyngeal plexus; Swallowing; Upper esophageal sphincter; Vagus nerve
2.  Submandibular Gland Biopsy for the Diagnosis of Parkinson Disease 
The clinical diagnosis of Parkinson disease (PD) is incorrect in 30% or more of subjects, particularly at the time of symptom onset. Because Lewy-type α-synucleinopathy (LTS) is present in the submandibular glands of PD patients, we assessed the feasibility of submandibular gland biopsy for diagnosing PD. We performed immunohistochemical staining for LTS in sections of large segments (simulating open biopsy) and needle cores of submandibular gland from 128 autopsied and neuropathologically classified subjects, including 28 PD, 5 incidental Lewy body disease, 5 progressive supranuclear palsy ([PSP] 3 with concurrent PD), 3 corticobasal degeneration, 2 multiple system atrophy, 22 Alzheimer disease with Lewy bodies (ADLB), 16 Alzheimer disease without Lewy bodies and 50 normal elderly. Immunoreactive nerve fibers were present in large submandibular gland sections of all 28 PD subjects (including 3 that also had PSP); 3 ADLB subjects were also positive, but none of the other subjects were positive. Cores from frozen submandibular glands taken with 18 gauge needles (total length 15–38 mm, between 10 and 118 sections per subject examined) were positive for LTS in 17 of 19 PD patients. These results suggest that biopsy of the submandibular gland may be a feasible means of improving PD clinical diagnostic accuracy. This would be particularly advantageous for subject selection in early-stage clinical trials, for invasive therapies or for verifying other biomarker studies.
doi:10.1097/NEN.0b013e3182805c72
PMCID: PMC3571631  PMID: 23334596
α-Synuclein; Biomarker; Clinical trial; Deep brain stimulation; Gene therapy; Lewy body; Parkinson disease; Surgery; Transplantation
3.  Changes in Properties of Serine 129 Phosphorylated α-Synuclein with Progression of Lewy Type Histopathology in Human Brains 
Experimental neurology  2012;240:190-204.
Modifications of α-synuclein resulting in changes in its conformation are considered to be key pathological events for Lewy body diseases (LBD), which include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). We have previously described a histopathological Unified Staging System for LBD that classifies the spread of α-synuclein phosphorylated at serine 129 (pS129-α-synuclein) from olfactory bulb to brainstem or limbic regions, and finally neocortex. Lewy bodies and Lewy neurites are highly enriched in pS129-α-synuclein. Increased formation of pS129-α-synuclein changes its solubility properties enhancing its tendency to aggregate and disrupt normal function. As in vitro and animal studies have shown that inhibiting formation of pS129-α-synuclein can prevent toxic consequences, this has become one of the therapeutic targets for LBD. However, detailed biochemical descriptions of the changes in pS129-α-synuclein properties in diseased human brains are needed to further our understanding of how these might contribute to molecular pathogenesis. In this study, we used 130 separate brain samples from cingulate cortex (limbic cortex) and 131 from temporal cortex (neocortex) that had been staged according to our Unified Staging System to examine progressive changes in properties of pS129-α-synuclein with the formation of progressively more severe histological Lewy-type pathology. The brain samples from these staged cases had been separated into cytosol-enriched, membrane-enriched (detergent soluble) and insoluble (ureas/SDS soluble) fractions. We also characterized the nature and appearance of higher molecular weight forms of pS129-α-synuclein. The major species was the 16 kD monomeric form; this accumulated with increasing stage with a large increase in Stage IV samples. By comparing two brain regions, we showed higher accumulation of insoluble pS129-α-synuclein in cingulate cortex, where histological deposits occur first, than in temporal cortex in samples with advanced (Stage IV) LB pathology.
doi:10.1016/j.expneurol.2012.11.020
PMCID: PMC3720241  PMID: 23201181
Western blots; Parkinson’s disease; antibodies; fractionation; post-translational modification; postmortem brain tissue; dementia with Lewy bodies; incidental Lewy body disease; pathogenesis; aggregation
4.  SMG1 Identified as a Regulator of Parkinson’s Disease-Associated alpha-Synuclein through siRNA Screening 
PLoS ONE  2013;8(10):e77711.
Synucleinopathies are a broad class of neurodegenerative disorders characterized by the presence of intracellular protein aggregates containing α-synuclein protein. The aggregated α-synuclein protein is hyperphosphorylated on serine 129 (S129) compared to the unaggregated form of the protein. While the precise functional consequences of S129 hyperphosphorylation are still being clarified, numerous in vitro and in vivo studies suggest that S129 phosphorylation is an early event in α-synuclein dysfunction and aggregation. Identifying the kinases and phosphatases that regulate this critical phosphorylation event may ultimately prove beneficial by allowing pharmacological mitigation of synuclein dysfunction and toxicity in Parkinson’s disease and other synucleinopathies. We report here the development of a high-content, fluorescence-based assay to quantitate levels of total and S129 phosphorylated α-synuclein protein. We have applied this assay to conduct high-throughput loss-of-function screens with siRNA libraries targeting 711 known and predicted human kinases and 206 phosphatases. Specifically, knockdown of the phosphatidylinositol 3-kinase related kinase SMG1 resulted in significant increases in the expression of pS129 phosphorylated α-synuclein (p-syn). Moreover, SMG1 protein levels were significantly reduced in brain regions with high p-syn levels in both dementia with Lewy bodies (DLB) and Parkinson’s disease with dementia (PDD). These findings suggest that SMG1 may play an important role in increased α-synuclein pathology during the course of PDD, DLB, and possibly other synucleinopathies.
doi:10.1371/journal.pone.0077711
PMCID: PMC3813773  PMID: 24204929
5.  Bid signal pathway components are identified in the temporal cortex with Parkinson disease 
Neurology  2012;79(17):1767-1773.
Objective:
Parkinson disease (PD), a devastating neurodegenerative disorder, affects motor abilities and cognition as well. It is not clear whether the proapoptotic protein, Bid, is involved in tumor necrosis factor death receptor I (TNFRI)–mediated destructive signal transduction pathways such as cell dysfunction or neurodegeneration in the temporal cortex of patients with PD.
Methods:
Molecular and biochemical approaches were used to dissect mitochondrial related components of the destructive signaling pathway in the temporal cortex from rapidly autopsied brains (postmortem interval mean 2.6 hours). Brains from patients with PD (n = 15) had an average age of 81.4 years, compared to the average age of 84.36 years in age-matched control patient brains (n = 15).
Results:
TNFRI and its adaptor protein, TRADD, were not only present in the cytoplasm of the temporal cortex, but were significantly elevated (42.3% and 136.1%, respectively) in PD brains compared to age-matched control brains. Bid in the PD temporal cortex could be further cleaved into tBid in the cytosol, which is translocated into the mitochondria, where cytochrome c is then released and caspase-3 is subsequently activated.
Conclusion:
Patients with PD have an activated Bid-mediated destructive signal pathway via TNFRI in the temporal cortex. Such deficits are pervasive, suggesting that they might contribute to cortex degeneration as PD manifests.
doi:10.1212/WNL.0b013e3182703f76
PMCID: PMC3475620  PMID: 23019260
6.  Parkinson Disease Affects Peripheral Sensory Nerves in the Pharynx 
Dysphagia is very common in patients with Parkinson’s disease (PD) and often leads to aspiration pneumonia, the most common cause of death in PD. Unfortunately, current therapies are largely ineffective for dysphagia. As pharyngeal sensation normally triggers the swallowing reflex, we examined pharyngeal sensory nerves in PD for Lewy pathology. Sensory nerves supplying the pharynx were excised from autopsied pharynges obtained from patients with clinically diagnosed and neuropathologically confirmed PD (n = 10) and healthy age-matched controls (n = 4). We examined: the glossopharyngeal nerve (IX); the pharyngeal sensory branch of the vagus nerve (PSB-X); and the internal superior laryngeal nerve (ISLN) innervating the laryngopharynx. Immunohistochemistry for phosphorylated α-synuclein was used to detect potential Lewy pathology. Axonal α-synuclein aggregates in the pharyngeal sensory nerves were identified in all of the PD subjects but not in the controls. The density of α-synuclein-positive lesions was significantly greater in PD subjects with documented dysphagia compared to those without dysphagia. In addition, α-synuclein-immunoreactive nerve fibers in the ISLN were much more abundant than those in the IX and PSBX. These findings suggest that pharyngeal sensory nerves are directly affected by the pathologic process of PD. This anatomic pathology may decrease pharyngeal sensation impairing swallowing and airway protective reflexes, thereby contributing to dysphagia and aspiration.
doi:10.1097/NEN.0b013e3182965886
PMCID: PMC3695629  PMID: 23771215
Alpha-synuclein aggregates; Dysphagia; Glossopharyngeal nerve; Immunohistochemistry; Internal superior laryngeal nerve; Lewy neurites; Nerve degeneration; Parkinson disease; Peripheral nervous system; Pharyngeal sensory nerves; Pharynx; Swallowing; Vagus nerve
7.  Cerebrospinal fluid biomarkers of neuropathologically diagnosed Parkinson's disease subjects 
Neurological research  2012;34(7):669-676.
1. Objectives
Parkinson's disease (PD) afflicts approximately 1-2% of the population over 50 years of age. No cures or effective modifying treatments exist and clinical diagnosis is currently confounded by a lack of definitive biomarkers. We sought to discover potential biomarkers in the cerebrospinal fluid (CSF) of neuropathologically confirmed PD cases.
2. Methods
We compared postmortem ventricular CSF (V-CSF) from PD and normal control (NC) subjects using two-dimensional difference gel electrophoresis (2D-DIGE). Spots exhibiting a 1.5-fold or greater difference in volume between PD patients and controls were excised from the 2D gels, subjected to tryptic digestion and identification of peptides assigned using mass spectrometric/data bank correlation methods.
3. Results
Employing this strategy six molecules: fibrinogen, transthyretin, apolipoprotein E, clusterin, apolipoprotein A-1 and glutathione-S-transferase-Pi were found to be different between PD and NC populations.
4: Discussion
These molecules have been implicated in PD pathogenesis. Combining biomarker data from multiple laboratories may create a consensus panel of proteins that may serve as a diagnostic tool for this neurodegenerative disorder.
doi:10.1179/1743132812Y.0000000063
PMCID: PMC3681206  PMID: 22889670
2D-DIGE; cerebrospinal fluid; Parkinson's disease; proteomics
8.  Altered Pharyngeal Muscles in Parkinson Disease 
Dysphagia (impaired swallowing) is common in Parkinson disease (PD) patients and is related to aspiration pneumonia, the primary cause of death in PD. Therapies that ameliorate the limb motor symptoms of PD are ineffective for dysphagia. This suggests that the pathophysiology of PD dysphagia may differ from that affecting limb muscles but little is known about potential neuromuscular abnormalities in the swallowing muscles in PD. This study examined the fiber histochemistry of pharyngeal constrictor (PC) and cricopharyngeal (CP) sphincter muscles in postmortem specimens from 8 PD and 4 age-matched control patients. Pharyngeal muscles in PD patients exhibited many atrophic fibers, fiber type grouping, and fast-to-slow myosin heavy chain transformation. These alterations indicate that the pharyngeal muscles experienced neural degeneration and regeneration over the course of PD. Notably, the PD patients with dysphagia had a higher percentage of atrophic myofibers vs. with those without dysphagia and controls. The fast-to-slow fiber type transition is consistent with abnormalities in swallowing, slow movement of food and increased tone in the CP sphincter in PD patients. The alterations in the pharyngeal muscles may play a pathogenic role in the development of dysphagia in PD patients.
doi:10.1097/NEN.0b013e318258381b
PMCID: PMC3358551  PMID: 22588389
Dysphagia; Fiber types; Immunohistochemistry; Muscle fiber atrophy; Myosin heavy chain isoforms; Parkinson disease; Pharyngeal constrictor muscles; Swallowing; Upper esophageal sphincter
9.  Autonomic function, as self-reported on the SCOPA-autonomic questionnaire, is normal in essential tremor but not in Parkinson’s disease 
Parkinsonism & related disorders  2012;18(10):1089-1093.
Objective
To compare autonomic function of subjects with Parkinson’s disease (PD) and essential tremor (ET) relative to controls.
Background
It has been reported that patients with PD have autonomic dysfunction while no literature exists regarding autonomic function in ET.
Methods
Subjects with PD, ET, and controls had autonomic function measured using the SCOPA-Autonomic questionnaire, with the total and domain scores transformed to a scale of 0–100 points.
Results
62 subjects with PD, 84 with ET, and 291 controls were included. Women were more prevalent in control (69%) compared to PD (44%) and ET (44%) groups, and mean age was significantly younger in PD (73 yrs) and older in ET (83) compared to controls (81). The mean SCOPA-Aut Total score in PD was significantly higher than controls, with no difference in ET. No autonomic dysfunction was found in any domain in ET but in PD there were significant abnormalities in gastrointestinal, cardiovascular, urinary, and thermoregulatory domains. Individual question data revealed a significantly higher percentage of subjects with dysfunction on 11/23 questions in the PD group but only 1 question (sialorrhea) in the ET group compared with controls.
Conclusion
Autonomic scores, particularly gastrointestinal, cardiovascular, urinary, and thermoregulatory were increased in patients with PD, as assessed by SCOPA-Aut. Patients with ET did not exhibit autonomic dysfunction, with the exception of sialorrhea.
doi:10.1016/j.parkreldis.2012.06.008
PMCID: PMC3665503  PMID: 22771283
Autonomic dysfunction; Parkinson’s disease; Essential tremor
10.  Essential tremor is not a neurodegenerative disease 
SUMMARY
The pathophysiology of essential tremor (ET) remains unknown. Standard neuropathological studies have reported no consistent changes but a detailed study found neurodegeneration in all ET cases – 24% demonstrated lower brainstem Lewy body (LB) inclusions and 76% experienced a loss of cerebellar Purkinje cells (PCs) and its sequelae. We review the evidence on neurodegeneration in ET. The prevalence of LB inclusions in ET brains is similar to that in the asymptomatic general population. These incidental LB disease cases have evidence for reduced striatal tyrosine hydroxylase levels, as found in Parkinson’s disease, but there is no evidence for reduced tyrosine hydroxylase levels in ET patients. Reduced mean PC counts in ET cases compared with the controls reported by some studies could not be replicated by others. Most ET cases have the same number of PCs as controls of a comparable age. Neither the lower brainstem LB inclusions nor the cerebellar PC loss represent the neurodegenerative basis of ET. Further studies are needed to determine the pathophysiology of ET.
doi:10.2217/nmt.12.23
PMCID: PMC3478956  PMID: 23105950
11.  Quantitative Appraisal of Ventricular Cerebrospinal Fluid Biomarkers in Neuropathologically Diagnosed Parkinson’s Disease Cases Lacking Alzheimer’s Disease Pathology 
Biomarker Insights  2013;8:19-28.
Identifying biomarkers that distinguish Parkinson’s disease (PD) from normal control (NC) individuals has the potential to increase diagnostic sensitivity for the detection of early-stage PD. A previous proteomic study identified potential biomarkers in postmortem ventricular cerebrospinal fluid (V-CSF) from neuropathologically diagnosed PD subjects lacking Alzheimer’s disease (AD) neuropathology. In the present study, we assessed these biomarkers as well as p-tau181, Aβ42, and S100B by ELISA in PD (n = 43) and NC (n = 49) cases. The p-tau181/Aβ42 ratio and ApoA-1 showed statistically significant differences between groups. Multiple regression analysis demonstrated that p-tau181/Aβ42 had a significant odds ratio: OR = 1.42 (95% confidence interval [CI], 1.12–1.84), P = 0.006. Among the molecules investigated, intriguing correlations were observed that require further investigation. Our results suggest coexistent AD CSF biomarkers within the PD group notwithstanding that it was selected to minimize AD neuropathological lesions.
doi:10.4137/BMI.S11422
PMCID: PMC3603385  PMID: 23533154
Parkinson’s disease; biomarkers; ventricular cerebrospinal fluid; apolipoprotein A-1; p-tau181/Aβ42 ratio
12.  Brain biochemistry in autopsied patients with essential tremor 
Movement Disorders  2011;27(1):113-117.
Background
The pathology of essential tremor is increasingly being studied; however, there are limited studies of biochemical changes in this condition.
Methods
We studied several candidate biochemical/anatomical systems in the brainstem, striatum and cerebellum of 23 essential tremor subjects who came to autopsy, comparing them to a control population.
Results
Striatal tyrosine hydroxylase, a marker of dopaminergic neurons, was 91.7 ±113.2 ng/mg versus 96.4±102.7 ng/mg (not significant) in cases and controls. Locus ceruleus dopamine beta-hydroxylase, a marker of noradrenergic neurons, was not significantly different between essential tremor and control groups. Parvalbumin, a marker of GABAergic neurons, was 199.3±42.0 versus 251.4±74.8 ng/mg (p=0.025) in the pons in the region of the locus ceruleus of essential tremor versus controls, while there was no difference in cerebellar parvalbumin.
Conclusion
These results are supportive of a possible role for reduced GABAergic function within the locus ceruleus in essential tremor. The hypothesis that essential tremor represents early Parkinson’s disease was not supported as striatal dopaminergic markers were not reduced compared to control subjects.
doi:10.1002/mds.24004
PMCID: PMC3261329  PMID: 22038525
tremor; pathology; GABA; norepinephrine
13.  Presence of Striatal Amyloid Plaques in Parkinson’s Disease Dementia Predicts Concomitant Alzheimer’s Disease: Usefulness for Amyloid Imaging 
Dementia is a frequent complication of Parkinson’s disease (PD). About half of PD dementia (PDD) is hypothesized to be due to progression of the underlying Lewy body pathology into limbic regions and the cerebral cortex while the other half is thought to be due to coexistent Alzheimer’s disease. Clinically, however, these are indistinguishable. The spread of amyloid plaques to the striatum has been reported to be a sensitive and specific indicator of dementia due to Alzheimer’s disease (AD). The purpose of the present study was to determine if the presence of striatal plaques might also be a useful indicator of the presence of diagnostic levels of AD pathology within PD subjects. We analyzed neuropathologically-confirmed cases of PD without dementia (PDND, N = 31), PDD without AD (PDD, N = 31) and PD with dementia meeting clinicopathological criteria for AD (PDAD, N =40). The minimum diagnostic criterion for AD was defined as including a clinical history of dementia, moderate or frequent CERAD cortical neuritic plaque density and Braak neurofibrillary stage III–VI. Striatal amyloid plaque densities were determined using Campbell-Switzer and Thioflavine S stains. Striatal plaque densities were significantly higher in PDAD compared to PDD (p<0.001). The presence of striatal plaques was approximately 80% sensitive and 80% specific for predicting AD. In comparison, the presence of cerebral cortex plaques alone was highly sensitive (100%) but had poor specificity (48% to 55%). The results suggest that striatal amyloid imaging may be clinically useful for making the distinction between PDD and PDAD.
doi:10.3233/JPD-2012-11073
PMCID: PMC3423968  PMID: 22924088
striatum; Lewy body; diagnosis; autopsy; neuropathology; biomarker
14.  Incidental Lewy Body Disease: Electrophysiological Findings Suggesting Pre-clinical Lewy Body Disorders 
Objective
Evaluate electrophysiologic findings in incidental Lewy Body disease (ILBD).
Methods
ILBD, Control, and Parkinson's disease (PD) subjects had electrophysiological evaluation within two years prior to autopsy. Data analyzed included surface electromyography (EMG) of upper extremity muscles during rest and muscle activation, and electroencephalography (EEG) recording at rest. For EMG, gross tracings and spectral peaks were analyzed. EEG measures analyzed were background frequency and power in delta, theta, alpha, and beta bands.
Results
Three of ten ILBD subjects (30%) showed unilateral rhythmic EMG discharges at rest without a visually apparent rest tremor. The ILBD resting EMG frequency was lower than in the Control group with no overlap (P=0.03) and close to that of the PD group. The ILBD group had significantly lower background rhythm frequency than the Control group (P=0.001) but was greater than the PD group (P=0.01).
Conclusions
The electrophysiologic changes in ILBD cases are between those of Control and PD, suggesting that these findings may reflect changes correlating with ILBD as a possible precursor to PD.
Significance
Electrophysiologic changes in ILBD may assist with the identification of a preclinical stage for Lewy body disorders and help the development of a therapeutic agent for modifying Lewy body disease progression.
doi:10.1016/j.clinph.2011.03.033
PMCID: PMC3164932  PMID: 21616709
Lewy body; Electromyography; Electroencephalography; Pathology; Parkinson's disease; Tremor
15.  Auditory instructional cues benefit unimanual and bimanual drawing in Parkinson’s disease patients 
Human movement science  2010;30(4):770-782.
The present study investigated performance of unimanual and bimanual anti-phase and in-phase upper limb line drawing using three different types of cues. Fifteen Parkinson’s disease (PD) patients, 15 elderly, and 15 young adults drew lines away from and towards their body on a tabletop every 1000 ms for 30 s under three different cueing conditions: (1) verbal (‘up’, ‘down’); (2) auditory (high tone, low tone); (3) visual (target line switched from top to bottom). PD patients had larger and more variable amplitudes which may be related to the finding that they also produced more curvilinear movements than young and elderly adults. Consistent with previous research, when compared to the elderly and young adult group PD patients produced a mean relative phase which deviated more from the instructed coordination modes and they showed larger variability of relative phase in bimanual coordination, especially in anti-phase conditions. For all groups, auditory and verbal cues resulted in lower coefficient of variance of cycle time, lower variability of amplitude and lower variability of relative phase than visual cues. The benefit of auditory cues may be related to the timing nature of the task or factors related to the auditory cues (e.g., reduced attentional demands, more kinesthetic focus).
doi:10.1016/j.humov.2010.08.018
PMCID: PMC3081521  PMID: 21168929
Timing; Motor control; Drawing; Cues; Movement disorders
16.  Probable RBD is Increased in Parkinson’s Disease But Not in Essential Tremor or Restless Legs Syndrome 
Parkinsonism & related disorders  2011;17(6):456-458.
Objective
Compare the frequency of REM sleep behavior disorder (RBD) and excessive daytime sleepiness (EDS) in Parkinson’s disease (PD), restless legs syndrome (RLS), essential tremor (ET), and control subjects.
Methods
Subjects enrolled in a longitudinal clinicopathologic study, and when available an informant, completed the Mayo Sleep Questionnaire, which asks “Have you ever been told that you act out your dreams?”, and the Epworth Sleepiness Scale (ESS).
Results
Probable RBD (based on informant response to the questionnaire) was much more frequent in PD (34/49, 69%, p<0.001) than in RLS (6/30, 20%), ET (7/53, 13%), or control subjects (23/175, 13%), with an odds ratio of 11 for PD compared to controls. The mean ESS and the number of subjects with an ESS ≥ 10 was higher in PD (29/60, 48%, p<0.001) and RLS (12/39, 31%, p<0.001) compared with ET (12/93, 13%) and Controls (34/296, 11%).
Conclusions
Probable RBD is much more frequent in PD with no evidence to suggest an increase in either RLS or ET. Given the evidence that RBD is a synucleinopathy, the lack of an increased frequency of RBD in subjects with ET or RLS suggests the majority of ET and RLS subjects are unlikely to be at increased risk for developing PD.
doi:10.1016/j.parkreldis.2011.03.007
PMCID: PMC3119772  PMID: 21482171
Parkinson’s disease; REM sleep behavior disorder; essential tremor; restless legs syndrome; excessive daytime sleepiness
17.  Parkinson’s Disease, Cortical Dysfunction, and Alpha-Synuclein 
Background
The ability to understand how Parkinson’s disease (PD) neurodegeneration leads to cortical dysfunction will be critical for developing therapeutic advances in PD dementia (PD-D). The overall purpose of this project was to study the small amplitude cortical myoclonus in PD as an in vivo model of focal cortical dysfunction secondary to PD neurodegeneration. The objectives were to test the hypothesis that cortical myoclonus in PD is linked to abnormal levels of α-synuclein in primary motor cortex and to define its relationship to various biochemical, clinical, and pathological measures.
Methods
Primary motor cortex was evaluated for 11 PD subjects with (PD+Myoclonus group) and 8 without (PD group) electrophysiologically confirmed cortical myoclonus 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 primary motor cortex.
Results
A 36% increase in α-synuclein was found in the motor cortex of PD+Myoclonus cases when compared to PD 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.
Conclusions
These results suggest an association between elevated α-synuclein and the dysfunctional physiology arising from the motor cortex in PD+Myoclonus cases. Alzheimer’s disease pathology was not associated with cortical myoclonus in PD. Cortical myoclonus arising from motor cortex is a model to study cortical dysfunction in PD.
doi:10.1002/mds.23697
PMCID: PMC3154995  PMID: 21542019
18.  Latrepirdine, a potential novel treatment for Alzheimer’s disease and Huntington’s chorea 
Latrepirdine (Dimebon) is a novel compound currently under development by Medivation Inc and Pfizer Inc for the treatment of Alzheimer’s disease and Huntington’s chorea. Originally developed and marketed as an antihistamine in Russia, it has potential for the treatment of neurodegenerative diseases. Early research suggested that the mechanism of action is centered on AChE inhibition and NMDA antagonism. Newer research casts some doubt regarding these early findings and other mechanisms of action have been proposed and investigated. In phase II clinical trials, latrepirdine demonstrated clinically relevant improvements in patients with Alzheimer’s disease and Huntington’s chorea. At the time of publication, phase III clinical trials had been initiated. Given the robustness of the phase II clinical data, latrepirdine has a high likelihood of success in phase III trials and in subsequently being granted regulatory approval.
PMCID: PMC3346261  PMID: 20047162
19.  Multi-organ distribution of phosphorylated α-synuclein histopathology in subjects with Lewy body disorders 
Acta neuropathologica  2010;119(6):689-702.
A sensitive immunohistochemical method for phosphorylated α-synuclein was used to stain sets of sections of spinal cord and tissue from 41 different sites in the bodies of 92 subjects, including 23 normal elderly, 7 with incidental Lewy body disease (ILBD), 17 with Parkinson’s disease (PD), 9 with dementia with Lewy bodies (DLB), 19 with Alzheimer’s disease with Lewy bodies (ADLB) and 17 with Alzheimer’s disease with no Lewy bodies (AD-NLB). The relative densities and frequencies of occurrence of phosphorylated α-synuclein histopathology (PASH) were tabulated and correlated with diagnostic category. The greatest densities and frequencies of PASH occurred in the spinal cord, followed by the paraspinal sympathetic ganglia, the vagus nerve, the gastrointestinal tract and endocrine organs. The frequency of PASH within other organs and tissue types was much lower. Spinal cord and peripheral PASH was most common in subjects with PD and DLB, where it appears likely that it is universally widespread. Subjects with ILBD had lesser densities of PASH within all regions, but had frequent involvement of the spinal cord and paraspinal sympathetic ganglia, with less-frequent involvement of end-organs. Subjects with ADLB had infrequent involvement of the spinal cord and paraspinal sympathetic ganglia with rare involvement of end-organs. Within the gastrointestinal tract, there was a rostrocaudal gradient of decreasing PASH frequency and density, with the lower esophagus and submandibular gland having the greatest involvement and the colon and rectum the lowest.
doi:10.1007/s00401-010-0664-3
PMCID: PMC2866090  PMID: 20306269
Parkinson’s disease; Parkinsonism; Dementia with Lewy bodies; Alzheimer’s disease; Incidental Lewy bodies; α-Synuclein; Spinal cord; Sympathetic nervous system; Peripheral nervous system; Autonomic nervous system; Enteric nervous system; Submandibular gland; Esophagus; Adrenal gland; Heart; Stomach; Gastrointestinal system
22.  Incidental Lewy Body Disease: Clinical Comparison to a Control Cohort 
Limited clinical information has been published on cases pathologically diagnosed with incidental Lewy body disease (ILBD). Standardized, longitudinal movement and cognitive data was collected on a cohort of subjects enrolled in the Sun Health Research Institute Brain and Body Donation Program. Of 277 autopsied subjects who had antemortem clinical evaluations within the previous 3 years, 76 did not have Parkinson’s disease, a related disorder, or dementia of which 15 (20%) had ILBD. Minor extrapyramidal signs were common in subjects with and without ILBD. Cognitive testing revealed an abnormality in the ILBD group in the Trails B test only. ILBD cases had olfactory dysfunction; however, sample size was very small. This preliminary report revealed ILBD cases have movement and cognitive findings that for the most part were not out of proportion to similarly assessed and age-similar cases without Lewy bodies. Larger sample size is needed to have the power to better assess group differences.
doi:10.1002/mds.22971
PMCID: PMC2935627  PMID: 20175211
incidental Lewy body disease; Lewy bodies; Parkinson’s disease; demential with Lewy bodies
23.  No Evidence for Cognitive Dysfunction or Depression in Patients with Mild Restless Legs Syndrome 
Restless legs syndrome is a common disoder that may interrupt sleep and has been reported to produce daytime fatigue and/or mood changes. This study assessed whether patients with RLS have more cognitive dysfunction and depression than individuals of the same age and education who do not have RLS. The study showed that older individuals with mild RLS for at least 1 year do not have cognitive dysfunction and are not depressed compared with a control group of similar age and education.
doi:10.1002/mds.22701
PMCID: PMC2935658  PMID: 19609905
restless legs syndrome; cognitive dysfunction
24.  Parkinson's disease with dementia: comparing patients with and without Alzheimer pathology 
Subjects with Parkinson's disease (PD) frequently develop dementia with greater than one-third meeting neuropathologic diagnostic criteria for Alzheimer's disease (AD). The objective is to identify clinical and neuropathological differences between PDD (PD with dementia) subjects, with and without coexistent AD pathology. Neuropathologic examination was available on subjects diagnosed by clinicopathologic criteria with PDD-AD (N = 23) and PDD+AD (N = 28). A small subset of subjects with PDD-AD and PDD+AD had received at least one standardized neuropsychological assessment. PDD+AD subjects were significantly older at age of PD onset and death, progressed to onset of dementia in less time, and had a shorter duration of PD symptoms prior to the onset of dementia. Education, responsiveness of L-Dopa and dopaminergic medications, presence of cognitive fluctuations and hallucinations, mean MMSE, GDS, FAST and UPDRS scores did not differ significantly between the two groups. The PDD+AD group had significantly greater total plaques, neuritic plaques, total tangles, and Braak stages compared to PDD-AD. This study suggests that it is difficult to distinguish PDD+AD and PDD-AD on the basis of movement, clinical, and neuropsychological assessment. PDD-AD and PDD+AD have similar degrees of dementia and approximately half of PDD subjects have enough AD pathology to attain a neuropathological diagnosis of AD. PDD can develop in the absence of significant Alzheimer pathology.
doi:10.1097/WAD.0b013e31819c5ef4
PMCID: PMC2760034  PMID: 19812474
Parkinson' disease with dementia; Alzheimer's Disease; Dementia with Lewy Bodies; assessment of dementia
25.  Correlation of Clinical Features with Argyrophilic Grains at Autopsy 
Argyrophilic grains (AGs) are a pathologic feature found in association with neurodegenerative disease. Some have suggested that these features may occur as a distinctive condition. We reviewed 80 subjects from our tissue bank with pathologically confirmed AGs and identified their clinical features. We compared these subjects' features to the features of subjects with matched clinical diagnoses but without AGs. Subjects with AGs represented 21.7% of the entire autopsy sample from 1999 through 2005 (80/367). Of AD subjects, 43 /233 had AGs (18.4% of AD subjects); 11 /42 PD-D subjects had AGs (26.1% of PDD subjects); 2 / 9 DLB subjects had AGs (22.2% of DLB subjects); 4 /15 MCI subjects had AGs (26.7% of MCI subjects); and 20 /68 cognitively normal subjects had AGs (29.4% of NC). Subjects with AGs tended to be older but only significantly so in AD. Many co-morbid non-neurological health conditions were seen in cases of AGs without any single predilection emerging. AGs occur in approximately 22% of the entire autopsy cohort and likely are associated with advanced age. No distinctive antemortem clinical features were overrepresented in the AG cases. AGs can occur with or without neurodegenerative conditions and can occur in the absence of significant cognitive decline. AGs are not clearly associated with any single co-morbid health condition.
doi:10.1097/WAD.0b013e318199d833
PMCID: PMC2760041  PMID: 19812464
Argyrophilic grains; dementia; neurodegeneration; neuropathology

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