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1.  Autonomic complaints in patients with Restless Leg Syndrome 
Sleep medicine  2013;14(12):1413-1416.
Data regarding autonomic function in restless legs syndrome (RLS) is limited to heart rate and blood pressure changes in cases having periodic limb movements (PLMS).
We compared autonomic symptoms of 49 subjects with RLS vs. 291 Controls using the SCOPA-Autonomic questionnaire (23 items in six domains scored 0–3). The total score and domain scores were transformed to 0 to 100 points. Subjects with neurodegenerative disorders (i.e. dementia, parkinsonism) were excluded.
The RLS group was younger (mean±SD 77.9 ± 8.0 vs. 80.5 ± 7.9 yrs, p=.03) and had more women (84% vs. 69%, p=.04). The mean SCOPA-Aut Total score was higher in the RLS group compared with Controls (20 ± 11 vs. 16 ± 9, p= .005). Additionally the RLS group had abnormalities in GI, cardiovascular, and pupillomotor domains. When comparing the percentage of subjects with any complaint on individual questions (score of ≥ 1) the RLS group had a greater number of subjects with sialorrhea, constipation, early abdominal fullness, lightheadedness when standing, and heat intolerance.
Autonomic complaints, especially GI, cardiovascular, and oversensitivity to light, are significantly increased in subjects with RLS. Causes for autonomic dysfunction in RLS require further investigation.
PMCID: PMC4105217  PMID: 24152795
Restless Leg Syndrome; Autonomic symptoms
2.  Prevalence of Hippocampal Sclerosis in a Clinicopathologically Characterized Cohort 
Hippocampal sclerosis (HS) is a neuropathological finding that frequently occurs with pathologies, such as Alzheimer's disease (AD). Prevalence estimates of HS in autopsy-confirmed dementia samples have varied between 0.4% and 24.5%. However, the prevalence of HS within other pathologic groups has not been well characterized.
Utilizing a sample of 910 prospectively followed and clinicopathologically confirmed dementia cases, we determined the prevalence of HS among the sample and within specific pathologic groups. HS prevalence of the sample was compared to reported HS prevalence rates in other autopsy-confirmed dementia samples.
The age range of the sample was 43 to 106 years, with a mean of 81.49±8.45. Of the 910 cases, 505 were male and 405 were female. For the entire sample, the average educational level was 14.59±2.65years. Of the 910 individuals, 47 (5.16%) cases had HS pathology present at autopsy. Among the 561 AD cases, 26 (4.43%) had HS pathology present. The frontotemporal dementia (FTD)/Pick's group had the highest percentage of cases with HS pathology (23.08%) followed by primary progressive aphasia (PPA) (16.67%) and Parkinson's disease with dementia (PDD) (5.34%). The HS prevalence rate of this study was not significantly different from all but 2 studies.
The prevalence of HS pathology in this sample of autopsy-confirmed dementia cases was similar to other reported HS prevalence rates. This study is the first to report the presence of HS pathology in PDD cases.
PMCID: PMC4196704  PMID: 25324686
hippocampal sclerosis; dementia; neuropathology; TDP-43; Alzheimer's disease; Parkinson's disease
3.  Profiles of Extracellular miRNA in Cerebrospinal Fluid and Serum from Patients with Alzheimer's and Parkinson's Diseases Correlate with Disease Status and Features of Pathology 
PLoS ONE  2014;9(5):e94839.
The discovery and reliable detection of markers for neurodegenerative diseases have been complicated by the inaccessibility of the diseased tissue- such as the inability to biopsy or test tissue from the central nervous system directly. RNAs originating from hard to access tissues, such as neurons within the brain and spinal cord, have the potential to get to the periphery where they can be detected non-invasively. The formation and extracellular release of microvesicles and RNA binding proteins have been found to carry RNA from cells of the central nervous system to the periphery and protect the RNA from degradation. Extracellular miRNAs detectable in peripheral circulation can provide information about cellular changes associated with human health and disease. In order to associate miRNA signals present in cell-free peripheral biofluids with neurodegenerative disease status of patients with Alzheimer's and Parkinson's diseases, we assessed the miRNA content in cerebrospinal fluid and serum from postmortem subjects with full neuropathology evaluations. We profiled the miRNA content from 69 patients with Alzheimer's disease, 67 with Parkinson's disease and 78 neurologically normal controls using next generation small RNA sequencing (NGS). We report the average abundance of each detected miRNA in cerebrospinal fluid and in serum and describe 13 novel miRNAs that were identified. We correlated changes in miRNA expression with aspects of disease severity such as Braak stage, dementia status, plaque and tangle densities, and the presence and severity of Lewy body pathology. Many of the differentially expressed miRNAs detected in peripheral cell-free cerebrospinal fluid and serum were previously reported in the literature to be deregulated in brain tissue from patients with neurodegenerative disease. These data indicate that extracellular miRNAs detectable in the cerebrospinal fluid and serum are reflective of cell-based changes in pathology and can be used to assess disease progression and therapeutic efficacy.
PMCID: PMC4010405  PMID: 24797360
4.  PET imaging of amyloid with Florbetapir F 18 and PET imaging of dopamine degeneration with 18F-AV-133 (florbenazine) in patients with Alzheimer’s disease and Lewy body disorders 
BMC Neurology  2014;14:79.
Biomarkers based on the underlying pathology of Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB) have the potential to improve diagnosis and understanding of the substrate for cognitive impairment in these disorders. The objective of this study was to compare the patterns of amyloid and dopamine PET imaging in patients with AD, DLB and Parkinson’s disease (PD) using the amyloid imaging agent florbetapir F 18 and 18F-AV-133 (florbenazine), a marker for vesicular monamine type 2 transporters (VMAT2).
Patients with DLB and AD, Parkinson’s disease (PD) and healthy controls (HC) were recruited for this study. On separate days, subjects received intravenous injections of florbetapir, and florbenazine. Amyloid burden and VMAT2 density were assessed quantitatively and by binary clinical interpretation. Imaging results for both tracers were compared across the four individual diagnostic groups and for combined groups based on underlying pathology (AD/DLB vs. PD/HC for amyloid burden and PD/DLB vs. AD/HC for VMAT binding) and correlated with measures of cognition and parkinsonism.
11 DLB, 10 AD, 5 PD, and 5 controls participated in the study. Amyloid binding was significantly higher in the combined AD/DLB patient group (n = 21) compared to the PD/HC groups (n = 10, mean SUVr: 1.42 vs. 1.07; p = 0.0006). VMAT2 density was significantly lower in the PD/DLB group (n = 16) compared to the AD/ HC group (n = 15; 1.83 vs. 2.97; p < 0.0001). Within the DLB group, there was a significant correlation between cognitive performance and striatal florbenazine binding (r = 0.73; p = 0.011).
The results of this study show significant differences in both florbetapir and florbenazine imaging that are consistent with expected pathology. In addition, VMAT density correlated significantly with cognitive impairment in DLB patients ( identifier: NCT00857506, registered March 5, 2009).
PMCID: PMC4027995  PMID: 24716655
PET imaging; Alzheimer’s disease; Parkinson’s disease; Biomarkers
5.  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.
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
6.  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.
PMCID: PMC3571631  PMID: 23334596
α-Synuclein; Biomarker; Clinical trial; Deep brain stimulation; Gene therapy; Lewy body; Parkinson disease; Surgery; Transplantation
7.  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.
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
8.  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.
PMCID: PMC3813773  PMID: 24204929
9.  Bid signal pathway components are identified in the temporal cortex with Parkinson disease 
Neurology  2012;79(17):1767-1773.
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.
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).
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.
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.
PMCID: PMC3475620  PMID: 23019260
10.  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.
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
11.  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.
PMCID: PMC3681206  PMID: 22889670
2D-DIGE; cerebrospinal fluid; Parkinson's disease; proteomics
12.  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.
PMCID: PMC3358551  PMID: 22588389
Dysphagia; Fiber types; Immunohistochemistry; Muscle fiber atrophy; Myosin heavy chain isoforms; Parkinson disease; Pharyngeal constrictor muscles; Swallowing; Upper esophageal sphincter
13.  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.
To compare autonomic function of subjects with Parkinson’s disease (PD) and essential tremor (ET) relative to controls.
It has been reported that patients with PD have autonomic dysfunction while no literature exists regarding autonomic function in ET.
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.
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.
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.
PMCID: PMC3665503  PMID: 22771283
Autonomic dysfunction; Parkinson’s disease; Essential tremor
14.  Essential tremor is not a neurodegenerative disease 
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.
PMCID: PMC3478956  PMID: 23105950
15.  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.
PMCID: PMC3603385  PMID: 23533154
Parkinson’s disease; biomarkers; ventricular cerebrospinal fluid; apolipoprotein A-1; p-tau181/Aβ42 ratio
16.  Brain biochemistry in autopsied patients with essential tremor 
Movement Disorders  2011;27(1):113-117.
The pathology of essential tremor is increasingly being studied; however, there are limited studies of biochemical changes in this condition.
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.
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.
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.
PMCID: PMC3261329  PMID: 22038525
tremor; pathology; GABA; norepinephrine
17.  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.
PMCID: PMC3423968  PMID: 22924088
striatum; Lewy body; diagnosis; autopsy; neuropathology; biomarker
18.  Incidental Lewy Body Disease: Electrophysiological Findings Suggesting Pre-clinical Lewy Body Disorders 
Evaluate electrophysiologic findings in incidental Lewy Body disease (ILBD).
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.
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).
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.
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.
PMCID: PMC3164932  PMID: 21616709
Lewy body; Electromyography; Electroencephalography; Pathology; Parkinson's disease; Tremor
19.  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).
PMCID: PMC3081521  PMID: 21168929
Timing; Motor control; Drawing; Cues; Movement disorders
20.  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.
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.
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).
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%).
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.
PMCID: PMC3119772  PMID: 21482171
Parkinson’s disease; REM sleep behavior disorder; essential tremor; restless legs syndrome; excessive daytime sleepiness
21.  Parkinson’s Disease, Cortical Dysfunction, and Alpha-Synuclein 
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.
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.
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.
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.
PMCID: PMC3154995  PMID: 21542019
22.  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
23.  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.
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

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