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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.  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
4.  Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease 
Brain  2013;136(8):2419-2431.
The pace of nigrostriatal degeneration, both with regards to striatal denervation and loss of melanin and tyrosine hydroxylase-positive neurons, is poorly understood especially early in the Parkinson’s disease process. This study investigated the extent of nigrostriatal degeneration in patients with Parkinson’s disease at different disease durations from time of diagnosis. Brains of patients with Parkinson’s disease (n = 28) with post-diagnostic intervals of 1–27 years and normal elderly control subjects (n = 9) were examined. Sections of the post-commissural putamen and substantia nigra pars compacta were processed for tyrosine hydroxylase and dopamine transporter immunohistochemistry. The post-commissural putamen was selected due to tissue availability and the fact that dopamine loss in this region is associated with motor disability in Parkinson’s disease. Quantitative assessments of putaminal dopaminergic fibre density and stereological estimates of the number of melanin-containing and tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta (both in total and in subregions) were performed by blinded investigators in cases where suitable material was available (n = 17). Dopaminergic markers in the dorsal putamen showed a modest loss at 1 year after diagnosis in the single case available for study. There was variable (moderate to marked) loss, at 3 years. At 4 years post-diagnosis and thereafter, there was virtually complete loss of staining in the dorsal putamen with only an occasional abnormal dopaminergic fibre detected. In the substantia nigra pars compacta, there was a 50–90% loss of tyrosine hydroxylase-positive neurons from the earliest time points studied with only marginal additional loss thereafter. There was only a ∼10% loss of melanized neurons in the one case evaluated 1 year post-diagnosis, and variable (30 to 60%) loss during the first several years post-diagnosis with more gradual and subtle loss in the second decade. At all time points, there were more melanin-containing than tyrosine hydroxylase-positive cells. Loss of dopaminergic markers in the dorsal putamen occurs rapidly and is virtually complete by 4 years post-diagnosis. Loss of melanized nigral neurons lags behind the loss of dopamine markers. These findings have important implications for understanding the nature of Parkinson’s disease neurodegeneration and for studies of putative neuroprotective/restorative therapies.
PMCID: PMC3722357  PMID: 23884810
Parkinsons disease; human brain; morphometry; substantia nigra; neuroscience
5.  Quantitative Measurement of Intact Alpha-Synuclein Proteoforms from Post-Mortem Control and Parkinson's Disease Brain Tissue by Intact Protein Mass Spectrometry 
Scientific Reports  2014;4:5797.
A robust top down proteomics method is presented for profiling alpha-synuclein species from autopsied human frontal cortex brain tissue from Parkinson's cases and controls. The method was used to test the hypothesis that pathology associated brain tissue will have a different profile of post-translationally modified alpha-synuclein than the control samples. Validation of the sample processing steps, mass spectrometry based measurements, and data processing steps were performed. The intact protein quantitation method features extraction and integration of m/z data from each charge state of a detected alpha-synuclein species and fitting of the data to a simple linear model which accounts for concentration and charge state variability. The quantitation method was validated with serial dilutions of intact protein standards. Using the method on the human brain samples, several previously unreported modifications in alpha-synuclein were identified. Low levels of phosphorylated alpha synuclein were detected in brain tissue fractions enriched for Lewy body pathology and were marginally significant between PD cases and controls (p = 0.03).
PMCID: PMC4107347  PMID: 25052239
7.  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
8.  Cervical dystonia and pain: characteristics and treatment patterns from CD PROBE (Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy) 
Journal of Neurology  2014;261(7):1309-1319.
To compare profiles of subjects with and without cervical dystonia (CD)-associated pain, to evaluate the contribution of pain and the motor component of CD on quality of life, and to compare the initial botulinum toxin treatment paradigm between pain groups, baseline data were used from the CD Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE), a multicenter, prospective, observational registry designed to capture real-world practices and outcomes for onabotulinumtoxinA CD treatment. Subjects were divided into no/mild pain [Pain Numeric Rating Scale (PNRS) score 0–3] and moderate/severe pain groups (PNRS score 4–10). Descriptive and differential statistics were utilized to compare groups. 1,037 subjects completed the first treatment session, reported baseline botulinum toxin status, and completed baseline PNRS. Those with no/mild pain were significantly older at baseline. Those subjects with moderate/severe pain had higher Toronto Western Spasmodic Torticollis Rating Scale Severity (17.7 ± 5.1 vs. 16.2 ± 5.6, p < 0.0001) and Disability (12.7 ± 6.1 vs. 7.5 ± 5.6, p < 0.0001). CD subjects with moderate/severe pain received a higher mean dose (177.3 ± 82.9 vs. 158.0 ± 67.1 U, p = 0.0001) of onabotulinumtoxinA and were injected in more muscles (4.1 ± 1.4 vs. 3.7 ± 1.2, p < 0.0001) at initial treatment. CD PROBE clearly demonstrates the frequency of pain in CD and substantiates its importance when determining an optimal treatment paradigm. Future analyses of CD PROBE will further our understanding of the treatment patterns and outcomes related to onabotulinumtoxinA therapy for this disabling condition.
Electronic supplementary material
The online version of this article (doi:10.1007/s00415-014-7343-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4098041  PMID: 24752807
Botulinum toxin; Cervical dystonia; Dystonia; Pain
9.  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
10.  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
11.  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
12.  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
13.  Genomic investigation of α-Synuclein multiplication and parkinsonism 
Annals of neurology  2008;63(6):10.1002/ana.21380.
Copy number variation is a common polymorphic phenomenon within the human genome. While the majority of these events are non-deleterious they can also be highly pathogenic. Herein we characterize five families with parkinsonism that have been identified to harbor multiplication of the chromosomal 4q21 locus containing the α-synuclein gene (SNCA).
A methodological approach employing fluorescent in situ hybridization (FISH) and Affymetrix 250K SNP microarrays (CHIPs) was used to characterize the multiplication in each family and identify the genes encoded within the region. The telomeric and centromeric breakpoints of each family were further narrowed using semi-quantitative PCR with microsatellite markers and then screened for transposable repeat elements.
The severity of clinical presentation is correlated with SNCA dosage and does not appear to be overtly effected by the presence of other genes in the multiplicated region. With the exception of the Lister kindred, in each family the multiplication event appears de novo. The type and position of Alu/LINE repeats are also different at each breakpoint. Microsatellite analysis demonstrates two genomic mechanisms are responsible for chromosome 4q21 multiplications, including both SNCA duplication and triplication.
SNCA dosage is responsible for parkinsonism, autonomic dysfunction and dementia observed within each family. We hypothesize dysregulated expression of wild-type α-synuclein results in parkinsonism and may explain the recent association of common SNCA variants in sporadic Parkinson’s disease. SNCA genomic duplication results from intra-allelic (segmental duplication) or inter-allelic recombination with unequal crossing-over, whereas both mechanisms appear to be required for genomic SNCA triplication.
PMCID: PMC3850281  PMID: 18571778
Parkinsonism; SNCA; Genomic multiplication; Alu repeat; Parkinson’s disease
14.  Parkinson’s disease is not associated with gastrointestinal myenteric ganglion neuron loss 
Acta neuropathologica  2012;124(5):665-680.
Gastrointestinal dysfunction is a prominent non-motor feature of Parkinson’s disease (PD) that contributes directly to the morbidity of patients, complicates management of motor symptoms, and may herald incipient PD in patients without motor disability. Although PD has traditionally been considered a disease of dopaminergic neurons in the substantia nigra, analyses of gastrointestinal samples from PD patients have consistently revealed pathology in the enteric nervous system (ENS). The relationship of PD pathology to GI dysmotility is poorly understood, and this lack of understanding has led to limited success in developing treatments for PD-related GI symptoms. We have quantitatively compared myenteric neuron density and relative abundance of NO, VIP, and catecholamine neurons between patients with PD and control individuals along the length of the GI tract. In addition, we have examined the frequency of GI α-synuclein neuritic pathology and its co-localization with the same neuronal markers. We have included a comparison with a small population of patients with incidental Lewy bodies (ILB) found at autopsy. These data indicate there is no neuronal loss in the myenteric plexus in PD. Lewy body pathology parallels parasympathetic autonomic input from the DMV, not the distribution of extrinsic sympathetic input or intrinsic enteric neurons, and is only rarely co-localized with tyrosine hydroxylase. These data provide a critical background to which further analyses of the effect of PD on the GI tract may be compared and suggest that neuropathology in myenteric neurons is unlikely to be a causative factor in PD-related GI dysmotility.
PMCID: PMC3473167  PMID: 22941241
enteric; gastrointestinal; nitric oxide; vasoactive intestinal peptide; catecholamine; acetylcholine; constipation; gastroparesis; Lewy body; synuclein
15.  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
16.  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
17.  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.
PMCID: PMC2935627  PMID: 20175211
incidental Lewy body disease; Lewy bodies; Parkinson’s disease; demential with Lewy bodies
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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