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1.  Incidence and pathology of synucleinopathies and tauopathies related to parkinsonism 
JAMA neurology  2013;70(7):859-866.
Objectives
To investigate the incidence and distribution of specific types of parkinsonism and related proteinopathies.
Design
We used the medical records-linkage system of the Rochester Epidemiology Project to identify all subjects who received a screening diagnostic code of interest. A movement disorders specialist reviewed the complete medical records of each subject to confirm the type of parkinsonism and the presumed proteinopathy using specified criteria.
Setting
Olmsted County, MN, from 1991 through 2005 (15 years)
Participants
All residents of Olmsted County, MN
Main Outcome Measure
Incidence of parkinsonism
Results
Among 542 incident cases of parkinsonism, 409 (75.5%) were classified as proteinopathies. Of 389 patients with presumed synucleinopathies (71.8% of cases), 264 had Parkinson's disease (48.7% of all cases). The incidence rate (per 100,000 person-years) of synucleinopathies was 21.0 overall and increased steeply with age. The incidence rate of tauopathies was 1.1 overall (20 cases) and the most common tauopathy was progressive supranuclear palsy (16 cases). Thirty-six subjects had drug-induced parkinsonism (6.6%), 11 had vascular parkinsonism (2.0%), 1 had amyotropic lateral sclerosis in parkinsonism (0.2%), 1 had parkinsonism secondary to surgery (0.2%), and 84 remained unspecified (15.5%). Men had higher incidence than women for most types of parkinsonism. Findings at brain autopsy confirmed the clinical diagnosis in 53 out of 65 patients who underwent autopsy (81.5%).
Conclusions
The incidence of proteinopathies related to parkinsonism increases steeply with age and is consistently higher in men than women. Clinically-diagnosed synucleinopathies are much more common than tauopathies. Findings at autopsy confirm the clinical diagnosis.
doi:10.1001/jamaneurol.2013.114
PMCID: PMC3707980  PMID: 23689920
incidence; sex differences; epidemiology; pathology; proteinopathies; synucleinopathies; tauopathies
2.  Risk factors for Parkinson’s disease may differ in men and women: An exploratory study 
Hormones and behavior  2012;63(2):308-314.
Although several environmental and genetic risk or protective factors have been associated with Parkinson’s disease (PD), their interactions overall and in men and women separately remain unknown. We used the medical records-linkage system of the Rochester Epidemiology Project to identify 196 subjects who developed PD in Olmsted County, MN, from 1976 through 1995. Each incident case was matched by age (±1 year) and sex to a general population control. We considered the following 12 risk or protective factors: personal history of head trauma, pesticide use, immunologic diseases, anemia, hysterectomy (in women only), cigarette smoking, coffee consumption, and education; and family history of parkinsonism, essential tremor, dementia, or psychiatric disorders. We used recursive partitioning analyses to explore interactions overall and in men and women separately and used logistic regression analyses to test for interactions. In the overall group, we observed the independent effects of anemia, lack of coffee consumption (never vs. ever), and head trauma; however, the findings were different in men and women. In men, we observed the independent effects of lack of coffee consumption (never vs. ever), head trauma, and pesticide use, and a suggestive synergistic interaction between immunologic diseases and family history of dementia. By contrast, in women, anemia was the most important factor and we observed a suggestive synergistic interaction between anemia and higher education. Risk factors for PD and their interactions may differ in men and women.
doi:10.1016/j.yhbeh.2012.05.013
PMCID: PMC3477259  PMID: 22687345
3.  Research on the Premotor Symptoms of Parkinson’s Disease: Clinical and Etiological Implications 
Environmental Health Perspectives  2013;121(11-12):1245-1252.
Background: The etiology and natural history of Parkinson’s disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years.
Objectives: We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications.
Methods: This review was based on a workshop, Parkinson’s Disease Premotor Symptom Symposium, held 7–8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina.
Discussion: Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood.
Conclusion: This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis.
Citation: Chen H, Burton EA, Ross GW, Huang X, Savica R, Abbott RD, Ascherio A, Caviness JN, Gao X, Gray KA, Hong JS, Kamel F, Jennings D, Kirshner A, Lawler C, Liu R, Miller GW, Nussbaum R, Peddada SD, Comstock Rick A, Ritz B, Siderowf AD, Tanner CM, Tröster AI, Zhang J. 2013. Research on the premotor symptoms of Parkinson’s Disease: clinical and etiological implications. Environ Health Perspect 121:1245–1252; http://dx.doi.org/10.1289/ehp.1306967
doi:10.1289/ehp.1306967
PMCID: PMC3855519  PMID: 23933572
4.  Plasma Ceramide and Glucosylceramide Metabolism Is Altered in Sporadic Parkinson's Disease and Associated with Cognitive Impairment: A Pilot Study 
PLoS ONE  2013;8(9):e73094.
Background
Mutations in the gene coding for glucocerebrosidase (GBA), which metabolizes glucosylceramide (a monohexosylceramide) into glucose and ceramide, is the most common genetic risk factor for sporadic Parkinson's disease (PD). GBA mutation carriers are more likely to have an earlier age of onset and to develop cognitive impairment and dementia. We hypothesized that plasma levels of lipids involved in ceramide metabolism would also be altered in PD non-GBA mutation carriers and associated with worse cognition.
Methods
Plasma ceramide, monohexosylceramide, and lactosylceramide levels in 26 cognitively normal PD patients, 26 PD patients with cognitive impairment or dementia, and 5 cognitively normal non-PD controls were determined by LC/ESI/MS/MS.
Results
Levels of all lipid species were higher in PD patients versus controls. Among PD patients, levels of ceramide C16:0, C18:0, C20:0, C22:0, and C24:1 and monohexosylceramide C16:0, C20:0 and C24:0 species were higher (all P<0.05) in those with versus without cognitive impairment.
Conclusion
These results suggest that plasma ceramide and monohexosylceramide metabolism is altered in PD non-GBA mutation carriers and that higher levels are associated with worse cognition. Additional studies with larger sample sizes, including cognitively normal controls, are needed to confirm these findings.
doi:10.1371/journal.pone.0073094
PMCID: PMC3776817  PMID: 24058461
5.  Metabolic Markers or Conditions Preceding Parkinson’s Disease: A Case-Control Study 
Background
Several metabolic markers or conditions have been explored as possible risk or protective factors for Parkinson’s disease (PD); however, results remain conflicting. We further investigated these associations using a case-control study design.
Methods
We used the medical records-linkage system of the Rochester Epidemiology Project to identify 196 subjects who developed PD in Olmsted County, MN, from 1976 through 1995. Each incident case was matched by age (± 1 year) and sex to a general population control. We reviewed the complete medical records of cases and controls in the medical records-linkage system to abstract information about body mass index (BMI), cholesterol levels, hypertension, and diabetes mellitus preceding the onset of PD (or the index year).
Results
There were no significant differences between cases and controls for the metabolic markers or conditions investigated. No significant associations were found using 2 cut-offs for BMI levels (BMI ≥ 25 or BMI ≥ 30 kg/m2) and 3 cut-offs for cholesterol levels (> 200, > 250, or > 300 mg/dl). A diagnosis of hypertension or the documented use of anti-hypertensive medications were not significantly associated with the subsequent risk of PD (odds ratio [OR], 1.00; 95% confidence interval [CI], 0.65–1.54; P = .99), nor was a diagnosis of diabetes mellitus or the use of glucose-lowering medications (OR, 0.77; 95% CI, 0.37–1.57; P =.47).
Conclusions
Our study, based on historical information from a records-linkage system, does not support an association between BMI, cholesterol levels, hypertension, or diabetes mellitus and later development of PD.
doi:10.1002/mds.25016
PMCID: PMC3539719  PMID: 22674432
Parkinson’s disease; body mass index; cholesterol level; hypertension; diabetes mellitus
6.  Characterization of a Family With c9FTD/ALS Associated With the GGGGCC Repeat Expansion in C9ORF72 
Archives of neurology  2012;69(9):1164-1169.
Background
The hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene was recently discovered as the pathogenic mechanism underlying many families with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) linked to chromosome 9 (c9FTD/ALS). We report the clinical, neuropsychological, and neuroimaging findings of a family with the C9ORF72 mutation and clinical diagnoses bridging the FTD, parkinsonism and ALS spectrum.
Objective
To characterize the antemortem characteristics of a family with c9FTD/ALS associated with the GGGGCC repeat expansion in C9ORF72
Design
Clinical series.
Setting
Tertiary care academic medical center.
Patients
The members of the family affected by the mutation with features of FTD and/or ALS.
Main Outcome Measures
Clinical, neuropsychological, and neuroimaging assessments.
Results
All three examined subjects had the hexanucleotide expansion detected in C9ORF72. All had personality/behavioral changes early in the course of the disease. One case had levodopa-unresponsive parkinsonism, and one had ALS. MRI showed symmetric bilateral frontal, temporal, insular and cingulate atrophy.
Conclusions
This report highlights the clinical and neuroimaging characteristics of a family with c9FTD/ALS. Further studies are needed to better understand the phenotypical variability and the clinico-neuroimaging-neuropathologic correlations.
doi:10.1001/archneurol.2012.772
PMCID: PMC3625860  PMID: 22637471
7.  High School Football and Risk of Neurodegeneration: A Community-Based Study 
Mayo Clinic Proceedings  2012;87(4):335-340.
Objective
To assess whether high school football played between 1946 and 1956, when headgear was less protective than today, was associated with development of neurodegenerative diseases later in life.
Methods
All male students who played football from 1946 to 1956 in the high schools of Rochester, Minnesota, plus a non–football-playing referent group of male students in the band, glee club, or choir were identified. Using the records-linkage system of the Rochester Epidemiology Project, we reviewed (from October 31, 2010, to March 30, 2011) all available medical records to assess later development of dementia, Parkinson disease (PD), or amyotrophic lateral sclerosis (ALS). We also compared the frequency of dementia, PD, or ALS with incidence data from the general population of Olmsted County, Minnesota.
Results
We found no increased risk of dementia, PD, or ALS among the 438 football players compared with the 140 non–football-playing male classmates. Parkinson disease and ALS were slightly less frequent in the football group, whereas dementia was slightly more frequent, but not significantly so. When we compared these results with the expected incidence rates in the general population, only PD was significantly increased; however, this was true for both groups, with a larger risk ratio in the non–football group.
Conclusion
Our findings suggest that high school students who played American football from 1946 to 1956 did not have an increased risk of later developing dementia, PD, or ALS compared with non–football-playing high school males, despite poorer equipment and less regard for concussions compared with today and no rules prohibiting head-first tackling (spearing).
doi:10.1016/j.mayocp.2011.12.016
PMCID: PMC3538465  PMID: 22469346
ALS, amyotrophic lateral sclerosis; CTE, chronic traumatic encephalopathy; PD, Parkinson disease; REP, Rochester Epidemiology Project
8.  Deep Brain Stimulation in Tourette Syndrome: A Description of 3 Patients With Excellent Outcome 
Mayo Clinic Proceedings  2012;87(1):59-62.
Tourette syndrome (TS) is a complex neuropsychiatric disorder often starting in childhood and characterized by the presence of multiple motor and vocal tics and psychiatric comorbidities. Patients with TS usually respond to medical treatment, and the condition often improves during adolescence; however, surgery has been considered a possible approach for the subset of patients with ongoing medically refractory disease. Ablative procedures have been associated with unsatisfactory results and major adverse effects, prompting trials of deep brain stimulation (DBS) as an alternative therapy. It remains unclear which of the various nuclear targets is most effective in TS. We describe 3 patients with TS who underwent DBS targeting the bilateral thalamic centromedian/parafascicular complex (CM/Pf) with an excellent clinical outcome. At 1-year follow-up, the mean reduction in the total Yale Global Tic Severity Scale score in the 3 patients was 70% (range, 60%-80%).Our study further supports the role of the CM/Pf DBS target in medically intractable TS.
doi:10.1016/j.mayocp.2011.08.005
PMCID: PMC3538384  PMID: 22212969
9.  Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72 
Brain  2012;135(3):765-783.
Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.
doi:10.1093/brain/aws004
PMCID: PMC3286335  PMID: 22366793
frontotemporal dementia; amyotrophic lateral sclerosis; motor neuron disease; TDP-43; neurogenetics; chromosome 9

Results 1-9 (9)