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1.  Genomic determinants of motor and cognitive outcomes in Parkinson’s disease 
Parkinsonism & related disorders  2012;18(7):881-886.
Little is known regarding genetic factors associated with motor or cognitive outcomes in Parkinson’s disease (PD).
To identify common genetic variants associated with motor and cognitive outcomes in PD.
The sample consisted of 443 PD cases included in the first genome-wide association study (GWAS) of PD. Methods included telephone interview assessments of motor and cognitive outcomes, a median 9 years following the initial clinical assessments. Analyses included Cox proportional hazard models to study the association of 198,345 single nucleotide polymorphisms (SNPs) with survival free of Hoehn-Yahr Stage ≥4 (motor outcome), and either TICS-M ≤27 or AD-8 ≥2 (cognitive outcomes).
The SNP rs10958605 in the C8orf4 gene had the smallest p-value in analyses of the motor outcome (HR = 1.81; 95% CI = 1.42 – 2.31; p = 1.51 × 10−6). The SNP rs6482992 in the CLRN3 gene had the smallest p-value in analyses of the cognitive outcome (HR = 2.03, 95% CI 1.47–2.79, p = 4.08 × 10−6). However, no SNP associations were significant after Bonferroni correction. The C8orf4 gene had small p-values for both motor and cognitive outcomes, highlighting inflammation as a possible pathogenesis mechanism for progression in PD.
This study suggests that common variants in several genes may be associated with motor and cognitive outcomes in PD, with biological plausibility.
PMCID: PMC3606821  PMID: 22658654
Genome wide association studies; Parkinson’s disease; outcomes
2.  Incidental Lewy Body Disease: Do some cases represent a preclinical stage of Dementia with Lewy Bodies? 
Neurobiology of Aging  2009;32(5):857-863.
Lewy pathology occurs in 8–17% of neurologically-normal people >age 60, termed incidental Lewy body disease, (iLBD). It is often assumed to represent preclinical Parkinson disease (PD). However, some iLBD cases have diffuse pathology inconsistent with preclinical PD. We analyzed iLBD cases (α-synuclein immunohistochemistry) using the Braak PD staging scheme and determined if some had a neuropathological pattern suggestive of preclinical Dementia with Lewy bodies (DLB). Of the 235 brains examined, 34 had iLBD (14.5%) and all but one could be assigned a Braak PD stage. The distribution of α-synuclein pathology in the 33 cases fell into three patterns: (1) Diffuse cortical and subcortical α-synuclein pathology; (2) No cortical a-synuclein pathology, but a caudal-to-rostral ascending pattern, primarily involving brainstem; (3) Intermediate between these two categories. Also, 6/33 cases failed to follow the pattern of contiguous spread proposed by Braak. These findings suggest dichotomy in the distribution of iLBD: some cases fit the Braak ascending scheme, conceptually consistent with preclinical PD, whereas others displayed prominent cortical involvement that might represent preclinical DLB.
PMCID: PMC3366193  PMID: 19560232
incidental Lewy body disease; parkinson disease; dementia with Lewy bodies
3.  Glial cytoplasmic inclusions in neurologically normal elderly: Prodromal multiple system atrophy? 
Acta neuropathologica  2008;116(3):269-275.
In this study we used immunohistochemistry to screen for α-synuclein pathology in the brains of 241 individuals without clinical evidence of neurologic disease, and discovered 36 cases (15%) with incidental Lewy bodies (LBs) and one case, a 96-year-old woman (0.4%), with inclusions similar to those seen in multiple system atrophy (MSA), a nonfamilial neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction and α-synuclein immunoreactive glial cytoplasmic inclusions (GCI). In a routine hospital autopsy series of 125 brains, we detected GCI in a neurologically normal 82-year-old man (0.8%). Both cases showed widespread GCI in the central nervous system, as well as a few neuronal cytoplasmic inclusions, but no neuronal loss or gliosis in vulnerable brain regions, including the substantia nigra, putamen, inferior olive and pontine base. Applying a recently proposed grading scale for MSA, the two cases showed pathology far below that detected in patients with clinically overt MSA, suggesting the possibility that these two individuals had preclinical MSA. The prevalence of clinically overt MSA is estimated to be about 4 per 100,000 persons (0.004%), which is far less than the frequency of GCI in this series (0.4%–0.8%). Further studies are needed to determine is GCI in neurologically normal elderly represents prodromal MSA or a rare non-progressive age-related α-synucleinopathy.
PMCID: PMC2880173  PMID: 18553090
α-synuclein; clinicopathologic; glial cytoplasmic inclusion; multiple system atrophy; preclinical
4.  Is Incidental Lewy Body Disease Related to Parkinson Disease? Comparison of Risk Factor Profiles 
Archives of neurology  2009;66(9):1114.
To explore whether associations of potential risk factors for incidental Lewy Body Disease (iLBD) may be similar to Parkinson Disease (PD).
Design, Setting, and Patients
We identified brain-autopsied residents of Olmsted County, MN and immediate vicinity(1988–2004), age>60, without evidence of neurodegenerative disease or tremor, and evaluated by at least one physician within one year of death. Analysis for “incidental” Lewy pathology was done blinded to clinical abstraction.
Main Outcome Measures
Whether risk factors previously associated with PD in Olmsted County, MN are also associated with iLBD.
Of 235 subjects, 34 had iLBD(14.5%). The overall risk factor profiles for iLBD and PD were fairly similar between the two sets of OR estimates, with 11/16 ORs in the same direction. Prior Olmsted County studies documented 7 risk factors with statistically significant associations with PD; for two of these, the ORs for iLBD were in the same direction and statistically significant (physician, caffeine), whereas for three, they were in the same direction but not significant (education, head injury, number-of-children); they were in the opposite direction but not statistically significant for 2 (depression, anxiety). ILBD was not associated with various end-of-life conditions or causes-of-death, although they were slightly older and more likely cachectic.
Based on this exploratory study, iLBD and PD appear to have similar risk factor profiles. Thus, at least some cases of ILBD might represent preclinical PD, arrested PD or a partial syndrome due to a lesser burden of causative factors. ILBD is not explained by non-specific end-of-life brain insults.
PMCID: PMC2813519  PMID: 19752300

Results 1-4 (4)