Multi-tracer PET correlation analysis reveals disease-specific patterns in Parkinson's disease and asymptomatic LRRK2 pathogenic variant carriers compared to healthy controls.

Several genetic pathogenic variants increase the risk of Parkinson's disease (PD) with pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene being among the most common. A joint pattern analysis based on multi-set canonical correlation analysis (MCCA) was utilized to extract PD and LRRK2 pathogenic variant-specific spatial patterns in relation to healthy controls (HCs) from multi-tracer Positron Emission Tomography (PET) data. Spatial patterns were extracted for individual subject cohorts, as well as for pooled subject cohorts, to explore whether complementary spatial patterns of dopaminergic denervation are different in the asymptomatic and symptomatic stages of PD. The MCCA results are also compared to the traditional univariate analysis, which serves as a reference. We identified PD-induced spatial distribution alterations common to DAT and VMAT2 in both asymptomatic LRRK2 pathogenic variant carriers and PD subjects. The inclusion of HCs in the analysis demonstrated that the dominant common PD-induced pattern is related to an overall dopaminergic terminal density denervation, followed by asymmetry and rostro-caudal gradient with deficits in the less affected side still being the best marker of disease progression. The analysis was able to capture a trend towards PD-related patterns in the LRRK2 pathogenic variant carrier cohort with increasing age in line with the known increased risk of this patient cohort to develop PD as they age. The advantage of this method thus resides in its ability to identify not only regional differences in tracer binding between groups, but also common disease-related alterations in the spatial distribution patterns of tracer binding, thus potentially capturing more complex aspects of disease induced alterations.

Neuropsychological profile of CSF1R-related leukoencephalopathy.

Introduction: The neuropsychological profile of CSF1R-related leukoencephalopathy (CRL) is undefined. This study defines the profile, contrasts it with that of other dementia syndromes, and highlights measures sensitive to cognitive impairment. Methods: We administered a standardized battery of neuropsychological tests to five consecutive CRL cases. Results: The neuropsychological profile of CRL reflects impaired general cognitive function, processing speed, executive function, speeded visual problem solving, verbal fluency, and self-reported depression and anxiety. Confrontation naming and memory are preserved. Within cognitive domains, certain measures more frequently identified impairment than others. Discussion: CRL impairs general cognitive function, processing speed, executive function. Language and visual problem solving may be impaired if processing speed is required. Confrontation naming and memory are uniquely preserved, contrasting CRL to other dementia syndromes. Cognitive screens excluding processing speed and executive function may not detect CRL cognitive manifestations. Findings sharply define cognitive impairment of CRL and inform cognitive test selection.

Perry syndrome: Novel DCTN1 mutation in a large kindred and first observation of prodromal disease.

INTRODUCTION: Perry syndrome (PS) is a hereditary neurodegenerative disorder caused by mutations in the DCTN1 gene and characterized by TDP-43 pathology. As the diagnosis is usually made at the advanced stages of the disease, there are no studies on the asymptomatic mutation carriers and their conversion to overt disease. METHODS: We personally examined 27 members of the large kindred of 104 individuals with familial parkinsonism. We evaluated each case with clinical (neurological examination; motor and non-motor scales), genetic testing (whole-exome or Sanger sequencing), and laboratory (neurofilament light, NFL; glial fibrillary acidic protein, GFAP) measures. Autopsy study was done on two individuals. RESULTS: The mean age at evaluation was 49 years. Comorbidities were present in 20 cases, including sleep problems (n = 15 total, sleep apnea in 7), dysautonomia (n = 10), weight loss (n = 8), and anxiety/depression (n = 8). Neurological abnormalities were present in 18, including parkinsonism (n = 7), isolated tremor (n = 2), and varied isolated signs in individual cases. Cognition and smell were preserved. Genetic testing revealed a novel c.200G > T (Gly67Val) mutation in the DCTN1 gene in 10 individuals. The mutation, segregated with the PS phenotype (n = 4), was absent in gnomAD, and in silico predictions indicated it was pathogenic. Three young mutation carriers were monosymptomatic (prodromal), and three were asymptomatic. Plasma NFL and GFAP values were similar among the cases. Autopsy studies showed typical PS neuropathological findings. CONCLUSIONS: We identified a novel pathogenic Gly67Val DCTN1 mutation. We report prodromal disease of PS in some mutation carriers; however, more investigation is necessary to confirm this observation.

Expanding the spectrum of KIF5A mutations-case report of a large kindred with familial ALS and overlapping syndrome.

OBJECTIVES: This paper presents the first report of amyotrophic lateral sclerosis (ALS) kindred due to the KIF5A p.Arg1007Lys, a splice-altering variant. METHODS: An index case was a 54-year-old male who developed progressive gait difficulty and imbalance followed by mild parkinsonism, spasticity, neuropathy, ataxia, and cognitive impairment with predominant subcortical frontal involvement. Brain MRI showed marked bilateral parietal lobes atrophy. Electromyography demonstrated chronic diffuse neurogenic changes. Due to the positive history of similar symptoms in his father and the diagnosis of ALS in 10 other family members, extensive genetic testing was pursued. RESULTS: Genetic screening for GRN, C9orf72, TARDBP, SOD1, FUS, MAPT mutations, and hereditary ataxia panel, was unremarkable. Whole-exome sequencing revealed c.3020G > A (p.Arg1007Lys) mutation in the KIF5A gene, later confirmed in two affected relatives. DISCUSSION: Similar to previous reports on KIF5A-related ALS, our index case, had a mild disease course with prolonged survival. However, as the rate of progression and survival time differed even among the same family members, other factors were probably at play. Additionally, our index case and his father displayed features overlapping ALS, spastic paraplegia, Charcot-Marie-Tooth disease type 2, and frontotemporal dementia. Therefore, we suggest considering KIF5A mutations in the differential diagnosis, particularly in the presence of overlapping features of spasticity, neuropathy, cerebellar ataxia, and dementia.

Cathepsin B p.Gly284Val Variant in Parkinson's Disease Pathogenesis.

Parkinson's disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk.

Clinical, pathological and genetic characteristics of Perry disease-new cases and literature review.

BACKGROUND AND PURPOSE: Perry disease (or Perry syndrome) is an autosomal dominant neurodegenerative disorder characterized by parkinsonism, neuropsychiatric symptoms, central hypoventilation, weight loss and distinct TDP-43 pathology. It is caused by mutations of the DCTN1 gene encoding an essential component of axonal transport. The objectives were to provide the current state of knowledge on clinical, pathological and genetic aspects of Perry disease, as well as practical suggestions for the management of the disease. METHODS: Data on new patients from New Zealand, Poland and Colombia were collected, including autopsy report. Also all of the published papers since the original work by Perry in 1975 were gathered and analyzed. RESULTS: Parkinsonism was symmetrical, progressed rapidly and was poorly responsive to L-Dopa; nonetheless, a trial with high doses of L-Dopa is warranted. Depression was severe, associated with suicidal ideations, and benefited from antidepressants and L-Dopa. Respiratory symptoms were the leading cause of death, and artificial ventilation or a diaphragm pacemaker prolonged survival. Weight loss occurred in most patients and was of multifactorial etiology. Autonomic dysfunction was frequent but underdiagnosed. There was a clinical overlap with other neurodegenerative disorders. An autopsy showed distinctive pallidonigral degeneration with TDP-43 pathology. Genetic testing provided evidence of a common founder for two families. There was striking phenotypic variability in DCTN1-related disorders. It is hypothesized that oligogenic or polygenic inheritance is at play. CONCLUSIONS: Perry disease and other DCTN1-related diseases are increasingly diagnosed worldwide. Relatively effective symptomatic treatments are available. Further studies are needed to pave the way toward curative/gene therapy.

Spinocerebellar ataxia type 6 family with phenotypic overlap with Multiple System Atrophy.

AIM OF THE STUDY: Multiple system atrophy (MSA) and spinocerebellar ataxia (SCA) share similar symptomatology. We describe a rare occurrence of familial MSA that proved to be SCA6 upon genetic analysis. MATERIALS AND METHODS: Eighty MSA patients were enrolled in our study; blood samples were collected and genetic screening of the familial case for known SCA loci was performed. RESULTS: A 68-year-old woman presented with recurrent and severe episodes of light-headedness, imbalance, frequent falls, neck and lower back stiffness, subjective arm and leg weakness, and numbness and tingling in both feet. One year later, her condition had declined; she experienced more falls, worsening instability, again more generalised but still subjective weakness, impaired fine motor movements, slurred speech, difficulty swallowing, episodes of choking, bladder incontinence, and constipation. Clinical suspicion included parkinsonism, MSA, and SCA. The patient was enrolled in our MSA study and was found to have 22 and 12 CAG repeats in CACNA1A. The other 79 clinical MSA patients were negative for SCA6 screening. CONCLUSIONS AND CLINICAL IMPLICATIONS: While MSA and SCA may have similar presentations during early disease stages, the presence of both conditions on the list of differential diagnoses can be a diagnostic dilemma. Further analysis will aid in developing a biomarker to distinguish between the two conditions and guide proper management.

Crohn's and Parkinson's Disease-Associated LRRK2 Mutations Alter Type II Interferon Responses in Human CD14+ Blood Monocytes Ex Vivo.

The Leucine Rich Repeat Kinase 2 (LRRK2) is one of causative genes of familial Parkinson's disease (PD). The M2397T polymorphism in LRRK2 is genetically associated with sporadic Crohn's disease (CD). LRRK2 is expressed in human CD14+ monocytes, induced by interferon-γ (IFN-γ) and suppresses inflammatory activation. We hypothesize that IFN-γ-induced LRRK2 and inflammatory gene expression is altered by LRRK2 genetic polymorphism found in CD and PD cases. A total of 46 CD and 51 control cases, and 16 PD cases and 16 PD-linked LRRK2 mutation cases were recruited. Live human CD14+ monocytes were isolated from donors for ex vivo IFN-γ stimulation and gene expression analysis. IFN-γ potently enhanced TNFA, IL12, HLADRA1 and LRRK2 expression, which was suppressed by FK506, a calcineurin-specific inhibitor, but further enhanced by LRRK2-specific kinase inhibitor (GSK2578215A). The 2397-M/M CD risk allele enhanced IFN-γ responses of CD14+ cells in CD but not in control group. CD14+ monocytes from G2019S and R1441C LRRK2 mutated PD cases and carriers show no changes in IFN-γ responses for TNFA or IL12, reduced response for HLADRA1, and enhanced responses for LRRK2 in FK506-sensitive manner. These data demonstrate that CD-associated LRRK2 mutations are significant modifiers of innate immune response in CD14+ monocytes, and PD-associated LRRK2 mutation may contribute to reduced antigen presentation response. Graphical Abstract.

Early-Onset Parkinson Disease Screening in Patients From Nigeria.

Introduction: Nigeria is one of the most populated countries in the world; however, there is a scarcity of studies in patients with age-related neurodegenerative diseases, such as Parkinson disease (PD). The aim of this study was to screen patients with PD including a small cohort of early-onset PD (EOPD) cases from Nigeria for PRKN, PINK1, DJ1, SNCA multiplication, and LRRK2 p.G2019S. Methods: We assembled a cohort of 109 Nigerian patients with PD from the four main Nigerian tribes: Yoruba, Igbo, Edo, and Hausa. Fifteen cases [14 from the Yoruba tribe (93.3%)] had EOPD (defined as age-at-onset <50 years). All patients with EOPD were sequenced for the coding regions of PRKN, PINK1, and DJ1. Exon dosage analysis was performed with a multiplex ligation-dependent probe amplification assay, which also included a SNCA probe and LRRK2 p.G2019S. We screened for LRRK2 p.G2019S in the entire PD cohort using a genotyping assay. The PINK1 p.R501Q functional analysis was conducted. Results: In 15 patients with EOPD, 22 variants were observed [PRKN, 9 (40.9%); PINK1, 10 (45.5%); and DJ1, 3 (13.6%)]. Three (13.6%) rare, nonsynonymous variants were identified, but no homozygous or compound heterozygous carriers were found. No exonic rearrangements were present in the three genes, and no carriers of SNCA genomic multiplications or LRRK2 p.G2019S were identified. The PINK1 p.R501Q functional analysis revealed pathogenic loss of function. Conclusion: More studies on age-related neurodegenerative diseases are needed in sub-Saharan African countries, including Nigeria. Population-specific variation may provide insight into the genes involved in PD in the local population but may also contribute to larger studiesperformed in White and Asian populations.

TRIO gene segregation in a family with cerebellar ataxia.

AIM OF THE STUDY: To report a family with a novel TRIO gene mutation associated with phenotype of cerebellar ataxia. MATERIALS AND METHODS: Seven family members of Caribbean descent were recruited through our ataxia research protocol; of the family members, the mother and all 3 children were found to be affected with severe young-onset and rapidly progressive truncal and appendicular ataxia leading to early disability. Array comparative genomic hybridization, mitochondrial DNA analysis, and whole-exome sequencing were performed on 3 of the family members (mother and 2 daughters). RESULTS: While the maternal grandmother, great uncle and great aunt were unaffected, the mother and 3 children displayed cognitive dysfunction, severe ataxia, spasticity, and speech disturbances. Age of onset ranged between 3 and 17 years, with average current disease duration of 21 years. Whole-exome sequencing showed a variant p.A1214V in exon 22 of the TRIO gene in 3 of the family members. Array comparative genomic hybridization and mitochondrial DNA analysis were normal. The same variant was later discovered in all but one family member. CONCLUSIONS AND CLINICAL IMPLICATIONS: The TRIO p.A1214V variant is associated with cerebellar ataxia in the studied family; it was present in all affected and unaffected family members. Phenotype is severe and broad. Anticipation seems to be present (based on 2 affected generations). It is warranted to screen additional familial early-onset and rapidly progressive ataxia cases for this genotype. TRIO gene mutations may well represent a novel spinocerebellar ataxia subtype.

Comparison of clinical features among Parkinson's disease subtypes: A large retrospective study in a single center.

INTRODUCTION: Tremor dominant (TD), postural instability/gait difficulty (PIGD), and akinetic-rigid (AR) subtypes are widely used in classifying patients with Parkinson's disease (PD). METHODS: We compared clinical characteristics between PD subtypes in a large retrospective cohort. Between 1998 and 2016, we included a total of 1003 patients with PD in this retrospective study. Six hundred ninety-four patients had more than one visit. Data were collected regarding motor/non-motor symptoms at the initial/final visits. Based on the prominent symptom at the initial visit, we classified patients into one of the four subtypes: TD, AR, gait difficulty, and mixed. Rapid progression was defined by emergence of falls, dementia, or dependency within 5years after onset. RESULTS: TD was the most prevalent subtype (44%), followed by AR (29%), mixed (18%), and gait difficulty (9%). Rapid progression was observed more frequently in gait difficulty compared to AR (OR: 3.59 P<0.001). Hallucinations at the final visit were more likely to occur in AR (OR: 2.36, P=0.005) and mixed (OR: 3.28, P<0.001) compared to TD. CONCLUSIONS: Our findings provide support for a distinction of four different PD subtypes: TD, AR, gait difficulty, and mixed. The gait difficulty subtype was distinguishable from the AR subtype.

Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies.

BACKGROUND: People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinson's disease and individuals with sporadic Parkinson's disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes. METHODS: We did two cross-sectional PET studies at the Pacific Parkinson's Research Centre in Vancouver, BC, Canada. We included LRRK2 mutation carriers with or without manifest Parkinson's disease, people with sporadic Parkinson's disease, and age-matched healthy controls, all aged 18 years or older. People with Parkinson's disease were diagnosed by a neurologist with movement disorder training, in accordance with the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. In the first study, LRRK2 mutation carriers with or without manifest Parkinson's disease who were referred for investigation between July, 1999, and January, 2012, were scanned with PET tracers for the membrane dopamine transporter, and dopamine synthesis and storage (18F-6-fluoro-L-dopa; 18F-FDOPA). We compared findings with those in people with sporadic Parkinson's disease and age-matched healthy controls. In the second study, distinct groups of LRRK2 mutation carriers, individuals with sporadic Parkinson's disease, and age-matched healthy controls seen from November, 2012, to May, 2016, were studied with tracers for the serotonin transporter and vesicular monoamine transporter 2 (VMAT2). Striatal dopamine transporter binding, VMAT2 binding, 18F-FDOPA uptake, and serotonin transporter binding in multiple brain regions were compared by ANCOVA, adjusted for age. FINDINGS: Between January, 1997, and January, 2012, we obtained data for our first study from 40 LRRK2 mutation carriers, 63 individuals with sporadic Parkinson's disease, and 35 healthy controls. We identified significant group differences in striatal dopamine transporter binding (all age ranges in caudate and putamen, p<0·0001) and 18F-FDOPA uptake (in caudate: age ≤50 years, p=0·0002; all other age ranges, p<0·0001; in putamen: all age ranges, p<0·0001). LRRK2 mutation carriers with manifest Parkinson's disease (n=15) had reduced striatal dopamine transporter binding and 18F-FDOPA uptake, comparable with amounts seen in individuals with sporadic Parkinson's disease of similar duration. LRRK2 mutation carriers without manifest Parkinson's disease (n=25) had greater 18F-FDOPA uptake and dopamine transporter binding than did individuals with sporadic Parkinson's disease, with 18F-FDOPA uptake comparable with controls and dopamine transporter binding lower than in controls. Between November, 2012, and May, 2016, we obtained data for our second study from 16 LRRK2 mutation carriers, 13 individuals with sporadic Parkinson's disease, and nine healthy controls. Nine LRRK2 mutation carriers without manifest Parkinson's disease had significantly elevated serotonin transporter binding in the hypothalamus (compared with controls, individuals with LRRK2 Parkinson's disease, and people with sporadic Parkinson's disease, p<0·0001), striatum (compared with people with sporadic Parkinson's disease, p=0·02), and brainstem (compared with LRRK2 mutation carriers with manifest Parkinson's disease, p=0·01), after adjustment for age. Serotonin transporter binding in the cortex did not differ significantly between groups after age adjustment. Striatal VMAT2 binding was reduced in all individuals with manifest Parkinson's disease and reduced asymmetrically in one LRRK2 mutation carrier without manifest disease. INTERPRETATION: Dopaminergic and serotonergic changes progress in a similar fashion in LRRK2 mutation carriers with manifest Parkinson's disease and individuals with sporadic Parkinson's disease, but LRRK2 mutation carriers without manifest Parkinson's disease show increased serotonin transporter binding in the striatum, brainstem, and hypothalamus, possibly reflecting compensatory changes in serotonergic innervation preceding the motor onset of Parkinson's disease. Increased serotonergic innervation might contribute to clinical differences in LRRK2 Parkinson's disease, including the emergence of non-motor symptoms and, potentially, differences in the long-term response to levodopa. FUNDING: Canada Research Chairs, Michael J Fox Foundation, National Institutes of Health, Pacific Alzheimer Research Foundation, Pacific Parkinson's Research Institute, National Research Council of Canada.

Occurrence of Crohn's disease with Parkinson's disease.

We retrospectively investigated the co-occurrence of Crohn's disease in a cohort of 876 patients with Parkinson's disease, based on the observation that LRRK2 is a shared genetic risk factor. We identified 2 patients with Crohn's disease; this number was consistent with the number of cases expected in the general population.

Spinocerebellar ataxia 15: A phenotypic review and expansion.

Spinocerebellar ataxia 15 (SCA15) is a clinically heterogeneous movement disorder characterized by the adult onset of slowly progressive cerebellar ataxia. ITPR1 is the SCA15 causative gene. However, despite numerous reports of genetically-confirmed SCA15, phenotypic uncertainty persists. We reviewed the phenotypes of 60 patients for whom SCA15 was confirmed by the presence of a genetic deletion involving ITPR1. The most prevalent symptoms were gait ataxia (88.3%), dysarthria (75.0%), nystagmus (73.3%), and limb ataxia (71.7%). We also present a novel SCA15 phenotype in a woman with an ITPR1 variant found to have hydrocephalus that improved with ventriculoperitoneal shunting. This is the first reported case of hydrocephalus associated with SCA15. In this review, we analyzed previously reported SCA15 phenotypes and present a novel SCA15 phenotype. We also address important considerations for evaluating patients with complex hereditary movement disorders.

Assessment of Olfactory Function in MAPT-Associated Neurodegenerative Disease Reveals Odor-Identification Irreproducibility as a Non-Disease-Specific, General Characteristic of Olfactory Dysfunction.

Olfactory dysfunction is associated with normal aging, multiple neurodegenerative disorders, including Parkinson's disease, Lewy body disease and Alzheimer's disease, and other diseases such as diabetes, sleep apnea and the autoimmune disease myasthenia gravis. The wide spectrum of neurodegenerative disorders associated with olfactory dysfunction suggests different, potentially overlapping, underlying pathophysiologies. Studying olfactory dysfunction in presymptomatic carriers of mutations known to cause familial parkinsonism provides unique opportunities to understand the role of genetic factors, delineate the salient characteristics of the onset of olfactory dysfunction, and understand when it starts relative to motor and cognitive symptoms. We evaluated olfactory dysfunction in 28 carriers of two MAPT mutations (p.N279K, p.P301L), which cause frontotemporal dementia with parkinsonism, using the University of Pennsylvania Smell Identification Test. Olfactory dysfunction in carriers does not appear to be allele specific, but is strongly age-dependent and precedes symptomatic onset. Severe olfactory dysfunction, however, is not a fully penetrant trait at the time of symptom onset. Principal component analysis revealed that olfactory dysfunction is not odor-class specific, even though individual odor responses cluster kindred members according to genetic and disease status. Strikingly, carriers with incipient olfactory dysfunction show poor inter-test consistency among the sets of odors identified incorrectly in successive replicate tests, even before severe olfactory dysfunction appears. Furthermore, when 78 individuals without neurodegenerative disease and 14 individuals with sporadic Parkinson's disease were evaluated twice at a one-year interval using the Brief Smell Identification Test, the majority also showed inconsistency in the sets of odors they identified incorrectly, independent of age and cognitive status. While these findings may reflect the limitations of these tests used and the sample sizes, olfactory dysfunction appears to be associated with the inability to identify odors reliably and consistently, not with the loss of an ability to identify specific odors. Irreproducibility in odor identification appears to be a non-disease-specific, general feature of olfactory dysfunction that is accelerated or accentuated in neurodegenerative disease. It may reflect a fundamental organizational principle of the olfactory system, which is more "error-prone" than other sensory systems.

Cancer in Parkinson's disease.

INTRODUCTION: We examined the prevalence of cancer in patients with Parkinson's disease (PD) and controls evaluated at the Mayo Clinic in Jacksonville, Florida, between 2003 and 2014. METHODS: We retrospectively collected information regarding cancer diagnoses and diagnosis of PD from 971 unrelated PD patients and 478 controls, and all were white. For PD patients, we examined cancers diagnosed before and after PD diagnosis separately in addition to considering all cancer diagnoses. RESULTS: Twenty different cancers were identified. In PD patients, the most common types of cancer were skin cancer (17.3% overall; 10.6% before PD), followed by nonmelanoma skin cancer (16.0% overall; 9.7% before PD), prostate cancer in men (12.8% overall; 9.2% before PD), breast cancer in women (10.6% overall; 6.3% before PD), and melanoma (2.4% overall; 1.1% before PD). Compared to controls, a significantly lower frequency of nonmelanoma skin cancer (odds ratio [OR]: 0.62, P = 0.0024) and any skin cancer (OR: 0.57, P = 0.0002) was observed in PD patients. These differences were greater when considering only cases with cancers that occurred before PD diagnosis (OR: 0.49, P < 0.0001; OR: 0.45, P < 0.0001, respectively), and there was a lower frequency of melanoma and any cancer preceding PD diagnosis compared to controls (OR: 0.31, P = 0.003; OR: 0.36, P < 0.0001). There was no evidence of a frequency difference for any other cancer. CONCLUSIONS: PD patients had a lower frequency of skin cancers or any cancer prior to PD diagnosis compared to controls, suggesting that cancer may have a protective effect on PD risk.

RAB39B gene mutations are not a common cause of Parkinson's disease or dementia with Lewy bodies.

Mutations in Ras-related protein Rab-39B (RAB39B) gene have been linked to X-linked early-onset Parkinsonism with intellectual disabilities. The aim of this study was to address the genetic contribution of RAB39B to Parkinson's disease (PD), dementia with Lewy bodies (DLB), and pathologically confirmed Lewy body dementia (pLBD) cases. A cohort of 884 PD, 399 DLB, and 379 pLBD patients were screened for RAB39B mutations, but no coding variants were found, suggesting RAB39B mutations are not a common cause of PD, DLB, or pLBD in Caucasian population.

Mitochondrial targeting sequence variants of the CHCHD2 gene are a risk for Lewy body disorders.

OBJECTIVE: To assess the role of CHCHD2 variants in patients with Parkinson disease (PD) and Lewy body disease (LBD) in Caucasian populations. METHODS: All exons of the CHCHD2 gene were sequenced in a US Caucasian patient-control series (878 PD, 610 LBD, and 717 controls). Subsequently, exons 1 and 2 were sequenced in an Irish series (355 PD and 365 controls) and a Polish series (394 PD and 350 controls). Immunohistochemistry and immunofluorescence studies were performed on pathologic LBD cases with rare CHCHD2 variants. RESULTS: We identified 9 rare exonic variants of unknown significance. These variants were more frequent in the combined group of PD and LBD patients compared to controls (0.6% vs 0.1%, p = 0.013). In addition, the presence of any rare variant was more common in patients with LBD (2.5% vs 1.0%, p = 0.050) compared to controls. Eight of these 9 variants were located within the gene's mitochondrial targeting sequence. CONCLUSIONS: Although the role of variants of the CHCHD2 gene in PD and LBD remains to be further elucidated, the rare variants in the mitochondrial targeting sequence may be a risk factor for Lewy body disorders, which may link CHCHD2 to other genetic forms of parkinsonism with mitochondrial dysfunction.