Effect of Advancing Age on Outcomes of Deep Brain Stimulation for Parkinson Disease

JAMA Neurol. 2014 Aug 25. doi: 10.1001/jamaneurol.2014.1272. [Epub ahead of print]

DeLong MR, Huang KT, Gallis J, Lokhnygina Y, Parente B, Hickey P, Turner DA, Lad SP.

IMPORTANCE:

Deep brain stimulation (DBS) is a well-established modality for the treatment of advanced Parkinson disease (PD). Recent studies have found DBS plus best medical therapy to be superior to best medical therapy alone for patients with PD and early motor complications. Although no specific age cutoff has been defined, most clinical studies have excluded patients older than 75 years of age. We hypothesize that increasing age would be associated with an increased number of postoperative complications.

OBJECTIVE:

To evaluate the stepwise effect of increasing age (in 5-year epochs) on short-term complications following DBS surgery.

DESIGN, SETTING, AND PARTICIPANTS:

A large, retrospective cohort study was performed using the Thomson Reuters MarketScan national database that examined 1757 patients who underwent DBS for PD during the period from 2000 to 2009.

MAIN OUTCOMES AND MEASURES:

Primary measures examined included hospital length of stay and aggregate and individual complications within 90 days following surgery. Multivariate logistic regression analysis was used to calculate complication-related odds ratios (ORs) for each 5-year age epoch after controlling for covariates.

RESULTS:

Overall, 132 of 1757 patients (7.5%) experienced at least 1 complication within 90 days, including wound infections (3.6%), pneumonia (2.3%), hemorrhage or hematoma (1.4%), or pulmonary embolism (0.6%). After adjusting for covariates, we found that increasing age (ranging from <50 to 90 years of age) did not significantly affect overall 90-day complication rates (OR, 1.10 per 5-year increase [95% CI, 0.96-1.25]; P = .17). The 2 most common procedure-related complications, hemorrhage (OR, 0.82 [95% CI, 0.63-1.07]; P = .14) and infection (OR, 1.04 [95% CI, 0.87-1.24]; P = .69), did not significantly increase with age.

CONCLUSIONS AND RELEVANCE:

Older patients with PD (>75 years) who were selected to undergo DBS surgery showed a similar 90-day complication risk (including postoperative hemorrhage or infection) compared with younger counterparts. Our findings suggest that age alone should not be a primary exclusion factor for determining candidacy for DBS. Instead, a clear focus on patients with medication-refractory and difficult to control on-off fluctuations with preserved cognition, regardless of age, may allow for an expansion of the traditional therapeutic window.

PREDICT-PD aligns with the highest priorities for clinical research in PD

Prioritized Research Recommendations from NINDS Parkinson's Disease 2014

Ann Neurol. 2014 Aug 28. doi: 10.1002/ana.24261. [Epub ahead of print]

Sieber BA, Landis S, Koroshetz W, Bateman R, Siderowf A, Galpern WR, Dunlop J, Finkbeiner S, Sutherland M, Wang H, Lee VM, Orr HT, Gwinn K, Ludwig K, Taylor A, Torborg C, Montine TJ; for the Parkinson's Disease 2014: Advancing Research, Improving Lives Conference Organizing Committee.

Abstract

Parkinson's disease (PD) is a serious and rapidly growing public health problem. Growing understanding of PD has unveiled substantial medical and biological complexity including preclinical disease, motor and non-motor symptoms, multi-organ involvement, co-morbidity, and an array of potential molecular drivers and mechanisms of disease that likely vary among patients. The National Institute of Neurological Disorders and Stroke (NINDS) convened Parkinson's Disease 2014: Advancing Research, Improving Lives to build consensus on PD research priorities. Our thirty-one recommendations form a foundation for precision medicine that will bring individual clarity to the medical and biological complexity of PD. 

http://onlinelibrary.wiley.com/doi/10.1002/ana.24261/abstract

Phenotypic variability of PINK1 expression: 12 Years' clinical follow-up of two Italian families

Interesting observations about PINK1 Parkinson's... raises important questions about why these patients exhibit different features to those with Parkin-related disease...

Mov Disord. 2014 Aug 27. doi: 10.1002/mds.25994. [Epub ahead of print]

Ricciardi L, Petrucci S, Guidubaldi A, Ialongo T, Serra L, Ferraris A, Spanò B, Bozzali M, Valente EM, Bentivoglio AR.

BACKGROUND:

Mutations in the PINK1 gene are the second most frequent cause of autosomal recessive early-onset parkinsonism.

METHODS:

We evaluated five affected PINK1 homozygous and 14 heterozygous mutation carriers from two large Italian families over a 12-year follow-up period. Motor, nonmotor, cognitive, psychiatric, and behavioral profiles were systematically assessed. Four homozygotes and eight heterozygotes underwent magnetic resonance imaging.

RESULTS:

All homozygotes showed a mild progression of motor signs and a persistent excellent response to levodopa. All but one patient complained of nonmotor symptoms and sleep impairment. Three presented impulse control disorders and two anxiety and apathy. All obtained abnormal scores at Montreal Cognitive Assessment (MoCA) and in tests sensitive to frontal functions; one presented a global cognitive impairment. Three heterozygotes showed motor signs and were diagnosed as possibly affected. They had nonmotor symptoms and cognitive impairment, and two of them showed mild bilateral temporal atrophy. Five unaffected heterozygotes reported abnormal scores at MoCA and low performances at tests sensitive to frontal functions.

CONCLUSION:

We expanded the phenotypic profile of PINK1-related parkinsonism, including psychiatric and cognitive features as part of clinical presentation.

And now back to PD with this excellent video about visual hallucinations

This video was prepared by Professor Joseph Friedman MD at Brown University

Momentary departure from PD to raise awareness for another awful neurodegenerative disease

MND Ice Bucket Challenge

Glucocerebrosidase depletion enhances cell-to-cell transmission of ​α-synuclein

Eun-Jin Bae,

Na-Young Yang,

Miyoung Song,

Cheol Soon Lee,

Jun Sung Lee,

Byung Chul Jung,

He-Jin Lee,

Seokjoong Kim,

Eliezer Masliah,

Sergio Pablo Sardi

& Seung-Jae Lee

• Nature Communications
   
  5,
   
  Article number:
   
  4755
   
  doi:10.1038/ncomms5755

Received

 

22 February 2014 

Accepted

 

18 July 2014 

Published

 

26 August 2014

Deposition of ​α-synuclein aggregates occurs widely in the central and peripheral nervous systems in Parkinson’s disease (PD). Although recent evidence has suggested that cell-to-cell transmission of ​α-synuclein aggregates is associated with the progression of PD, the mechanism by which ​α-synuclein aggregates spread remains undefined. Here, we show that ​α-synuclein aggregates are transmitted from cell to cell through a cycle involving uptake of external aggregates, co-aggregation with endogenous ​α-synuclein and exocytosis of the co-aggregates. Moreover, we find that ​glucocerebrosidase depletion, which has previously been strongly associated with PD and increased cognitive impairment, promotes propagation of ​α-synuclein aggregates. These studies define how ​α-synuclein aggregates spread among neuronal cells and may provide an explanation for how ​glucocerebrosidase mutations increase the risk of developing PD and other synucleinopathies.

Guidelines for uniform reporting of body fluid biomarker studies in neurologic disorders

1. Sharmilee Gnanapavan, MD, PhD, 
2. Harald Hegen, MD, PhD, 
3. Michael Khalil, MD, PhD, 
4. Bernhard Hemmer, MD, PhD,
5. Diego Franciotta, MD, 
6. Steve Hughes, MD, 
7. Rogier Hintzen, MD, PhD, 
8. Andreas Jeromin, PhD, 
9. Eva Havrdova, MD, PhD, 
10. Hayrettin Tumani, MD, PhD, 
11. Antonio Bertolotto, MD, PhD, 
12. Manuel Comabella, MD, 
13. Jette Frederiksen, MD, DMSc, 
14. José C. Álvarez-Cermeño, MD, PhD, 
15. Luisa Villar, PhD, 
16. Daniela Galimberti, MD, PhD, 
17. Kjell-Morten Myhr, MD, PhD, 
18. Irena Dujmovic, MD, PhD, 
19. Franz Fazekas, MD, 
20. Carolina Ionete, MD, PhD, 
21. Til Menge, MD, PhD, 
22. Geoffrey Keir, PhD, 
23. Florian Deisenhammer, MD, MSc, 
24. Charlotte Teunissen, PhD and 
25. Gavin Giovannoni, MBBCh, PhD

1. Published online before print August 22, 2014Neurology 

Objective: The aim of these guidelines is to make the process of reporting body fluid biomarker studies in neurologic disorders more uniform and transparent, in line with existing standards for reporting research in other biomedical areas. Although biomarkers have been around for decades, there are concerns over the high attrition rate of promising candidate biomarkers at later phases of development.

Methods: BioMS-eu consortium, a collaborative network working toward improving the quality of biomarker research in neurologic disorders, discussed the merits of standardizing the reporting of body fluid biomarker research. A checklist of items integrating the results of other published guidances, literature, conferences, regulatory opinion, and personal expertise was created to ultimately form a structured summary guidance incorporating the key features.

Results: The summary guidance is comprised of a 10-point uniform reporting format ranging from introduction, materials and methods, through to results and discussion. Each item is discussed in detail in the guidance report.

Conclusions: To enhance the future development of body fluid biomarkers, it will be important to standardize the reporting of studies. This guideline by the BioMS-eu consortium is aimed at setting a standard for the reporting of future body fluid biomarker research studies in neurologic disorders. We anticipate that following these guidelines will help to accelerate the selection of biomarkers for clinical development.

Zolpidem and the risk of Parkinson's disease: A nationwide population-based study

J Psychiatr Res. 2014 Jul 25. pii: S0022-3956(14)00200-3. doi: 10.1016/j.jpsychires.2014.07.003. [Epub ahead of print]

Yang YW, Hsieh TF, Yu CH, Huang YS, Lee CC, Tsai TH.

BACKGROUND:

This nationwide population-based study investigated the risk of Parkinson's disease (PD) after zolpidem use in patients with sleep disturbance using the National Health Insurance Research Database (NHIRD) in Taiwan.

MATERIAL AND METHODS:

In total, 59,548 adult patients newly diagnosed with sleep disturbance and who used zolpidem were recruited as the study cohort, along with 42,171 subjects who did not use zolpidem as a comparison cohort from 2002 to 2009. Each patient was monitored for 5 years, and those who subsequently had PD were identified. A Cox proportional hazards model was used to compare the risk of PD between the study and comparison cohorts after adjusting for possible confounding risk factors.

RESULTS:

The patients who received zolpidem had a higher cumulative rate of PD than those who did not receive zolpidem during the 5-year follow-up period (1.2% vs. 0.5%, P < 0.001). The adjusted hazard ratios were 1.10 (95% CI, 0.88-1.37), 1.41 (95% CI, 1.17-1.72), and 1.27 (95% CI, 1.05-1.55) for zolpidem use with 28-90, 91-365, and more than 365 cumulative defined daily doses (cDDDs), respectively, compared to those who did not use zolpidem.

CONCLUSIONS:

Among the patients with sleep disturbance, zolpidem use increased the risk of PD after 5 years of follow-up. Further mechanistic research of zolpidem effect in PD is needed.

Presence and progression of non-motor symptoms in relation to uric acid in de novo Parkinson's disease

Eur J Neurol. 2014 Aug 7. doi: 10.1111/ene.12533. [Epub ahead of print]

Moccia M, Picillo M, Erro R, Vitale C, Longo K, Amboni M, Santangelo G, Palladino R, Capo G, Orefice G, Barone P, Pellecchia MT.

BACKGROUND AND PURPOSE:

Uric acid (UA) has been studied extensively as a valuable biomarker of Parkinson's disease (PD), but its relationship with non-motor symptoms (NMS) in de novo PD has been poorly investigated. Our aim was to evaluate the usefulness of baseline serum UA as a marker of NMS progression in newly diagnosed PD.

METHODS:

Sixty-nine newly diagnosed PD patients were enrolled. At baseline, all patients completed the NMS questionnaire (NMSQuest), and serum UA levels were measured. After 2 years, the NMSQuest was completed again and patients were categorized into four groups: NMS improvement (domain involvement at baseline but not at 2-year follow-up visit), NMS absence (domain not involved at baseline or 2-year follow-up visits), NMS presence (domain involvement both at baseline and 2-year follow-up visits) and NMS worsening (domain not involved at baseline but involved at 2-year follow-up).

RESULTS:

anova with post hoc Bonferroni correction showed that patients with NMS absence presented significantly higher UA values than patients with NMS presence with regard to the attention/memory (P = 0.023), depression/anxiety (P = 0.028) and cardiovascular domains (P = 0.002), whilst no differences were found with regard to both the NMS improvement and worsening groups. In addition, multinomial regression analysis showed that the lowest tertile of NMS progression presented higher UA levels (P = 0.023; odds ratio 0.488) compared with patients with greater NMS progression.

CONCLUSIONS:

This is the first report of a relationship between serum UA and presence/progression of multiple NMS in de novo PD, providing additional evidence of the reliability of UA as a biomarker of PD and opening new insights on PD neuroprotection.

Occupational exposure to pesticides and endotoxin and Parkinson disease in the Netherlands.

Occup Environ Med. 2014 Aug 7. pii: oemed-2014-102170. doi: 10.1136/oemed-2014-102170. [Epub ahead of print]

van der Mark M, Vermeulen R, Nijssen PC, Mulleners WM, Sas AM, van Laar T, Brouwer M, Huss A, Kromhout H.

OBJECTIVES:

Previous research has indicated that occupational exposure to pesticides and possibly airborne endotoxin may increase the risk of developing Parkinson disease (PD). We studied the associations of PD with occupational exposure to pesticides, specifically to the functional subclasses insecticides, herbicides and fungicides, and to airborne endotoxin. In addition we evaluated specific pesticides (active ingredients) previously associated with PD.

METHODS:

We used data from a hospital-based case-control study, including 444 patients with PD and 876 age and sex matched controls. Exposures to pesticides from application and re-entry work were estimated with the ALOHA+job-exposure matrix and with an exposure algorithm based on self-reported information on pesticide use. To assess exposure to specific active ingredients a crop-exposure matrix was developed. Endotoxin exposure was estimated with the DOM job-exposure matrix.

RESULTS:

The results showed almost no significant associations. However, ORs were elevated in the higher exposure categories for pesticides in general, insecticides, herbicides and fungicides, and below unity for endotoxin exposure. The analyses on specific active ingredients showed a significant association of PD risk with the fungicide benomyl.

CONCLUSIONS:

This study did not provide evidence for a relation between pesticide exposure and PD. However, the consistently elevated ORs in the higher exposure categories suggest that a positive association may exist. The possible association with the active ingredient benomyl requires follow-up in other studies. This study did not provide support for a possible association between endotoxin exposure and PD.

In vivo gastric detection of α-synuclein inclusions in Parkinson's disease.

Alpha-synuclein in the stomach... 

Mov Disord. 2014 Aug 11. doi: 10.1002/mds.25988. [Epub ahead of print]

Sánchez-Ferro A, Rábano A, Catalán MJ, Rodríguez-Valcárcel FC, Díez SF, Herreros-Rodríguez J, García-Cobos E, Alvarez-Santullano MM, López-Manzanares L, Mosqueira AJ, Desojo LV, López-Lozano JJ, López-Valdés E, Sánchez-Sánchez R, Molina-Arjona JA.

Abstract

α-Synuclein inclusions have been identified in the brain and some parts of the enteric nervous system in Parkinson's disease cases. We aimed to assess these inclusions in gastric mucosa samples from patients with symptomatic Parkinson's disease. Random biopsies were performed by gastroscopy in 28 patients with Parkinson's disease and in 29 age- and sex-matched controls. Gastroscopy was performed to start enteral levodopa (l-dopa) therapy in cases and for diagnostic purposes in controls (gastroesophageal reflux, anemia, and abdominal pain were the main indications). The clinical definition of cases and controls was made a priori. Six controls had data suggestive of "mild presymptomatic parkinsonism". Biopsy specimens were immunostained for α-synuclein. The neuropathological diagnosis was established post hoc. No differences were found in the baseline characteristics of the groups. Positive fibers for the α-synuclein protein were observed in 17 of 28 (60.7%) Parkinson's disease patients, 1 of 23 controls (4.3%), and 1 of 6 (16.7%) cases of incident "mild presymptomatic parkinsonism." Neuropathological diagnosis based on α-synuclein immunostaining showed a sensitivity of 85% (95% confidence interval [CI] 62.1-96.8), specificity of 95% (95% CI 76.2-99.9) and area under the receiver operating characteristics curve (AUC) of 0.90 (95% CI 0.80-1.00). No adverse events occurred. Detection of α-synuclein inclusions in the gastric mucosa is a useful and safe tool providing in vivo evidence of the underlying neurodegenerative peripheral involvement linked to Parkinson's disease. Further studies are warranted to determine its pathophysiological implications.

Inverse association between cancer and neurodegenerative disease: review of the epidemiologic and biological evidence

Biogerontology. 2014 Aug 12. [Epub ahead of print]

Driver JA.

Abstract

Growing evidence suggests an unusual epidemiologic association between cancer and certain neurological conditions, particularly age-related neurodegenerative diseases. Cancer survivors have a 20-50 % lower risk of developing Parkinson's and Alzheimer's disease, and patients with these neurodegenerative conditions have a substantially lower incidence of cancer. We review the epidemiologic evidence for this inverse co-morbidity and show that it is not simply an artifact of survival bias or under-diagnosis. We then review the potential biological explanations for this association, which is intimately linked to the very different nature of dividing cells and neurons. The known genetic and metabolic connections between cancer and neurodegeneration generally fall within two categories. The first includes shared genes and pathways such as Pin1 and the ubiquitin proteasome system that are dysregulated in different directions to cause one disease or the other. The second includes common pathophysiological mechanisms such as mitochondrial dysfunction, oxidative stress and DNA damage that drive both conditions, but with different cellular fates. We discuss examples of these biological links and their implications for developing new approaches to prevention and treatment of both diseases.

Cortical thinning associated with mild cognitive impairment in Parkinson's disease.

Mov Disord. 2014 Aug 7. doi: 10.1002/mds.25982. [Epub ahead of print]

Segura B, Baggio HC, Marti MJ, Valldeoriola F, Compta Y, Garcia-Diaz AI, Vendrell P, Bargallo N, Tolosa E, Junque C.

Abstract

The aim of this study was to investigate patterns of cortical atrophy associated with mild cognitive impairment in a large sample of nondemented Parkinson's disease (PD) patients, and its relation with specific neuropsychological deficits. Magnetic resonance imaging (MRI) and neuropsychological assessment were performed in a sample of 90 nondemented PD patients and 32 healthy controls. All underwent a neuropsychological battery including tests that assess different cognitive domains: attention and working memory, executive functions, memory, language, and visuoperceptual-visuospatial functions. Patients were classified according to their cognitive status as PD patients without mild cognitive impairment (MCI; n = 43) and PD patients with MCI (n = 47). Freesurfer software was used to obtain maps of cortical thickness for group comparisons and correlation with neuropsychological performance. Patients with MCI showed regional cortical thinning in parietotemporal regions, increased global atrophy (global cortical thinning, total gray matter volume reduction, and ventricular enlargement), as well as significant cognitive impairment in memory, executive, and visuospatial and visuoperceptual domains. Correlation analyses showed that all neuropsychological tests were associated with cortical thinning in parietotemporal regions and to a lesser extent in frontal regions. These results provide neuroanatomic support to the concept of MCI classified according to Movement Disorders Society criteria. The posterior pattern of atrophy in temporoparietal regions could be a structural neuroimaging marker of cognitive impairment in nondemented PD patients. All of the neuropsychological tests reflected regional brain atrophy, but no specific patterns were seen corresponding to impairment in distinct cognitive domains.

Gene-Gene and Gene-Environment Interaction on the Risk of Parkinson's Disease.

Curr Aging Sci. 2014 Aug 5. [Epub ahead of print]

Singh NK, Banerjee BD, Bala K, Basu M, Chhillar N.

Abstract

Background: Even with numerous studies the cause of Parkinson's disease (PD) remains elusive. It has been hypothesized that interactions between genetic and environmental factors may play an important role in the pathogenesis of PD. Objectives: To examine the gene-gene and gene-environment interaction on PD risk with respect to gene polymorphism of cytochrome P450 2D6 (CYP2D6) and glutathione S-transferases pi 1 (GSTP1), organochlorine pesticides (OCPs) and metals. Methods: This study included 70 patients of PD and 100 age-matched controls. The restriction fragment length polymorphism was used for analysis of genetic polymorphism. OCPs and serum metal levels were estimated by using gas chromatography and an autoanalyser respectively. Results: The CYP2D6*4 mt and GSTP1 *B allelic variants were significantly associated with increase in PD risk. We found a statistically significant difference in β-hexachlorocyclohexane (β-HCH), dieldrin, 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (pp'-DDE) and copper levels between the patients and controls. We found significantly high levels of β-HCH, dieldrin and pp'-DDE in the CYP2D6*4 mt allelic variants, β-HCH and pp'-DDE in the GSTP1*B allelic variants and dieldrin in the GSTP1*C allelic variants when comparing CYP2D6*4 non-mt, GSTP1 non-*B and GSTP1 non-*C allelic variants in patients of PD respectively. Conclusion: This study demonstrates that the CYP2D6*4 and GSTP1 genes may be considered as candidate genes for PD and they may also interact with β- HCH, dieldrin and pp'-DDE to influence the risk for PD.

REM sleep behavior disorder: Association with motor complications and impulse control disorders in Parkinson's disease

Parkinsonism Relat Disord. 2014 Apr 1. pii: S1353-8020(14)00132-1. doi: 10.1016/j.parkreldis.2014.03.022. [Epub ahead of print]

Kim YE, Jeon BS, Yang HJ, Ehm G, Yun JY, Kim HJ, Kim JM.

OBJECTIVE:

Clinical phenotypes such as old age, longer disease duration, motor disability, akineto-rigid type, dementia and hallucinations are known to be associated with REM sleep behavior disorder (RBD) in Parkinson's disease (PD). However, the relationship between motor fluctuations/impulse control and related behaviors (ICRB) and RBD is not clear. We designed this study to elucidate the clinical manifestations associated with RBD to determine the implications of RBD in PD.

DESIGN:

In a cross-sectional study, a total of 994 patients with PD were interviewed to determine the presence of RBD and their associated clinical features including motor complications and ICRB.

RESULTS:

Of the 944 patients, 578 (61.2%) had clinical RBD. When comparing the clinical features between patients with RBD (RBD group) and without RBD (non-RBD group), older age, longer disease duration, higher Hoehn and Yahr stage (H&Y stage), higher levodopa equivalent daily dose (LEDD), and the existence of wearing off, dyskinesia, freezing, and ICRB, especially punding, were associated with the RBD group compared to the non-RBD group (P < .05 in all). Multivariate analysis showed that motor complications including wearing off, peak dose dyskinesia, and diphasic dyskinesia were the only relevant factors for RBD after adjusting for age and disease duration.

CONCLUSION:

Motor complications and ICRB are more frequent in patients with RBD than in patients without RBD. In addition, motor complications are related to RBD even after adjusting for age and disease duration.

Genetic impact on cognition and brain function in newly diagnosed Parkinson's disease: ICICLE-PD study

Brain. 2014 Jul 30. pii: awu201. [Epub ahead of print]

Nombela C, Rowe JB, Winder-Rhodes SE, Hampshire A, Owen AM, Breen DP, Duncan GW, Khoo TK, Yarnall AJ, Firbank MJ, Chinnery PF, Robbins TW, O'Brien JT, Brooks DJ, Burn DJ; the ICICLE-PD study group, Barker RA.

Parkinson's disease is associated with multiple cognitive impairments and increased risk of dementia, but the extent of these deficits varies widely among patients. The ICICLE-PD study was established to define the characteristics and prevalence of cognitive change soon after diagnosis, in a representative cohort of patients, using a multimodal approach. Specifically, we tested the 'Dual Syndrome' hypothesis for cognitive impairment in Parkinson's disease, which distinguishes an executive syndrome (affecting the frontostriatal regions due to dopaminergic deficits) from a posterior cortical syndrome (affecting visuospatial, mnemonic and semantic functions related to Lewy body pathology and secondary cholinergic loss). An incident Parkinson's disease cohort (n = 168, median 8 months from diagnosis to participation) and matched control group (n = 85) were recruited to a neuroimaging study at two sites in the UK. All participants underwent clinical, neuropsychological and functional magnetic resonance imaging assessments. The three neuroimaging tasks (Tower of London, Spatial Rotations and Memory Encoding Tasks) were designed to probe executive, visuospatial and memory encoding domains, respectively. Patients were also genotyped for three polymorphisms associated with cognitive change in Parkinson's disease and related disorders: (i) rs4680 for COMT Val158Met polymorphism; (ii) rs9468 for MAPT H1 versus H2 haplotype; and (iii) rs429358 for APOE-ε2, 3, 4. We identified performance deficits in all three cognitive domains, which were associated with regionally specific changes in cortical activation. Task-specific regional activations in Parkinson's disease were linked with genetic variation: the rs4680 polymorphism modulated the effect of levodopa therapy on planning-related activations in the frontoparietal network; the MAPT haplotype modulated parietal activations associated with spatial rotations; and APOE allelic variation influenced the magnitude of activation associated with memory encoding. This study demonstrates that neurocognitive deficits are common even in recently diagnosed patients with Parkinson's disease, and that the associated regional brain activations are influenced by genotype. These data further support the dual syndrome hypothesis of cognitive change in Parkinson's disease. Longitudinal data will confirm the extent to which these early neurocognitive changes, and their genetic factors, influence the long-term risk of dementia in Parkinson's disease. The combination of genetics and functional neuroimaging provides a potentially useful method for stratification and identification of candidate markers, in future clinical trials against cognitive decline in Parkinson's disease.