Predictors of dementia in Parkinson's disease; findings from a 5-year prospective study using the SCOPA-COG

Parkinsonism Relat Disord. 2014 Jun 26. pii: S1353-8020(14)00226-0. doi: 10.1016/j.parkreldis.2014.06.006. [Epub ahead of print]

Zhu K, van Hilten JJ, Marinus J.

OBJECTIVE:

Aim of this study was to identify risk factors for the development of dementia in patients with Parkinson's disease (PD).

METHODS:

A broad range of motor and non-motor features was assessed at baseline and the following five years in 406 PD patients. Cross-sectional analyses of baseline data and longitudinal analyses of follow-up data were performed to identify risk factors for dementia.

RESULTS:

Thirty-two percent of patients (n = 129) had dementia at baseline, while 26% of patients (n = 68) without dementia at baseline developed dementia during follow-up. Univariate survival analysis showed that higher age, fewer years of education, longer disease duration, higher age-at-onset, higher levodopa dose, higher Hoehn & Yahr stage, presence of dyskinesias, excessive daytime sleepiness (EDS), presence of hallucinations, and more severe autonomic and depressive symptoms were associated with an increased risk of dementia. Higher baseline Postural-Instability-and-Gait-Difficulty scores were also associated with an increased risk of dementia, whereas no effect of tremor severity was found. These findings largely corresponded with the variables that were associated with the presence of dementia at baseline. In a stepwise regression model, higher age at baseline, fewer years of education, higher daily levodopa dose and excessive daytime sleepiness (EDS) emerged as independent risk factors of future dementia.

CONCLUSIONS:

In this large prospective cohort study, we identified a combination of potentially interacting risk factors for dementia in PD that are associated with higher age and more advanced disease.

The association between chronic obstructive pulmonary disease and Parkinson's disease: a nationwide population-based retrospective cohort study

This surprises me given the strong negative associations with PD and smoking. In fact I can't remember ever having seen someone with PD and COPD in clinic...

QJM. 2014 Jul 14. pii: hcu136. [Epub ahead of print]

Li CH, Chen WC, Liao WC, Tu CY, Lin CL, Sung FC, Chen CH, Hsu WH.

OBJECTIVE:

Previous research has shown that patients with chronic obstructive pulmonary disease (COPD) tend to have a higher risk for cognitive impairment and dementia, a neurodegenerative disorder. The goal of this study was to examine what relationship, if any, exists between COPD and Parkinson's disease (PD), which is also a neurodegenerative disorder.

METHOD:

Our study analyzed medical data from the population of Taiwan from 1998 to 2008, with a follow-up period extending to the end of 2010. We identified patients with COPD by the Taiwan National Health Insurance Research Database (NHIRD). We selected a comparison cohort from the general population that was random frequency-matched by age (in 5-year increments), sex and index year, and further analyzed the risk of PD using Cox's regression model, including sex, age and comorbidities.

RESULTS:

The study enrolled 20 728 COPD patients (71.1% male, mean age = 68.2 years) and 41 147 controls. The risk of developing PD was 1.37 times greater in patients with COPD compared with patients without COPD after adjusting for age, sex and comorbidities. A significantly increased risk of PD was also found in patients with COPD who had any comorbidity other than diabetes.

CONCLUSION:

This nationwide retrospective cohort study demonstrates that PD risk is significantly increased in patients with COPD compared with those of the general population.

A review of the use of magnetic resonance imaging in Parkinson's disease.

Ther Adv Neurol Disord. 2014 Jul;7(4):206-20. doi: 10.1177/1756285613511507.

Pyatigorskaya N, Gallea C, Garcia-Lorenzo D, Vidailhet M, Lehericy S.

Abstract

To date, the most frequently used Parkinson's disease (PD) biomarkers are the brain imaging measures of dopaminergic dysfunction using positron emission tomography and single photon emission computed tomography. However, major advances have occurred in the development of magnetic resonance imaging (MRI) biomarkers for PD in the past decade. Although conventional structural imaging remains normal in PD, advanced techniques have shown changes in the substantia nigra and the cortex. The most well-developed MRI markers in PD include diffusion imaging and iron load using T2/T2* relaxometry techniques. Other quantitative biomarkers such as susceptibility-weighted imaging for iron load, magnetization transfer and ultra-high-field MRI have shown great potential. More sophisticated techniques such as tractography and resting state functional connectivity give access to anatomical and functional connectivity changes in the brain, respectively. Brain perfusion can be assessed using non-contrast-agent techniques such as arterial spin labelling and spectroscopy gives access to metabolites concentrations. However, to date these techniques are not yet fully validated and standardized quantitative metrics for PD are still lacking. This review presents an overview of new structural, perfusion, metabolic and anatomo-functional connectivity biomarkers, their use in PD and their potential applications to improve the clinical diagnosis of Parkinsonian syndromes and the quality of clinical trials.

Stage-dependent nigral neuronal loss in incidental Lewy body and Parkinson's disease

Mov Disord. 2014 Jul 3. doi: 10.1002/mds.25952. [Epub ahead of print]

Dijkstra AA, Voorn P, Berendse HW, Groenewegen HJ; Netherlands Brain Bank, Rozemuller AJ, van de Berg WD.

Abstract

To gain a better understanding of the significance of α-synuclein pathological conditions during disease progression in Parkinson's disease, we investigated whether 1) nigral neuronal loss in incidental Lewy body disease and Parkinson's disease donors is associated with the local burden α-synuclein pathological conditions during progression of pathological conditions; 2) the burden and distribution of α-synuclein pathological conditions are related to clinical measures of disease progression. Post-mortem tissue and medical records of 24 Parkinson's disease patients, 20 incidental Lewy body disease donors, and 12 age-matched controls were obtained from the Netherlands Brain Bank for morphometric analysis. We observed a 20% decrease in nigral neuronal cell density in incidental Lewy body disease compared with controls. Nigral neuronal loss (12%) was already observed before the appearance α-synuclein aggregates. The progression from Braak α-synuclein stage 3 to 4 was associated with a significant decline in neuronal cell density (46%). Nigral neuronal loss increased with later Braak α-synuclein stages but did not vary across consecutive Braak α-synuclein stages. We observed a negative correlation between neuronal density and local α-synuclein burden in the substantia nigra of Parkinson's disease patients (ρ = -0.54), but no relationship with Hoehn & Yahr stage or disease duration. In conclusion, our findings cast doubt on the pathogenic role of α-synuclein aggregates in elderly, but do suggest that the severity of neurodegeneration and local burden of α-synuclein pathological conditions are closely coupled during disease progression in Parkinson's disease.

Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.

Another genetic risk factor for PD...?

Brain. 2014 Jul 2. pii: awu179. [Epub ahead of print]

Mencacci NE, Isaias IU, Reich MM, Ganos C, Plagnol V, Polke JM, Bras J, Hersheson J, Stamelou M, Pittman AM, Noyce AJ, Mok KY, Opladen T, Kunstmann E, Hodecker S, Münchau A, Volkmann J, Samnick S, Sidle K, Nanji T, Sweeney MG, Houlden H, Batla A, Zecchinelli AL, Pezzoli G, Marotta G, Lees A, Alegria P, Krack P, Cormier-Dequaire F, Lesage S, Brice A, Heutink P, Gasser T, Lubbe SJ, Morris HR, Taba P, Koks S, Majounie E, Raphael Gibbs J, Singleton A, Hardy J, Klebe S, Bhatia KP, Wood NW; on behalf of the International Parkinson’s Disease Genomics Consortium and UCL-exomes consortium.

Abstract

GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.

Individual and joint prevalence of three nonmotor symptoms of PD in the US general population

Important for groups like us who are looking combination of early features...

Mov Disord. 2014 Jul 1. doi: 10.1002/mds.25950. [Epub ahead of print]

Chen H, Huang X, Guo X, Peddada S.

BACKGROUND:

Some nonmotor symptoms may precede the clinical diagnosis of Parkinson's disease (PD) by years.

METHODS:

We examined the individual and joint prevalence of depression, daytime sleepiness, and infrequent bowel movement among 10,477 participants of the US National Health and Nutrition Examination Surveys 2005-2008.

RESULTS:

For all symptoms, the prevalence was higher in women than in men. Importantly, few participants had two or more symptoms: 1.3% at ages 20 to 29, 1.0% at 30 to 39, 1.2% at 40 to 49, 3.5% at 50 to 59, 1.7% at 60 to 69, 1.1% at 70 to 79, and 1.2% at ages 80 years or older in men; the corresponding prevalence in women was 3.1%, 5.2%, 5.7%, 4.1%, 3.1%, 2.3%, and 1.2%, respectively. In both men and women, depression was correlated with infrequent bowel movement and daytime sleepiness, but the latter two were mutually independent.

CONCLUSION:

The presence of multiple nonmotor symptoms was uncommon in the general population and the prevalence was higher in women than in men.

Comparison between visual assessment of dopaminergic degeneration pattern and semi-quantitative ratio calculations in patients with Parkinson's disease and Atypical Parkinsonian syndromes using DaTSCAN® SPECT.

Better characterisation of imaging differences between PD and atypical PD will really help us in the clinic...

Ann Nucl Med. 2014 Jul 6. [Epub ahead of print]

Davidsson A, Georgiopoulos C, Dizdar N, Granerus G, Zachrisson H.

OBJECTIVE:

To verify if 123I-FP-CIT, DaTSCAN® can differentiate early stages of Parkinson's disease (PD) as well as patients with Atypical Parkinsonian syndromes (APS) from manifest Parkinson's disease.

METHODS:

128 consecutive patients were investigated with 123I-FP-CIT SPECT during a 4-year period. All patients were diagnosed according to the established consensus criteria for diagnosis of PD (n = 53) and APS (n = 19). Remaining patients were grouped early PD (before onset of L-DOPA medication), (n = 20), vascular PD (n = 6), and non-PD syndromes (n = 30) and SWEDD (n = 1). SPECT images were analyzed visually according to a predefined ranking scale of dopaminergic nerve cell degeneration, distinguishing a posterior-anterior degeneration pattern (egg shape) from a more global and severe degeneration pattern (burst striatum). Striatum uptake ratios were quantitatively analyzed with the 3D software, EXINI.

RESULTS:

In the group of APS patients, the burst striatum pattern was most frequent and found in 61 % (11/18 patients). In PD patients, the egg shape pattern was dominating, especially in early PD where it was present in 95 % (19/20 patients). The positive predictive value for the egg shape pattern to diagnose PD was 92 % in this material (APS and all PD patients) and the specificity 90 % for the burst striatum pattern to exclude APS. The uptake ratios were reduced in both PD and APS patients and closely related to the image ranking.

CONCLUSION:

In this study, we found that in more than half of the patients it was possible to differentiate between PD and APS by visual interpretation only. Similar results were obtained using semi-quantitative uptake ratios. Combining visual assessment with uptake ratios did not add to the discriminating power of DaTSCAN® SPECT in this material.

Low clinical diagnostic accuracy of early vs advanced Parkinson disease: Clinicopathologic study

Neurology. 2014 Jun 27. pii: 10.1212/WNL.0000000000000641. [Epub ahead of print]

Adler CH, Beach TG, Hentz JG, Shill HA, Caviness JN, Driver-Dunckley E, Sabbagh MN, Sue LI, Jacobson SA, Belden CM, Dugger BN.

Abstract

Determine diagnostic accuracy of a clinical diagnosis of Parkinson disease (PD) using neuropathologic diagnosis as the gold standard.

Data from the Arizona Study of Aging and Neurodegenerative Disorders were used to determine the predictive value of a clinical PD diagnosis, using 2 clinical diagnostic confidence levels, PossPD (never treated or not clearly responsive) and ProbPD (responsive to medications). Neuropathologic diagnosis was the gold standard.

Based on first visit, 9 of 34 (26%) PossPD cases had neuropathologically confirmed PD while 80 of 97 (82%) ProbPD cases had confirmed PD. PD was confirmed in 8 of 15 (53%) ProbPD cases with <5 years of disease duration and 72 of 82 (88%) with ≥5 years of disease duration. Using final diagnosis at time of death, 91 of 107 (85%) ProbPD cases had confirmed PD. Clinical variables that improved diagnostic accuracy were medication response, motor fluctuations, dyskinesias, and hyposmia.

Using neuropathologic findings of PD as the gold standard, this study establishes the novel findings of only 26% accuracy for a clinical diagnosis of PD in untreated or not clearly responsive subjects, 53% accuracy in early PD responsive to medication (<5 years' duration), and >85% diagnostic accuracy of longer duration, medication-responsive PD. Caution is needed when interpreting clinical studies of PD, especially studies of early disease that do not have autopsy confirmation. The need for a tissue or other diagnostic biomarker is reinforced.

This study provides Class II evidence that a clinical diagnosis of PD identifies patients who will have pathologically confirmed PD with a sensitivity of 88% and specificity of 68%.

The prevalence of Parkinson's disease: A systematic review and meta-analysis

Mov Disord. 2014 Jun 28. doi: 10.1002/mds.25945. [Epub ahead of print]

Pringsheim T, Jette N, Frolkis A, Steeves TD.

Abstract

Parkinson's Disease (PD) is a common neurodegenerative disorder. We sought to synthesize studies on the prevalence of PD to obtain an overall view of how the prevalence of this disease varies by age, by sex, and by geographic location. We searched MEDLINE and EMBASE for epidemiological studies of PD from 1985 to 2010. Data were analyzed by age group, geographic location, and sex. Geographic location was stratified by the following groups: 1) Asia, 2) Africa, 3) South America, and 4) Europe/North America/Australia. Meta-regression was used to determine whether a significant difference was present between groups. Forty-seven studies were included in the analysis. Meta-analysis of the worldwide data showed a rising prevalence of PD with age (all per 100,000): 41 in 40 to 49 years; 107 in 50 to 59 years; 173 in 55 to 64 years; 428 in 60 to 69 years; 425 in 65 to 74 years; 1087 in 70 to 79 years; and 1903 in older than age 80. A significant difference was seen in prevalence by geographic location only for individuals 70 to 79 years old, with a prevalence of 1,601 in individuals from North America, Europe, and Australia, compared with 646 in individuals from Asia (P < 0.05). A significant difference in prevalence by sex was found only for individuals 50 to 59 years old, with a prevalence of 41 in females and 134 in males (P < 0.05). PD prevalence increases steadily with age. Some differences in prevalence by geographic location and sex can be detected.

Premotor and nonmotor features of Parkinson's disease

Curr Opin Neurol. 2014 Aug;27(4):434-441.

Goldman JG, Postuma R.

PURPOSE OF REVIEW:

This review highlights recent advances in premotor and nonmotor features in Parkinson's disease, focusing on these issues in the context of prodromal and early-stage Parkinson's disease.

RECENT FINDINGS:

Although Parkinson's disease patients experience a wide range of nonmotor symptoms throughout the disease course, studies demonstrate that nonmotor features are not solely a late manifestation. Indeed, disturbances of smell, sleep, mood, and gastrointestinal function may herald Parkinson's disease or related synucleinopathies and precede these neurodegenerative conditions by 5 or more years. In addition, other nonmotor symptoms such as cognitive impairment are now recognized in incident or de-novo Parkinson's disease cohorts. Many of these nonmotor features reflect disturbances in nondopaminergic systems and early involvement of peripheral and central nervous systems, including olfactory, enteric, and brainstem neurons as in Braak's proposed pathological staging of Parkinson's disease. Current research focuses on identifying potential biomarkers that may detect persons at risk for Parkinson's disease and permit early intervention with neuroprotective or disease-modifying therapeutics.

SUMMARY:

Recent studies provide new insights into the frequency, pathophysiology, and importance of nonmotor features in Parkinson's disease as well as the recognition that these nonmotor symptoms occur in premotor, early, and later phases of Parkinson's disease.

Inflammation and insulin/IGF-1 resistance as the possible link between obesity and neurodegeneration

J Neuroimmunol. 2014 Jun 12. pii: S0165-5728(14)00175-1. doi: 10.1016/j.jneuroim.2014.06.004. [Epub ahead of print]

Spielman LJ, Little JP, Klegeris A.

Author information

Abstract

Obesity is a growing epidemic that contributes to several brain disorders including Alzheimer's, Parkinson's, and Huntington's diseases. Obesity could promote these diseases through several different mechanisms. Here we review evidence supporting the involvement of two recently recognized factors linking obesity with neurodegeneration: the induction of pro-inflammatory cytokines and onset of insulin and insulin-like growth factor 1 (IGF-1) resistance. Excess peripheral pro-inflammatory mediators, some of which can cross the blood brain barrier, may trigger neuroinflammation, which subsequently exacerbates neurodegeneration. Insulin and IGF-1 resistance leads to weakening of neuroprotective signaling by these molecules and can contribute to onset of neurodegenerative diseases.