Combining (relatively) cheap investigations to differentiate Parkinson's from atypical Parkinson's may prove fruitful... certainly in most centres it is difficult to differentiate these conditions using SPECT imaging... and many people are not confident with the MRI differences...
PLoS One. 2016 Nov 3;11(11):e0165869. doi: 10.1371/journal.pone.0165869. eCollection 2016. Fujita H1, Suzuki K1, Numao A1, Watanabe Y1, Uchiyama T1,2, Miyamoto T3, Miyamoto M4, Hirata K1.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165869
BACKGROUND:
We aimed to evaluate the utility of the combined use of cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy, olfactory testing, and substantia nigra (SN) hyperechogenicity on transcranial sonography (TCS) in differentiating Parkinson's disease (PD) from atypical parkinsonian syndromes (APSs), such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP).
METHODS:
Cardiac MIBG scintigraphy, card-type odor identification testing (Open Essence (OE), Wako, Japan), and TCS were performed with 101 patients with PD and 38 patients with APSs (MSA and PSP). Receiver operating characteristic (ROC) curve analysis was used to assess the sensitivity and specificity of these batteries for diagnosing PD from APSs. The diagnostic accuracy of the three tests was also assessed among patients at the early disease stage (drug-naïve patients with a disease duration of 3 years or less).
RESULTS:
In differentiating PD from APSs, the area under the ROC curve was 0.74 (95% CI, 0.65-0.83), 0.8 (95% CI, 0.73-0.87), and 0.75 (95% CI, 0.67-0.82) for TCS, cardiac MIBG scintigraphy, and olfactory testing, respectively. The diagnostic sensitivity and specificity were 53.1% and 91.7%, respectively, for TCS, 70.3% and 86.8%, respectively, for cardiac MIBG scintigraphy, 58.4% and 76.3%, respectively, for OE. Among early-stage patients, sensitivity and specificity were 50.0% and 93.8%, respectively, for TCS, 57.1% and 87.5%, respectively, for cardiac MIBG scintigraphy, and 54.8% and 79.2%, respectively, for OE. At least one positive result from 3 tests improved sensitivity (86.1%) but decreased specificity (63.2%). In contrast, at least 2 positive results from 3 tests had good discrimination for both early-stage patients (50.0% sensitivity and 93.8% specificity) and patients overall (57.8% sensitivity and 95.8% specificity). Positive results for all 3 tests yielded 100% specificity but low sensitivity (25%).
CONCLUSIONS:
At least 2 positive results from among TCS, cardiac MIBG scintigraphy, and olfactory testing can support clinical diagnosis in distinguishing PD from APSs.
Tuesday, 8 November 2016
Saturday, 5 November 2016
Genome-wide association study in essential tremor identifies three new loci
Understanding the genetics of essential tremor has been difficult, but this is now a reasonably large GWAS study conducted by investigators who will have accurately characterise the phenotype... GWAS (like anything) depends on accurate diagnosis of the cases and ideally confident exclusion of the disease in controls... interestingly some of the previously reported 'hits' for essential tremor are not replicated here...
Brain. 2016 Oct 20. pii: aww242. [Epub ahead of print]
Müller SH, Girard SL, Hopfner F, Merner ND, Bourassa CV, Lorenz D, Clark LN, Tittmann L, Soto-Ortolaza AI, Klebe S, Hallett M, Schneider SA, Hodgkinson CA, Lieb W, Wszolek ZK, Pendziwiat M, Lorenzo-Betancor O, Poewe W, Ortega-Cubero S, Seppi K, Rajput A, Hussl A, Rajput AH, Berg D, Dion PA, Wurster I, Shulman JM, Srulijes K, Haubenberger D, Pastor P, Vilariño-Güell C, Postuma RB, Bernard G, Ladwig KH, Dupré N, Jankovic J, Strauch K, Panisset M, Winkelmann J, Testa CM, Reischl E, Zeuner KE, Ross OA, Arzberger T, Chouinard S, Deuschl G, Louis ED, Kuhlenbäumer G, Rouleau GA.
We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.
Tuesday, 1 November 2016
Additional Rare Variant Analysis in Parkinson's Disease Cases with and Without Known Pathogenic Mutations: Evidence for Oligogenic Inheritance
Great to see this paper published... it provides evidence for another layer of complexity to the genetics of Parkinson's, but also provides further explanation for this complexity... as time passes we realise there is not just genetic and non-genetic Parkinson's, but instead that genetic variability underpins a great deal of the heterogeneity of all Parkinson's disease...
Hum Mol Genet. 2016 Oct 18. pii: ddw348. [Epub ahead of print]
Lubbe SJ, Escott-Price V, Gibbs JR, Nalls MA, Bras J, Price TR, Nicolas A, Jansen IE, Mok KY, Pittman AM, Tomkins JE, Lewis PA, Noyce AJ, Lesage S, Sharma M, Schiff ER, Levine AP, Brice A, Gasser T, Hardy J, Heutink P, Wood NW, Singleton AB, Williams NM, Morris HR; for International Parkinson’s Disease Genomics Consortium.
Abstract
Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson's (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (≥30%) of cases with a recognized primary genetic cause had ≥1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our hypothesis. Carriers of additional Mendelian gene variants have younger ages at onset (AAO). The effect of additional Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variation is particularly common, may account for some of the variation in penetrance. About 10% of no known mutation PD cases harbor a rare GBA variant compared to known pathogenic mutation PD cases (8%) and controls (5%), with carriers having earlier AAOs. Together, the data suggest that the oligogenic inheritance of rare Mendelian variants may be important in patient with a primary pathogenic cause, whereas GBA increases risk across all forms of PD. This study highlights potential genetic complexity of Mendelian PD. The identification of potential modifying variants provides new insights into disease mechanisms by potentially separating relevant from benign variants and by the interaction between genes in specific pathways. In the future this may be relevant to genetic testing and counselling of PD patients and their families.
Saturday, 29 October 2016
Neuropsychiatric characteristics of GBA-associated Parkinson disease
These findings support earlier observations about GBA-related PD... there does seem to be a tendency for increased neuro-psychiatric features, cognitive impairment and perhaps a more severe motor phenotype...
J Neurol Sci. 2016 Nov 15;370:63-69. doi: 10.1016/j.jns.2016.08.059. Epub 2016 Aug 30.
Swan M, Doan N, Ortega RA, Barrett M, Nichols W, Ozelius L, Soto-Valencia J, Boschung S, Deik A, Sarva H, Cabassa J, Johannes B, Raymond D, Marder K, Giladi N, Miravite J, Severt W, Sachdev R, Shanker V, Bressman S, Saunders-Pullman R.
Mutations in GBA1 are a well-established risk factor for Parkinson disease (PD). GBA-associated PD (GBA-PD) may have a higher burden of nonmotor symptoms than idiopathic PD (IPD). We sought to characterize the relationship between GBA-PD and neuropsychiatric symptoms. Subjects were screened for common GBA1 mutations. GBA-PD (n=31) and non-carrier (IPD; n=55) scores were compared on the Unified Parkinson Disease Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA), Beck Depression Inventory (BDI), and the State-Trait Anxiety Index (STAI). In univariate comparisons, GBA-PD had a greater prevalence of depression (33.3%) versus IPD (13.2%) (p<0.05). In regression models controlling for age, sex, disease duration, motor disability, and MoCA score, GBA-PD had an increased odds of depression (OR 3.66, 95% CI 1.13-11.8) (p=0.03). Post-hoc analysis stratified by sex showed that, among men, GBA-PD had a higher burden of trait anxiety and depression than IPD; this finding was sustained in multivariate models. Among women, GBA-PD did not confer greater psychiatric morbidity than IPD. These results suggest that GBA1 mutations confer greater risk of neuropsychiatric morbidity in PD, and that sex may affect this association.
Wednesday, 26 October 2016
Associations between plasma ceramides and cognitive and neuropsychiatric manifestations in Parkinson's disease dementia
Here we see differences in levels of ceramides not only in those PD patients with cognitive impairment, but also in those without cognitive impairment compared with controls... I think we are going to hear a lot more about ceramides in the future...
J Neurol Sci. 2016 Nov 15;370:82-87. doi: 10.1016/j.jns.2016.09.028. Epub 2016 Sep 19.
Xing Y, Tang Y, Zhao L, Wang Q, Qin W, Ji X, Zhang J, Jia J.
BACKGROUND:
The abnormal metabolism of ceramides may account for the pathogenesis of Parkinson's disease dementia (PDD). However, the effect of ceramides on cognitive domain impairments and neuropsychiatric symptoms of PDD remains unknown.
METHODS:
A total of 38 PDD, 40 PD with no cognitive impairment (PD-NC) and 40 normal controls were included. A series of cognitive tests and the Neuropsychiatric Inventory (NPI) were used to assess cognitive domains and neuropsychiatric symptoms. A non-fasting blood sample was obtained from each subject. Plasma ceramide levels were tested by HPLC-MS/MS analysis.
RESULTS:
C14:0 and C24:1 levels were significantly higher in PDD than in PD-NC and normal controls. Verbal memory was negatively correlated with C14:0 and C24:1. After controlling for confounding factors, C22:0, C20:0 and C18:0 were significantly associated with hallucinations, anxiety and sleep behavior disturbances, respectively.
CONCLUSION:
In PDD, the increase in ceramide levels was correlated with decreased memory function and associated with higher odds of multiple neuropsychiatric symptoms.
Tuesday, 25 October 2016
Brain MR Contribution to the Differential Diagnosis of Parkinsonian Syndromes: An Update
Up-to-date article about the use of MRI in parkinsonian syndromes... it is likely that MRI will play a leading role in the future identification of prodromal PD in my opinion...
Parkinsons Dis. 2016;2016:2983638. Epub 2016 Sep 28.
Rizzo G, Zanigni S, De Blasi R, Grasso D, Martino D, Savica R, Logroscino G.
Brain magnetic resonance (MR) represents a useful and feasible tool for the differential diagnosis of Parkinson's disease. Conventional MR may reveal secondary forms of parkinsonism and may show peculiar brain alterations of atypical parkinsonian syndromes. Furthermore, advanced MR techniques, such as morphometric-volumetric analyses, diffusion-weighted imaging, diffusion tensor imaging, tractography, proton MR spectroscopy, and iron-content sensitive imaging, have been used to obtain quantitative parameters useful to increase the diagnostic accuracy. Currently, many MR studies have provided both qualitative and quantitative findings, reflecting the underlying neuropathological pattern of the different degenerative parkinsonian syndromes. Although the variability in the methods and results across the studies limits the conclusion about which technique is the best, specific radiologic phenotypes may be identified. Qualitative/quantitative MR changes in the substantia nigra do not discriminate between different parkinsonisms. In the absence of extranigral abnormalities, the diagnosis of PD is more probable, whereas basal ganglia changes (mainly in the putamen) suggest the diagnosis of an atypical parkinsonian syndrome. In this context, changes in pons, middle cerebellar peduncles, and cerebellum suggest the diagnosis of MSA, in midbrain and superior cerebellar peduncles the diagnosis of PSP, and in whole cerebral hemispheres (mainly in frontoparietal cortex with asymmetric distribution) the diagnosis of Corticobasal Syndrome.
Sunday, 23 October 2016
Cognitive impairment in Parkinson's disease: Association between patient-reported and clinically measured outcomes
Interesting to see that these are the bits that patients notice when cognition starts to deteriorate... I always feel that patients have a bit of agnosia, at least for the motor features, and I wonder if its the same for cognition...
Parkinsonism Relat Disord. 2016 Sep 27. pii: S1353-8020(16)30383-2. doi: 10.1016/j.parkreldis.2016.09.025. [Epub ahead of print]
Mills KA, Mari Z, Pontone GM, Pantelyat A, Zhang A, Yoritomo N, Powers E, Brandt J, Dawson TM, Rosenthal LS.
BACKGROUND:
In Parkinson's disease, the association between objective and patient-reported measures of cognitive dysfunction is unknown and highly relevant to research and clinical care.
OBJECTIVE:
To determine which cognitive domain-specific Montreal Cognitive Assessment (MoCA) subscores are most strongly associated with patient-reported cognitive impairment on question 1 (Q1) of the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS).
METHODS:
We analyzed data from 759 PD participants and 481 persons without PD with in a retrospective, cross sectional analysis using data from the NINDS Parkinson's Disease Biomarkers Program (PDBP), a longitudinal, multicenter biomarker study. The relationship between a patient-reported cognitive rating (MDS-UPDRS q1.1) and objective cognitive assessments (MoCA) was assessed using multinomial logistic regression modeling and the outcomes reported as conditional odds ratios (cOR's) representing the relative odds of a participant reporting cognitive impairment that is "slight" versus "normal" on MDS-UPDRSq1.1 for a one unit increase in a MoCA sub-score, adjusted for age and education.
RESULTS:
In PD participants, changes in visuospatial-executive performance and memory had the most significant impact on subjective cognitive impairment. A 1-point increase in visuospatial-executive function decreased the chance of reporting a MDS-UPDRS Q1 score of "slight" versus "normal" by a factor of 0.686 (p < 0.001) and each 1 point improvement in delayed recall decreased the odds of reporting "slight" cognitive impairment by a factor of 0.836 (p < 0.001).
CONCLUSIONS:
Conversion from a PD patient's report of "normal" to "slight" cognitive impairment may be associated with changes in visuospatial-executive dysfunction and memory more than other cognitive domains.
Saturday, 22 October 2016
Transcranial Sonography and DaTSCAN in Early Stage Parkinson's Disease and Essential Tremor
Both imaging modalities demonstrating reasonable diagnostic accuracy here. The problem with TCS is the subjectivity of the assessment and the fact that is (probably) a static risk marker rather than and diagnostic aid...
Eur Neurol. 2016 Oct 18;76(5-6):252-255. [Epub ahead of print]
Jesus-Ribeiro J, Freire A, Sargento-Freitas J, Sousa M, Silva F, Moreira F, Cunha MJ, Walter U, Januário C.
BACKGROUND:
The diagnosis of Parkinson's disease (PD) can sometimes be a challenge in the early stages of the disease. Both transcranial sonography (TCS) and DaTSCAN are recommended as auxiliary examinations for the differential diagnosis of PD; however, only few data exist regarding their diagnostic accuracy in the early stage of PD and essential tremor (ET).
METHODS:
We evaluated patients with clinically suspected diagnosis of PD at early stages (Hoehn and Yahr ≤2) or ET. All patients underwent DaTSCAN and TCS with a maximum interval of 6 months. Final diagnosis was established after 1-year follow-up.
RESULTS:
From the 63 patients recruited, 3 were excluded due to transcranial insonability and 2 for uncertain clinical diagnosis. The final clinical diagnosis was ET in 44.8% and PD in 55.2%. Compared to clinical diagnosis of PD, TCS had a sensitivity of 87.5% and specificity of 96.2%; DaTSCAN sensitivity was 84.4% and specificity was 96.2%. Both diagnostic tests demonstrated a substantial level of agreement (Cohen's kappa coefficient: 0.83, 95% CI 0.68-0.97, p < 0.001).
CONCLUSION:
TCS and DaTSCAN have similar diagnostic accuracy for the diagnosis of early stage PD versus ET.
Thursday, 20 October 2016
Digitized Spiral Drawing: A Possible Biomarker for Early Parkinson's Disease
This is useful... it is likely that subtle motor dysfunction emerges a long time before a clinical diagnosis can be made on classical clinical criteria... evidence is accumulating on this subject. We need to find good ways of measuring this motor dysfunction and monitoring it in the pre-diagnostic phase...
PLoS One. 2016 Oct 12;11(10):e0162799. doi: 10.1371/journal.pone.0162799. eCollection 2016.
San Luciano M, Wang C, Ortega RA, Yu Q, Boschung S, Soto-Valencia J, Bressman SB, Lipton RB, Pullman S, Saunders-Pullman R.
INTRODUCTION:
Pre-clinical markers of Parkinson's Disease (PD) are needed, and to be relevant in pre-clinical disease, they should be quantifiably abnormal in early disease as well. Handwriting is impaired early in PD and can be evaluated using computerized analysis of drawn spirals, capturing kinematic, dynamic, and spatial abnormalities and calculating indices that quantify motor performance and disability. Digitized spiral drawing correlates with motor scores and may be more sensitive in detecting early changes than subjective ratings. However, whether changes in spiral drawing are abnormal compared with controls and whether changes are detected in early PD are unknown.
METHODS:
138 PD subjects (50 with early PD) and 150 controls drew spirals on a digitizing tablet, generating x, y, z (pressure) data-coordinates and time. Derived indices corresponded to overall spiral execution (severity), shape and kinematic irregularity (second order smoothness, first order zero-crossing), tightness, mean speed and variability of spiral width. Linear mixed effect adjusted models comparing these indices and cross-validation were performed. Receiver operating characteristic analysis was applied to examine discriminative validity of combined indices.
RESULTS:
All indices were significantly different between PD cases and controls, except for zero-crossing. A model using all indices had high discriminative validity (sensitivity = 0.86, specificity = 0.81). Discriminative validity was maintained in patients with early PD.
CONCLUSION:
Spiral analysis accurately discriminates subjects with PD and early PD from controls supporting a role as a promising quantitative biomarker. Further assessment is needed to determine whether spiral changes are PD specific compared with other disorders and if present in pre-clinical PD.
Wednesday, 19 October 2016
Transcranial sonography in dopa-responsive dystonia
This is interesting... GCH-1 mutations which cause DRD are a risk factor for PD it seems. Hyperechogenicity of the nigra also appears to be a risk factor for PD and is present in up to 80-90% of patients. Here we see a significant proportion of DRD patients have hyperechogenicity (albeit small sample size)....
Eur J Neurol. 2016 Oct 12. doi: 10.1111/ene.13172. [Epub ahead of print]
Svetel M, Tomić A, Mijajlović M, Dobričić V, Novaković I, Pekmezović T, Brajković L, Kostić VS.
BACKGROUND AND PURPOSE:
Mutations in the GCH1 gene, encoding GTP cyclohydrolase 1, the enzyme critically important for dopamine production in nigrostriatal neurons, are the most common cause of dopa-responsive dystonia (DRD), characterized predominantly by limb dystonia, although parkinsonian features may also be present. It has been suggested that DRD is a neurochemical rather than neurodegenerative disorder.
METHODS:
Transcranial brain sonography, which might be a risk marker for nigral injury, was obtained from 141 subjects divided into four groups: (i) 11 patients with genetically confirmed DRD; (ii) 55 consecutive patients with Parkinson's disease (PD); (iii) 30 patients diagnosed as isolated adult-onset focal dystonia; and (iv) 45 healthy controls (HCs).
RESULTS:
Substantia nigra hyperechogenicity was present in 63.6% of patients with DRD, which was significantly different in comparison to patients with dystonia (20%) and HCs (6.7%), but not in comparison to the PD group (87.3%). Also, values of the maximal areas of substantia nigra hyperechogenicity in patients with DRD were higher in comparison to HCs, but significantly lower than among the PD group.
CONCLUSIONS:
We suggested that the observed transcranial brain sonography features in patients with DRD might primarily be risk markers for particular clinical features (parkinsonism, dystonia) occurring in the specific genetic context (i.e. GCH1 mutations), or might reflect compensated neurodegenerative processes triggered by the long-lasting dopamine deficiency due to the profound delay in levodopa treatment in our patients with DRD.
Monday, 10 October 2016
Study of LRRK2 variation in tauopathy: Progressive supranuclear palsy and corticobasal degeneration
This paper confirms that LRRK2 mutations can be found in pathologically confirmed cases of PSP and CBD... however they are much more common in PD and LRRK2 remains the most common dominantly inherited form of PD...
Mov Disord. 2016 Oct 6. doi: 10.1002/mds.26815. [Epub ahead of print]
Sanchez-Contreras M, Heckman MG, Tacik P, Diehl N, Brown PH, Soto-Ortolaza AI, Christopher EA, Walton RL, Ross OA, Golbe LI, Graff-Radford N, Wszolek ZK, Dickson DW, Rademakers R.
BACKGROUND:
Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common genetic cause of Parkinson's disease (PD). Unexpectedly, tau pathology has been reported in a subset of LRRK2 mutation carriers.
METHODS:
To estimate the frequency of pathogenic LRRK2 mutations and to evaluate the association of common LRRK2 variants with risk of primary tauopathies, we studied 1039 progressive supranuclear palsy (PSP) and 145 corticobasal degeneration patients from the Mayo Clinic Florida brain bank and 1790 controls ascertained at Mayo Clinic. Sanger sequencing of LRRK2 exons 30, 31, 35, and 41 was performed in all patients, and genotyping of all 17 known exonic variants with minor allele frequency >0.5% was performed in patients and controls.
RESULTS:
LRRK2 mutational screening identified 2 known pathogenic mutations (p.G2019S and p.R1441C), each in 1 PSP patient, the novel p.A1413T mutation in a PSP patient and the rare p.R1707K mutation in a corticobasal degeneration patient. Both p.A1413T and p.R1707K mutations were predicted damaging by at least 2 of 3 prediction programs and affect evolutionary conserved sites of LRRK2. Association analysis using common LRRK2 variants only showed nominal association of the p.L153L variant with PSP.
CONCLUSIONS:
Our study confirms the presence of pathogenic and potentially pathogenic LRRK2 mutations in pathologically confirmed primary tauopathies, albeit with low frequency. In contrast to PD, common LRRK2 variants do not appear to play a major role in determining PSP and corticobasal degeneration risk.
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