Disease modifying treatment trials in Parkinson's disease: how to balance expectations and interests of patients, physicians and industry partners?

BACKGROUND: The advent of therapeutic strategies designed to modify the disease course in Parkinson's disease has raised great expectations in the currently conducted clinical trials. However, we see ethical challenges in the cooperation of industry and clinical partners, specifically evident in the way recruitment is performed.We here discuss the different positions and challenges of all involved to set the stage for a study and recruitment culture taking into account the expectations of all: (i) patients and their caregivers, ready to take the considerable burden of clinical trials in hope for the development of disease-modifying treatments; (ii) physicians and study nurses, obligated to the patients' well-being and benefit who accompany and supervise patients closely as basis for the performance of elaborate clinical trials (iii) industrial partners, investing years of efforts and finances to develop new treatments. CONCLUSIONS: We conclude that the current competitive race for enrollment in clinical studies in PD is challenging the primary goal to ensure patients' benefit and formulate requests to the industrial partners to encounter these concerns.

Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in nonhuman primates.

Dopaminergic neuronal cell death, associated with intracellular α-synuclein (α-syn)-rich protein aggregates [termed "Lewy bodies" (LBs)], is a well-established characteristic of Parkinson's disease (PD). Much evidence, accumulated from multiple experimental models, has suggested that α-syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here, we have used a machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct α-syn pathogenic structures derived from patients with PD. Unexpectedly, our results show that, in nonhuman primates, a small amount of singular α-syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD, as multiple causes can induce a similar outcome regarding dopaminergic neurodegeneration.

Basic clinical features do not predict dopamine transporter binding in idiopathic REM behavior disorder.

REM sleep behavior disorder (RBD) is strongly associated with development of Parkinson's Disease and other α-synuclein-related disorders. Dopamine transporter (DAT) binding deficit predicts conversion to α-synuclein-related disorders in individuals with RBD. In turn, identifying which individuals with RBD have the highest likelihood of having abnormal DAT binding would be useful. The objective of this analysis was to examine if there are basic clinical predictors of DAT deficit in RBD. Participants referred for inclusion in the RBD cohort of the Parkinson Progression Markers Initiative were included. Assessments at the screening visit including DAT SPECT imaging, physical examination, cognitive function screen, and questionnaire-based non-motor assessment. The group with DAT binding deficit (n = 49) was compared to those without (n = 26). There were no significant differences in demographic or clinical features between the two groups. When recruiting RBD cohorts enriched for high risk of neurodegenerative disorders, our data support the need for objective biomarker assessments.

Diagnostic exome sequencing in early-onset Parkinson's disease confirms VPS13C as a rare cause of autosomal-recessive Parkinson's disease.

Parkinson's disease (PD) is a genetically heterogeneous disorder and new putative disease genes are discovered constantly. Therefore, whole-exome sequencing could be an efficient approach to genetic testing in PD. To evaluate its performance in early-onset sporadic PD, we performed diagnostic exome sequencing in 80 individuals with manifestation of PD symptoms at age 40 or earlier and a negative family history of PD. Variants in validated and candidate disease genes and risk factors for PD and atypical Parkinson syndromes were annotated, followed by further analysis for selected variants. We detected pathogenic variants in Mendelian genes in 6.25% of cases and high-impact risk factor variants in GBA in 5% of cases, resulting in overall maximum diagnostic yield of 11.25%. One individual was compound heterozygous for variants affecting canonical splice sites in VPS13C, confirming the causal role of protein-truncating variants in this gene linked to autosomal-recessive early-onset PD. Despite the low diagnostic yield of exome sequencing in sporadic early-onset PD, the confirmation of the recently discovered VPS13C gene highlights its advantage over using predefined gene panels.

Verbal memory declines more in female patients with Parkinson's disease: the importance of gender-corrected normative data.

BACKGROUND: Data on gender-specific profiles of cognitive functions in patients with Parkinson's disease (PD) are rare and inconsistent, and possible disease-confounding factors have been insufficiently considered. METHOD: The LANDSCAPE study on cognition in PD enrolled 656 PD patients (267 without cognitive impairment, 66% male; 292 with mild cognitive impairment, 69% male; 97 with PD dementia, 69% male). Raw values and age-, education-, and gender-corrected Z scores of a neuropsychological test battery (CERAD-Plus) were compared between genders. Motor symptoms, disease duration, l-dopa equivalent daily dose, depression - and additionally age and education for the raw value analysis - were taken as covariates. RESULTS: Raw-score analysis replicated results of previous studies in that female PD patients were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.03), while men outperformed women in visuoconstruction (p = 0.002) and figural memory (p = 0.005). In contrast, gender-corrected Z scores showed that men were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.02; recognition, p = 0.04), while no difference was found for visuospatial tests. This picture could be observed both in the overall analysis of PD patients as well as in a differentiated group analysis. CONCLUSIONS: Normative data corrected for gender and other sociodemographic variables are relevant, since they may elucidate a markedly different cognitive profile compared to raw scores. Our study also suggests that verbal memory decline is stronger in women than in men with PD. Future studies are needed to replicate these findings, examine the progression of gender-specific cognitive decline in PD and define different underlying mechanisms of this dysfunction.

[Early recognition of Parkinson's disease. Objectifiable non-motor symptoms and biomarkers]. / Früherkennung der Parkinson-Krankheit. Objektivierbare nichtmotorische Symptome und Biomarker.

The clinical diagnosis of Parkinson's disease (PD) according to the UK Brain Bank criteria is based on the presence of motor symptoms and the response to dopaminergic medication. According to these criteria the clinical diagnosis is delineated too late when more than 50 % of the dopaminergic neurons are already degenerated. In recent years interest has shifted increasingly more towards non-motor symptoms (NMS), such as rapid eye movement (REM) sleep behavior disorder (RBD), constipation, hyposmia and neuropsychiatric as well as cognitive symptoms. It was shown that NMS can precede the motor symptoms by some years and may thus possibly enable support of an earlier clinical diagnosis. Furthermore, cerebrospinal fluid or blood biomarkers as well as brain imaging techniques can objectively support an earlier diagnosis of PD. This article reviews important NMSs (e.g. RBD, hyposmia and neuropsychiatric/cognitive symptoms) as well as the current status on biomarkers and brain imaging in early (premotor) phases of PD and their relevance for the early diagnosis.

Validation of amyloid-beta peptides in CSF diagnosis of neurodegenerative dementias.

Biomarkers for differential diagnosis of the three most frequent degenerative forms of dementia, Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementias (FTD), are currently under intensive investigation, but disease-specific biomarkers for FTD and DLB are still lacking. We analyzed 303 cerebrospinal fluid (CSF) samples of 71 AD, 32 DLB and 36 FTD patients in comparison to 93 various other dementias (OD), 20 peripheral neurologic disease (PND) controls, 25 neurodegenerative disorders without dementia (ND) and 26 depressive cognitive complainers (DCC) for distinct CSF amyloid-beta (Abeta) peptide patterns, using the quantitative Abeta-SDS-PAGE/immunoblot. Additionally, the novel electrochemiluminescence technique (MSD) was used to validate the measures on Abeta1-38. The main outcome measures were a striking decrease of Abeta1-42 in AD (P=7.4 x 10(-19)), and most interestingly a pronounced decrease of Abeta1-38 in FTD (P=9.6 x 10(-7)). Moreover, a novel peptide that most probably represents an oxidized alpha-helical form of Abeta1-40 (Abeta1-40(ox)) displayed a highly significant increase in DLB (P=3.7 x 10(-3)) as compared to non-demented disease controls. The overall diagnostic accuracy of percentage Abeta peptide abundances (Abeta1-X%) was clearly superior to absolute CSF Abeta levels. Abeta1-42% and Abeta1-38% enabled contrasts of 85% or beyond to distinguish AD and FTD, respectively, from all other investigated subjects. Abeta1-40(ox)% yielded a diagnostic sensitivity and specificity of 88 and 73% for the detection of DLB among all other investigated patients. We found a strong correlation between Abeta1-38 levels as measured by the Abeta-SDS-PAGE/immunoblot and MSD, respectively. CSF Abeta peptides may reflect disease-specific impact of distinct neurodegenerative processes on Abeta peptide metabolism and represent a potential diagnostic biomarker for AD, FTD and DLB.

Tauopathies and synucleinopathies: do cerebrospinal fluid beta-amyloid peptides reflect disease-specific pathogenesis?

To evaluate variations in amyloid beta (Abeta) peptide pattern in cerebrospinal fluid (CSF) in neurodegenerative disorders. A recently established quantitative urea-based Abeta-sodium-dodecylsulfate-polyacrylamide-gel-electrophoresis with western immunoblot (Abeta-SDS-PAGE/immunoblot) revealed a highly conserved Abeta peptide (Abeta1-37, 1-38, 1-39, 1-40, 1-42) pattern in CSF. We asked whether the variation might be useful to further elucidate the overlap between or distinctions among neurodegenerative diseases in Abeta-processing. We used the Abeta-SDS-PAGE/immunoblot to investigate CSF for disease-specific Abeta peptide patterns. CSF samples from 96 patients with mainly clinically diagnosed Alzheimer's disease (n = 15), progressive supranuclear palsy (n = 20), corticobasal degeneration (n = 12), Parkinson's disease (n = 11), multiple systems atrophy (n = 18), and dementia with Lewy-bodies (n = 20) were analysed as well a comparison group (n = 19). The Abeta peptide patterns varied between tauopathies and synucleinopathies and between all diseases and the comparison group, possibly due to the influence of tau and alpha-synuclein on Abeta-processing.

Reduced CSF carboxyterminally truncated Abeta peptides in frontotemporal lobe degenerations.

Cerebrospinal fluid (CSF) carboxyterminally truncated amyloid-beta (Abeta) peptides, Abeta1-42 and tau protein were evaluated in 30 patients with frontotemporal lobe degenerations (FTLD), 30 Alzheimer's disease (AD) patients and 30 non-demented disease controls (NDC) by Abeta-SDS-PAGE/immunoblot as well as commercial ELISAs for Abeta1-42 and total tau. FTLD displayed a significant drop of Abeta1-37 (p = 2.7 x 10(-4)), Abeta1-38 (p = 4.2 x 10(-5)) and Abeta1-42 (p = 3.3 x 10(-4)). Abeta1-42 was selectively decreased in AD (p = 8.5 x 10(-10)). Decreased Abeta1-38 enabled contrasts of beyond 85% to distinguish FTLD from AD and NDC patients, alone or in combination. Accordingly, low CSF Abeta1-37 and Abeta1-38 represent a biomarker candidate for FTLD and may reflect disease-specific changes of APP metabolism. Further validation should be carried out on dementias other than AD, diagnostically relevant control groups without dementia and without any evident affection of the central nervous system and subgroups of FTLD. Moreover, independent methods of measurement should be applied to CSF Abeta1-38.

[Diagnosis and clinical therapy for Parkinson's disease]. / Diagnostik und Therapie von Parkinson-Demenz in der klinischen Praxis.

For decades, awareness of Parkinson's disease mainly focused on the presence and treatment of motor symptoms. More and more other symptoms of this disease not related to the motor system now receive increased attention, including cognitive decline. Dementia in Parkinson's disease occurs more often than initially was thought. After an average of 8 years, about 40% of these patients suffer from cognitive decline. The difficulties and related problems affect prognosis more than do the motor symptoms. There is a need for standardized diagnostic and specific therapeutic intervention, but appropriate studies are still lacking.

CSF diagnosis of Alzheimer's disease and dementia with Lewy bodies.

Differential diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) is often crucial. CSF Tau protein and Amyloid-beta (A beta) peptides have shown diagnostic value for the diagnosis of AD, but discrimination from DLB was poor.Herein, we investigate CSF of 18 patients with probable AD, 25 with probable DLB and 14 non-demented disease controls (NDC) by A beta-SDS-PAGE/immunoblot and commercially available ELISAs for A beta1-42 and tau. CSF A beta peptide patterns and tau exhibited disease specific alterations among AD and DLB. The ratio of A beta1-42 to A beta1-38 and A beta1-42 to A beta1-37, respectively, in combination with absolute tau, yielded a sensitivity and specificity of 100 and 92%, respectively. We conclude that CSF A beta peptide patterns and tau levels reflect disease-specific pathophysiological pathways of these dementias as distinct neurochemical phenotypes. Combined evaluation of these biomarkers provides a reasonable accuracy for differential diagnosis of AD and DLB.

Follow-up investigations in cerebrospinal fluid of patients with dementia with Lewy bodies and Alzheimer's disease.

Measuring proteins in cerebrospinal fluid (CSF) has gained wide acceptance for the differential diagnosis of dementia. Some groups have already extended these investigations in Alzheimer's disease (AD) by asking how stable these markers are in follow-up analysis, if they depend on the stage of disease and whether they can be used to monitor the progression and biological effects of treatment. We evaluated 21 patients with dementia with Lewy bodies (DLB) and 19 patients with AD, on two occasions, with regard to levels of tau protein, tau protein phosphorylated at threonine 181 (p-tau), Abeta42, Abeta40 and S-100B protein, using a set of commercially available assays. Tau protein levels were lower in DLB in first and second LP compared to AD and decreased during course of both groups. P-tau levels were increased in AD and DLB and decreased during follow-up. Abeta42 and Abeta40 remained relatively stable during follow-up but we found a slight increase of the median Abeta42 level in DLB, whereas in AD, Abeta42 tends to decrease during follow-up. S-100B protein increased during follow-up in both diseases. The protein dynamics in DLB and AD are relatively similar. S-100B protein may be a useful marker for follow-up in neurodegenerative diseases but has to be analysed in longer follow-up periods. Tau protein may be used to differentiate between DLB and AD. Follow-up CSF analyses are of limited value for the differentiation of AD and DLB. We conclude that more specific markers have to be established for the differentiation and follow-up of these diseases.

Sporadic Creutzfeldt-Jakob disease: magnetic resonance imaging and clinical findings.

OBJECTIVE: To assess if clinical features, prion protein codon 129, and molecular subtype correlate with MRI basal ganglia hyperintensity in sporadic Creutzfeldt-Jakob disease (CJD). METHODS: The authors studied 219 patients including 153 confirmed CJD cases for their neurologic symptoms and MRI findings. The MRI was assessed by a blinded investigator for the presence of high signal intensity on T2-weighted images in the basal ganglia. RESULTS: Patients with basal ganglia high signal on T2-weighted images were more likely to present with rapid progressive dementia in an early stage and shorter disease duration (median 6.7 months and 8.6 months). Surprisingly, among the CJD cases, patients without signal increase of the basal ganglia were shown to have a higher frequency of extrapyramidal disturbances (82% vs 70%). More striking differences were found for symptoms such as depression and sensory disturbances, which were more frequent among cases without signal increase. MRI was more likely to be diagnostic in patients with MV2 molecular subtype. CONCLUSIONS: Selected clinical and pathologic features correlate with the presence of basal ganglia high signal on T2-weighted MRI in patients with definite or probable CJD.

[Epidemiology and clinical symptomatology of Creutzfeldt-Jakob disease]. / Epidemiologie und klinische Symptomatik der Creutzfeldt-Jakob-Krankheit.

OBJECTIVE: Analogous to prospective studies in other countries, prevalance and symptoms of sporadic Creutzfeldt-Jakob disease (CJD) were recorded in order to assess irregularities in the incidence of the disease in Germany since the onset of bovine spongioform encephalopathy (BSE). PATIENTS AND METHODS: SInce 1993 all suspected case of CJD reported in the Federal Republic of Germany have been analysed by a unified schema and classified by standardised criteria. In addition to voluntary reporting two other systems were accessed: (1) compulsory reporting to the Robert Koch Institute via the appropriate Health Department and (2) cause of death statistics of the Federal Office of Statistics. RESULTS: Between June 1993 and May 2001, a total of 1247 patients with suspected CJD, obtained by the angle quotation mark, rightStudy of the epidemiology and early diagnosis of human spongioform encephalopathiesangle quotation mark, left at Göttingen University, were examined. The suspected disease was confirmed by autopsy in 404 cases, the diagnosis of probable CJD was made in 369 cases on the basis of clinical data and additional investigation. At the beginning of the Göttingen Study in 1993 the incidence in Germany was 0.7 per mill. population, while in the year 2000 it had risen to 1.3 per mill. population. Corresponding increases in the number of cases since 1993 have been noted also by the Robert Koch Institute and the Federal Office of Statistics. CONCLUSIONS: The increased incidence can be explained primarily by a decrease in previously unknown cases. Concerted action as part of the Göttingen Study has increased the cooperation of associated clinics. In addition to sporadic cases of CJD, genetic and, more rarely, iatrogenic forms have been seen in Germany. But no cases of new variant CJD have been reported so far.

Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt-Jakob disease.

BACKGROUND: Diagnosis of Creutzfeldt-Jakob disease (CJD) is made according to the typical clinical picture and can be supported by a positive 14-3-3 CSF immunoblot. Promising results for the diagnostic sensitivity and specificity of tau-protein measurement in CSF already have been described in a smaller group of patients. Both tests in a larger group of patients with the differential diagnosis of CJD were evaluated. METHODS: CSF of 297 patients under the differential diagnosis of CJD (109 definite, 55 probable, 39 possible; 85 others, 1 iatrogenic, 8 genetic), 23 nondemented control subjects, and 15 non-CJD patients with positive 14-3-3 immunoblots were analyzed. The 14-3-3 immunoblot bands were semiquantitatively rated as strong, medium, and weak. Tau-protein was analyzed using a commercially available ELISA. In addition, patients were neuropathologically classified according to prion protein type and polymorphism at codon 129. RESULTS: A diagnostic sensitivity of 94%, a diagnostic specificity of 90%, and a positive predictive value of 92% were achieved for tau-protein at a cut-off of 1,300 pg/mL. These results are comparable with those of the 14-3-3 immunoblot. For patients with type II prion protein and methionine/valine or valine/valine polymorphism at codon 129, tau-protein has a higher diagnostic sensitivity than 14-3-3 protein. Tau-protein levels were significantly higher in patients with higher-rated 14-3-3 immunoblot bands. CONCLUSION: The differential diagnostic significance of the 14-3-3 immunoblot is similar to that of the tau-protein ELISA. The advantage of the tau-protein ELISA is that it is easy to use in routine laboratories. Patients with a negative 14-3-3 immunoblot already have measurable tau-protein levels. This increases information on 14-3-3-negative patients with CJD and especially on patients with other diseases.