Ann-Kathrin Hauser

GBA-associated PD presents with nonmotor characteristics

Objective: To evaluate whether there exists distinct characteristics in glucocerebrosidase (GBA)–associated Parkinson disease (PD) with regard to motor and nonmotor symptoms as well as imaging characteristics assessed by transcranial sonography (TCS). Methods: Twenty patients with PD with heterozygous GBA mutations (N370S, L444P) (GBA-PD) in comparison to 20 patients with sporadic PD negative for GBA mutations (sPD) were included. We assessed motor impairment with the Unified Parkinson’s Disease Rating Scale–III. Nonmotor symptoms were evaluated using the Montreal Cognitive Assessment, Neuropsychiatric Inventory, revised form of the Beck Depression Inventory, Parkinson Disease Sleep Scale, Sniffin’ Sticks, and Unified Multiple System Atrophy Rating Scale items 9–12. TCS imaging was used to detect morphologic characteristics. Results: Patients with GBA-PD more often had a variety of nonmotor symptoms, namely dementia, neuropsychiatric disturbances, and autonomic dysfunction, and had more severe cases, than patients with sPD. They also demonstrated a higher prevalence of a reduced echogenicity of the brainstem raphe assessed by TCS. Conclusions: Especially nonmotor symptoms seem to be very common in GBA-PD. Further studies are needed to validate these observations in order to better understand the pathogenesis of GBA-PD and develop specific therapeutic concepts.

GBA-Associated Parkinson's Disease: Reduced Survival and More Rapid Progression in a Prospective Longitudinal Study

Parkinsons disease (PD) patients with GBA mutations show an earlier age at onset and more severe non‐motor symptoms compared with PD patients without GBA mutations.

Serum and Cerebrospinal Fluid Uric Acid Levels in Lewy Body Disorders: Associations with Disease Occurrence and Amyloid-β Pathway

Recent studies have provided evidence that uric acid (UA), a natural antioxidant, may play a role in the development and progression of Parkinsons disease (PD) and of dementia. In this clinical study we were therefore interested in the role of UA in Lewy body disorders (LBD), which includes Parkinsons disease (PD) and a common form of neurodegenerative dementias, dementia with Lewy bodies (DLB). Ninety-five LBD patients (55 non-demented PD patients, PDND; 20 PD patients with dementia, PDD; and 20 DLB patients) and 76 controls underwent clinical and biochemical analyses including, from a subcohort, cerebrospinal fluid (CSF) analyses, and analysis of three single nucleotide polymorphisms (SNPs) known to be associated with altered serum UA levels. We confirmed previous findings of lowered serum UA levels in LBD patients compared to controls. In CSF, UA levels were significantly higher in PDND patients (median 0.7 mg/dl) compared only to demented LBD patients (0.4 mg/dl; p = 0.03), but not to controls (0.5 mg/dl; p = 0.12). CSF UA levels correlated positively with CSF Aβ42 levels. This correlation was highest in controls (ρ = 0.67), intermediate in PDND (ρ = 0.49), but not observable in demented LBD patients (ρ = 0.10). These findings suggest an involvement of serum UA in LBD occurrence, and an involvement of CSF UA in cognitive decline in LBD, possibly through the Aβ pathway. SNP rs1165205 (SLC17A3) was weakly associated with altered CSF UA levels. Taken together, our results provide first evidence for disease-relevant but potentially distinct roles of UA in the blood and CSF compartment, respectively, in LBD.

SNCA: Major genetic modifier of age at onset of Parkinson's disease

Age at onset serves as a predictor of progression and mortality in sporadic Parkinsons disease (PD). Therefore, the identification of genetic modifiers for age at onset might lead to a better understanding of disease pathogenesis. We performed multivariate linear regression analysis in 1396 sporadic PD patients assessing 21 single‐nucleotide polymorphisms (SNPs) that have been previously suggested to be associated with sporadic PD. Moreover, a cumulative risk score was assigned to each patient and correlated with age at onset. We identified the rs356219 risk allele in the SNCA gene as significantly contributing to earlier age at onset. Neither one of the other 21 SNPs tested in this analysis nor the cumulative number of risk alleles showed a significant impact on PD onset. Because sequence variants in the SNCA gene are not only associated with autosomal dominantly inherited PD and increased susceptibility for sporadic PD but also have been found to modify the phenotype such as age at onset in both sporadic and various monogenic forms of PD, this gene serves as an outstanding target for further research on PD pathogenesis, which in return might provide potential therapeutic options.

GBA-associated PD Neurodegeneration, altered membrane metabolism, and lack of energy failure

Objective: To elucidate possible mechanisms leading to neurodegeneration in patients with glucocerebrosidase (GBA)–associated Parkinson disease (PD) using combined proton (1H) and phosphorus (31P) magnetic resonance spectroscopic imaging (MRSI) in vivo. Methods: 1H and 1H-decoupled 31P MRSI was performed in 13 patients with PD with heterozygous GBA mutations (GBA-PD) and 19 age- and sex-matched healthy controls to investigate metabolite concentrations in the mesostriatal target regions of PD pathology. NAA as marker of neuronal integrity, choline and ethanolamine containing compounds as markers of membrane phospholipid metabolism, and energy metabolites (notably high-energy phosphates) were quantified. Results: Compared to controls, NAA was significantly reduced in the putamen (p = 0.012) and in the midbrain of GBA-PD (p = 0.05). The choline concentration obtained from 1H MRSI was significantly decreased in the midbrain of GBA-PD (p = 0.010). The phospholipid degradation product glycerophosphoethalonamine was increased in the putamen of GBA-PD (p = 0.05). Changes of energy metabolism were not detected in any region of interest. Conclusion: The pattern of neurodegeneration in GBA-associated PD is more pronounced in the putamen than in the midbrain. Our MRSI findings suggest that the neurodegenerative process in GBA-PD is associated with alterations of membrane phospholipid metabolism which might be also involved in abnormal α-synuclein aggregation.

Neprilysin Activity in Cerebrospinal Fluid is Associated with Dementia and Amyloid-β42 Levels in Lewy Body Disease

Lewy body disease, defined by the occurrence of α-synuclein aggregates as fibrils in Lewy bodies and Lewy neurites, is associated with increased probabilities for both co-occurrence of dementia, and co-occurrence of Alzheimers disease (AD)-like pathology, in particular amyloid-β (Aβ) plaques and lowered cerebrospinal fluid (CSF) Aβ42 levels. Not surprisingly, in patients with Lewy body disease patients, there is a strong association between dementia and Aβ pathology. Neprilysin (NEP) is an Aβ-degrading protein found at presynaptic terminals and in body fluids. Reduced CSF NEP activity levels have been shown to occur in early AD, suggesting that altered CSF NEP activity levels may also be associated with dementia and lowered CSF Aβ42 levels in Lewy body disease. Hypothesizing a relation between CSF NEP activity and dementia in Lewy body disease, we determined CSF and serum NEP activity, and Aβ42 levels of 41 demented Lewy body disease patients, 38 non-demented Lewy body disease patients, and of 23 elderly controls. Demented Lewy body disease patients had lowered CSF NEP activity levels (0.3 pmol/min*ml, 0.2-81.5), compared to both non-demented Lewy body disease subjects (8.5 pmol/min*ml, 0.2-87.2; p=0.004) and controls (21.5 pmol/ml*min, 0.15-413.4; p=0.02). In addition, CSF NEP activity levels correlated positively with CSF Aβ42 levels (Rho=0.28, p=0.008) which was not explained by the presence or absence of ApoE4. Serum NEP activity levels were not significantly different between the groups. We conclude that, in Lewy body disease, CSF NEP activity levels are associated with dementia, probably via the Aβ pathway.

Cerebrospinal Fluid Fatty Acids in Glucocerebrosidase-Associated Parkinson's Disease

Heterozygous mutations in the glucocerebrosidase gene lead to an increased risk for and to more severe alpha‐synuclein‐associated pathology in Parkinsons disease. As both glucocerebrosidase and alpha‐synuclein interact with fatty acids, we hypothesized that cerebrospinal fluid fatty acid levels are altered in these Parkinsons disease patients.

Long-term follow-up of subthalamic nucleus stimulation in glucocerebrosidase-associated Parkinson's disease.

Heterozygous mutations in the gene encoding the lysosomal enzyme beta-glucocerebrosidase (GBA) are associated with an increased susceptibility to Parkinson’s disease (PD) and dementia with Lewy body disease [1, 2] and some cases with phenotypes similar to multiple system atrophy were reported [3]. GBA mutation carriers generally present with an earlier age at onset and particularly severe motor [2, 5] and non-motor [6] genotype-phenotype relations probably reflecting the more pronounced neocortical Lewy body-type pathology in GBA-associated PD [4]. Therefore, these were predicted to show an unfavorable therapeutic outcome from Deep-brain stimulation of the subthalamic nucleus (STN-DBS). Here, we provide the first quantitative data on the therapeutic outcomes of GBA-associated PD in response to L-Dopa and STN-DBS in a series of three cases followed for up to 10 years. Ninety-eight PD patients treated with STN-DBS at the Department of Neurology of the Tubingen University between 1999 and 2011 were screened for the two most common GBA mutations (N370S and L444P) after written informed consent in accordance to the local ethics committee. Three GBA mutation carriers were identified (one N370S, two L444P; Table 1) and compared to two nonmutation carriers with Idiopathic Parkinson’s disease (iPD) matched for ‘age’, ‘gender’, and ‘disease duration at DBS implant’. The mutation carrier status was unknown to the raters until final 2010 when genetic testing was performed. Postoperative imaging confirmed correct electrode placement and no surgical complications were reported. All patients underwent regular standardized clinical follow-up assessments before and after surgery on therapeutic efficacy of L-Dopa and STN-DBS on Unified Parkinson’s disease rating scale (UPDRS) III motor scores (1) ‘OnMedication-OnStimulation’, (2) ‘OffMedication-OffStimulation’, (3) ‘OffMedication-OnStimulation’, and (4) ‘OnMedication-OffStimulation’ including subscores for ‘segmental’ (items 20–26) and ‘axial’ motor symptoms (items 27–31). Motor fluctuations were monitored with UPDRS IV scores. Dopaminergic medication was expressed as L-Dopa equivalent dosage. Moreover, retrospective analyses of non-motor symptoms based on consecutive assessments of the Mini Mental State Examination, neuropsychological testings, Beck’s Depression Inventory, Electronic supplementary material The online version of this article (doi:10.1007/s00415-012-6469-7) contains supplementary material, which is available to authorized users.

Subthalamic nucleus stimulation restores the efferent cortical drive to muscle in parallel to functional motor improvement

Pathological synchronization in large‐scale motor networks constitutes a pathophysiological hallmark of Parkinson’s disease (PD). Corticomuscular synchronization in PD is pronounced in lower frequency bands (< 10 Hz), whereas efficient cortical motor integration in healthy persons is driven in the beta frequency range. Electroencephalogram and electromyogram recordings at rest and during an isometric precision grip task were performed in four perioperative sessions in 10 patients with PD undergoing subthalamic nucleus deep‐brain stimulation: (i) 1 day before (D0); (ii) 1 day after (D1); (iii) 8 days after implantation of macroelectrodes with stimulation off (D8StimOff); and (iv) on (D8StimOn). Analyses of coherence and phase delays were performed in order to challenge the effects of microlesion and stimulation on corticomuscular coherence (CMC). Additionally, local field potentials recorded from the subthalamic nucleus on D1 allowed comprehensive mapping of motor‐related synchronization in subthalamocortical and cerebromuscular networks. Motor performance improved at D8StimOn compared with D0 and D8StimOff paralleled by a reduction of muscular activity and CMC in the theta band (3.9–7.8 Hz) and by an increase of CMC in the low‐beta band (13.7–19.5 Hz). Efferent motor cortical drives to muscle presented mainly below 10 Hz on D8StimOff that were suppressed on D8StimOn and occurred on higher frequencies from 13 to 45 Hz. On D1, coherence of the high‐beta band (20.5–30.2 Hz) increased during movement compared with rest in subthalamomuscular and corticomuscular projections, whereas it was attenuated in subcorticocortical projections. The present findings lend further support to the concept of pathological network synchronization in PD that is beneficially modulated by stimulation.

Neurodegenerative CSF markers in genetic and sporadic PD: Classification and prediction in a longitudinal study

BACKGROUND Parkinsons disease (PD) patients show a large phenotypic variability probably reflecting inter-individual pathologic heterogeneity. Next to typical Lewy-body pathology, β-amyloid (Aβ) and tau pathology have been found at autopsy and several studies have reported altered CSF levels of Aβ1-42, total-Tau (t-Tau) and phosphorylated-Tau (p-Tau). OBJECTIVES To evaluate whether CSF levels of neurodegenerative markers are influenced by genetics and whether specific subgroups of PD are more prone to a concomitant pathology possibly reflecting aspects of disease progression. METHODS In an explorative study we assessed CSF profiles of Aβ1-42, t-Tau, and p-Tau longitudinally in PD patients carrying LRRK2 (n = 5) or GBA mutations (n = 12), sporadic PD patients (n = 30) and healthy controls (n = 16). RESULTS Compared to healthy controls, all three PD cohorts showed lower levels of Aβ1-42. Moreover, sporadic PD and GBA-PD patients presented with lower levels of t-Tau and p-Tau whereas this phenomenon was not seen in LRRK2-PD patients. Regression analyses revealed an association between higher levels of Baseline p-Tau with more accelerated cognitive deterioration over time in LRRK2-PD and GBA-PD patients, but not in sporadic PD. CONCLUSION PD patients present with disease-specific CSF profiles of Aβ1-42, t-Tau and p-Tau arguing in favor of an involvement of these proteins in PD pathogenesis in both sporadic and genetic forms. Moreover, we found first hints for differences in these CSF profiles between genetically determined PD cohorts but that CSF constellations which tend to predict aspects of disease progression such as cognitive decline seem similar across subgroups of PD.