Walter Maetzler

A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies

IMPORTANCEnWhile mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders.nnnOBJECTIVEnTo establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB). DESIGN We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity.nnnSETTINGnEleven centers from sites around the world performing genotyping.nnnPARTICIPANTSnSeven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity.nnnMAIN OUTCOME MEASURESnFrequency of GBA1 mutations in cases and controls. RESULTS We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78-14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53-15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P < .001), with higher disease severity scores.nnnCONCLUSIONS AND RELEVANCEnMutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.

Quantitative wearable sensors for objective assessment of Parkinson's disease

There is a rapidly growing interest in the quantitative assessment of Parkinsons disease (PD)‐associated signs and disability using wearable technology. Both persons with PD and their clinicians see advantages in such developments. Specifically, quantitative assessments using wearable technology may allow for continuous, unobtrusive, objective, and ecologically valid data collection. Also, this approach may improve patient‐doctor interaction, influence therapeutic decisions, and ultimately ameliorate patients global health status. In addition, such measures have the potential to be used as outcome parameters in clinical trials, allowing for frequent assessments; eg, in the home setting. This review discusses promising wearable technology, addresses which parameters should be prioritized in such assessment strategies, and reports about studies that have already investigated daily life issues in PD using this new technology.

Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies

Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinsons and Alzheimers diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.

Changing the research criteria for the diagnosis of Parkinson's disease: obstacles and opportunities

Recent findings question our present understanding of Parkinsons disease and suggest that new research criteria for the diagnosis of Parkinsons disease are needed, similar to those recently defined in Alzheimers disease. However, our ability to redefine Parkinsons disease is hampered by its complexity and heterogeneity in genetics, phenotypes, and underlying molecular mechanisms; the absence of biochemical markers or ability to image Parkinsons disease-specific histopathological changes; the long prodromal period during which non-motor manifestations might precede classic motor manifestations; and uncertainty about the status of disorders diagnosed clinically as Parkinsons disease but without Lewy pathology. Although it is too early to confidently redefine Parkinsons disease, the time has come to establish a research framework that could lead to new diagnostic criteria. We propose the establishment of three tiers encompassing clinical features, pathological findings, and genetics or molecular mechanisms. Specific advances in each tier, bridged by neuroimaging and biochemical data, will eventually lead to a redefinition of Parkinsons disease.

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.

Plasma Ceramide and Glucosylceramide Metabolism Is Altered in Sporadic Parkinson's Disease and Associated with Cognitive Impairment: A Pilot Study

Background Mutations in the gene coding for glucocerebrosidase (GBA), which metabolizes glucosylceramide (a monohexosylceramide) into glucose and ceramide, is the most common genetic risk factor for sporadic Parkinsons disease (PD). GBA mutation carriers are more likely to have an earlier age of onset and to develop cognitive impairment and dementia. We hypothesized that plasma levels of lipids involved in ceramide metabolism would also be altered in PD non-GBA mutation carriers and associated with worse cognition. Methods Plasma ceramide, monohexosylceramide, and lactosylceramide levels in 26 cognitively normal PD patients, 26 PD patients with cognitive impairment or dementia, and 5 cognitively normal non-PD controls were determined by LC/ESI/MS/MS. Results Levels of all lipid species were higher in PD patients versus controls. Among PD patients, levels of ceramide C16:0, C18:0, C20:0, C22:0, and C24:1 and monohexosylceramide C16:0, C20:0 and C24:0 species were higher (all P<0.05) in those with versus without cognitive impairment. Conclusion These results suggest that plasma ceramide and monohexosylceramide metabolism is altered in PD non-GBA mutation carriers and that higher levels are associated with worse cognition. Additional studies with larger sample sizes, including cognitively normal controls, are needed to confirm these findings.

Aging-related cortical reorganization of verbal fluency processing: a functional near-infrared spectroscopy study

While progressive neurocognitive impairments are associated with aging and Alzheimers disease (AD), cortical reorganization might delay difficulties in effortful word retrieval, which represent one of the earliest cognitive signs of AD. Using functional near-infrared spectroscopy (fNIRS), we investigated cortical hemodynamic responses elicited by phonological and semantic verbal fluency in non-demented, healthy subjects (n = 325; age: 51-82 years). Age predicted bilaterally reduced inferior frontal junction (IFJ) and increased middle frontal and supramarginal gyri activity in both task conditions using multiple regressions. Compared with age the years of education as well as sex (IFJ activation in females > males) partly predicted opposite effects on activation, while task performance was not significant predictor. All predictors showed small effect sizes. IFJ activation was more pronounced during phonological compared with semantic fluency, and higher in the left hemisphere. Age only marginally predicted relative lateralization. Middle frontal and supramarginal gyri activity may compensate for an aging-related decrease in IFJ recruitment during verbal fluency. Longitudinal observations will further investigate these neural changes regarding an early AD prediction, while individuals are still cognitively healthy.

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration

Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total nxa0=xa03,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2xa0% was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RRxa0=xa02.18 [95xa0% CI 1.24–3.85]; corrected p valuexa0=xa00.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.

Evidence for altered transport of insulin across the blood–brain barrier in insulin-resistant humans

AbstractnEating behavior, body weight regulation, peripheral glucose metabolism, and cognitive function depend on adequate insulin action in the brain, and recent studies in humans suggested that impaired insulin action in the brain emerges upon fat intake, obesity, and genetic variants. As insulin enters into the brain in a receptor-mediated fashion, we hypothesized that whole-body insulin sensitivity might affect the transport of insulin into the brain and contribute to the aversive effect of insulin resistance in the central nervous system. In this study, we aimed to determine the ratio of insulin in the cerebrospinal fluid and serum to whole-body insulin sensitivity. Healthy human subjects participated in an oral glucose tolerance test to determine whole-body insulin sensitivity and underwent lumbar puncture. Blood and CSF concentrations of insulin were significantly correlated. The CSF/serum ratio for insulin was significantly associated with whole body insulin sensitivity with reduced insulin transported into the CSF in insulin-resistant subjects. nTogether, our data suggest that transport of insulin into the CSF relates to peripheral insulin sensitivity and impairs insulin action in the brain. This underlines the need for sensitizing measures in insulin-resistant subjects.n

Emerging therapies for gait disability and balance impairment: Promises and pitfalls

Therapeutic management of gait and balance impairment during aging and neurodegeneration has long been a neglected topic. This has changed considerably during recent years, for several reasons: (1) an increasing recognition that gait and balance deficits are among the most relevant determinants of an impaired quality of life and increased mortality for affected individuals; (2) the arrival of new technology, which has allowed for new insights into the anatomy and functional (dis)integrity of gait and balance circuits; and (3) based in part on these improved insights, the development of new, more specific treatment strategies in the field of pharmacotherapy, deep brain surgery, and physiotherapy. The initial experience with these emerging treatments is encouraging, although much work remains to be done. The objective of this narrative review is to discuss several promising developments in the field of gait and balance treatment. We also address several pitfalls that can potentially hinder a fast and efficient continuation of this vital progress. Important issues that should be considered in future research include a clear differentiation between gait and balance as two distinctive targets for treatment and recognition of compensatory mechanisms as a separate target for therapeutic intervention.