Faculty Bibliography

Background and Purpose- Absent or diminished α-galactosidase A (GLA) and acid α-glucosidase (GAA) enzyme activity are core features of Fabry and Pompe disease, respectively. Patients with Fabry or Pompe disease may have dilated intracranial arteries but whether lower GLA or GAA enzyme activity relates to brain arterial dilatation in other populations is unknown. Methods- Participants included Parkinson disease patients and nonblood-related controls, whose GLA and GAA enzymatic activities were measured in dried blood spots. Independent readers measured the axial arterial diameter of the ascending portion of the cavernous internal carotid arteries and the most proximal segment of the basilar artery in T2 black voids. Linear regression models were built to investigate the relationship between brain arterial diameters and lysosomal enzymatic activities. Results- The cohort included 107 participants (mean age, 66.5±10.3; 67% men). In an adjusted linear regression model, lower GLA activity was associated with larger brain arterial diameters (B=0.50±0.23, P=0.03). The strength of association was the greatest for the basilar artery diameter (B=0.80±0.33, P=0.02). Similarly, lower GAA activity was associated with an increased basilar arterial diameter (B=0.73±0.35, P=0.04). Conclusions- Lower GLA and GAA enzymatic activities were associated with larger brain arterial diameters, particularly the basilar artery diameter. Lower lysosomal enzymatic function in patients without Fabry or Pompe disease may play a role in brain arterial dilatation.

INTRODUCTION/BACKGROUND:The current study was designed to determine whether the degree of presynaptic striatal dopamine depletion can predict the later development of freezing of gait (FOG) in Parkinson's disease (PD). METHODS:This retrospective cohort study included 390 de novo patients with PD without FOG at baseline. The participants were divided into tertiles according to the baseline dopamine transporter (DAT) uptake of each striatal subregion, and the cumulative risk of FOG was compared using the Kaplan-Meier method. Cox proportional hazard models were used to assess the predictive power of DAT uptake of striatal subregions for the development of FOG. RESULTS:During a median follow-up period of 4.0 years, 143 patients with PD (36.7%) developed FOG. The severe reduction group of DAT uptake in the caudate nucleus and putamen had a significantly higher incidence of FOG than that of the mild and moderate reduction groups. Multivariate Cox regression analyses showed that DAT uptakes in the caudate nucleus (hazard ratio [HR] 0.551; 95% confidence interval [CI] 0.392-0.773; p = 0.001) and putamen (HR 0.441; 95% CI 0.214-0.911; p = 0.027) predicted the development of FOG. In addition, male sex, higher postural instability and gait difficulty score, and a lower Montreal Cognitive Assessment score were also significant predictors of FOG. CONCLUSION/CONCLUSIONS:Our finding suggests that presynaptic striatal dopaminergic denervation predicts the later development of FOG in de novo patients with PD, which may provide reliable insight into the mechanism of FOG in terms of nigrostriatal involvement.

Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann-Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (n = 648) and controls (n = 317) recruited from Columbia University. Full sequencing of glucocerebrosidase (GBA) and the LRRK2 G2019S mutation was performed. Enzymatic activities were compared between PD cases and controls using t-test and regression models adjusted for age, gender, and GBA and LRRK2 G2019S mutation status. Alpha galactosidase A activity was lower in PD cases compared to controls both when only non-carriers were included (excluding all GBA and LRRK2 G2019S carriers and PD cases with age-at-onset below 40) [2.85 μmol/l/h versus 3.12 μmol/l/h, p = 0.018; after controlling for batch effect, p = 0.006 (468 PD cases and 296 controls)], and when including the entire cohort (2.89 μmol/l/h versus 3.10 μmol/l/h, p = 0.040; after controlling for batch effect, p = 0.011). Because the alpha galactosidase A gene is X-linked, we stratified the analyses by sex. Among women who were non-carriers of GBA and LRRK2 G2019S mutations (PD, n = 155; control, n = 194), alpha galactosidase A activity was lower in PD compared to controls (2.77 μmol/l/h versus 3.10 μmol/l/h, p = 0.044; after controlling for a batch effect, p = 0.001). The enzymatic activity of acid sphingomyelinase, acid alpha-glucosidase and galactosylceramidase was not significantly different between PD and controls. In non-carriers, most lysosomal enzyme activities were correlated, with the strongest association in GCase, acid alpha-glucosidase, and alpha galactosidase A (Pearson correlation coefficient between 0.382 and 0.532). In a regression model with all five enzymes among non-carriers (adjusted for sex and age), higher alpha galactosidase A activity was associated with lower odds of PD status (OR = 0.54; 95% CI:0.31-0.95; p = 0.032). When LRRK2 G2019S PD carriers (n = 37) were compared to non-carriers with PD, carriers had higher GCase, acid sphingomyelinase and alpha galactosidase A activity. We conclude that alpha galactosidase A may have a potential independent role in PD, in addition to GCase.

OBJECTIVE:Examine relationships among neurodegenerative biomarkers and PD motor and nonmotor symptoms. BACKGROUND:CSF alpha-synuclein is decreased in PD versus healthy controls, but whether plasma and saliva alpha-synuclein differentiate these groups is controversial. Correlations of alpha-synuclein among biofluids (CSF, plasma, saliva) or biomarkers (eg, beta-amyloid, tau [total, phosphorylated]) are not fully understood. The relationships of these biomarkers with PD clinical features remain unclear. METHODS:BioFIND, a cross-sectional, observational study, examines clinical and biomarker characteristics in moderate-advanced PD and matched healthy controls. We compared alpha-synuclein concentrations across diagnosis, biofluids, and CSF biomarkers. Correlations of CSF biomarkers and MDS-UPDRS, motor phenotype, MoCA, and rapid eye movement sleep behavior disorder questionnaire scores in PD were examined. RESULTS:, total-tau, and phosphorylated-tau (r = 0.41, 0.81, 0.43, respectively; Ps < .001). CONCLUSION/CONCLUSIONS:remains a potential biomarker for cognitive impairment in PD. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Multiple system atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gaps despite recent gains in basic and clinical research. In order to make further advances, concerted international collaboration is vital. In 2014, an international meeting involving leaders in the field and MSA advocacy groups was convened in Las Vegas, Nevada, to identify critical research areas where consensus and progress was needed to improve understanding, diagnosis, and treatment of the disease. Eight topic areas were defined: pathogenesis, preclinical modeling, target identification, endophenotyping, clinical measures, imaging biomarkers, nonimaging biomarkers, treatments/trial designs, and patient advocacy. For each topic area, an expert served as a working group chair and each working group developed priority-ranked research recommendations with associated timelines and pathways to reach the intended goals. In this report, each groups' recommendations are provided.

The diagnosis of Parkinson's disease (PD) occurs after pathogenesis is advanced and many substantia nigra (SN) dopamine neurons have already died. Now that therapies to block this neuronal loss are under development, it is imperative that the disease be diagnosed at earlier stages and that the response to therapies is monitored. Recent studies suggest this can be accomplished by magnetic resonance imaging (MRI) detection of neuromelanin (NM), the characteristic pigment of SN dopaminergic, and locus coeruleus (LC) noradrenergic neurons. NM is an autophagic product synthesized via oxidation of catecholamines and subsequent reactions, and in the SN and LC it increases linearly during normal aging. In PD, however, the pigment is lost when SN and LC neurons die. As shown nearly 25 years ago by Zecca and colleagues, NM's avid binding of iron provides a paramagnetic source to enable electron and nuclear magnetic resonance detection, and thus a means for safe and noninvasive measure in living human brain. Recent technical improvements now provide a means for MRI to differentiate between PD patients and age-matched healthy controls, and should be able to identify changes in SN NM with age in individuals. We discuss how MRI detects NM and how this approach might be improved. We suggest that MRI of NM can be used to confirm PD diagnosis and monitor disease progression. We recommend that for subjects at risk for PD, and perhaps generally for older people, that MRI sequences performed at regular intervals can provide a pre-clinical means to detect presymptomatic PD.

Gait and balance disorders are major problems that contribute to falls among subjects with Parkinson's disease (PD). Strengthening the compensatory responses through the use of balance perturbations may improve balance in PD. To date, it is unclear how PD affects the ability to react and adapt to perturbations delivered while walking. This study aims to investigate how PD affects the ability to walk, respond to balance perturbations, and produce acute short-term effects to improve compensatory reactions and gait stability. A cable-driven robot was used to train nine patients with PD and nine age-matched controls with multidirectional waist-pull perturbations while walking on a treadmill. Margin of stability and base of support were evaluated while walking without cables and reacting to the perturbations. PD was associated with a reduced stability in the forward direction and the inability to produce proactive anticipatory adjustments. Both groups were able to improve the response to the disturbances and produce short-term aftereffects of increased gait stability once the cables were removed. A single session of perturbation-based balance training produced acute effects that ameliorated gait instability in PD. This result is encouraging for designing new therapeutic interventions that remediate falls risk.

BACKGROUND:Multiple system atrophy (MSA) is marked by abnormal inclusions of alpha-synuclein in oligodendrogliocytes. Etiology remains unknown. Variants in the glucocerebrosidase gene have been associated with other synucleinopathies, dementia with Lewy bodies and Parkinson disease. It is unclear whether glucocerebrosidase variants are associated with MSA. OBJECTIVES/OBJECTIVE:To analyze the frequency of glucocerebrosidase gene variants among autopsy-proven cases of MSA at a brain bank in New York City. METHODS:genotype was available (n=82). RESULTS:variants (P = 0.0127, Fisher exact test), including one case each of N370S homozygote, and R496H and T369M heterozygous variant. CONCLUSION/CONCLUSIONS:We found a higher frequency of glucocerebrosidase variants among pathologically diagnosed MSA cases in our brain bank compared to AD autopsies. This study demonstrates the need for further investigation into the role of glucocerebrosidase and lysosomal dysfunction in the etiology of MSA.