Publications

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder marked by cognitive impairment, movement abnormalities, and behavioral disturbances. The Stroop Color Word Test (SCWT) is a widely used tool to detect cognitive decline in HD. Variations in SCWT formats-horizontal (original) and vertical (Golden)-may influence performance, given HD's impact on cognitive and oculomotor abilities.

OBJECTIVE: This study aimed to compare the effectiveness of the horizontal and Golden vertical SCWT formats in detecting cognitive decline in HD, and to determine how performance may have been influenced by eye movement abnormalities.

METHODS: Forty-five participants with genetically confirmed HD were recruited. Both SCWT formats were administered to each participant in a counterbalanced fashion. Individual performance of all three sections on each format was standardized across 2 different norms. Raw and normed scores on each variation were compared and correlated with eye movement ratings on the Unified Huntington's Disease Rating Scale.

RESULTS: The Golden variation elicited significantly slower responses, particularly in the Word Reading section, across two benchmark norms. Statistical analysis revealed significant performance differences between the two formats. Correlations between vertical eye movement ratings and performance on the Golden SCWT were highly significant, highlighting the impact of oculomotor coordination on cognitive assessments in HD.

CONCLUSION: This study underscores the importance of considering test format in cognitive assessments for HD. The Golden vertical SCWT demonstrates increased sensitivity in detecting deficits in HD, possibly linked to vertical saccade abnormalities. These insights are important for improving the sensitivity of cognitive assessments and monitoring disease progression in HD research and clinical practice.

BACKGROUND: In the present study we assessed the protective effects of a pharmacological approach to stabilize the retromer complex in a PD mouse model. Missense mutations in the VPS35 gene are a rare cause of familial PD. The VPS35 protein is a subunit of the retromer cargo recognition complex and has a variety of functions within neurons, many of which are potentially relevant for the pathophysiology of PD. Prior studies have revealed a role for the retromer complex in controlling accumulation and clearance of α-synuclein aggregates. We previously identified an aminoguanidine hydrazone, 1,3 phenyl bis guanylhydrazone (compound 2a), as a pharmacological stabilizer of the retromer complex that increases retromer subunit protein levels and function.

METHODS: Here, we validate the efficacy of 2a in protecting against αSynuclein pathology and dopaminergic neuronal degeneration in a PD mouse model generated by unilateral injection of AAV-A53T-αSynuclein in the substantia nigra.

RESULTS: Daily intraperitoneal administration of 2a at 10 mg/Kg for 100 days led to robust protection against behavioral deficits, dopaminergic neuronal loss and loss of striatal dopaminergic fibers and striatal monoamines. Treatment with 2a activated αSynuclein degradation pathways in the SN and led to significant reductions in aggregates and pathological αSynuclein.

CONCLUSION: These data suggest retromer stabilization as a promising therapeutic strategy for Parkinson's disease leading to neuroprotection of dopaminergic neurons and rescue in the accumulation of pathological and aggregates αSynuclein. We identified 2a compound as potential clinical drug candidate for future testing in Parkinson's disease patients.

BACKGROUND AND OBJECTIVES: Cognitive decline is an important early sign in pre-motor manifest Huntington's disease (preHD) and is characterized by deficits across multiple domains including executive function, psychomotor processing speed, and memory retrieval. Prior work suggested that the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L)-a verbal learning task that simultaneously targets these domains - could capture early cognitive changes in preHD. The current study aimed to replicate, validate and further analyze the LASSI-L in preHD using larger datasets.

METHODS: LASSI-L was administered to 50 participants (25 preHD and 25 Healthy Controls) matched for age, education, and sex in a longitudinal study of disease progression and compared to performance on MMSE, Trail A & B, SCWT, SDMT, Semantic Fluency (Animals), and CVLT-II. Performance was then compared to a separate age-education matched-cohort of 25 preHD participants. Receiver operating curve (ROC) and practice effects (12 month interval) were investigated. Group comparisons were repeated using a preHD subgroup restricted to participants predicted to be far from diagnosis (Far subgroup), based on CAG-Age-Product scaled (CAPs) score. Construct validity was assessed through correlations with previously established measures of subcortical atrophy.

RESULTS: PreHD performance on all sections of the LASSI-L was significantly different from controls. The proactive semantic interference section (PSI) was sensitive (p = 0.0001, d = 1.548), similar across preHD datasets (p = 1.0), reliable on test-retest over 12 months (spearman rho = 0.88; p = <0.00001) and associated with an excellent area under ROC (AUROC) of 0.855. In the preHD Far subgroup comparison, PSI was the only cognitive assessment to survive FDR < 0.05 (p = 0.03). The number of intrusions on PSI was negatively correlated with caudate volume.

DISCUSSION: The LASSI-L is a sensitive, reliable, efficient tool for detecting cognitive decline in preHD. By using a unique verbal learning test paradigm that simultaneously targets executive function, processing speed and memory retrieval, the LASSI-L outperforms many other established tests and captures early signs of cognitive impairment. With further longitudinal validation, the LASSI-L could prove to be a useful biomarker for clinical research in preHD.

BACKGROUND AND OBJECTIVES: People with Parkinson disease (PD) commonly experience cognitive decline, which may relate to increased α-synuclein, tau, and β-amyloid accumulation. This study examines whether the different proteins predict longitudinal cognitive decline in PD.

METHODS: All participants (PD n = 152, controls n = 52) were part of a longitudinal study and completed a lumbar puncture for CSF protein analysis (α-synuclein, total tau [tau], and β-amyloid42 [β-amyloid]), a β-amyloid PET scan, and/or provided a blood sample for APOE genotype (ε4+, ε4-), which is a risk factor for β-amyloid accumulation. Participants also had comprehensive, longitudinal clinical assessments of overall cognitive function and dementia status, as well as cognitive testing of attention, language, memory, and visuospatial and executive function. We used hierarchical linear growth models to examine whether the different protein metrics predict cognitive change and multivariate Cox proportional hazard models to predict time to dementia conversion. Akaike information criterion was used to compare models for best fit.

RESULTS: Baseline measures of CSF β-amyloid predicted decline for memory (p = 0.04) and overall cognitive function (p = 0.01). APOE genotypes showed a significant group (ε4+, ε4-) effect such that ε4+ individuals declined faster than ε4- individuals in visuospatial function (p = 0.03). Baseline β-amyloid PET significantly predicted decline in all cognitive measures (all p ≤ 0.004). Neither baseline CSF α-synuclein nor tau predicted cognitive decline. All 3 β-amyloid–related metrics (CSF, PET, APOE) also predicted time to dementia. Models with β-amyloid PET as a predictor fit the data the best.

DISCUSSION: Presence or risk of β-amyloid accumulation consistently predicted cognitive decline and time to dementia in PD. This suggests that β-amyloid has high potential as a prognostic indicator and biomarker for cognitive changes in PD.

BACKGROUND: The dystonias are phenotypically and etiologically heterogenous disorders. Many proposals and a consensus recommendation have been provided for the diagnosis and classification of the dystonias, but these recommendations serve only as general guidelines. Current diagnosis and classification may still depend on clinical judgment causing different opinions.

OBJECTIVE: To delineate clinical features used by movement disorder specialists in the diagnosis and classification of isolated focal cervical dystonia, and to develop recommendations for a more consistent approach to classification according to anatomical regions involved.

METHODS: Cross-sectional data for subjects diagnosed with isolated dystonia were acquired from the Dystonia Coalition, an international, multicenter collaborative research network. Data from many movement disorder specialists were evaluated to determine how diagnoses of cervical dystonia related to their recorded examinations. Cases were included if they were given a diagnosis of focal cervical dystonia. Cases were also included if they had dystonia of the neck on exam, but were given an alternative diagnosis such as segmental dystonia.

RESULTS: Among 2916 subjects with isolated dystonia, 1258 were diagnosed with focal cervical dystonia. Among these 1258 cases, 28.3% had dystonia outside of the neck region. Regions involved outside of the neck included the shoulder, larynx, and sometimes other regions. Analysis of the results pointed to several factors that may influence specialists' use of current diagnostic guidelines for making a diagnosis of isolated focal cervical dystonia including varied interpretations of involvement of nearby regions (shoulder, larynx, platysma), severity of dystonia across different regions, and occurrence of tremor in different regions.

CONCLUSIONS: Although focal cervical dystonia is the most common type of dystonia, a high percentage of subjects given this diagnosis had dystonia outside of the neck region. This observation points to the need for more specific guidelines for defining this common disorder. Such guidelines are proposed here.