Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disease characterized by progressive motor, behavioral, and cognitive decline, ending in death. Despite the discovery of the underlying genetic mutation more than 20 years ago, treatment remains focused on symptomatic management. Chorea, the most recognizable symptom, responds to medication that reduces dopaminergic neurotransmission. Psychiatric symptoms such as depression and anxiety may also respond well to symptomatic therapies. Unfortunately, many other symptoms do not respond to current treatments. Furthermore, high-quality evidence for treatment of HD in general remains limited. To date, there has been minimal success with identifying a disease-modifying therapy based upon molecular models. However, one of the emerging gene silencing techniques may provide a breakthrough in treating this devastating disease.
Objectives Dopaminergic degeneration affects both nigrostriatal projection neurons and retinal amacrine cells in Parkinson disease (PD). Parkinsonian retinopathy is associated with impaired color discrimination and contrast sensitivity. Some prior studies described associations between color discrimination deficits and cognitive deficits in PD, suggesting that contrast discrimination deficits are due, at least in part, to cognitive deficits in PD. We investigated the relationship between cognitive deficits and impaired contrast sensitivity in PD. Methods PD subjects, n=43; 15F/28M; mean age 66.5±8.2, Hoehn and Yahr stage 2.6±0.6, and duration of disease of 6.2±5.0 years underwent neuropsychological and Rabin contrast sensitivity testing. Results Mean Rabin contrast sensitivity score was 1.34±0.40. Bivariate analyses showed significant correlation between Rabin contrast sensitivity scores and global cognitive z-scores (R=0.54, P=0.0002). Cognitive domain Z-score post hoc analysis demonstrated most robust correlation between Rabin scores and executive functions (R=0.49, P=0.0009), followed by verbal learning (R=0.44, P=0.0028), visuospatial (R=0.39, P=0.001) and attention z-scores (R=0.32, P=0.036). Conclusions Impaired contrast sensitivity in PD is robustly associated with cognitive deficits, particularly executive function deficits. These results suggest that contrast sensitivity may be a useful biomarker for cognitive changes in PD and may have implications for driving safety evaluations in PD.
doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
Gait abnormalities and cognitive dysfunction are common in patients with Parkinson's disease (PD) and get worst with disease progression. Recent evidence has suggested a strong relationship between gait abnormalities and cognitive dysfunction in PD patients and impaired cognitive control could be one of the causes for abnormal gait patterns. However, the pathophysiological mechanisms of cognitive dysfunction in PD patients with gait problems are unclear. Here, we collected scalp electroencephalography (EEG) signals during a 7-second interval timing task to investigate the cortical mechanisms of cognitive dysfunction in PD patients with (PDFOG+, n=34) and without (PDFOG-, n=37) freezing of gait, as well as control subjects (n=37). Results showed that the PDFOG+ group exhibited the lowest maximum response density at around 7 seconds compared to PDFOG- and control groups, and this response density peak correlated with gait abnormalities as measured by FOG scores. EEG data demonstrated that PDFOG+ had decreased midfrontal delta-band power at the onset of the target cue, which was also correlated with maximum response density and FOG scores. In addition, our classifier performed better at discriminating PDFOG+ from PDFOG- and controls with an area under the curve of 0.93 when midfrontal delta power was chosen as a feature. These findings suggest that abnormal midfrontal activity in PDFOG+ is related to cognitive dysfunction and describe the mechanistic relationship between cognitive and gait functions in PDFOG+. Overall, these results could advance the development of novel biosignatures and brain stimulation approaches for PDFOG+.
Background Visual function deficits are more common in imbalance-predominant compared to tremor-predominant PD suggesting a pathophysiological role of impaired visual functions in axial motor impairments. Objective To investigate the relationship between changes in color discrimination and motor impairments in PD while accounting for cognitive or other confounder factors. Methods PD subjects (n=49, age 66.7±8.3 years; Hoehn & Yahr stage 2.6±0.6) completed color discrimination assessment using the Farnsworth-Munsell 100 Hue Color Vision Test, neuropsychological, motor assessments and [11C]dihydrotetrabenazine vesicular monoamine transporter type 2 PET imaging. MDS-UPDRS sub-scores for cardinal motor features were computed. Timed up and go mobility and walking tests were assessed in 48 subjects. Results Bivariate correlation coefficients between color discrimination and motor variables were significant only for the Timed up and go (RS=0.44, P=0.0018) and the MDS-UPDRS axial motor scores (RS=0.38, P=0.0068). Multiple regression confounder analysis using the Timed up and go as outcome parameter showed a significant total model (F(5,43)= 7.3, P<0.0001) with significant regressor effects for color discrimination (standardized β=0.32, t=2.6, P=0.012), global cognitive Z-score (β=−0.33, t=−2.5, P=0.018), duration of disease (β=0.26, t=1.8, P=0.038), but not for age or striatal dopaminergic binding. The color discrimination test was also a significant independent regressor in the MDS-UPDRS axial motor model (standardized β=0.29, t=2.4, P=0.022; total model t(5,43)= 6.4, P=0.0002). Conclusions Color discrimination errors associate with axial motor features in PD independent of cognitive deficits, nigrostriatal dopaminergic denervation, and other confounder variables. These findings may reflect shared pathophysiology between color discrimination visual impairments and axial motor burden in PD.
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