Cognitive and Antipsychotic Medication Use in Monoallelic GBA-Related Parkinson Disease.

Mutations in glucosidase, beta, acid (GBA) are associated with cognitive impairment in Parkinson disease (PD) as well as dementia with Lewy bodies. For both of these diseases, dementia and hallucinations are typically treated with cholinesterase inhibitors and antipsychotics. However, in some lysosomal storage disorders certain antipsychotic medications are poorly tolerated. This study examined cholinesterase inhibitor and antipsychotic use in monoallelic GBA-related PD to explore potential pharmacogenetic relationships. Monoallelic GBA mutation carriers with PD (GBA-PD) with at least two clinic visits (n = 34) were matched for age-of-onset and gender to GBA and leucine-rich repeat kinase 2 (LRRK2) mutation negative idiopathic PD subjects (IPD) (n = 60). Information regarding cholinesterase inhibitor and antipsychotic use as well as impaired cognition (UPDRS Mentation >1) and hallucinations (UPDRS Thought Disorder >1) were obtained. GBA-PD more frequently reported hallucinations (HR = 5.0; p = 0.01) and they were more likely to have cognitive impairment but this was not statistically significant (HR 2.2, p = 0.07). Antipsychotic use was not significantly different between GBA-PD and IPD (HR = 1.9; p = 0.28), but GBA-PD were more likely to have sustained cholinesterase inhibitor use (HR = 3.1; p = 0.008), even after adjustment for cognition and hallucinations. Consistent with reports of worse cognition, GBA-PD patients are more likely to use cholinesterase inhibitors compared to IPD. While there was no difference in antipsychotic use between IPD and GBA-PD, persistent use of quetiapine in GBA-PD suggests that it is tolerated and that a significant interaction is unlikely. Further prospective study in larger samples with more extensive cognitive assessment is warranted to better understand pharmacogenetic relationships in GBA-PD.

Comparison of three tests using the frequency doubling illusion to diagnose glaucoma.

PURPOSE: The introduction of the FDT perimeter prompted the comparison of three tests employing frequency doubling (FD) stimuli. These measures compared different visual field locations and contrast ranges. Frequency of seeing curves were examined for the method most similar to FDT. METHODS: For 146 eyes the following were obtained: (i) contrast matches to two suprathreshold FD stimuli (normal subjects, ocular hypertensve suspects, primary open angle glaucoma subjects); (ii) two alternative forced choice (2AFC) thresholds for horizontally versus vertically orientated FD gratings: and (iii) contrast thresholds determined by method of adjustment (MOA) for five different stimulus types. RESULTS: A model based on the worst of the MOA hemifield thresholds performed best. The suprathreshold contrast matching tests performed worst. Frequency of seeing curves were fitted for the 146 eyes of the 2AFC tests. Although the MOA thresholds were higher than the 2AFC thresholds (for normals mean +/- SE, 8.47 +/- 0.43 dL, P < 0.0000), the best diagnostic concordance was at lower limens (75% or 80% correct) of the fitted frequency of seeing curves. CONCLUSIONS: There was good diagnostic concordance between the MOA and 2AFC methods although the thresholds were 1.8-fold different on a log-scale. This suggests that the same neural mechanism mediates both thresholds for rapidly flickering, spatially coarse, patterns.

Employing following eye movements to discriminate normal from glaucoma subjects.

We recorded optokinetic nystagmus (OKN) to see if slow phase velocity, duration or other measures were affected by glaucoma. Drifting grating patterns that either weakly or strongly evoked the spatial frequency doubling illusion were employed. Analysis of 68 variables characterizing the OKN revealed that small subsets of these variables were good at discriminating normal from primary open angle glaucoma subjects. The variables were related to the regularity of following eye movements. Models including the best five variables selected in two different ways classified about 90% of subjects correctly. Impaired accuracy of eye movements suggests that glaucoma changes the signal to noise ratio available to the brain. The gross changes observed permit the use of electro-oculography or other simple methods in the clinic.

The suppression of testis-brain RNA binding protein and kinesin heavy chain disrupts mRNA sorting in dendrites.

Ribonucleoprotein particles (RNPs) are thought to be key players in somato-dendritic sorting of mRNAs in CNS neurons and are implicated in activity-directed neuronal remodeling. Here, we use reporter constructs and gel mobility shift assays to show that the testis brain RNA-binding protein (TB-RBP) associates with mRNPs in a sequence (Y element) dependent manner. Using antisense oligonucleotides (anti-ODN), we demonstrate that blocking the TB-RBP Y element binding site disrupts and mis-localizes mRNPs containing (alpha)-calmodulin dependent kinase II (alpha)-CAMKII) and ligatin mRNAs. In addition, we show that suppression of kinesin heavy chain motor protein alters only the localization of (alpha)-CAMKII mRNA. Thus, differential sorting of mRNAs involves multiple mRNPs and selective motor proteins permitting localized mRNAs to utilize common mechanisms for shared steps.

Testing for glaucoma with the frequency-doubling illusion in the whole, macular and eccentric visual fields.

PURPOSE: The frequency doubling (FD) illusion is the basis for new diagnostic methods for glaucoma. The FD illusion is seen when low spatial frequency grating patterns are contrast modulated at high rates. The present experiments examined which spatial frequencies might be optimal and whether high flicker rates are required. METHODS: We determined contrast thresholds for the following: W1, a wide-field 0.25 c/deg grating at 27 Hz contrast reversal; W2, as W1 but no flicker; MAC, 27 Hz, 4 c/deg grating presented to the central 4 degrees; and E1 to E7, seven spatial frequencies in the range 0.063-0.813 c/deg, 27 Hz, presented in a 5 degrees aperture at 15 degrees (nasal) eccentricity. RESULTS: W1 was the best predictor of glaucoma. Of the eccentrically presented stimuli, E6 (0.688 c/deg) was the best predictor of glaucoma while the lower spatial frequencies performed less well. Only MAC was significantly age-dependent.