GBA-associated Parkinson’s disease in Hungary: clinical features and genetic insights

Introduction: Parkinson’s disease (PD) has a complex genetic background involving both rare and common genetic variants. Although a small percentage of cases show a clear Mendelian inheritance pattern, it is much more relevant to identify patients who present with a complex genetic profile of risk variants with different severity. The ß-glucocerebrosidase coding gene (GBA1) is recognized as the most frequent genetic risk factor for PD and Lewy body dementia, irrespective of reduction of the enzyme activity due to genetic variants. Methods: In a selected cohort of 190 Hungarian patients with clinical signs of PD and suspected genetic risk, we performed the genetic testing of the GBA1 gene. As other genetic hits can modify clinical features, we also screened for additional rare variants in other neurodegenerative genes and assessed the APOE-ε genotype of the patients. Results: In our cohort, we identified 29 GBA1 rare variant (RV) carriers. Out of the six different detected RVs, the highly debated E365K and T408M variants are composed of the majority of them (22 out of 32). Three patients carried two GBA1 variants, and an additional three patients carried rare variants in other neurodegenerative genes (SMPD1, SPG11, and SNCA). We did not observe differences in age at onset or other clinical features of the patients carrying two GBA1 variants or patients carrying heterozygous APOE-ε4 allele. Conclusion: We need further studies to better understand the drivers of clinical differences in these patients, as this could have important therapeutic implications. © 2023, The Author(s)

Preconditioning tDCS facilitates subsequent tDCS effect on skill acquisition in older adults.

Functional motor declines that often occur with advancing age-including reduced efficacy to learn new skills-can have a substantial impact on the quality of life. Recent studies using noninvasive brain stimulation indicate that priming the corticospinal system by lowering the threshold for the induction of long-term potentiation-like plasticity before skill training may facilitate subsequent skill learning. Here, we used "priming" protocol, in which we used transcranial direct current stimulation (tDCS) applying the cathode over the primary motor cortex (M1) before the anode placed over M1 during unimanual isometric force control training (FORCEtraining). Older individuals who received tDCS with the cathode placed over M1 before tDCS with the anode placed over M1 concurrent with FORCEtraining showed greater skill improvement and corticospinal excitability increases following the tDCS/FORCEtraining protocol compared with both young and older individuals who did not receive the preceding tDCS with the cathode placed over M1. The results suggested that priming tDCS protocols may be used in clinical settings to improve motor function and thus maintain the functional independence of older adults

Balancing with Vibration: A Prelude for “Drift and Act” Balance Control

Stick balancing at the fingertip is a powerful paradigm for the study of the control of human balance. Here we show that the mean stick balancing time is increased by about two-fold when a subject stands on a vibrating platform that produces vertical vibrations at the fingertip (0.001 m, 15–50 Hz). High speed motion capture measurements in three dimensions demonstrate that vibration does not shorten the neural latency for stick balancing or change the distribution of the changes in speed made by the fingertip during stick balancing, but does decrease the amplitude of the fluctuations in the relative positions of the fingertip and the tip of the stick in the horizontal plane, A(x,y). The findings are interpreted in terms of a time-delayed “drift and act” control mechanism in which controlling movements are made only when controlled variables exceed a threshold, i.e. the stick survival time measures the time to cross a threshold. The amplitude of the oscillations produced by this mechanism can be decreased by parametric excitation. It is shown that a plot of the logarithm of the vibration-induced increase in stick balancing skill, a measure of the mean first passage time, versus the standard deviation of the A(x,y) fluctuations, a measure of the distance to the threshold, is linear as expected for the times to cross a threshold in a stochastic dynamical system. These observations suggest that the balanced state represents a complex time–dependent state which is situated in a basin of attraction that is of the same order of size. The fact that vibration amplitude can benefit balance control raises the possibility of minimizing risk of falling through appropriate changes in the design of footwear and roughness of the walking surfaces

Mechanomyographic amplitude and frequency responses during dynamic muscle actions: a comprehensive review

The purpose of this review is to examine the literature that has investigated mechanomyographic (MMG) amplitude and frequency responses during dynamic muscle actions. To date, the majority of MMG research has focused on isometric muscle actions. Recent studies, however, have examined the MMG time and/or frequency domain responses during various types of dynamic activities, including dynamic constant external resistance (DCER) and isokinetic muscle actions, as well as cycle ergometry. Despite the potential influences of factors such as changes in muscle length and the thickness of the tissue between the muscle and the MMG sensor, there is convincing evidence that during dynamic muscle actions, the MMG signal provides valid information regarding muscle function. This argument is supported by consistencies in the MMG literature, such as the close relationship between MMG amplitude and power output and a linear increase in MMG amplitude with concentric torque production. There are still many issues, however, that have yet to be resolved, and the literature base for MMG during both dynamic and isometric muscle actions is far from complete. Thus, it is important to investigate the unique applications of MMG amplitude and frequency responses with different experimental designs/methodologies to continually reassess the uses/limitations of MMG

Bcl-2 expression restores the leukemogenic potential of a BCR/ABL mutant defective in transformation.

Growth factor-dependent hematopoietic cell lines expressing the BCR/ABL oncoprotein of the Ph chromosome show growth factor-independent proliferation and resistance to apoptosis. Apoptosis resistance of BCR/ABL-expressing cells may depend on enhanced expression of anti-apoptotic proteins as well as reduced expression and/or inactivation of pro-apoptotic proteins. Compared to myeloid precursor 32Dcl3 cells expressing wild type BCR/ABL, cells expressing a BCR/ABL mutant lacking amino acids 176-426 in the BCR domain (p185 delta BCR) are susceptible to apoptosis induced by interleukin-3 (IL-3) deprivation. These cells exhibited the hypophosphorylated apoptotic BAD and markedly reduced levels of Bcl-2. Upon ectopic expression of Bcl-2, these cells showed no changes in BAD phosphorylation, but they became apoptosis-resistant and proliferated in the absence of IL-3, albeit more slowly than cells expressing wild type BCR/ABL. Moreover, the p185 delta BCR/Bcl-2 double transfectants were leukemogenic when injected into immunodeficient mice, but Bcl-2 expression did not restore the leukemia-inducing effects of p185 delta BCR to the levels of wild type BCR/ABL. Leukemic cells recovered from the spleen of mice injected with p185 delta BCR/Bcl-2 cells did not show rearrangements in the Bcl-2 genomic locus, but they exhibited enhanced proliferation in culture and induced a rapidly fatal disease process when inoculated in secondary recipient mice. Together, these data support the importance of anti-apoptotic pathways for BCR/ABL-dependent leukemogenesis and suggest that Bcl-2 expression promotes secondary changes leading to a more aggressive tumor phenotype. (Blood. 2000;96:3915-3921

Changes in fluctuation of isometric force following eccentric and concentric exercise of the elbow flexors

The original publication can be found at www.springerlink.comThis study tested the hypothesis that eccentric exercise (ECC) would increase force fluctuation for several days following exercise; however, concentric exercise (CON) would not produce such an effect. Twelve men performed six sets of five reps of dumbbell exercise of the elbow flexors eccentrically with one arm and concentrically with the other, separated by 4-6 weeks, using a dumbbell set at 50% of maximal voluntary isometric contraction (MVC) measured at 90 degrees of elbow flexion. MVC, range of motion (ROM), upper arm circumference, plasma creatine kinase activity (CK), myoglobin concentration (Mb) and muscle soreness were assessed before, immediately after, 1 h and 1-5 days following both exercise bouts. Force fluctuations during 30, 50 and 80% MVC were quantified by coefficient of variation (CV) of the force data (sampling frequency: 100 Hz) for 4 s. Significantly (P < 0.01) larger changes in MVC, ROM, and upper arm circumference were evident following ECC compared to CON, and only ECC resulted in significant (P < 0.01) increases in CK and Mb, and development of muscle soreness. Significant (P < 0.01) differences existed between ECC and CON for changes in force fluctuations. CV increased significantly (P < 0.01) immediately and 1 h after ECC from baseline for 30, 50, and 80% MVC without a significant difference among the intensities, and no significant changes in CV were evident following CON. It was concluded that increases in force fluctuation were peculiar to ECC, but did not necessarily reflect muscle damage.Andrew P. Lavender and Kazunori Nosak