Faculty Bibliography

Background and aims: Dementia is considered a nonsupportive diagnostic feature for multiple system atrophy (MSA). Nevertheless, post-mortem verified dementia with Lewy bodies and Parkinson's disease masquerade as MSA. Cognitive impairment (CI), especially executive dysfunction, may occur in MSA patients. It is, however, unclear whether CI manifests in early disease stages.
Objective(s): To compare the prevalence of CI in MSA versus other Lewy Body disorders (LBD), including dementia with Lewy bodies and Parkinson's disease, in early (<3 years from symptom onset) versus more advanced disease stages (>=3 years from symptom onset).
Method(s): A total of 364 patients (LBD: n=83; MSA: n=281) of the natural history study of synucleinopathies register have been analysed. Consensus diagnostic criteria for dementia with Lewy bodies, Parkinson's disease and MSA were applied. To assess CI, the Montreal Cognitive Assessment (MoCA) has been used.
Result(s): In early disease stages, median MoCA scores did not differ significantly between MSA and LBD. In advanced disease stages, MSA patients had a significantly higher median MoCA score compared to LBD patients (27 versus 25, p=0.006). Comparison of the median MoCA Scores of LBD versus MSA patients at early and advanced disease stages
Conclusion(s): In patients with longer disease duration severity of CI helps to differentiate LBD from MSA

PURPOSE:To develop criteria to interpret mitochondrial transfer RNA (mt-tRNA) variants based on unique characteristics of mitochondrial genetics and conserved structural/functional properties of tRNA. METHODS:We developed rules on a set of established pathogenic/benign variants by examining heteroplasmy correlations with phenotype, tissue distribution, family members, and among unrelated families from published literature. We validated these deduced rules using our new cases and applied them to classify novel variants. RESULTS:Evaluation of previously reported pathogenic variants found that 80.6% had sufficient evidence to support phenotypic correlation with heteroplasmy levels among and within families. The remaining variants were downgraded due to the lack of similar evidence. Application of the verified criteria resulted in rescoring 80.8% of reported variants of uncertain significance (VUS) to benign and likely benign. Among 97 novel variants, none met pathogenic criteria. A large proportion of novel variants (84.5%) remained as VUS, while only 10.3% were likely pathogenic. Detection of these novel variants in additional individuals would facilitate their classification. CONCLUSION:Proper interpretation of mt-tRNA variants is crucial for accurate clinical diagnosis and genetic counseling. Correlations with tissue distribution, heteroplasmy levels, predicted perturbations to tRNA structure, and phenotypes provide important evidence for determining the clinical significance of mt-tRNA variants.

OBJECTIVES/OBJECTIVE:Cochlear implants (CIs) restore speech perception in quiet but they also eliminate or distort many acoustic cues that are important for music enjoyment. Unfortunately, quantifying music enjoyment by CI users has been difficult because comparisons must rely on their recollection of music before they lost their hearing. Here, we aimed to assess music enjoyment in CI users using a readily interpretable reference based on acoustic hearing. The comparison was done by testing "single-sided deafness" (SSD) patients who have normal hearing (NH) in one ear and a CI in the other ear. The study also aimed to assess binaural musical enjoyment, with the reference being the experience of hearing with a single NH ear. Three experiments assessed the effect of adding different kinds of input to the second ear: electrical, vocoded, or unmodified. DESIGN/METHODS:In experiment 1, music enjoyment in SSD-CI users was investigated using a modified version of the MUSHRA (MUltiple Stimuli with Hidden Reference and Anchor) method. Listeners rated their enjoyment of song segments on a scale of 0 to 200, where 100 represented the enjoyment obtained from a song segment presented to the NH ear, 0 represented a highly degraded version of the same song segment presented to the same ear, and 200 represented enjoyment subjectively rated as twice as good as the 100 reference. Stimuli consisted of acoustic only, electric only, acoustic and electric, as well as other conditions with low pass filtered acoustic stimuli. Acoustic stimulation was provided by headphone to the NH ear and electric stimulation was provided by direct audio input to the subject's speech processor. In experiment 2, the task was repeated using NH listeners who received vocoded stimuli instead of electric stimuli. Experiment 3 tested the effect of adding the same unmodified song segment to the second ear, also in NH listeners. RESULTS:Music presented through the CI only was very unpleasant, with an average rating of 20. Surprisingly, the combination of the unpleasant CI signal in one ear with acoustic stimulation in the other ear was rated more enjoyable (mean = 123) than acoustic processing alone. Presentation of the same monaural musical signal to both ears in NH listeners resulted with even greater enhancement of the experience compared with presentation to a single ear (mean = 159). Repeating the experiment using a vocoder to one ear of NH listeners resulted in interference rather than enhancement. CONCLUSIONS:Music enjoyment from electric stimulation is extremely poor relative to a readily interpretable NH baseline for CI-SSD listeners. However, the combination of this unenjoyable signal presented through a CI and an unmodified acoustic signal presented to a NH (or near-NH) contralateral ear results in enhanced music enjoyment with respect to the acoustic signal alone. Remarkably, this two-ear enhancement experienced by CI-SSD listeners represents a substantial fraction of the two-ear enhancement seen in NH listeners. This unexpected benefit of electroacoustic auditory stimulation will have to be considered in theoretical accounts of music enjoyment and may facilitate the quest to enhance music enjoyment in CI users.

This review explores the relationship between vitamin D supplementation and lithogenesis. A causal relationship has been assumed despite myriad studies demonstrating that therapeutic doses of vitamin D do not increase lithogenic risk. Select stone formers may be at increased risk for recurrence with vitamin D supplementation, possibly from CYP24A1 gene mutations. Additionally, the evidence for who is vitamin D deficient, and the benefits of supplementation in those not at risk for rickets, is sparse. Concerns may be avoidable as vitamin D screening appears unnecessary in most patients, and superior pharmacology is available which increases bone density, while decreasing stone formation.

Background and aims: Distinguishing neurogenic orthostatic hypotension (nOH) from other causes of blood pressure (BP) instability is of pivotal importance in clinical practice. Norcliffe-Kaufmann et al. recently showed that when the ratio between the heart rate increase and the systolic BP fall after 3 minutes of passive head-up tilt (HUT) is <0.492, this indicates nOH. Here we aimed at validating this nOH ratio with standard arm-cuff BP measurements upon active standing (AS).
Method(s): We screened all patients who had undergone cardiovascular autonomic function testing at the Innsbruck Medical University between January 2008 and September 2019.
Result(s): We included 51 patients (27 with Parkinson's disease, 22 with multiple system atrophy) diagnosed with orthostatic hypotension either upon AS or HUT. 49 patients showed no BP overshoot after the Valsalva maneuver and were thus classified as having nOH. Out of these, 27 patients showed a systolic BP fall >=20mmHg in both the HUT and the AS and were considered for further analysis. The nOH ratio was <0.492 for 20 patients during HUT and for 19 patients during the AS. The sensitivity of the nOH ratio for neurogenic OH was therefore 74% upon HUT and 70% upon AS. The correlation between the nOH-ratio upon HUT and AS was strong (rho=0.86, p<0.001).
Conclusion(s): A nOH ratio <0.492 evaluated with standard arm-cuff heart rate and BP measurements has a good sensitivity for nOH both upon HUT and AS. This ratio can be therefore used as bedside nOH screening measure, if no tilt-test facilities are available

INTRODUCTION The mechanisms underlying B cell-mediated autoimmune disease and the origin of autoreactive B cells are not well understood. Human monoclonal autoantibodies (mAbs) are valuable tools for investigating both. In this study, we used mAbs derived from patients with the autoimmune disorder, myasthenia gravis (MG). A subset of patients with MG have pathogenic autoantibodies that recognize muscle specific tyrosine kinase (MuSK). The autoantibodies of MuSK MG are predominantly of the IgG4 subclass and functionally monovalent as a result of Fab-arm exchange. OBJECTIVE To gain insight into the origin and development of these unique autoantibodies. METHODS AND RESULTS We examined MG patient-derived mAbs, their corresponding germline-encoded unmutated common ancestors (UCA) and monovalent antigen-binding fragments (Fabs) to investigate how antigen-driven affinity maturation contributes to both binding and immunopathology. Mature mAbs, their UCA counterparts and mature monovalent Fabs bound to the MuSK autoantigen and retained their pathogenic capacity. However, monovalent UCA Fabs, which still bound the autoantigen, lost their pathogenic capacity. The mature Fabs were characterized by very high affinity (sub-nanomolar) driven by a rapid on-rate and slow off-rate. However, the UCA affinity was approximately 100-fold less than the mature Fabs, which was driven by a rapid off-rate. SUMMARY/CONCLUSION These findings indicate that the autoantigen initiates the autoimmune response in MuSK MG and drives autoimmunity through the accumulation of somatic hypermutations such that monovalent IgG4 Fab-arm exchanged MG autoantibodies reach a high affinity threshold required for pathogenic capacity

The majority of clinical trials targeting the tau protein in Alzheimer's disease and other tauopathies are tau immunotherapies. Because tau pathology correlates better with the degree of dementia than amyloid-β lesions, targeting tau is likely to be more effective in improving cognition than clearing amyloid-β in Alzheimer's disease. However, the development of tau therapies is in many ways more complex than for amyloid-β therapies as briefly outlined in this review. Most of the trials are on humanized antibodies, which may have very different properties than the original mouse antibodies. The impact of these differences are to a large extent unknown, can be difficult to decipher, and may not always be properly considered. Furthermore, the ideal antibody properties for efficacy are not well established and can depend on several factors. However, considering the varied approaches in clinical trials, there is a general optimism that at least some of these trials may provide functional benefits to patients suffering of various tauopathies.

The combination of in vivo extracellular recording and genetic-engineering-assisted optical stimulation is a powerful tool for the study of neuronal circuits. Precise analysis of complex neural circuits requires high-density integration of multiple cellular-size light sources and recording electrodes. However, high-density integration inevitably introduces stimulation artifact. We present minimal-stimulation-artifact (miniSTAR) μLED optoelectrodes that enable effective elimination of stimulation artifact. A multi-metal-layer structure with a shielding layer effectively suppresses capacitive coupling of stimulation signals. A heavily boron-doped silicon substrate silences the photovoltaic effect induced from LED illumination. With transient stimulation pulse shaping, we reduced stimulation artifact on miniSTAR μLED optoelectrodes to below 50 μV_pp, much smaller than a typical spike detection threshold, at optical stimulation of >50 mW mm^-2 irradiance. We demonstrated high-temporal resolution (<1 ms) opto-electrophysiology without any artifact-induced signal quality degradation during in vivo experiments. MiniSTAR μLED optoelectrodes will facilitate functional mapping of local circuits and discoveries in the brain.