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Progressive supranuclear palsy (PSP) is a pure tauopathy, implicating davunetide, enhancing Tau-microtubule interaction, as an ideal drug candidate. However, pooling patient data irrespective of sex concluded no efficacy. Here, analyzing sex-dependency in a 52 week-long- PSP clinical trial (involving over 200 patients) demonstrated clear baseline differences in brain ventricular volumes, a secondary endpoint. Dramatic baseline ventricular volume-dependent/volume increase correlations were observed in 52-week-placebo-treated females (r = 0.74, P = 2.36-9), whereas davunetide-treated females (like males) revealed no such effects. Assessment of primary endpoints, by the PSP Rating Scale (PSPRS) and markedly more so by the Schwab and England Activities of Daily Living (SEADL) scale, showed significantly faster deterioration in females, starting at trial week 13 (P = 0.01, and correlating with most other endpoints by week 52). Twice daily davunetide treatments slowed female disease progression and revealed significant protection according to the SEADL scale as early as at 39 weeks (P = 0.008), as well as protection of the bulbar and limb motor domains considered by the PSPRS, including speaking and swallowing difficulties caused by brain damage, and deterioration of fine motor skills, respectably (P = 0.01), at 52 weeks. Furthermore, at 52 weeks of trial, the exploratory Geriatric Depression Scale (GDS) significantly correlated with the SEADL scale deterioration in the female placebo group and demonstrated davunetide-mediated protection of females. Female-specific davunetide-mediated protection of ventricular volume corresponded to clinical efficacy. Together with the significantly slower disease progression seen in men, the results reveal sex-based drug efficacy differences, demonstrating the neuroprotective and disease-modifying impact of davunetide treatment for female PSP patients.
Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are both 4 microtubule binding repeat tauopathy related disorders. Clinical trials need new biomarkers to assess the effectiveness of tau-directed therapies. This study investigated the regional distribution of longitudinal diffusion tensor imaging changes, measured by fractional anisotropy, radial and axial diffusivity over 6 months median interval, in 23 normal control subjects, 35 patients with PSP, and 25 patients with CBS. A mixed-effects framework was used to test longitudinal changes within and between groups. Correlations between changes in diffusion variables and clinical progression were also tested. The study found that over a 6 month period and compared to controls, the most prominent changes in PSP were up to 3±1% higher rates of FA reduction predominantly in superior cerebellar peduncles, and up to 18±6% higher rates of diffusivity increases in caudate nuclei. The most prominent changes in CBS compared to controls were up to 4±1% higher rates of anisotropy reduction and 18±6% higher rates of diffusivity increase in basal ganglia and widespread white matter regions. Compared to PSP, CBS was mainly associated with up to 3±1% greater rates of anisotropy reduction around the central sulci, and 11±3% greater rates of diffusivity increase in superior fronto-occipital fascicules. Rates of diffusivity increases in the superior cerebellar peduncle correlated with rates of ocular motor decline in PSP patients. This study demonstrated that longitudinal diffusion tensor imaging measurement is a promising surrogate marker of disease progression in PSP and CBS over a relatively short period.
Brown-Vialetto-van Laere (BVVL) and Fazio-Londe (FL) are rare and clinically overlapping motor neurons syndromes. Recently BVVL has been associated with mutations in C20orf54/hRFT2 and defective riboflavin transport. We compared clinical and laboratory features of 6 patients (age range 11-17 years), with features of BVVL and FL overlap syndromes. Patients were assessed as following: blood levels of riboflavin and redox status, electrophysiological, neuroradiological and pulmonary studies, ALS functional rating scale and molecular genetic analysis. Two patients manifested deafness at ages of 3 and 10 years, and developed later subacute progressive ponto-bulbar palsy. A third patient markedly improved after intravenous immunoglobulins (IVIG), but then relapsed remaining unresponsive to treatment; he was not deaf although had abnormal auditory evoked responses (BAERs). The remaining 3 patients had no deafness, although likewise manifested subacute progressive ponto-bulbar palsy. We found hRFT2 mutations in 3/6 patients manifesting deafness or abnormal BAERs. No patient had reduced riboflavin blood levels. However, on riboflavin supplementation (10mg/kg/day) the most severely affected BVVL patient stopped progression of symptoms following 8 months of treatment. BVVL and FL are severe progressive diseases with overlapping symptoms although only hRFT2 mutated patients manifest deafness. Riboflavin supplementation seems to stabilize and improve progression of the disease.
We report seven Charcot-Marie-Tooth 4B1 (CMT4B1) patients from four families with distinctive features, presenting with severe distal weakness and cranial nerve involvement. Patient from family 1 presented with congenital varus foot deformity, progressive distal and proximal weakness leading to loss of ambulation at 14 years, bilateral facial palsy and prominent bulbar involvement. In three siblings from family 2, still ambulant in the second decade, neuropathy was associated with marked sweating and Arnold-Chiari syndrome. Patient from family 3, wheelchair-bound by 17 years, suffered from recurrent intestinal occlusion due to a mesenteric malformation. Patients from family 4, wheelchair-bound from age 6 years, were first diagnosed with type 1 Usher syndrome with congenital deafness and retinitis pigmentosa. CMT4B1 diagnosis was based upon suggestive clinical features and confirmed by the presence of recessive mutations in the MTMR2 gene. Our results expand the genetic and phenotypic spectrum of CMT4B1, which may include autonomic system involvement.
Motor neuron diseases (MNDs) are a group of neurodegenerative disorders with involvement of upper and/or lower motor neurons, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), progressive bulbar palsy, and primary lateral sclerosis. Recently, we have mapped a new locus for an atypical form of ALS/MND (atypical amyotrophic lateral sclerosis [ALS8]) at 20q13.3 in a large white Brazilian family. Here, we report the finding of a novel missense mutation in the vesicle-associated membrane protein/synaptobrevin-associated membrane protein B (VAPB) gene in patients from this family. Subsequently, the same mutation was identified in patients from six additional kindreds but with different clinical courses, such as ALS8, late-onset SMA, and typical severe ALS with rapid progression. Although it was not possible to link all these families, haplotype analysis suggests a founder effect. Members of the vesicle-associated proteins are intracellular membrane proteins that can associate with microtubules and that have been shown to have a function in membrane transport. These data suggest that clinically variable MNDs may be caused by a dysfunction in intracellular membrane trafficking.
The tongue plays a crucial role in the swallowing process, and impairment can lead to dysphagia, particularly in motor neuron diseases (MNDs) resulting in hypoglossal-tongue axis degeneration (e.g., amyotrophic lateral sclerosis and progressive bulbar palsy). This study utilized our previously established inducible rodent model of dysphagia due to targeted degeneration of the hypoglossal-tongue axis. This model was created by injecting cholera toxin B conjugated to saporin (CTB-SAP) into the genioglossus muscle of the tongue base for retrograde transport to the hypoglossal (XII) nucleus via the hypoglossal nerve, which provides the sole motor control of the tongue. Our goal was to investigate the effect of high-repetition/low-resistance tongue exercise on tongue function, strength, and structure in four groups of male rats: (1) control + sham exercise (n = 13); (2) control + exercise (n = 10); (3) CTB-SAP + sham exercise (n = 13); and (4) CTB-SAP + exercise (n = 12). For each group, a custom spout with adjustable lick force requirement for fluid access was placed in the home cage overnight on days 4 and 6 post-tongue injection. For the two sham exercise groups, the lick force requirement was negligible. For the two exercise groups, the lick force requirement was set to ∼40% greater than the maximum voluntary lick force for individual rats. Following exercise exposure, we evaluated the effect on hypoglossal-tongue axis function (via videofluoroscopy), strength (via force-lickometer), and structure [via Magnetic Resonance Imaging (MRI) of the brainstem and tongue in a subset of rats]. Results showed that sham-exercised CTB-SAP rats had significant deficits in lick rate, swallow timing, and lick force. In exercised CTB-SAP rats, lick rate and lick force were preserved; however, swallow timing deficits persisted. MRI revealed corresponding degenerative changes in the hypoglossal-tongue axis that were mitigated by tongue exercise. These collective findings suggest that high-repetition/low-resistance tongue exercise in our model is a safe and effective treatment to prevent/diminish signs of hypoglossal-tongue axis degeneration. The next step is to leverage our rat model to optimize exercise dosing parameters and investigate corresponding treatment mechanisms of action for future translation to MND clinical trials.
The hearing healthcare industry is evolving rapidly. A framework addressing provision options in contemporary hearing care could assist clinician and client navigate their options to find the most appropriate solution for each individual. A PRISMA approach was used followed by mapping, validation, and thematic analysis to produce a framework to better describe and discuss service and product delivery options in contemporary hearing care. No frameworks were identified to advise matching needs with current provision options in audiological care. Charting, mapping, and thematic analysis of the validation criteria and hearing care literature produced three core domains: Service, Channel, and Technology/Device. The framework developed in this review allows for an understanding of where innovation is occurring in hearing healthcare and differentiates between changes to technology, channel, and service. New questions open up such as whether one model is more effective than another or which model of hearing help is best for which type of person. This framework allows for the disambiguation of hearing health services, hearing loss technology, and the channel in which services and technology are delivered. It has potential to be a versatile and valuable addition to the industry of hearing healthcare.
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