NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson's disease.

Nicotinamide adenine dinucleotide (NAD) replenishment therapy using nicotinamide riboside (NR) shows promise for Parkinson's disease (PD) and other neurodegenerative disorders. However, the optimal dose of NR remains unknown, and doses exceeding 2000 mg daily have not been tested in humans. To evaluate the safety of high-dose NR therapy, we conducted a single-center, randomized, placebo-controlled, double-blind, phase I trial on 20 individuals with PD, randomized 1:1 on NR 1500 mg twice daily (n = 10) or placebo (n = 10) for four weeks. The trial was conducted at the Department of Neurology, Haukeland University Hospital, Bergen, Norway. The primary outcome was safety, defined as the frequency of moderate and severe adverse events. Secondary outcomes were tolerability defined as frequency of mild adverse events, change in the whole blood and urine NAD metabolome, and change in the clinical severity of PD, measured by MDS-UPDRS. All 20 participants completed the trial. The trial met all prespecified outcomes. NR therapy was well tolerated with no moderate or severe adverse events, and no significant difference in mild adverse events. NR therapy was associated with clinical improvement of total MDS-UPDRS scores. However, this change was also associated with a shorter interval since the last levodopa dose. NR greatly augmented the blood NAD metabolome with up to 5-fold increase in blood NAD+ levels. While NR-recipients exhibited a slight initial rise in serum homocysteine levels, the integrity of the methyl donor pool remained intact. Our results support extending the dose range of NR in phase II clinical trials to 3000 mg per day, with appropriate safety monitoring. Clinicaltrials.gov identifier: NCT05344404.

The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease.

We conducted a double-blinded phase I clinical trial to establish whether nicotinamide adenine dinucleotide (NAD) replenishment therapy, via oral intake of nicotinamide riboside (NR), is safe, augments cerebral NAD levels, and impacts cerebral metabolism in Parkinson's disease (PD). Thirty newly diagnosed, treatment-naive patients received 1,000 mg NR or placebo for 30 days. NR treatment was well tolerated and led to a significant, but variable, increase in cerebral NAD levels-measured by 31phosphorous magnetic resonance spectroscopy-and related metabolites in the cerebrospinal fluid. NR recipients showing increased brain NAD levels exhibited altered cerebral metabolism, measured by 18fluoro-deoxyglucose positron emission tomography, and this was associated with mild clinical improvement. NR augmented the NAD metabolome and induced transcriptional upregulation of processes related to mitochondrial, lysosomal, and proteasomal function in blood cells and/or skeletal muscle. Furthermore, NR decreased the levels of inflammatory cytokines in serum and cerebrospinal fluid. Our findings nominate NR as a potential neuroprotective therapy for PD, warranting further investigation in larger trials.

Neuroplastic Effects in Patients With Traumatic Brain Injury After Music-Supported Therapy.

Damage to the orbitofrontal cortex (OFC) often occurs following a traumatic brain injury (TBI) and can lead to complex behavioral changes, including difficulty with attention and concentration. We investigated the effects of musical training on patients with behavioral and cognitive deficits following a mild traumatic brain injury (mTBI) and found significant functional neuro-plastic changes in the OFC's networks. The results from neuropsychological tests revealed an improved cognitive performance. Moreover, six out of seven participants in this group returned to work post intervention and reported improved well-being and social behavior. In this study, we explore the functional changes in OFC following music-supported intervention in reference to connecting networks that may be responsible for enhanced social interaction. Furthermore, we discuss the factor of dopamine release during playing as an element providing a possible impact on the results. The intervention consisted of playing piano, two sessions per week in 8 weeks, 30 min each time, with an instructor. Additional playing was required with a minimum of 15 min per day at home. Mean time playing piano in reference to participant's report was 3 h per week during the intervention period. Three groups participated, one mTBI group (n = 7), two control groups consisting of healthy participants, one with music training (n = 11), and one baseline group without music training (n = 12). Participants in the clinical group had received standardized cognitive rehabilitation treatment during hospitalization without recovering from their impairments. The intervention took place 2 years post injury. All participants were assessed with neuropsychological tests and with both task and resting-state functional magnetic resonance imaging (fMRI) pre-post intervention. The results demonstrated a significant improvement of neuropsychological tests in the clinical group, consistent with fMRI results in which there were functional changes in the orbitofrontal networks (OFC). These changes were concordantly seen both in a simple task fMRI but also in resting-state fMRI, which was analyzed with dynamic causal modeling (DCM). We hypothesized that playing piano, as designed in the training protocol, may provide a positive increase in both well-being and social interaction. We suggest that the novelty of the intervention may have clinical relevance for patients with behavioral problems following a TBI.

Effects of music production on cortical plasticity within cognitive rehabilitation of patients with mild traumatic brain injury.

OBJECTIVE: We explored the effects of playing the piano on patients with cognitive impairment after mild traumatic brain injury (mTBI) and, addressed the question if this approach would stimulate neural networks in re-routing neural connections and link up cortical circuits that had been functional inhibited due to disruption of brain tissue. Functional neuroimaging scans (fMRI) and neuropsychological tests were performed pre-post intervention. METHOD: Three groups participated, one mTBI group (n = 7), two groups of healthy participants, one with music training (n = 11), one baseline group without music (n = 12). The music groups participated in 8 weeks music-supported intervention. RESULTS: The patient group revealed training-related neuroplasticity in the orbitofrontal cortex. fMRI results fit well with outcome from neuropsychological tests with significant enhancement of cognitive performance in the music groups. Ninety per cent of mTBI group returned to work post intervention. CONCLUSION: Here, for the first time, we demonstrated behavioural improvements and functional brain changes after 8 weeks of playing piano on patients with mTBI having attention, memory and social interaction problems. We present evidence for a causal relationship between musical training and reorganisation of neural networks promoting enhanced cognitive performance. These results add a novel music-supported intervention within rehabilitation of patients with cognitive deficits following mTBI.

The effect of group music therapy on mood, speech, and singing in individuals with Parkinson's disease--a feasibility study.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder where patients exhibit impairments in speech production. Few studies have investigated the influence of music interventions on vocal abilities of individuals with PD. OBJECTIVES: To evaluate the influence of a group voice and singing intervention on speech, singing, and depressive symptoms in individuals with PD. METHODS: Ten patients diagnosed with PD participated in this one-group, repeated measures design study. Participants received the sixty-minute intervention, in a small group setting once a week for 20 consecutive weeks. Speech and singing quality were acoustically analyzed using a KayPentax Multi-Dimensional Voice Program, voice ability using the Voice Handicap Index (VHI), and depressive symptoms using the Montgomery and Asberg Depression rating scale (MADRS). Measures were taken at baseline (Time 1), after 10 weeks of weekly sessions (Time 2), and after 20 weeks of weekly sessions (Time 3). RESULTS: Significant changes were observed for five of the six singing quality outcomes at Time 2 and 3, as well as voice range and the VHI physical subscale at Time 3. No significant changes were found for speaking quality or depressive symptom outcomes; however, there was an absence of decline on speaking quality outcomes over the intervention period. CONCLUSIONS: Significant improvements in singing quality and voice range, coupled with the absence of decline in speaking quality support group singing as a promising intervention for persons with PD. A two-group randomized control study is needed to determine whether the intervention contributes to maintenance of speaking quality in persons with PD.