1.
The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease.
Brakedal, B, Dölle, C, Riemer, F, Ma, Y, Nido, GS, Skeie, GO, Craven, AR, Schwarzlmüller, T, Brekke, N, Diab, J, et al
Cell metabolism. 2022;34(3):396-407.e6
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Plain language summary
Parkinson’s disease (PD) is a major cause of death and disability, and current treatments can provide partial symptomatic relief, mainly for motor symptoms but make no substantial impact on disease progression. A growing body of evidence supports that boosting cellular levels of nicotinamide adenine dinucleotide (NAD) may confer neuroprotective effects in both healthy aging and neurodegeneration. The primary aim of this study was to assess penetration and metabolic responses of the brain to nicotinamide riboside (NR) supplementation in patients with PD. This study is a double-blinded, randomised, placebo-controlled phase I study of NR in newly diagnosed PD patients, naïve to dopaminergic therapy. Participants (n=30) where randomly assigned (1:1) to one of the two groups: NR group or placebo group. Results show that: - oral NR therapy increases brain NAD levels and impacts cerebral metabolism in PD. - supplementation with NR may target multiple processes implicated in the pathophysiology of the disease by upregulating the expression of genes involved in mitochondrial respiration, oxidative damage response, lysosomal and proteasomal function and downregulating inflammatory cytokines in the central nervous system. Authors conclude that NR can be a potential neuroprotective agent against PD. However, further investigation in a larger trial is required to warrant these findings.
Abstract
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.
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Phase I/II multicenter ketogenic diet study for adult superrefractory status epilepticus.
Cervenka, MC, Hocker, S, Koenig, M, Bar, B, Henry-Barron, B, Kossoff, EH, Hartman, AL, Probasco, JC, Benavides, DR, Venkatesan, A, et al
Neurology. 2017;88(10):938-943
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Superrefractory status epilepticus (SRSE) is a neurologic emergency that persists despite anti-seizure medication. The ketogenic diet (KD) has been shown to be successful for treating epilepsy and recent retrospective studies suggest KD may be effective for treating SRSE. The aim of this clinical trial was to investigate the feasibility, safety and efficacy of a ketogenic diet on SRSE in adults. After screening, this prospective multi-centre study enrolled 15 participants with SRSE. Participants received a classic ketogenic diet via gastronomy tube. Of the 14 participants whom completed KD treatment SRSE resolved in 11 participants. Five patients ultimately died. This study found KD is feasible in adults with SRSE, and further randomised controlled trials are required to establish comparative safety and efficacy.
Abstract
OBJECTIVE To investigate the feasibility, safety, and efficacy of a ketogenic diet (KD) for superrefractory status epilepticus (SRSE) in adults. METHODS We performed a prospective multicenter study of patients 18 to 80 years of age with SRSE treated with a KD treatment algorithm. The primary outcome measure was significant urine and serum ketone body production as a biomarker of feasibility. Secondary measures included resolution of SRSE, disposition at discharge, KD-related side effects, and long-term outcomes. RESULTS Twenty-four adults were screened for participation at 5 medical centers, and 15 were enrolled and treated with a classic KD via gastrostomy tube for SRSE. Median age was 47 years (interquartile range [IQR] 30 years), and 5 (33%) were male. Median number of antiseizure drugs used before KD was 8 (IQR 7), and median duration of SRSE before KD initiation was 10 days (IQR 7 days). KD treatment delays resulted from intravenous propofol use, ileus, and initial care received at a nonparticipating center. All patients achieved ketosis in a median of 2 days (IQR 1 day) on KD. Fourteen patients completed KD treatment, and SRSE resolved in 11 (79%; 73% of all patients enrolled). Side effects included metabolic acidosis, hyperlipidemia, constipation, hypoglycemia, hyponatremia, and weight loss. Five patients (33%) ultimately died. CONCLUSIONS KD is feasible in adults with SRSE and may be safe and effective. Comparative safety and efficacy must be established with randomized placebo-controlled trials. CLASSIFICATION OF EVIDENCE This study provides Class IV evidence that in adults with SRSE, a KD is effective in inducing ketosis.