👤 Rachel M Mayfield

Impaired cerebral glucose metabolism is a hallmark of Alzheimer's disease (AD). Lactate is an alternative brain fuel; however, whole-body lactate metabolism has not been measured in AD. The Lactate for Energy and Neurocognition Trial (NCT05207397) was a single-arm trial that enrolled 24 cognitively healthy (CH) older adults and 12 cognitively impaired (CI) participants. Subjects underwent a stable isotope lactate infusion to evaluate lactate metabolism, cognitive testing, and blood biomarker analyses. pTau217, brain-derived tau (BD-tau), pTau181, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), total tau, and brain-derived neurotrophic factor (BDNF) were analyzed by Simoa HD-X (Quanterix). Lactate metabolic clearance rate did not differ between CH and CI subjects (p = 0.988). After infusion, global cognition was improved (p < 0.001) and plasma pTau217 (-33.8%, p < 0.001), BD-tau (-32.6%, p < 0.001), pTau181 (-21.4%, p < 0.001), GFAP (-39.7%, p < 0.001), and NfL (-19.5%, p < 0.001) were reduced. Lactate turnover was not different between diagnosis groups. Lactate infusion improved cognition and reduced AD fluid biomarkers. Individuals with Alzheimer's disease (AD) can metabolize lactate as well as healthy controls. Lactate infusion might improve global cognition and processing speed. Lactate infusion results in significant decrease of AD fluid biomarkers. Show less

Alzheimer's disease (AD) pathology is complex and involves mitochondrial dysfunction. There are emerging therapies targeting mitochondrial function in clinical trials for AD. This highlights the need for biomarkers that measure mitochondrial function. We determined the utility of a novel blood-based mitochondrial biomarker, the mitochondrial functional index (MFI), in the context of AD in a pilot study. In vitro and in vivo models of AD had a reduced MFI. MFI was lower in human AD subjects and APOE 𝜀4 carriers. Receiver operating characteristic analysis showed MFI had a higher area under the curve than other plasma biomarkers. The MFI biomarker correlated with the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating (CDR) scale. This study highlights the potential utility of MFI as a functional blood-based mitochondrial biomarker to interrogate energy metabolism. Ongoing studies are examining the relationship of MFI with brain energy metabolism outcomes. The MFI biomarker is reduced in cell and animal models of AD. The MFI biomarker is reduced in human AD subjects and APOE ε4 carriers. The MFI biomarker can discriminate between subjects with normal cognition and AD with better performance than other plasma biomarkers. The MFI biomarker correlates with cognitive scores. Show less

The leiomodin (Lmod) family of actin-binding proteins play a critical role in muscle function, highlighted by the fact that mutations in all three family members (LMOD1-3) result in human myopathies. Mutations in the cardiac predominant isoform, LMOD2 lead to severe neonatal dilated cardiomyopathy. Most of the disease-causing mutations in the LMOD gene family are nonsense, or frameshift, mutations predicted to result in expression of truncated proteins. However, in nearly all cases of disease, little to no LMOD protein is expressed. We show here that nonsense-mediated mRNA decay, a cellular mechanism which eliminates mRNAs with premature termination codons, underlies loss of mutant protein from two independent LMOD2 disease-causing mutations. Furthermore, we generated steric-blocking oligonucleotides that obstruct deposition of the exon junction complex, preventing nonsense-mediated mRNA decay of mutant LMOD2 transcripts, thereby restoring mutant protein expression. Our investigation lays the initial groundwork for potential therapeutic intervention in LMOD-linked myopathies. Show less

Neonatal heart failure is a rare, poorly-understood presentation of familial dilated cardiomyopathy (DCM). Exome sequencing in a neonate with severe DCM revealed a homozygous nonsense variant in leiomodin 2 ( Show less