Markers of Vitamin B12 Status in Relation to Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Cognitive Performance.

BACKGROUND: The association between markers of vitamin B12 status and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD), which precede cognitive impairment, has been investigated by only a few small studies and results have been inconsistent. AIM: The aim of this study was to investigate the associations of vitamin B12-related markers with CSF biomarkers of AD and cognitive performance. METHODS: Data included 462 patients aged 40 to 94 years referred to the Memory Clinic of the Ulm University Hospital, Ulm, Germany. Vitamin B12, holotranscobalamin (HoloTC), homocysteine (tHcy), and methylmalonic acid (MMA) have been measured. CSF values of amyloid ß42 (Aß42 ) and total-tau have been assessed in 227 participants. CERAD battery was administered to examine the cognitive status, and different domains were derived. Regression models were used to investigate the associations. RESULTS: In the multi-adjusted model, higher levels of MMA were associated with raised CSF total-tau values: the odds ratios (ORs) 95% confidence intervals (CIs) were 3.25 (95% CI = 1.35-7.76) for the highest quartile of MMA compared to the lowest. Furthermore, moderately increased MMA were related to lower Aß42 levels: the ORs and 95% CIs were 3.06 (95% CI = 1.22-7.67) for the third quartile of MMA compared to the lowest. All B12 indicators except B12 itself were related to several cognitive domains, such as episodic memory and executive functioning. CONCLUSIONS: Markers of vitamin B12 may be independent predictors of CSF biomarkers of AD and cognitive functioning, with MMA showing the most consistent effects. Randomized controlled trials are needed to determine the importance of vitamin B12 supplementation on slowing structural brain changes and cognitive decline. ANN NEUROL 2023;94:223-231.

Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity.

Pathogenic variants in SOD1, encoding superoxide dismutase 1, are responsible for about 20% of all familial amyotrophic lateral sclerosis cases, through a gain-of-function mechanism. Recently, two reports showed that a specific homozygous SOD1 loss-of-function variant is associated with an infantile progressive motor-neurological syndrome. Exome sequencing followed by molecular studies, including cDNA analysis, SOD1 protein levels and enzymatic activity, and plasma neurofilament light chain levels, were undertaken in an infant with severe global developmental delay, axial hypotonia and limb spasticity. We identified a homozygous 3-bp in-frame deletion in SOD1. cDNA analysis predicted the loss of a single valine residue from a tandem pair (p.Val119/Val120) in the wild-type protein, yet expression levels and splicing were preserved. Analysis of SOD1 activity and protein levels in erythrocyte lysates showed essentially no enzymatic activity and undetectable SOD1 protein in the child, whereas the parents had ∼50% protein expression and activity relative to controls. Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration. Thus, we provide confirmatory evidence of a second biallelic variant in an infant with a severe neurological syndrome and suggest that the in-frame deletion causes instability and subsequent degeneration of SOD1. We highlight the importance of the valine residues at positions V119-120, and suggest possible implications for future therapeutics research.

Abnormal pain perception is associated with thalamo-cortico-striatal atrophy in C9orf72 expansion carriers in the GENFI cohort.

OBJECTIVE: Frontotemporal dementia (FTD) is typically associated with changes in behaviour, language and movement. However, recent studies have shown that patients can also develop an abnormal response to pain, either heightened or diminished. We aimed to investigate this symptom in mutation carriers within the Genetic FTD Initiative (GENFI). METHODS: Abnormal responsiveness to pain was measured in 462 GENFI participants: 281 mutation carriers and 181 mutation-negative controls. Changes in responsiveness to pain were scored as absent (0), questionable or very mild (0.5), mild (1), moderate (2) or severe (3). Mutation carriers were classified into C9orf72 (104), GRN (128) and MAPT (49) groups, and into presymptomatic and symptomatic stages. An ordinal logistic regression model was used to compare groups, adjusting for age and sex. Voxel-based morphometry was performed to identify neuroanatomical correlates of abnormal pain perception. RESULTS: Altered responsiveness to pain was present to a significantly greater extent in symptomatic C9orf72 expansion carriers than in controls: mean score 0.40 (SD 0.71) vs 0.00 (0.04), reported in 29% vs 1%. No significant differences were seen between the other symptomatic groups and controls, or any of the presymptomatic mutation carriers and controls. Neural correlates of altered pain perception in C9orf72 expansion carriers were the bilateral thalamus and striatum as well as a predominantly right-sided network of regions involving the orbitofrontal cortex, inferomedial temporal lobe and cerebellum. CONCLUSION: Changes in pain perception are a feature of C9orf72 expansion carriers, likely representing a disruption in somatosensory, homeostatic and semantic processing, underpinned by atrophy in a thalamo-cortico-striatal network.

Lipid Mediator Profiles Predict Response to Therapy with an Oral Frankincense Extract in Relapsing-Remitting Multiple Sclerosis.

Lipid mediators (LMs) are a unique class of immunoregulatory signalling molecules and known to be affected by frankincense extracts. We performed LM profiling by metabololipidomics in plasma samples from 28 relapsing-remitting multiple sclerosis (RR-MS) patients who took a standardised frankincense extract (SFE) daily for eight months in a clinical phase IIa trial (NCT01450124) and in 28 age- and gender-matched healthy controls. Magnetic resonance imaging, immunological outcomes and serum neurofilament light chain levels were correlated to changes in the LM profiles of the RR-MS cohort. Eight out of 44 analysed LMs were significantly reduced during an eight-month treatment period by the SFE and seven of these eight significant LM derive from the 5-lipoxygenase (5-LO) pathway. Baseline levels of 12- and 15-LO products were elevated in patients who exhibited disease activity (EDA) during SFE treatment compared to no-evidence-of-disease-activity (NEDA) patients and could predict treatment response to the SFE in a prediction model at baseline. Oral treatment with an SFE significantly reduces 5-LO-derived LMs in RR-MS patients during an eight-month treatment period. Treatment response to an SFE, however, seems to be related to 12-,15-LO and cyclooxygenase product levels before SFE exposure. Further studies should confirm their biomarker potential in RR-MS and SFE treatment.

FDG-PET underscores the key role of the thalamus in frontotemporal lobar degeneration caused by C9ORF72 mutations.

C9ORF72 mutations are the most common cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). MRI studies have investigated structural changes in C9ORF72-associated FTLD (C9FTLD) and provided first insights about a prominent involvement of the thalamus and the cerebellum. Our multicenter, 18F-fluorodeoxyglucose positron-emission tomography study of 22 mutation carriers with FTLD, 22 matched non-carriers with FTLD, and 23 cognitively healthy controls provided valuable insights into functional changes in C9FTLD: compared to non-carriers, mutation carriers showed a significant reduction of glucose metabolism in both thalami, underscoring the key role of the thalamus in C9FTLD. Thalamic metabolism did not correlate with disease severity, duration of disease, or the presence of psychotic symptoms. Against our expectations we could not demonstrate a cerebellar hypometabolism in carriers or non-carriers. Future imaging and neuropathological studies in large patient cohorts are required to further elucidate the central role of the thalamus in C9FTLD.

Relationship between cerebrospinal fluid concentrations of orexin A/hypocretin-1 and body composition in humans.

The hypothalamic neuropeptide orexin A (hypocretin-1) is a key signal in sleep/wake regulation and promotes food intake. We investigated the relationship between cerebrospinal fluid orexin A concentrations and body composition in non-narcoleptic human subjects with a wide range of body weight to gain insight into the role of orexin A in human metabolism. We collected cerebrospinal fluid and blood samples and measured body composition by bioelectric impedance analysis in 36 subjects (16 women and 20 men) with body mass indices between 16.24 and 38.10 kg/m2 and an age range of 19-80 years. Bivariate Pearson correlations and stepwise multiple regressions were calculated to determine associations between orexin A and body composition as well as biometric variables. Concentrations of orexin A in cerebrospinal fluid averaged 315.6 ±â€¯6.0 pg/ml, were comparable between sexes (p > 0.15) and unrelated to age (p > 0.66); they appeared slightly reduced in overweight/obese compared to normal-weight subjects (p = .07). Orexin A concentrations decreased with body weight (r = -0.38, p = .0229) and fat-free mass (r = -0.39, p = .0173) but were not linked to body fat mass (p > 0.24). They were inversely related to total body water (r = -0.39, p = .0174) as well as intracellular (r = -0.41, p = .0139) and extracellular water (r = -0.35, p = .0341). Intracellular water was the only factor independently associated with cerebrospinal fluid orexin A concentrations (p = .0139). We conclude that cerebrospinal fluid orexin A concentrations do not display associations with body adiposity, but are inversely related to intracellular water content. These cross-sectional findings suggest a link between orexin A signaling and the regulation of water homeostasis in humans.