カナバン病

PURPOSE: Canavan disease (CD) is a leukodystrophy marked by deficiency in the aspartoacylase enzyme and accumulation of N-acetyl aspartate (NAA) in the white matter. MRI and MRS are crucial diagnostic tools for CD. MRS shows a distinctive, significant elevation of the NAA peak, which is typically not quantified and thus not objectively assessed as a diagnostic criterion. This study aimed to establish quantitative cutoff values for the elevated NAA peak on proton MR spectroscopy (1H-MRS) in patients with CD and hence, incorporate MRS into the diagnostic algorithm. METHODS: A cross-sectional retrospective diagnostic study involving 18 confirmed CD cases and 10 healthy individuals was conducted to assess metabolic profiles and determine a diagnostic cutoff for NAA in CD. 1H MRS (TE: 135 ms) was utilized, and data were post-processed using specialized software to quantify the ratios of the three primary metabolites: NAA, Cho, and Cr. RESULTS: The analysis of the CD cases demonstrated substantial elevation in NAA levels compared to the standard control group with the NAA/Cr and NAA/Cho ratios significantly increased in CD patients compared to controls (p < 0.001 for both). Diagnostic cut-off values of 2.75 for NAA/Cr and 7.18 for NAA/Cho yielded an optimism-corrected AUC = 0.96 (95% CI 0.95-1.00) after bootstrap validation. CONCLUSION: This study represents one of the larger single-center cohorts evaluating quantitative MRS metabolite ratios in Canavan disease and proposes preliminary diagnostic thresholds for improved diagnostic objectivity.

Inflammatory arthritis is characterized by neovascularization, leukocyte extravasation and synovial hyperplasia, leading to joint destruction and functional disability. Although increased synovial angiogenesis is a hallmark of synovial inflammation, efficiency of the oxygen supply to the synovium is poor, leading to a hypoxic gradient that impacts differential cellular responses. This hypoxic gradient occurs as infiltrating cells and cells that reside within the joint increase their metabolic demand beyond what the highly dysregulated vasculature can supply. This hypoxic environment favours an increase in reactive oxygen species, leading to oxidative damage that further promotes inflammation. In this adverse microenvironment, synovial cells adapt to generate energy and switch their cellular metabolism from a resting regulatory state to a highly metabolically active state, enabling them to produce essential building blocks to support their proliferation. This metabolic shift results in the accumulation of metabolic intermediates that function as signalling molecules, which further dictate the inflammatory response. However, the synovium is a complex multicellular tissue, and the specific cellular reliance on oxygen and metabolites differs across the synovium. Cellular demands depend on anatomical location, cell-cell interactions and competition for nutrients. Understanding the complex interplay between hypoxia-induced signalling pathways, oxidative stress and inflammatory responses will provide a better insight into the underlying mechanisms of disease pathogenesis.

BACKGROUND: Leukodystrophies are inherited disorders that primarily affect the central nervous system white matter and often present with nonspecific symptoms, making early diagnosis difficult. Magnetic resonance imaging (MRI) is the key initial imaging test because it reveals characteristic myelin patterns that can guide biochemical and genetic workups. OBJECTIVE: To review clinically useful MRI and MR spectroscopy (MRS) patterns in major leukodystrophies and emphasize their diagnostic relevance using a practical, pattern-recognition approach. METHODS: Narrative review of the literature integrating conventional MRI, including T1/T2 fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI), as well as advanced techniques (MRS), with a pictorial, case-based approach. RESULTS: The pivotal imaging distinction is between hypomyelination-diffuse, persistent T2/FLAIR hyperintensity with relative temporal stability and absent enhancement-and demyelination, characterized by confluent, progressive lesions with disorder-specific topographic predilection. Recognizable signatures include U-fiber sparing and a tigroid pattern in metachromatic leukodystrophy (MLD); parieto-occipital predominance with trizonal enhancement and restricted diffusion in X-linked adrenoleukodystrophy (X-ALD); frontal predominance and the "tadpole sign" in Alexander's disease; optic pathway and thalamic involvement in Krabbe's disease; markedly elevated N-acetylaspartate (NAA) on MRS in Canavan's disease; and tract-selective leukoencephalopathy brainstem/spinal cord involvement with a lactate peak (LBSL). These imaging clues refine differential diagnosis, guide targeted genetic testing, and support longitudinal monitoring. CONCLUSION: The use of MRI-especially when complemented by DWI and MRS-remains central for early recognition and classification of leukodystrophies. A structured, pattern-based approach integrating clinical context with imaging topography can reduce diagnostic delay and support timely management.

BACKGROUND: Orthostatic hypotension (OH) is a common cause of falls, and key source of morbidity and mortality due to injury (e.g. hip fracture). Current guidelines recommend increasing salt intake in patients with symptomatic orthostatic hypotension. However, the evidence underpinning this recommendation is poor, based primarily on small trials with very short-term follow-up (<8 weeks). High salt intake might improve quality of life and reduce the risk of falls, but might also increase the long-term risk of cardiovascular disease, in patients with OH. METHODS: STOOD is a two-group, parallel, open-label, randomised controlled, single centre trial. Adults aged ≥65 years with symptomatic orthostatic hypotension, and estimated moderate salt intake (based on screening questions) will be eligible. Exclusion criteria include uncontrolled hypertension (>180/110 mmHg), heart failure (NYHA class III/IV, or ejection fraction < 30%), loop diuretic use, chronic kidney disease (eGFR < 30 ml/min/1.73m2), hyponatraemia (serum sodium < 125 mmol), evidence based clinician recommendation of high or low salt diet, and inability to provide informed consent. Participants will be randomised to receive salt supplementation of 5 g encapsulated sodium chloride per day (in addition to usual care) or usual care alone. The primary feasibility outcome will be recruitment and retention of the target sample size of 48 participants. The primary efficacy outcome is change in orthostatic hypotension questionnaire score from baseline to 6-month follow-up. DISCUSSION: A recommendation for long-term higher salt intake may have adverse cardiovascular consequences, which necessitates robust evidence of efficacy and identification of the optimal range of salt intake associated with the greatest reduction in falls risk and lowest cardiovascular risk. Our study will establish the feasibility and acceptability of evaluating the intervention (salt supplementation) in a single centre, and provide preliminary evidence of treatment effect of salt supplementation for management of orthostatic hypotension. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06188663. Registered on 17th December 2023.