Neurofilament light chain is a cerebrospinal fluid biomarker in hereditary spastic paraplegia.

OBJECTIVE: Despite the need for diagnostics and research, data on fluid biomarkers in hereditary spastic paraplegia (HSP) are scarce. We, therefore, explore Neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) of patients with hereditary spastic paraplegia and provide information on the influence of demographic factors. METHODS: The study recruited 59 HSP cases (33 genetically confirmed) and 59 controls matched in age and sex. Neurofilament light chain levels were assessed by enzyme-linked immunosorbent assay. The statistical analysis included the effects of age, sex, and genetic status (confirmed vs. not confirmed). RESULTS: Levels of CSF NfL were significantly increased in patients with hereditary spastic paraplegia compared to controls (median 741 pg/mL vs. 387 pg/mL, p < 0.001). Age (1.4% annual increase) and male sex (81% increase) impacted CSF NfL levels in patients. The age-dependent increase of CSF NfL levels was steeper in controls (2.6% annual increase). Thus, the CSF NfL ratio of patients and matched controls-expressing patients' fold increases in CSF NfL-declined considerably with age. INTERPRETATION: CSF NfL is a reliable cross-sectional biomarker in hereditary spastic paraplegia. Sex is a relevant factor to consider, as male patients have remarkably higher CSF NfL levels. While levels also increase with age, the gap between patients and controls is narrowing in older subjects. This indicates distinct temporal dynamics of CSF NfL in patients with hereditary spastic paraplegia, with a rise around phenotypic conversion and comparatively static levels afterward.

Identification of 7α,24-dihydroxy-3-oxocholest-4-en-26-oic and 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acids in human cerebrospinal fluid and plasma.

Dihydroxyoxocholestenoic acids are intermediates in bile acid biosynthesis. Here, using liquid chromatography - mass spectrometry, we confirm the identification of 7α,24-dihydroxy-3-oxocholest-4-en-26-oic and 7α,25-dihydroxy-3-oxocholest-4-en-26-oic acids in cerebrospinal fluid (CSF) based on comparisons to authentic standards and of 7α,12α-dihydroxy-3-oxocholest-4-en-26-oic and 7α,x-dihydroxy-3-oxocholest-4-en-26-oic (where hydroxylation is likely on C-22 or C-23) based on exact mass measurement and multistage fragmentation. Surprisingly, patients suffering from the inborn error of metabolism cerebrotendinous xanthomatosis, where the enzyme CYP27A1, which normally introduces the (25 R)26-carboxylic acid group to the sterol side-chain, is defective still synthesise 7α,24-dihydroxy-3-oxocholest-4-en-26-oic acid and also both 25 R- and 25 S-epimers of 7α,12α-dihydroxy-3-oxocholest-4-en-26-oic acid. We speculate that the enzymes CYP46A1 and CYP3A4 may have C-26 carboxylase activity to generate these acids. In patients suffering from hereditary spastic paraplegia type 5 the CSF concentrations of the 7α,24- and 7α,25-dihydroxy acids are reduced, suggesting an involvement of CYP7B1 in their biosynthesis in brain.

Novel SPG11 Mutations in a Patient with Symptoms Mimicking Multiple Sclerosis.

We describe the cases of two sisters with spastic paraplegia 11 (SPG11). The younger sister developed relapsing lesions in the brain white matter with enhancement during the acute phase that mimicked multiple sclerosis (MS). The elevation of myelin basic protein in the cerebrospinal fluid (CSF) suggested demyelination, but a normal IgG index, the absence of oligoclonal bands, and the ineffectiveness of steroid treatment indicate that an autoimmune mechanism may not have been involved. In these affected sisters, we identified novel compound heterozygous mutations in the SPG11 gene. Our cases indicate the possible existence of a broader phenotypic spectrum of SPG11 mutations.

Neurotransmitter abnormalities and response to supplementation in SPG11.

OBJECTIVE: To report the detection of secondary neurotransmitter abnormalities in a group of SPG11 patients and describe treatment with l-dopa/carbidopa and sapropterin. DESIGN: Case reports. SETTING: National Institutes of Health in the Undiagnosed Disease Program; Children's National Medical Center in the Myelin Disorders Bioregistry Program. PATIENTS: Four SPG11 patients with a clinical picture of progressive spastic paraparesis complicated by extrapyramidal symptoms and maculopathy. INTERVENTIONS: L-Dopa/carbidopa and sapropterin. RESULTS: 3/4 patients presented secondary neurotransmitter abnormalities; 4/4 partially responded to L-dopa as well as sapropterin. CONCLUSIONS: In the SPG11 patient with extrapyramidal symptoms, a trial of L-dopa/carbidopa and sapropterin and/or evaluation of cerebrospinal fluid neurotransmitters should be considered.

Side chain-oxidized oxysterols regulate the brain renin-angiotensin system through a liver X receptor-dependent mechanism.

Disturbances in cholesterol metabolism have been associated with hypertension and neurodegenerative disorders. Because cholesterol metabolism in the brain is efficiently separated from plasma cholesterol by the blood-brain barrier (BBB), it is an unsolved paradox how high blood cholesterol can cause an effect in the brain. Here, we discuss the possibility that cholesterol metabolites permeable to the BBB might account for these effects. We show that 27-hydroxycholesterol (27-OH) and 24S-hydroxycholesterol (24S-OH) up-regulate the renin-angiotensin system (RAS) in the brain. Brains of mice on a cholesterol-enriched diet showed up-regulated angiotensin converting enzyme (ACE), angiotensinogen (AGT), and increased JAK/STAT activity. These effects were confirmed in in vitro studies with primary neurons and astrocytes exposed to 27-OH or 24S-OH, and were partially mediated by liver X receptors. In contrast, brain RAS activity was decreased in Cyp27a1-deficient mice, a model exhibiting reduced 27-OH production from cholesterol. Moreover, in humans, normocholesterolemic patients with elevated 27-OH levels, due to a CYP7B1 mutation, had markers of activated RAS in their cerebrospinal fluid. Our results demonstrate that side chain-oxidized oxysterols are modulators of brain RAS. Considering that levels of cholesterol and 27-OH correlate in the circulation and 27-OH can pass the BBB into the brain, we suggest that this cholesterol metabolite could be a link between high plasma cholesterol levels, hypertension, and neurodegeneration.

Hypercapnia is a possible determinant of the function of the blood-cerebrospinal fluid barrier in amyotrophic lateral sclerosis.

Elevated cerebrospinal fluid (CSF)/serum quotients of albumin (Q(Alb)) may occur in motor neuron diseases (MND) including amyotrophic lateral sclerosis (ALS), but the pathophysiologic mechanisms underlying these alterations are unclear. Evidence from animal experiments suggests that the arterial carbon dioxide level might affect the Q(Alb), i.e. the function of the blood-CSF barrier (BCB). We therefore compared basic CSF parameters in different forms of MND (ALS, n = 105; lower motor neuron diseases, n = 12; and upper motor neuron diseases, n = 7) and investigated the relationship between elevated Q(Alb) and the arterial partial pressure of carbon dioxide (pCO(2)) in ALS where respiratory insufficiency leads to hypercapnia in the course of the disease. Pathologic elevations of Q(Alb) occurred in 32 of 124 MND patients. In ALS, Q(Alb) significantly correlated with the arterial pCO(2) (r = 0.454; P = 0.001; n = 45). These data indicate that BCB dysfunction is a frequent finding in different forms of MND and may reflect distinct pathophysiological mechanisms. In ALS, an important underlying mechanism might be the influence of the arterial pCO(2) which may alter the CSF flow.

Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis.

Patients with a recessively inherited "pure" hereditary spastic paresis (SPG5) have mutations in the gene coding for the oxysterol 7 alpha hydroxylase (CYP7B1). One of the expected metabolic consequences of such mutations is accumulation of oxysterol substrates due to decreased enzyme activity. In accordance with this, we demonstrate here that four patients with the SPG5 disease have 6- to 9-fold increased plasma levels of 27-hydroxycholesterol. A much higher increase, 30- to 50-fold, was found in cerebrospinal fluid. The plasma levels of 25-hydroxycholesterol were increased about 100-fold. There were no measurable levels of this oxysterol in cerebrospinal fluid. The pattern of bile acids in serum was normal, suggesting a normal bile acid synthesis. The findings are discussed in relation to two transgenic mouse models with increased levels of 27-hydroxy cholesterol in the circulation but without neurological symptoms: the cyp27a1 transgenic mouse and the cyp7b1 knockout mouse. The absolute plasma levels of 27-hydroxycholesterol in the latter models are, however, only about 20% of those in the SPG5 patients. If the accumulation of 27-hydroxycholesterol is an important pathogenetic factor, a reduction of its levels may reduce or prevent the neurological symptoms. A possible strategy to achieve this is discussed.