Serum Neurofilament light correlates with CADASIL disease severity and survival

Abstract

ObjectiveTo validate whether serum Neurofilament Light‐chain (NfL) levels correlate with disease severity in CADASIL, and to determine whether serum NfL predicts disease progression and survival.MethodsFourty‐one (pre‐) manifest individuals with CADASIL causing NOTCH3 mutations and 22 healthy controls were recruited from CADASIL families. At baseline, MRI‐lesion load and clinical severity was determined and serum was stored. Disease progression was measured in 30/41 patients at 7‐year follow‐up, and survival of all individuals was determined at 17‐year follow‐up. Serum NfL levels were quantified using an ultra‐sensitive molecule array. Generalized estimated equation regression (GEE) was used to analyze association between serum NfL, MRI‐lesion load, disease severity, and disease progression. With GEE‐based Cox regression, survival was analyzed.ResultsAt baseline, serum NfL levels correlated with MRI‐lesion load [lacune count (s = 0.64, P = 0.002), brain atrophy (r = −0.50, P = 0.001), and microbleed count (s = 0.48, P = 0.044)], cognition [CAMCOG (s = −0.45, P = 0.010), MMSE (r = −0.61, P = 0.003), GIT (r = −0.61, P < 0.001), TMT‐A (r = 0.70, P < 0.001)) and disability (mRS (r = 0.70, P = 0.002)]. Baseline serum NfL predicted 7‐year changes in disability (B = 0.34, P < 0.001) and cognition (CAMCOG B = −4.94, P = 0.032), as well as 17‐year survival. Higher NfL levels were associated with increased mortality (HR=1.8 per twofold increase in NfL levels, P = 0.006).InterpretationSerum NfL levels correlate with disease severity, disease progression and 17‐year survival in CADASIL patients. Serum NfL is a promising biomarker to monitor and predict disease course in CADASIL, as well as potentially assessing therapeutic response in future clinical trials.

Plasma neurofilament light chain and glial fibrillary acidic protein predict stroke in CADASIL

“…(10) Another study revealed that the serum NfL level not only correlated with cognition and functional disabilities at baseline but also predicted their longitudinal progression and overall survival. (11) Our study extended upon the previous findings by demonstrating that NfL can also be a useful marker for predicting stroke event in the future. Although neuroimaging lesion load or cognitive function were crucial prognostic factors in CADASIL, overt stroke event might engender greater threat to both patients and clinicians.…”

“…(22) The initial manifestations or reasons for screening for NOTCH3 mutation in these patients were as follows, stroke in 52 patients, cognitive or gait deterioration in 7, headache or dizziness in 5, asymptomatic family members of known CADASIL patients in 3, and incidentally found marked leurkoaraiosis in 1. The patients' blood collected from different hospitals underwent genetic diagnosed centrally by combining p.R544C hot-spot mutation screening followed by sequencing of the most frequently mutated NOTCH3 exons (3,4,5,6,11,18) weighted imaging signal intensities through computed tomography (CT) or magnetic resonance imaging (MRI), respectively, that corresponded to the clinical presentations. ICH was defined as the sudden onset of focal neurological deficit with non-traumatic intraparenchymal hemorrhage observed on head CT or MRI scans.…”

“…In CADASIL patients, the neurofilament light chain (NfL) blood level has been found to correlate with the clinical and neuroimaging burdens (10) and can predict their long-term disability and survival. (11) Fluid biomarkers are used for predicting the occurrences of IS and ICH in CADASIL patients; however, they have not been well studied. Glial fibrillary acidic protein (GFAP), a brain-specific intermediate filament protein produced by astrocytes in response to brain injury, has been found to be a reliable marker for differentiating ICH and IS in patients with acute stroke.…”

Plasma neurofilament light chain and glial fibrillary acidic protein predict stroke in CADASIL

“…The initial manifestations or reasons for screening for NOTCH3 mutation in these patients were as follows: stroke in 52 patients, cognitive or gait deterioration in 7, headache or dizziness in 5, asymptomatic family members of known CADASIL patients in 3, and incidentally found marked leukoaraiosis in 1. The patients' blood collected from different hospitals underwent genetic diagnosed centrally by combining p.R544C hot-spot mutation screening followed by sequencing of the most frequently mutated NOTCH3 exons (3,4,5,6,11,18) if p.R544C was not detected. Sixty-five patients (96%) had NOTCH3 mutation on exon 11 p.R544C.…”

“…Fluid biomarkers, especially blood-based, have the advantage of easy collection and repeat measurement over the relatively inconvenient neuroimaging tests. In CADASIL patients, the neurofilament light chain (NfL) blood level has been found to correlate with the clinical and neuroimaging burdens [10] and can predict their long-term disability and survival [11]. Fluid biomarkers are used for predicting the occurrences of IS and ICH in CADA-SIL patients; however, they have not been well studied.…”