Elevated CSF neurofilament proteins predict brain atrophy: A 15-year follow-up study

BACKGROUND: Body fluid and structural imaging biomarkers give information on neurodegeneration. The relationship over time is not known in multiple sclerosis. OBJECTIVE: To investigate the temporal relationship of elevated cerebrospinal fluid (CSF) neurofilament (Nf) protein levels, a biomarker for axonal loss, with magnetic resonance imaging (MRI) atrophy measures. METHODS: In patients with multiple sclerosis, CSF Nf heavy chain (NfH) phosphoform levels were quantified at baseline and dichotomised into ‘normal’ and ‘high’. Atrophy was assessed by MRI at baseline and 15-year follow-up using SIENAX and FreeSurfer software. RESULTS: High baseline CSF NfHSMI35 levels predicted pronounced atrophy at 15-year follow-up (odds ratio (OR): 36, p 80% is reached with 14–50 patients. CONCLUSION: These data suggest that high CSF NfH levels are an early predictor of later brain and spinal cord atrophy using structural imaging biomarkers and can be investigated in reasonably sized patient cohorts

Towards a standard MRI protocol for multiple sclerosis across the UK.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and degenerative disease of the central nervous system. It is the most common non-traumatic cause of chronic disability in young adults. An early and accurate diagnosis, and effective disease modifying treatment (DMT) are key elements of optimum care for people with MS (pwMS). Magnetic resonance imaging (MRI) has become a critical tool to confirm the presence of dissemination in space and time of lesions characteristic of inflammatory demyelination, a cornerstone of MS diagnosis, over and above exclusion of numerous differential diagnoses. In the modern era of early and highly effective DMT, follow-up of pwMS also relies heavily on MRI, to both confirm efficacy and for pharmacovigilance. Since criteria for MS rely heavily on MRI, an agreed standardized acquisition and reporting protocol enabling efficient and equitable application across the UK is desirable. Following a recent meeting of MS experts in London (UK), we make recommendations for a standardized UK MRI protocol that captures the diagnostic phase as well as monitoring for safety and treatment efficacy once the diagnosis is established. Our views take into account issues arising from the (repeated) use of contrast agents as well as the advent of (semi-) automated tools to further optimise disease monitoring in pwMS.Edmond J Safra FoundationLily SafraMRCUK Dementia Research InstituteImperial College Healthcare Trust Biomedical Research Centr

Asymptomatic spinal cord lesions do not predict the time to disability in patients with early multiple sclerosis

BACKGROUND: The presence of asymptomatic spinal cord (SC) lesions in patients with clinically isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (RRMS) predicts conversion to clinically definite multiple sclerosis (CDMS). The relation between asymptomatic SC abnormalities and disability progression warrants further investigation. OBJECTIVE: To determine the prognostic value of asymptomatic SC lesions in CIS and early RRMS with respect to the time to disability development. METHODS: Clinical and demographic data, brain and SC magnetic resonance imaging (MRI) were collected of CIS or early RRMS patients. Two main analyses were performed. For the first analysis, patients were divided into two groups: (1) patients with asymptomatic SC lesions and (2) patients without SC lesions and patients with symptomatic SC lesions. The second analysis excluded patients with symptomatic SC lesions. Incidence curves were used to analyse differences between these groups in time to the development of disability and time to a second relapse. RESULTS: A total of 178 patients were included, and 42 patients (23.6%) had asymptomatic SC lesions. No significant differences were found on the time to disability development or the time to a second event. CONCLUSION: Asymptomatic SC lesions early in the disease course do not predict the time to disability development in patients diagnosed with CIS or early RRMS

Clinico-radiological dissociation of disease activity in MS patients: frequency and clinical relevance

Objective: To investigate the prevalence and clinical relevance regarding disability progression in multiple sclerosis patients with a dissociation in clinical and radiological disease expression. / Methods: We prospectively selected patients with early relapsing–remitting multiple sclerosis (MS) or a clinically isolated syndrome (CIS) from the Amsterdam MS cohort. Patients underwent clinical examination at baseline, after 2 years, 6 years and a subset also after 11 years, including the Expanded Disability Status Scale (EDSS), 25-foot walk test (25-FWT) and 9-hole peg test (9-HPT). Brain and spinal cord MRI scans were obtained at baseline and after 2 years. Two years after baseline, patients with dissociation in their clinical and radiological disease progression were identified as: (1) patients with high clinical disease activity (defined by relapses) and low radiological disease activity (defined by white-matter lesions on T2-weighted imaging); or (2) patients with low clinical disease activity and high radiological disease activity. Binary logistic regression analyses were performed to predict disability progression after 6 and 11 years of follow-up. Patients with low clinical and low radiological disease activity were used as the reference group. / Results: The prevalence of clinico-radiological dissociation was low (6.4% had high clinical and low radiological disease activity and 5.1% had a combination of low clinical and high radiological disease activity) compared to 88.5% of patients without a dissociation. Patients with a dissociation of clinical and radiological disease activity did not show a statistically significant difference in risk of disability progression after 6 and 11 years. / Conclusions: A clinico-radiological dissociation is rather a rare phenomenon in MS patients. The clinical relevance of such a dissociation regarding the prediction of disability progression is questionable

The presence of cerebral white matter lesions and lower skin microvascular perfusion predicts lower cognitive performance in type 1 diabetes patients with retinopathy but not in healthy controls-A longitudinal study

OBJECTIVE: Cognitive impairments in type 1 diabetes may result from hyperglycemia-associated cerebral microangiopathy. We aimed to identify cerebral microangiopathy and skin microvascular dysfunction-as a surrogate marker for generalized microvascular function-as predictors of cognitive performance over time. METHODS: In this prospective cohort study, 25 type 1 diabetes patients with proliferative retinopathy and 25 matched healthy controls underwent neurocognitive testing at baseline and after follow-up (3.8 ± 0.8 years). At baseline, 1.5-T cerebral magnetic resonance imaging was used to detect WML and cerebral microbleeds. Skin capillary perfusion was assessed by means of capillary microscopy. RESULTS: In type 1 diabetes patients, but not in healthy controls, the presence of WML (ß = -0.419; P = 0.037) as well as lower skin capillary perfusion (baseline: ß = 0.753; P < 0.001; peak hyperemia: ß = 0.743; P = 0.001; venous occlusion: ß = 0.675; P = 0.003; capillary recruitment: ß = 0.549; P = 0.022) at baseline was associated with lower cognitive performance over time, independent of age, sex, HbA1c, and severe hypoglycemia. The relationship between WML and lower cognitive performance was significantly reduced after adjusting for capillary perfusion. CONCLUSIONS: These data fit the hypothesis that cerebral microangiopathy is a manifestation of generalized microvascular dysfunction, leading to lower cognitive performance

The value of subtraction MRI in detection of amyloid-related imaging abnormalities with oedema or effusion in Alzheimer's patients: An interobserver study

BACKGROUND: Immunotherapeutic treatments targeting amyloid-β plaques in Alzheimer's disease (AD) are associated with the presence of amyloid-related imaging abnormalities with oedema or effusion (ARIA-E), whose detection and classification is crucial to evaluate subjects enrolled in clinical trials. PURPOSE: To investigate the applicability of subtraction MRI in the ARIA-E detection using an established ARIA-E-rating scale. METHODS: We included 75 AD patients receiving bapineuzumab treatment, including 29 ARIA-E cases. Five neuroradiologists rated their brain MRI-scans with and without subtraction images. The accuracy of evaluating the presence of ARIA-E, intraclass correlation coefficient (ICC) and specific agreement was calculated. RESULTS: Subtraction resulted in higher sensitivity (0.966) and lower specificity (0.970) than native images (0.959, 0.991, respectively). Individual rater detection was excellent. ICC scores ranged from excellent to good, except for gyral swelling (moderate). Excellent negative and good positive specific agreement among all ARIA-E imaging features was reported in both groups. Combining sulcal hyperintensity and gyral swelling significantly increased positive agreement for subtraction images. CONCLUSION: Subtraction MRI has potential as a visual aid increasing the sensitivity of ARIA-E assessment. However, in order to improve its usefulness isotropic acquisition and enhanced training are required. The ARIA-E rating scale may benefit from combining sulcal hyperintensity and swelling. KEY POINTS: • Subtraction technique can improve detection amyloid-related imaging-abnormalities with edema/effusion in Alzheimer's patients. • The value of ARIA-E detection, classification and monitoring using subtraction was assessed. • Validation of an established ARIA-E rating scale, recommendations for improvement are reported. • Complementary statistical methods were employed to measure accuracy, inter-rater-reliability and specific agreement

Diagnostic Accuracy of the Frontotemporal Dementia Consensus Criteria in the Late-Onset Frontal Lobe Syndrome

BACKGROUND/AIMS: We aimed to prospectively assess the diagnostic accuracy of the revised criteria for behavioural variant frontotemporal dementia (bvFTD) among subjects presenting with a frontal lobe syndrome in middle-late adulthood. METHODS: Patients were included based on a predominant behavioural clinical presentation, a Frontal Behavioural Inventory (FBI) score of ≥11 and/or a Stereotypy Rating Inventory (SRI) score of ≥10. At baseline, the fulfilment of the international consensus criteria for behavioural variant FTD (FTDC) was systematically recorded. The 2-year follow-up consensus diagnosis was used as the gold standard to calculate sensitivity and specificity of the FTDC criteria for possible and probable bvFTD. RESULTS: Two-year follow-up data were available for 116 patients (85%). Two-year follow-up consensus diagnoses consisted of probable/definite bvFTD (n = 27), other dementia (n = 30), psychiatric disorders (n = 46) and other neurological disorders (n = 13). Sensitivity for possible bvFTD was 85% (95% CI 70-95%) at a specificity of 27% (95% CI 19-37%). Sensitivity for probable bvFTD was 85% (95% CI 69-95%), whereas their specificity was 82% (95% CI 73-89%). CONCLUSIONS: We found a good diagnostic accuracy for FTDC probable bvFTD. However, the specificity for FTDC possible bvFTD was low. Our results reflect the symptomatic overlap between bvFTD, other neurological conditions and psychiatric disorders, and the relevance of adding neuroimaging to the diagnostic process

Inflammatory natalizumab-associated PML: baseline characteristics, lesion evolution and relation with PML-IRIS

BACKGROUND AND OBJECTIVE: Natalizumab-associated progressive multifocal leukoencephalopathy (NTZ-PML) patients may show imaging signs suggestive of inflammation at diagnosis ('inflammatory PML'), reminiscent of PML-immune reconstitution inflammatory syndrome (PML-IRIS). We investigated the imaging characteristics of inflammatory NTZ-PML lesions and PML-IRIS to determine differentiating and overlapping features. METHODS: We scored the presence, localisation and pattern of imaging characteristics of inflammation on brain MRI scans of inflammatory NTZ-PML patients. The imaging characteristics were followed up until the occurrence of PML-IRIS. RESULTS: Ten out of the 44 NTZ-PML patients included showed signs suggestive of inflammation at the time of diagnosis. The inflammation pattern at diagnosis was similar to the pattern seen at PML-IRIS, with contrast enhancement representing the most frequent sign of inflammation (90% at diagnosis, 100% at PML-IRIS). However, the severity of inflammation differed, with absence of swelling and low frequency of perilesional oedema (10%) at diagnosis, as compared with the PML-IRIS stage (40%). CONCLUSION: Patterns of inflammation at the time of PML diagnosis and at the PML-IRIS stage overlap but differ in their severity of inflammation. This supports histopathological evidence that the inflammation seen at both stages of the same disease shares a similar underlying pathophysiology, representing the immune response to the JC virus to a variable extend