The role of amyloid-β in white matter damage: possible common pathogenetic mechanisms in neurodegenerative and demyelinating diseases

Just as multiple sclerosis (MS) has long been primarily considered a white matter (WM) disease, Alzheimer's disease (AD) has for decades been regarded only as a grey matter disorder. However, convergent evidences have suggested that WM abnormalities are also important components of AD, at the same extent as axonal and neuronal loss is critically involved in MS pathophysiology since early clinical stages. These observations have motivated a more thorough investigation about the possible mechanisms that could link neuroinflammation and neurodegeneration, focusing on amyloid-β (Aβ). Neuroimaging studies have found that patients with AD have widespread WM abnormalities already at the earliest disease stages and prior to the presence of Aβ plaques. Moreover, a correlation between cerebrospinal fluid (CSF) Aβ levels and WM lesion load was found. On the other hand, recent studies suggest a predictive role for CSF Aβ levels in MS, possibly due in the first instance to the reduced capacity for remyelination, consequently to a higher risk of WM damage progression, and ultimately to neuronal loss. We undertook a review of the recent findings concerning the involvement of CSF Aβ levels in the MS disease course and of the latest evidence of AD related WM abnormalities, with the aim to discuss the potential causes that may connect WM damage and amyloid pathology

Differentiating Vogt-Koyanagi-Harada syndrome from recurrent optic neuritis: a case report and review of the literature concerning Hispanic patients

Abstract Background First recognized at the beginning of twentieth century and named after three authors who independently described some affected patients, Vogt-Koyanagi-Harada syndrome is a rare multisystemic autoimmune disease targeting melanin-containing tissues of the eye, meninges, inner ear and skin. It predominantly affects Asian people, but also people with darker skin pigmentation such as Native Americans and Hispanics (Mestizos), whose ancestors moved from Asia across the Bering strait to North America and further down to Central and South America. Heterogenous presentation is observed, especially among different ethnic groups. Here we describe the case of an Hispanic South American patient presenting with multiple visual relapses and thus mimicking recurrent optic neuritis; we provide insights into the differential diagnosis and a brief review of the literature concerning the epidemiology of Vogt-Koyanagi-Harada syndrome in Hispanic patients compared with other ethnic groups. Case presentation A 34-year-old Ecuadorian woman presented over years with multiple relapses involving the visual system. She was investigated in both neurologic and ophthalmic clinical settings. Brain Magnetic Resonance Imaging, cerebrospinal fluid examination, Spectral Domain Optical Coherence Tomography and Fluorescein Angiography were performed. She was misdiagnosed first as an optic neuritis pointing to a demyelinating disorder, then as a posterior scleritis. Due to the protean manifestations of Vogt-Koyanagi-Harada syndrome and the incomplete clinical presentation at the beginning, the right diagnosis was made only at a later disease stage using retrospective criteria. Conclusions Hispanic patients often present without extraocular symptoms in early phases of the disease and they have globally lower rates of intertegumentary signs compared to Asian patients. The diagnosis of a multisystemic disease such as Vogt-Koyanagi-Harada syndrome is a challenge involving specialists operating in different medical fields; especially in urban multiethnic populations, rare etiologies of common symptoms have to be taken into account when performing a differential diagnosis

CSF β-amyloid predicts prognosis in patients with multiple sclerosis

Background: The importance of predicting disease progression in multiple sclerosis (MS) has increasingly been recognised, hence reliable biomarkers are needed. Objectives: To investigate the prognostic role of cerebrospinal fluid (CSF) Amyloid beta1-42 (A) levels by the determination of a cut-off value to classify patients in slow and fast progressors. To evaluate possible association with white (WM) and grey matter (GM) damage at early disease stages. Methods: Sixty patients were recruited and followed-up for three to five years. Patients underwent clinical assessment, CSF analysis to determine Aβ levels, and brain MRI (at baseline and after 1 year). T1-weighted volumes were calculated. T2-weighted scans were used to quantify WM lesion loads. Results: Lower CSF Aβ levels were observed in patients with a worse follow-up EDSS (r=−0.65, p0.05). Conclusions: Low CSF Aβ levels may represent a predictive biomarker of disease progression in MS

Amyloid PET imaging and dementias: potential applications in detecting and quantifying early white matter damage

Purpose Positron emission tomography (PET) with amyloid tracers (amy-PET) allows the quantification of pathological amyloid deposition in the brain tissues, including the white matter (WM). Here, we evaluate amy-PET uptake in WM lesions (WML) and in the normal-appearing WM (NAWM) of patients with Alzheimer’s disease (AD) and non-AD type of dementia. Methods Thirty-three cognitively impaired subjects underwent brain magnetic resonance imaging (MRI), Aβ1-42 (Aβ) determination in the cerebrospinal fluid (CSF) and amy-PET. Twenty-three patients exhibiting concordant results in both CSF analysis and amy-PET for cortical amyloid deposition were recruited and divided into two groups, amyloid positive (A+) and negative (A−). WML quantification and brain volumes’ segmentation were performed. Standardized uptake values ratios (SUVR) were calculated in the grey matter (GM), NAWM and WML on amy-PET coregistered to MRI images. Results A+ compared to A− showed a higher WML load (p = 0.049) alongside higher SUVR in all brain tissues (p < 0.01). No correlations between CSF Aβ levels and WML and NAWM SUVR were found in A+, while, in A−, CSF Aβ levels were directly correlated to NAWM SUVR (p = 0.04). CSF Aβ concentration was the only predictor of NAWM SUVR (adj R2 = 0.91; p = 0.04) in A−. In A+ but not in A− direct correlations were identified between WM and GM SUVR (p < 0.01). Conclusions Our data provide evidence on the role of amy-PET in the assessment of microstructural WM injury in non-AD dementia, whereas amy-PET seems less suitable to assess WM damage in AD patients due to a plausible amyloid accrual therein

Distinct patterns of brain atrophy in Genetic Frontotemporal Dementia Initiative (GENFI) cohort revealed by visual rating scales.

BACKGROUND: In patients with frontotemporal dementia, it has been shown that brain atrophy occurs earliest in the anterior cingulate, insula and frontal lobes. We used visual rating scales to investigate whether identifying atrophy in these areas may be helpful in distinguishing symptomatic patients carrying different causal mutations in the microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame (C9ORF72) genes. We also analysed asymptomatic carriers to see whether it was possible to visually identify brain atrophy before the appearance of symptoms. METHODS: Magnetic resonance imaging of 343 subjects (63 symptomatic mutation carriers, 132 presymptomatic mutation carriers and 148 control subjects) from the Genetic Frontotemporal Dementia Initiative study were analysed by two trained raters using a protocol of six visual rating scales that identified atrophy in key regions of the brain (orbitofrontal, anterior cingulate, frontoinsula, anterior and medial temporal lobes and posterior cortical areas). RESULTS: Intra- and interrater agreement were greater than 0.73 for all the scales. Voxel-based morphometric analysis demonstrated a strong correlation between the visual rating scale scores and grey matter atrophy in the same region for each of the scales. Typical patterns of atrophy were identified: symmetric anterior and medial temporal lobe involvement for MAPT, asymmetric frontal and parietal loss for GRN, and a more widespread pattern for C9ORF72. Presymptomatic MAPT carriers showed greater atrophy in the medial temporal region than control subjects, but the visual rating scales could not identify presymptomatic atrophy in GRN or C9ORF72 carriers. CONCLUSIONS: These simple-to-use and reproducible scales may be useful tools in the clinical setting for the discrimination of different mutations of frontotemporal dementia, and they may even help to identify atrophy prior to onset in those with MAPT mutations

CSF β-amyloid and white matter damage: a new perspective on Alzheimer's disease

Objective: To assess the connection between amyloid pathology and white matter (WM) macro- and micro-structural damage in demented patients compared with controls. Methods: Eighty-five participants were recruited: 65 with newly diagnosed Alzheimer’s disease (AD), non-AD dementia or mild cognitive impairment (MCI), and 20 age- and sex-matched heatlhy controls. β-amyloid1-42 (Aβ) levels were determined in cerebrospinal fluid (CSF) samples from all patients and 5 controls. Among patients, 42 had pathological CSF Aβ levels (Aβ+), while 23 had normal CSF Aβ levels (Aβ-). All participants underwent neurological examination, neuropsychological testing and brain magnetic resonance imaging (MRI). We used T2-weighted scans to quantify white matter (WM) lesion loads (LL), and diffusion weighted images (DWI) to assess their microstructural substrate. Non-parametric statistical tests were used for between-group comparisons and multiple regression analyses. Results: We found an increased WM-LL in Aβ(+) compared to both, healthy controls (p=0.003) and Aβ(-) patients (p=0.02). Interestingly, CSF Aβ concentration was the best predictor patients’ WM-LL (r=-0.30, p<0.05) when using age as a covariate. Lesion apparent diffusion coefficient (ADC) value was higher in all patients than in controls (p=0.0001), and correlated with WM-LL (r=0.41, p=0.001). In Aβ(+), WM-LL correlated with WM microstructural damage in the left peritrigonal WM (p<0.0001). Conclusions: WM damage is crucial in Alzheimer’s disease (AD) pathogenesis. The correlation between CSF Aβ levels and WM-LL suggests a direct link between amyloid pathology and WM macro- and microstructural damage

Amyloid PET as a marker of normal-appearing white matter early damage in multiple sclerosis: correlation with CSF β-amyloid levels and brain volumes

PURPOSE The disease course of multiple sclerosis (MS) is unpredictable, and reliable prognostic biomarkers are needed. Positron emission tomography (PET) with β-amyloid tracers is a promising tool for evaluating white matter (WM) damage and repair. Our aim was to investigate amyloid uptake in damaged (DWM) and normal-appearing WM (NAWM) of MS patients, and to evaluate possible correlations between cerebrospinal fluid (CSF) β-amyloid (Aβ) levels, amyloid tracer uptake, and brain volumes. METHODS Twelve MS patients were recruited and divided according to their disease activity into active and non-active groups. All participants underwent neurological examination, neuropsychological testing, lumbar puncture, brain magnetic resonance (MRI) imaging, and F-florbetapir PET. Aβ levels were determined in CSF samples from all patients. MRI and PET images were co-registered, and mean standardized uptake values (SUV) were calculated for each patient in the NAWM and in the DWM. To calculate brain volumes, brain segmentation was performed using statistical parametric mapping software. Nonparametric statistical analyses for between-group comparisons and regression analyses were conducted. RESULTS We found a lower SUV in DWM compared to NAWM (p < 0.001) in all patients. Decreased NAWM-SUV was observed in the active compared to non-active group (p < 0.05). Considering only active patients, NAWM volume correlated with NAWM-SUV (p = 0.01). Interestingly, CSF Aβ concentration was a predictor of both NAWM-SUV (r = 0.79; p = 0.01) and NAWM volume (r = 0.81, p = 0.01). CONCLUSIONS The correlation between CSF Aβ levels and NAWM-SUV suggests that the predictive role of β-amyloid may be linked to early myelin damage and may reflect disease activity and clinical progression

COVID-19 Severity in Multiple Sclerosis: Putting Data Into Context

Background and objectives: It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19-related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population. Methods: Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score &gt; 3 or at least 1 comorbidity, lower risk: EDSS score ≤ 3 and no comorbidities) by the χ2 test, and the risk excess was quantified by risk ratios (RRs). Results: The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization (p &lt; 0.001), RR = 2.19 for ICU admission (p &lt; 0.001), and RR = 2.43 for death (p &lt; 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, p = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, p = 0.04). Discussion: Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR&nbsp;=&nbsp;2.05, 95%CI&nbsp;=&nbsp;1.39–3.02, p&nbsp;&lt;&nbsp;0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR&nbsp;=&nbsp;0.42, 95%CI&nbsp;=&nbsp;0.18–0.99, p&nbsp;=&nbsp;0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon