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

Cognitive fatigue in multiple sclerosis is associated with alterations in the functional connectivity of monoamine circuits

Fatigue is a highly prevalent and debilitating symptom in multiple sclerosis, but currently the available treatment options have limited efficacy. The development of innovative and efficacious targeted treatments for fatigue in multiple sclerosis has been marred by the limited knowledge of the underlying mechanisms. One of the hypotheses postulates that multiple sclerosis pathology might cause reduced monoaminergic release in the central nervous system with consequences on motivation, mood and attention. Here, we applied the recently developed Receptor-Enriched Analysis of Functional Connectivity by Targets method to investigate whether patients with high and low fatigue differ in the functional connectivity (FC) of the monoamine circuits in the brain. We recruited 55 patients with multiple sclerosis, which were then classified as highly fatigued or mildly fatigued based on their scores on the cognitive sub-scale of the Modified Fatigue Impact scale. We acquired resting-state functional MRI scans and derived individual maps of connectivity associated with the distribution of the dopamine, noradrenaline and serotonin transporters as measured by positron emission tomography. We found that patients with high fatigue present decreased noradrenaline transporter (NAT)-enriched connectivity in several frontal and prefrontal areas when compared to those with lower fatigue. The NAT-enriched FC predicted negatively individual cognitive fatigue scores. Our findings support the idea that alterations in the catecholaminergic functional circuits underlie fatigue in multiple sclerosis and identify the NAT as a putative therapeutic target directed to pathophysiology

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

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

The distinct roles of monoamines in multiple sclerosis: a bridge between the immune and nervous systems?

The monoaminergic neurotransmitters dopamine, noradrenaline, and serotonin are pivotal actors of the interplay between the nervous and the immune system due to their ability of binding to cell-receptors of both systems, crucially regulating their function within the central nervous system and the periphery. As monoamines are dysfunctional in many neurological and psychiatric diseases, they have been successfully used as pharmacological targets. Multiple sclerosis (MS) is one of the best examples of neurological disease caused by an altered interaction between the nervous and immune system and emerging evidence supports a dysregulation of monoaminergic systems in the pathogenesis of MS, secondary to both inflammation-induced reduction of monoamines' synthesis and structural damage to monoaminergic pathways within the brain. Here we review the evidence for monoamines being key mediators of neuroimmune interaction, affecting MS pathogenesis and course. Moreover, we discuss how the reduction/dysfunction of monoamines in MS may contribute to some clinical features typical of the disease, particularly fatigue and depression. Finally, we summarize different drugs targeting monoamines that are currently under evaluation for their potential efficacy to treat MS, as well as to alleviate fatigue and depression in MS

The role of amyloid-ß 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-ß (Aß). Neuroimaging studies have found that patients with AD have widespread WM abnormalities already at the earliest disease stages and prior to the presence of Aß plaques. Moreover, a correlation between cerebrospinal fluid (CSF) Aß levels and WM lesion load was found. On the other hand, recent studies suggest a predictive role for CSF Aß 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 Aß 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