Clinical diagnosis of Alzheimer’s disease (AD) prior to the age of 65 years is classified as young-onset (YOAD), whereas diagnosis after the age of 65 years is considered late-onset (LOAD). Although rare autosomal mutations more commonly associate with YOAD, most YOAD and LOAD cases are sporadic. YOAD and LOAD share amyloid and tau pathology, but many YOAD patients show increased disease severity and rate of progression. The current study examined the microRNA (miRNA) expression profile from exosomes isolated from the cerebrospinal fluid (CSF) of YOAD patients with biomarker-confirmed AD. Results uncovered miR-16-5p, miR-125b-5p, miR-451a, and miR-605-5p as differentially expressed in the CSF-derived exosomes of YOAD patients when compared with healthy controls (HC). In a cohort of LOAD patients, miR-125b-5p, miR-451a, and miR-605-5p were similarly altered in expression, but miR-16-5p showed similar expression to control. Analysis of the mRNA targets of these miRNAs revealed transcripts enriched in biological processes relevant to the post-mortem posterior cingulate cortex transcriptome in YOAD from a previously published microarray study, including those related to neuron projections, synaptic signaling, metabolism, apoptosis, and the immune system. Hence, these miRNAs represent novel targets for uncovering disease mechanisms and for biomarker development in both YOAD and LOAD.Electronic supplementary materialThe online version of this article (10.1007/s12035-018-1032-x) contains supplementary material, which is available to authorized users.

The aim of this study was to examine the potential utility of a self-paced saccadic eye movement as a marker of post-concussion syndrome (PCS) and monitoring the recovery from PCS. Fifty-nine persistently symptomatic participants with at least two concussions performed the self-paced saccade (SPS) task. We evaluated the relationships between the number of SPSs and 1) number of self-reported concussion symptoms, and 2) integrity of major white matter (WM) tracts (as measured by fractional anisotropy [FA] and mean diffusivity) that are directly or indirectly involved in saccadic eye movements and often affected by concussion. These tracts included the uncinate fasciculus (UF), cingulum (Cg) and its three subcomponents (subgenual, retrosplenial, and parahippocampal), superior longitudinal fasciculus, and corpus callosum. Mediation analyses were carried out to examine whether specific WM tracts (left UF and left subgenual Cg) mediated the relationship between the number of SPSs and 1) interval from last concussion or 2) total number of self-reported symptoms. The number of SPSs was negatively correlated with the total number of self-reported symptoms (r = -0.419, p = 0.026). The number of SPSs were positively correlated with FA of left UF and left Cg (r = 0.421, p = 0.013 and r = 0.452, p = 0.008; respectively). FA of the subgenual subcomponent of the left Cg partially mediated the relationship between the total number of symptoms and the number of SPSs, while FA of the left UF mediated the relationship between interval from last concussion and the number of SPSs. In conclusion, SPS testing as a fast and objective assessment may reflect symptom burden in patients with PCS. In addition, since the number of SPSs is associated with the integrity of some WM tracts, it may be useful as a diagnostic biomarker in patients with PCS.

ObjectiveTo assess the efficacy and safety of cinnarizine for the prophylaxis of migraine associated vertigo in the vestibular migraine and migraine with brainstem aura.BackgroundVestibular migraine and migraine with brainstem aura are two principal clinical syndromes that frequently are associated with vertigo. Since cinnarizine is a well-tolerated calcium channel blocker which has acceptable effect on both vertigo and migraine headache, we carried out this study to evaluate the efficacy and safety of this medication in vestibular migraine and also migraine with brainstem aura associated with vertigo.MethodsThis was a retrospective, single-center, open-label, investigation of the effects of cinnarizine on vestibular migraine and migraine with associated with vertigo. We assessed the change in monthly frequency of vertigo and also frequency, duration and intensity of migraine attacks after one, two and three months of cinnarizine administration.ResultsThe mean frequency of vertigo and also the mean frequency, duration and intensity of migraine headaches per month were reduced significantly after three months of cinnarizine therapy (all p < 0.001).ConclusionThis study suggests that cinnarizine is safe and effective in reducing both headache and vertigo aspects of “migraine plus vertigo” among the patients who suffer from either vestibular migraine or migraine with brainstem aura associated with vertigo.

ObjectiveTo determine the relationship between alterations in resting state functional connectivity and social cognition dysfunction among patients with frontotemporal dementia (FTD), Alzheimer’s disease (AD), Parkinson’s disease (PD), and healthy controls (HC).MethodsFifty-seven participants (FTD = 10, AD = 18, PD = 19, and HC = 10) underwent structural and functional imaging and completed the Awareness of Social Inference Test-Emotion Evaluation Test (TASIT-EET), Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) scale, Revised Self-Monitoring Scale (RSMS), Interpersonal Reactivity Index (IRI), and Social Norms Questionnaire (SNQ). A multi-variate pattern analysis (MVPA) was carried out to determine activation differences between the groups. The clusters from the MVPA were used as seeds for the ROI-to-voxel analysis. Relationship between social cognition deficits and uncinate integrity was also investigated.ResultsBOLD signal activation differed among the four groups of AD, PD, FTD, and HC in the left inferior temporal gyrus-anterior division [L-ITG (ant)], right central opercular cortex (R-COp), right supramarginal gyrus, posterior division (R-SMG, post), right angular gyrus (R-AG), and R-ITG. The BOLD co-activation of the L-ITG (ant) with bilateral frontal pole (FP) and paracingulate gyrus was positively associated with IRI-perspective taking (PT) (r = 0.38, p = 0.007), SNQ total (r = 0.37, p = 0.009), and TASIT-EET (r = 0.47, p < 0.001).ConclusionPatients with neurodegenerative diseases showed alterations in connectivity in brain regions important for social cognition compared with HCs. Functional connectivity correlated with performance on social cognition tasks and alterations could be responsible for some of the social cognition deficits observed in all neurodegenerative diseases.

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Background/Objective: This study aimed to evaluate serum neurofilament light chain (NF-L) levels in former professional contact sports athletes with multiple concussions (ExPro) as a potential biomarker of neurodegeneration and predictor of white-matter (WM) abnormality progression. Methods: Concentrations of NF-L in the serum of fifty-two cognitively normal ExPro and twenty-one healthy controls (HC) with no history of concussions were measured using single molecule array (Simoa) technology. Both groups underwent neuroimaging at the time of serum collection. Eighteen of the participants in the ExPro underwent follow-up imaging after 2 years. Results: Levels of serum NF-L were not significantly different between the ExPro and HC. However, in the ExPro group, NF-L levels were positively correlated with the mean diffusivity (MD) of corpus callosum (CC) and fornix, and total ventricular volume. Moreover, NF-L levels in the ExPro group at the first visit were positively correlated with the amount of increase in CC MD at the 2-year follow-up. Conclusions: NF-L levels reflect neuronal changes in the ExPro group and predict the extent of decrease in white matter integrity over time. Serum NF-L might be a biomarker of neurodegeneration and WM abnormality progression in ExPro.

Our study aimed to: 1)investigate the diagnostic utility of CSF Aβ42, t-tau, and p-tau to differentiate normal-pressure-hydrocephalus(NPH) from Alzheimer's-disease(AD) and normal-controls; and 2) investigate if age and ventricular size affect the levels of CSF biomarkers in NPH patients. We recruited 131 participants: (a)Suspected-NPH: 72 with ventriculomegaly and clinical symptoms of NPH. These participants were then divided into two groups of 1)Probable-NPH (N = 38) and 2)Unlikely-NPH (n = 34) based on whether participants experienced gait improvement after removal of a large amount of CSF; (b)AD group: 30 participants with CSF biomarkers and cognitive symptoms consistent with AD; (c)Control-group: 29 participants who were cognitively and functionally normal. Lower levels of CSF Aβ42 and p-tau were observed in the probable-NPH compared to the normal controls(444.22 ± 163.3 vs. 1213.75 ± 556.5; and 26.05 ± 9.2 vs. 46.16 ± 13.3 pg/mL; respectively). Lower levels of CSF p-tau and t-tau were found in the probable-NPH compared to the AD(26.05 ± 9.2 vs. 114.95 ± 28.2; and 193.29 ± 92.3 vs. 822.65 ± 311.5 pg/mL; respectively) but the CSF-Aβ42 was low in both the probable-NPH and AD. CSF-Aβ42 correlated with age and Evans-index only in the probable-NPH(r = 0.460, p = 0.004; and r = −0.530, p = 0.001; respectively). Our study supports the hypothesis that agerelated atrophy results in better Aβ42 clearance in the CSF because of the increase in the interstitial space. Normal pressure hydrocephalus (NPH) is a syndrome associated with enlarged ventricles without marked elevation in cerebrospinal fluid (CSF) pressure 1. Clinical symptoms include gait and balance impairment, cognitive deficits, and urinary urgency/incontinence 1. In both NPH and Alzheimer's disease (AD) decreased CSF levels of the amyloid β−42 (Aβ42) have been found; however, in contrast to AD, total tau (t-tau) and phospho-tau (p-tau) levels are not increased in NPH cases 2,3. It has been hypothesized that the low Aβ42 in the presence of low t-tau and p-tau is due to the decrease in interstitial space that precludes amyloid precursor protein (APP) fragments and tau proteins from being effectively cleared by CSF and consequently the levels of these proteins decrease in the CSF 4. This hypothesis was based on two major observations: 1) low levels of all APP fragments (i.e., Aβ38, Aβ40, Aβ42, sAPPα, and sAPPβ) in CSF obtained both by lumbar and ventricular methods of patients with NPH compared to health controls, which all increased back to normal after shunting 1 and 2) Aβ clearance from the interstitial fluid is increased during sleep when the size of interstitial space increases by 60% 5. The aims of our study were to: 1) investigate the diagnostic utility of CSF Aβ42, t-tau, and p-tau to differentiate NPH from AD and normal controls; and 2) investigate if age and ventricular size affect the levels of these CSF biomarkers in NPH patients. Answers to these questions would improve understanding of CSF Aβ42, t-tau, and p-tau production/clearance and facilitate ...

Background: Considering the wide range of outcomes following sport-related concussions, biomarkers are needed to detect underlying pathological changes. The objective was to analyze the use of plasma phosphorylated tau 181 (pTau181) as a non-invasive measure of underlying brain changes in a cohort of retired contact sports athletes at risk of neurodegeneration.Methods: This study included 54 retired contact sport athletes and 27 healthy controls whose blood plasma was analyzed for pTau181. A portion (N=21) of retired athletes came for a 2-year follow-up visit. All participants had completed a neuropsychological battery and MRI imaging.Results: Plasma pTau181 was significantly higher in retired athletes compared to healthy controls (8.945.08 pg/mL vs. 6.002.53 pg/mL; 95% CI 0.87-5.01; p=.02). When the retired athletes cohort was divided into high vs. normal pTau181 groups, the corpus callosum (CC) and entorhinal volumes were significantly lower in high pTau181 compared to older healthy controls (1.570.19 vs. 2.020.32, p=.002; and 2.070.35 vs. 2.820.51, p=.003, respectively). Lower white matter integrity was observed in the high pTau181 group in comparison to healthy controls (CC medial diffusivity: 0.960.04 x10 -3 mm 2 /s vs. 0.900.03 x10 -3 mm 2 /s, p=.003; CC axial diffusivity: 1.490.04 x10 -3 mm 2 /s vs. 1.410.02 x10 -3 mm 2 /s, p<.001, respectively). Conclusions:Although high plasma pTau181 levels was associated with lower regional brain volumes and decreased white matter integrity, baseline pTau181 did not predict longitudinal changes in regional brain volumes or white matter integrity in retired contact sport athletes. pTau181 may be useful for identifying those with brain abnormalities related to repeated concussion but not for predicting progression.