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Background: Many transversal mechanisms act synergistically at different time-points in the cascade of Alzheimer’s disease (AD), since amyloid-β (Aβ) deposition, tau pathology, and neuroinflammation influence each other. Objective: We explored the contributions of microglia and astrocytes in patients with symptomatic sporadic AD stratified according to AT(N) system and APOE genotype. Methods: We compared the cerebrospinal fluid (CSF) levels of sTREM-2 and markers of astrocytic activation (GFAP; β-S100) from 71 patients with AD (23 A+T–,48 A+T+; 38 APOE ɛ3, 33 APOE ɛ4) and 30 healthy controls (HC). With multivariate analyses we investigated associations between glial biomarkers, Aβ42, and p-tau in all subgroups. Results: CSF sTREM-2 was higher in A+T+ [1.437 (0.264)] and A+T– [1.355 (0.213)] than in HC [1.042 (0.198); both p

Repetitive transcranial magnetic stimulation (rTMS) is emerging as a non-invasive therapeutic strategy in the battle against Alzheimer’s disease. Alzheimer’s disease patients primarily show alterations of the default mode network for which the precuneus is a key node. Here, we hypothesized that targeting the precuneus with TMS represents a promising strategy to slow down cognitive and functional decline in Alzheimer’s disease patients. We performed a randomized, double-blind, sham-controlled, phase 2, 24-week trial to determine the safety and efficacy of precuneus stimulation in patients with mild-to-moderate Alzheimer’s disease. Fifty Alzheimer’s disease patients were randomly assigned in a 1:1 ratio to either receive precuneus or sham rTMS (mean age 73.7 years; 52% female). The trial included a 24-week treatment, with a 2-week intensive course in which rTMS (or sham) was applied daily five times per week, followed by a 22-week maintenance phase in which stimulation was applied once weekly. The Clinical Dementia Rating Scale–Sum of Boxes was selected as the primary outcome measure, in which post-treatment scores were compared to baseline. Secondary outcomes included score changes in the Alzheimer’s Disease Assessment Scale–Cognitive Subscale, Mini-Mental State Examination and Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale. Moreover, single-pulse TMS in combination with EEG was used to assess neurophysiological changes in precuneus cortical excitability and oscillatory activity. Our findings show that patients that received precuneus repetitive magnetic stimulation presented a stable performance of the Clinical Dementia Rating Scale–Sum of Boxes score, whereas patients treated with sham showed a worsening of their score. Compared with the sham stimulation, patients in the precuneus stimulation group also showed also significantly better performances for the secondary outcome measures, including the Alzheimer’s Disease Assessment Scale–Cognitive Subscale, Mini-Mental State Examination and Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale. Neurophysiological results showed that precuneus cortical excitability remained unchanged after 24 weeks in the precuneus stimulation group, whereas it was significantly reduced in the sham group. Finally, we found an enhancement of local gamma oscillations in the group treated with precuneus stimulation but not in patients treated with sham. We conclude that 24 weeks of precuneus rTMS may slow down cognitive and functional decline in Alzheimer’s disease. Repetitive TMS targeting the default mode network could represent a novel therapeutic approach in Alzheimer’s disease patients.

In Alzheimer disease (AD) animal models, synaptic dysfunction has recently been linked to a disorder of high-frequency neuronal activity. In patients, a clear relation between AD and oscillatory activity remains elusive. Here, we attempt to shed light on this relation by using a novel approach combining transcranial magnetic stimulation and electroencephalography (TMS-EEG) to probe oscillatory activity in specific hubs of the frontoparietal network in a sample of 60 mild-to-moderate AD patients.Sixty mild-to-moderate AD patients and 21 age-matched healthy volunteers (HVs) underwent 3 TMS-EEG sessions to assess cortical oscillations over the left dorsolateral prefrontal cortex, the precuneus, and the left posterior parietal cortex. To investigate the relations between oscillatory activity, cortical plasticity, and cognitive decline, AD patients underwent a TMS-based neurophysiological characterization and a cognitive evaluation at baseline. The latter was repeated after 24 weeks to monitor clinical evolution.AD patients showed a significant reduction of frontal gamma activity as compared to age-matched HVs. In addition, AD patients with a more prominent decrease of frontal gamma activity showed a stronger impairment of long-term potentiation-like plasticity and a more pronounced cognitive decline at subsequent follow-up evaluation at 24 weeks.Our data provide novel evidence that frontal lobe gamma activity is dampened in AD patients. The current results point to the TMS-EEG approach as a promising technique to measure individual frontal gamma activity in patients with AD. This index could represent a useful biomarker to predict disease progression and to evaluate response to novel pharmacological therapies. ANN NEUROL 2022;92:464-475.

Although the cerebellum is not among the most renowned brain structures affected in Alzheimer`s disease (AD), recent evidence suggest that it undergoes degenerative changes during the course of the disease. A main neurophysiological feature of AD patients is the remarkable impairment of long term potentiation (LTP)-like cortical plasticity assessed in the primary motor cortex (M1) using theta burst stimulation (TBS) protocols. In healthy conditions, continuous (cTBS) and intermittent TBS (iTBS) of the cerebellum induce respectively long term depression (LTD)-like and LTP-like after effects in the contralateral M1. Here we aimed at examining the effects of cerebellar TBS on contralateral M1 excitability in a sample of 15 AD patients and 12 healthy age matched controls (HS). Motor evoked potentials (MEPs) were obtained in the contralateral M1 before and after cerebellar cTBS and iTBS protocols. As compared to HS, AD patients showed an impairment of LTP-like cortical plasticity mechanisms following cerebellar iTBS. No difference was observed for the cTBS protocol, in which both populations exhibited the expected LTD-like after effect. This study shows that mechanisms of cerebellar-cortical plasticity are impaired in AD. Given its role in high order cognitive functions, new potential therapeutic strategies could be built up in the future to modulate neural activity in the cerebellum in AD.

Background: Long-term potentiation (LTP) like-cortical plasticity impairment and cholinergic neurotransmission deficits have been widely demonstrated in Alzheimer’s disease (AD) patients. Objective: In this study we aim to investigate the neurophysiological features underlying cognitive decline in AD patients according to the National Institute on Aging-Alzheimer’s Association (NIA-AA) classification and APOE genotype. Methods: 65 newly diagnosed AD patients were enrolled. APOE genotype and lumbar puncture for the analysis of cerebrospinal fluid biomarkers were performed for diagnostic purposes. Patients were subdivided upon NIA-AA criteria, according to the presence of biomarkers of amyloid-β (Aβ) deposition (A) and fibrillar tau (T), in four groups: A+/T–E4 (n = 9), A+/T–E3 (n = 18), A+/T+ E4 (n = 21), and A+/T+ E3 (n = 17). We applied intermittent theta burst stimulation protocol over the primary motor cortex to assess LTP-like cortical plasticity and short latency afferent inhibition (SAI) protocol to investigate central cholinergic activity. Patients were followed over 24 months. Cognitive decline was evaluated considering changes in Mini-Mental State Examination (MMSE) scores respect to the baseline. Results: A+/T–E4 patients showed preserved LTP-like cortical plasticity as compared to A+/T–E3 and to A+/T+ patients independently from genotype (p 0.05). Conclusion: Our results suggest that APOE4 in patients with isolated Aβ pathology could exert positive effects on LTP-like cortical plasticity with a consequent slower cognitive decline.

Biobanking has emerged as a strategic challenge to promote knowledge on neurological diseases, by the application of translational research. Due to the inaccessibility of the central nervous system, the advent of biobanks, as structure collecting biospecimens and associated data, are essential to turn experimental results into clinical practice. Findings from basic research, omics sciences, and in silico studies, definitely require validation in clinically well-defined cohorts of patients, even more valuable when longitudinal, or including preclinical and asymptomatic individuals. Finally, collecting biological samples requires a great effort to guarantee respect for transparency and protection of sensitive data of patients and donors. Since the European General Data Protection Regulation 2016/679 has been approved, concerns about the use of data in biomedical research have emerged. In this narrative review, we focus on the essential role of biobanking for translational research on neurodegenerative diseases. Moreover, we address considerations for biological samples and data collection, the importance of standardization in the preanalytical phase, data protection (ethical and legal) and the role of donors in improving research in this field.

BACKGROUND AND PURPOSE Diabetes mellitus (DM) is considered a risk factor for Alzheimer's disease (AD) and shares some pathological pathways, such as activation of amyloid cascade and tau phosphorylation. The aim of the present study was to investigate to what extent DM could impact on neurodegeneration within the AD continuum, using β amyloid (A: Aβ1-42 ) and phosphorylated tau (T: p-tau) biomarkers to discriminate patients by Alzheimer's pathological change (A+/T-) and AD (A+/T+), according to the National Institute on Aging and Alzheimer's Association classification. In addition, we aimed to evaluate whether APOE genotype interacts with tau protein and glucose metabolism dysfunction to affect the pathological process. METHODS For this retrospective observational study, 1350 patients were recruited. The patients underwent a complete clinical investigation, neuropsychological assessment, lumbar puncture for cerebrospinal fluid (CSF) biomarkers analysis and APOE genotyping. RESULTS A total of 607 patients fulfilled the clinical criteria of mild cognitive impairment or early dementia. In A+T- patients (n = 350), DM did not influence CSF biomarker levels, while among A+T+ patients (n = 257) those with DM showed increased total tau (t-tau) levels compared to non-DM patients (DM: 919.4 ± 444 vs. non-DM: 773.1 ± 348.2; p = 0.04), but similar p-tau (p = 0.72) and Aβ1-42 levels (p = 0.83). Furthermore, multivariable regression analyses showed a significant association between DM and t-tau CSF levels, adjusting for age and sex, in APOE E4+ carriers (coefficient 222.83, 95% confidence interval 47.49-398.1; p = 0.01), but not in APOE E4- (p = 0.53). CONCLUSIONS The present study shows a clear dependency of CSF t-tau levels on DM for APOE E4+ AD patients, suggesting important differences between APOE E4-related and non-related disease, with key implications for AD pathophysiology and treatment.

Cognitive reserve is originally an epidemiological concept that encompasses individual abilities to cope with changes. It is considered the result of a balance between processes of cellular damage and repair, and its description raised much interest in predicting and preventing cognitive decline in aging and Alzheimer's disease (AD). In this study, we discussed the concept of cognitive reserve considering the recent definition of AD as a biological continuum and suggest that the protection of cognitive reserve may result from efficient synaptic plasticity mechanisms. Despite pathological changes of AD appearing very early during life, long before the onset of cognitive symptoms, different variables act together to keep repair mechanisms effective guaranteeing successful aging if environmental enrichment is maintained.

Background: Neuroinflammatory cytokines can play a pivotal role in Alzheimer's disease (AD) contributing to the evolution of degenerative processes. Objective: We aimed at evaluating the levels of cerebrospinal fluid (CSF) inflammatory cytokines, chemokines, and growth factors in subjects with diagnosis of amnestic mild cognitive impairment and mild AD. Methods: We evaluated CSF contents of inflammatory cytokines in 66 patients divided according to the NIA-AA research framework and the APOE genotype. CSF of a group of cognitively unimpaired individuals (n = 23) was evaluated as control. All patients were evaluated for 24 months using Mini-Mental State Examination (MMSE). Results: We found significant increased levels of IL-4, IL-6, IL-8, and G-CSF in the CSF of A+/T-APOE4 carriers, respect to A+/T-patients homozygous for APOE3, respect to A+/T+ patients, regardless the APOE status, and respect to controls. Over a period of 24 months, A+/T-APOE4 carriers, with increased levels of cytokines, showed a preserved cognitive evaluation when compared to the other subgroups of patients (delta MMSE at 24 months respect to baseline: 0.10±0.35; p < 0.05). Conclusion: Our data suggest that during early phases of AD, in APOE4 carriers, Aβ pathology likely induces a specific cytokines pattern synthesis associated to cognitive preservation. These data highlight the different role that neuroinflammation can play in AD pathology based on the presence of specific CSF biomarkers and on the APOE status.

Background: Frontotemporal dementia (FTD) is a presenile neurodegenerative disease for which there is no effective pharmacological treatment. Recently, a link has been proposed between neuroinflammation and FTD. Objective: Here, we aim to investigate the effects of palmitoylethanolamide (PEA) combined with luteoline (PEA-LUT), an endocannabinoid with anti-inflammatory and neuroprotective effects, on behavior, cognition, and cortical activity in a sample of FTD patients. Methods: Seventeen patients with a diagnosis of probable FTD were enrolled. Cognitive and neurophysiological evaluations were performed at baseline and after 4 weeks of PEA-LUT 700 mg×2/day. Cognitive effects were assessed by Neuropsychiatric Inventory (NPI), Mini-Mental State Examination, Frontal Assessment Battery (FAB), Screening for Aphasia in Neurodegeneration, Activities of Daily Living-Instrumental Activities of Daily Living, and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating scale. To investigate in vivo neurophysiological effects of PEA-LUT, we used repetitive and paired-pulse transcranial magnetic stimulation (TMS) protocols assessing LTP-like cortical plasticity, short-interval intracortical inhibition, long-interval intracortical inhibition (LICI), and short-latency afferent inhibition. Moreover, we used TMS combined with EEG to evaluate the effects on frontal lobe cortical oscillatory activity. Results: Treatment with PEA-LUT was associated with an improvement in NPI and FAB scores. Neurophysiological evaluation showed a restoration of LICI, in particular at ISI 100 ms, suggesting a modulation of GABA(B) activity. TMS-EEG showed a remarkable increase of TMS-evoked frontal lobe activity and of high-frequency oscillations in the beta/gamma range. Conclusion: PEA-LUT could reduce behavioral disturbances and improve frontal lobe functions in FTD patients through the modulation of cortical oscillatory activity and GABA(B)ergic transmission. Keywords: Brain inflammation; EEG; GABA activity; behavioral symptoms; executive functions; frontotemporal dementia; transcranial magnetic stimulation.

The cerebellum plays a critical role in promoting learning of new motor tasks, which is an essential function for motor recovery. Repetitive transcranial magnetic stimulation (rTMS) of the cerebellum can be used to enhance learning. In this study, we investigated the effects of cerebellar intermittent theta burst stimulation (c-iTBS), a high-frequency rTMS protocol, on visuo-motor learning in a sample of hemiparetic patients due to recent stroke in the territory of the contralateral middle cerebral artery. Eight stroke patients were enrolled for the purposes of the study in the chronic stage of recovery (i.e., at least 6 months after stroke). In two sessions, Patients were randomly assigned to treatment with real or sham c-iTBS applied over the cerebellar hemisphere ipsilateral to the affected body side. c-iTBS was applied immediately before the learning phase of a visuo-motor adaptation task. Real, but not sham, c-iTBS improved visuo-motor learning as revealed by an increased performance in of the learning phase of the visuo-moto adaptation task. Moreover, we also found that real but not sham c-iTBS induced a sustained improvement in the re-adaptation of the recently learned skill (i.e., when patients were re-tested after 30 min). Taken together, these data point to c-iTBS as a potential novel strategy to promote motor learning in patients with stroke.

The cerebellum is strongly implicated in learning new motor skills. Theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation, can be used to influence cerebellar activity. Our aim was to explore the potential of cerebellar TBS in modulating visuo-motor adaptation, a form of motor learning, in young healthy subjects. Cerebellar TBS was applied immediately before the learning phase of a visuo-motor adaptation task (VAT), in two different experiments. Firstly, we evaluated the behavioral effects of continuous (cTBS), intermittent (iTBS) or sham TBS on the learning, re-adaptation and de-adaptation phases of VAT. Subsequently, we investigated the changes induced by iTBS or sham TBS on motor cortical activity related to each phase of VAT, as measured by concomitant TMS/EEG recordings. We found that cerebellar TBS induced a robust bidirectional modulation of the VAT performance. More specifically, cerebellar iTBS accelerated visuo-motor adaptation, by speeding up error reduction in response to a novel perturbation. This gain of function was still maintained when the novel acquired motor plan was tested during a subsequent phase of re-adaptation. On the other hand, cerebellar cTBS induced the opposite effect, slowing the rate of error reduction in both learning and re-adaptation phases. Additionally, TMS/EEG recordings showed that cerebellar iTBS induced specific changes of cortical activity in the interconnected motor networks. The improved performance was accompanied by an increase of TMS-evoked cortical activity and a generalized desynchronization of TMS-evoked cortical oscillations. Taken together, our behavioral and neurophysiological findings provide the first-time multimodal evidence of the potential efficacy of cerebellar TBS in improving motor learning, by promoting successful cerebellar-cortical reorganization.

Background Mechanisms of cortical plasticity have been recently investigated in Alzheimer's disease (AD) patients with transcranial magnetic stimulation protocols showing a clear impairment of long-term potentiation (LTP) cortical-like plasticity mechanisms. Objective We aimed to investigate mechanisms of cortico-cortical spike-timing dependent plasticity (STDP) in AD patients investigating the connections between posterior parietal cortex (PPC) and primary motor cortex (M1). Methods We used a cortico-cortical paired associative stimulation (cc-PAS) protocol to repeatedly activate the connection between PPC and M1 of the left-dominant hemisphere in a sample of fifteen AD patients and ten age-matched healthy subjects. PPC transcranial magnetic stimulation preceded (ccPAS +5) or followed M1 stimulation (ccPAS - 5) by 5 ms. Motor-evoked potentials (MEPs) were collected to assess the time course of the after effects of cc-PAS protocol measuring MEP amplitude as index of cortico-cortical associative plasticity. Results In healthy subjects, ccPAS - 5 protocol induced the expected long-lasting increase of MEP amplitude compatible with LTP-like cortical plasticity while PAS +5 protocol induced the opposite effect. AD patients did not show any significant modification of the amplitude of MEP after both ccPAS protocols. Conclusions Our study shows that in AD patients the time-locked activation of human cortico-cortical connections is not able to form STDP, reflecting an impairment of a multi-factor plasticity process.

ObjectiveTo determine the ability of transcranial magnetic stimulation (TMS) in detecting synaptic impairment in patients with Alzheimer’s disease (AD) and predicting cognitive decline since the early phases of the disease.MethodsWe used TMS-based parameters to evaluate long-term potentiation (LTP)-like cortical plasticity and cholinergic activity as measured by short afferent inhibition (SAI) in 60 newly diagnosed patients with AD and 30 healthy age-matched subjects (HS). Receiver operating characteristic (ROC) curves were used to assess TMS ability in discriminating patients with AD from HS. Regression analyses examined the association between TMS-based parameters and cognitive decline. Multivariable regression model revealed the best parameters able to predict disease progression.ResultsArea under the ROC curve was 0.90 for LTP-like cortical plasticity, indicating an excellent accuracy of this parameter in detecting AD pathology. In contrast, area under the curve was only 0.64 for SAI, indicating a poor diagnostic accuracy. Notably, LTP-like cortical plasticity was a significant predictor of disease progression (p=0.02), while no other neurophysiological, neuropsychological and demographic parameters were associated with cognitive decline. Multivariable analysis then promoted LTP-like cortical plasticity as the best significant predictor of cognitive decline (p=0.01). Finally, LTP-like cortical plasticity was found to be strongly associated with the probability of rapid cognitive decline (delta Mini-Mental State Examination score ≤−4 points at 18 months) (p=0.04); patients with AD with lower LTP-like cortical plasticity values showed faster disease progression.ConclusionsTMS-based assessment of LTP-like cortical plasticity could be a viable biomarker to assess synaptic impairment and predict subsequent cognitive decline progression in patients with ADs.

OBJECTIVE Alzheimer's disease (AD) is considered an age-related disorder. However, it is unclear whether AD induces the same pathological and neurophysiological modifications in synaptic functions independently from age of disease onset. We used transcranial magnetic stimulation tools to investigate the mechanisms of cortical plasticity and sensory-motor integration in AD patients with a wide range of disease onset. METHODS We evaluated newly diagnosed sporadic AD (n = 54) in comparison with healthy age-matched controls (HS; n = 24). Cortical plasticity mechanisms of long-term potentiation (LTP) or of long-term depression (LTD) were assessed using respectively intermittent (iTBS) or continuous theta burst stimulation (cTBS) protocols. Sensory-motor integration was evaluated by means of short afferent inhibition (SAI) protocol. RESULTS AD patients show after iTBS an impairment of LTP-like cortical plasticity forming a paradoxical LTD in comparison to HS. LTD-like cortical plasticity is similar between AD and HS. LTP-like cortical plasticity is not associated with age, but AD patients presenting with more altered LTP-like cortical plasticity have more-severe cognitive decline at 18 months. SAI is impaired in AD and shows a strong association with the individual age of subjects rather than with disease age of onset. INTERPRETATION Cortical LTP disruption is a central mechanism of AD that is independent from age of onset. AD can be described primarily as a disorder of LTP-like cortical plasticity not influenced by physiological aging and associated with a more-severe cognitive decline. Ann Neurol 2016;80:202-210.

Background Painful distal symmetric polyneuropathy (pDSPN) is one of the most common and invalidating complications of diabetes mellitus, both of type 1 and type 2. Mechanisms responsible for the occurrence of the pDSPN are multifactorial and involve metabolic pathways regulating inflammation, microvessel circulation, axonal degeneration and so on. Several therapeutic approaches have been proposed to treat pain and each of them showed positive effects associated to drug-related side effects. Methods Twenty-five consecutive patients with diagnosis of diabetes mellitus and pDSPN and tried to manage pain with a dietary supplement composed of a mixture of natural extracts (β-caryophyllene, myrrh, carnosic acid) and PEA. This is a nutraceutical with potential multiple effects on metabolic, pain and vascular compartments, a profile considered useful in pDSPN. Patients were enrolled and polyneuropathy evaluated by means of nerve conduction study. Pain was assessed using VAS score scale and MNSI. Each patient was evaluated at T0 (time of enrollment) and at T1 (after 16 weeks of treatment). Results Supplement administration was well tolerated and induced unexpectedly significant amelioration of polyneuropathy with increase amplitude and reduction of pain. No side effects were reported. Conclusions This fixed combination could well be considered as a potential nutraceutical option to manage pDSPN in diabetic patients.

Background Alzheimer's disease (AD) is characterized by a primary impairment of long-term declarative memory caused by deposition of misfolded protein aggregates. Experimental studies showed that AD neuropathological alterations impair synaptic plasticity and memory performance. Transcranial Magnetic Stimulation protocols have been recently introduced to investigate altered mechanisms of cortical plasticity in AD patients. Aim To investigate relationship between Long-Term Potentiation (LTP)-like cortical plasticity and patients’ neuropsychological performance. Methods We applied intermittent theta burst stimulation and extensive neuropshycological battery in 75 newly diagnosed AD patients. Results We found that LTP-like cortical plasticity impairment is selectively associated to a less efficient verbal memory (r = 0.45; p = 0.002), but not to other cognitive functions, independently from biomarkers and other demographic and clinical factors. Conclusion These findings suggest that LTP-like cortical plasticity may represent a neurophysiological surrogate of memory in AD patients by evaluating the weight of pathological changes responsible for cognitive dysfunction.

Memory loss is one of the first symptoms of typical Alzheimer's disease (AD), for which there are no effective therapies available. The precuneus (PC) has been recently emphasized as a key area for the memory impairment observed in early AD, likely due to disconnection mechanisms within large-scale networks such as the default mode network (DMN). Using a multimodal approach we investigated in a two-week, randomized, sham-controlled, double-blinded trial the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the PC on cognition, as measured by the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite in 14 patients with early AD (7 females). TMS combined with electroencephalography (TMS-EEG) was used to detect changes in brain connectivity. We found that rTMS of the PC induced a selective improvement in episodic memory, but not in other cognitive domains. Analysis of TMS-EEG signal revealed an increase of neural activity in patients' PC, an enhancement of brain oscillations in the beta band and a modification of functional connections between the PC and medial frontal areas within the DMN. Our findings show that high-frequency rTMS of the PC is a promising, non-invasive treatment for memory dysfunction in patients at early stages of AD. This clinical improvement is accompanied by modulation of brain connectivity, consistently with the pathophysiological model of brain disconnection in AD.

BackgroundFew data exist on malignant middle cerebral artery infarction (MMI) among patients with acute ischemic stroke (AIS) after endovascular treatment (ET). Numerous predictors of MMI evolution have been proposed, but a comprehensive research of patients undergoing ET has never been performed. Our purpose was to find a practical model to determine robust predictors of MMI in patients undergoing ET.MethodsPatients from a prospective single-center database with AIS secondary to large intracranial vessel occlusion of the anterior circulation, treated with ET, were retrospectively analyzed. We investigated demographic, clinical, and radiological data. Multivariate regression analysis was used to identify clinical and imaging predictors of MMI.Results98 patients were included in the analysis, 35 of whom developed MMI (35.7%). No differences in the rate of successful reperfusion and time from stroke onset to reperfusion were found between the MMI and non-MMI groups. The following parameters were identified as independent predictors of MMI: systolic blood pressure (SBP) on admission (p=0.008), blood glucose (BG) on admission (p=0.024), and the CTangiography (CTA) Alberta Stroke Program Early CT Score (ASPECTS) (p=0.001). A scoreof ≤5 in CTA ASPECTS was the best cut-off to predict MMI evolution (sensitivity 46%; specificity 97%; positive predictive value 78%; negative predictive value 65%).Conclusionsin our study a clinical and radiological features-based model was strongly predictive of MMI evolution in AIS. High SBP and BG on admission and, especially, a CTA ASPECTS ≤5 may help to make decisions quickly, regardless of time to treatment and successful reperfusion.

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by persistent inflammation orchestrated by cluster of differentiation (CD) 4 T helper (Th) cells. In particular, Th1 and Th17 cells amplify, whereas T regulatory (Treg) cells moderate inflammation. The role of other Th subsets in MS is not clear. In the present study, we investigated the generation of different Th responses by human dendritic cells (DCs) in MS. We compared the production of several Th cytokines by naive CD4+ T-cells polarized with myeloid and plasmacytoid DCs (mDCs and pDCs) in healthy donors (HD) and relapsing–remitting (RR)-MS patients. We found that resiquimod-stimulated mDCs were able to activate Th17 differentiation, whereas pDCs induced interleukin (IL)-10-producing Th cells. Surprisingly, resiquimod-stimulated pDCs from MS patients also significantly induced the differentiation of Th9 cells, which produce IL-9 and are known to be involved in allergic diseases. We investigated the potential role of IL-9 in MS. We found that IL-9 activated signal transducer and activator of transcription (STAT) 1 and STAT5 phosphorylation and interfered with IL-17 and interferon (IFN) regulatory transcription factor (IRF)-4 expression in Th17-polarized cells. Moreover, in the cerebrospinal fluid (CSF) of 107 RR-MS patients, IL-9 inversely correlated with indexes of inflammatory activity, neurodegeneration and disability progression of MS. High levels of IL-9 were associated with the absence of IL-17 in the CSF of RR-MS patients. Our results demonstrate a Th9-inducing potential of pDCs in MS, suggesting an immunoregulatory role leading to attenuation of the exaggerated Th17 inflammatory response.

Background: Subtle diffuse intrathecal inflammation is undetectable by conventional neuroimaging, and could influence multiple sclerosis (MS) disease course. Objective: To explore the role of subclinical persisting intrathecal inflammation in radiologically isolated syndrome (RIS) or clinically isolated syndrome (CIS) conversion to MS, and in early MS disease reactivation. Methods: One-hundred ninety-three subjects with RIS, CIS, relapsing–remitting (RR), or primary progressive (PP) MS were included, along with 76 matched controls. Cerebrospinal fluid (CSF) levels of interleukin-8 (IL-8), a major proinflammatory cytokine, were measured as a biomarker of intrathecal inflammation. Patients were followed up for 2 years. Clinical and imaging measures of disease progression were recorded. Results: High central contents of IL-8 were associated to clinical progression in subjects with RIS, and to the risk of conversion to MS in subjects with CIS. Asymptomatic intrathecal inflammation placed subjects at risk for MS conversion, even regardless lesion load. CSF IL-8 levels were higher in RR MS with high disease activity. Higher number of relapses in the first two years since diagnosis and shorter first inter-attack intervals were observed in patients with high levels of IL-8. Conclusion: IL-8 might provide utility in determining the presence of active intrathecal inflammation, and could be important in diagnostically undefined cases.

In Alzheimer’s disease (AD) patients, apopoliprotein (APOE) polymorphism is the main genetic factor associated with more aggressive clinical course. However, the interaction between cerebrospinal fluid (CSF) tau protein levels and APOE genotype has been scarcely investigated. A possible key mechanism invokes the dysfunction of synaptic plasticity. We investigated how CSF tau interacts with APOE genotype in AD patients. We firstly explored whether CSF tau levels and APOE genotype influence disease progression and long-term potentiation (LTP)-like cortical plasticity as measured by transcranial magnetic stimulation (TMS) in AD patients. Then, we incubated normal human astrocytes (NHAs) with CSF collected from sub-groups of AD patients to determine whether APOE genotype and CSF biomarkers influence astrocytes survival. LTP-like cortical plasticity differed between AD patients with apolipoprotein E4 (APOE4) and apolipoprotein E3 (APOE3) genotype. Higher CSF tau levels were associated with more impaired LTP-like cortical plasticity and faster disease progression in AD patients with APOE4 but not APOE3 genotype. Apoptotic activity was higher when cells were incubated with CSF from AD patients with APOE4 and high tau levels. CSF tau is detrimental on cortical plasticity, disease progression and astrocyte survival only when associated with APOE4 genotype. This is relevant for new therapeutic approaches targeting tau.

Background Sympathovagal imbalance has been associated with poor prognosis in chronic diseases, but there is conflicting evidence in multiple sclerosis. Objectives The objective of this study was to investigate the autonomic nervous system dysfunction correlation with inflammation and progression in multiple sclerosis. Methods Heart rate variability was analysed in 120 multiple sclerosis patients and 60 healthy controls during supine rest and head-up tilt test; the normalised units of low frequency and high frequency power were considered to assess sympathetic and vagal components, respectively. Correlation analyses with clinical and radiological markers of disease activity and progression were performed. Results Sympathetic dysfunction was closely related to the progression of disability in multiple sclerosis: progressive patients showed altered heart rate variability with respect to healthy controls and relapsing–remitting patients, with higher rest low frequency power and lacking the expected low frequency power increase during the head-up tilt test. In relapsing–remitting patients, disease activity, even subclinical, was associated with lower rest low frequency power, whereas stable relapsing–remitting patients did not differ from healthy controls. Less sympathetic reactivity and higher low frequency power at rest were associated with incomplete recovery from relapse. Conclusions Autonomic balance appears to be intimately linked with both the inflammatory activity of multiple sclerosis, which is featured by an overall hypoactivity of the sympathetic nervous system, and its compensatory plastic processes, which appear inefficient in case of worsening and progressive multiple sclerosis.

Objectives To evaluate the safety and efficacy of endovascular therapy in elderly adults treated for acute ischemic stroke. Design Retrospective cohort study. Setting Comprehensive Stroke Center, University of Tor Vergata, Rome, Italy. Participants Elderly adults treated for acute ischemic stroke (N = 219). Measurements Participants were divided into two groups based on their age (n = 62, ≥80; n = 157, .99) or symptomatic (11% vs 14%, P = .6) ICH, or mortality (40.3% vs 29.2%, P = .14). Multivariable analysis revealed that, in the older group, onset National Institute of Health Stroke Scale (NIHSS) score (odds ratio (OR) = 0.65, 95% confidence interval (CI) = 0.44–0.96, P = .03) and 24-hour clinical improvement (OR = 141.13, 95% CI = 2.96–6,720.7, P = .01) were independent predictors of 3-month functional independence. Conclusion These findings suggest that endovascular treatment for stroke in selected elderly adults could be safe and effective. Major determinants of outcome in this subgroup of elderly patients are presentation NIHSS score and 24-hour clinical improvement.