Clinical and neuroimaging characterization of the first frontotemporal dementia family carrying the MAPT p.K298E mutation.

We present an in-depth clinical and neuroimaging analysis of a family carrying the MAPT K298E mutation associated with frontotemporal dementia (FTD). Initial identification of this mutation in a single clinical case led to a comprehensive investigation involving four affected siblings allowing to elucidate the mutation's phenotypic expression.A 60-year-old male presented with significant behavioral changes and progressed rapidly, exhibiting speech difficulties and cognitive decline. Neuroimaging via FDG-PET revealed asymmetrical frontotemporal hypometabolism. Three siblings subsequently showed varied but consistent clinical manifestations, including abnormal behavior, speech impairments, memory deficits, and motor symptoms correlating with asymmetric frontotemporal atrophy observed in MRI scans.Based on the genotype-phenotype correlation, we propose that the p.K298E mutation results in early-onset behavioral variant FTD, accompanied by a various constellation of speech and motor impairment.This detailed characterization expands the understanding of the p.K298E mutation's clinical and neuroimaging features, underlining its role in the pathogenesis of FTD. Further research is crucial to comprehensively delineate the clinical and epidemiological implications of the MAPT p.K298E mutation.

The role of 123-I-MIBG cardiac scintigraphy in the differential diagnosis between dementia with Lewy bodies and Alzheimer's disease.

Although detailed diagnostic guidelines are available, differentiating dementia with Lewy bodies from Alzheimer's disease is often difficult. 123-I-MIBG cardiac scintigraphy is one of the tools which have been proposed for the diagnostic procedure. The present review is aimed at evaluating the available literature about this topic. Studies assessing the use of this technique to differentiate between the two diseases have been examined and reported. Overall, despite a certain study-to-study variability, the available literature suggests that 123-I-MIBG cardiac scintigraphy is an effective tool in differentiating between the two diseases, with high sensitivity and specificity values. Although the large-scale application of this technique is limited by possible interactions with specific medications and comorbidities, the reported studies are supportive for the usefulness of this technique in clinical practice.

Left and right corticobasal syndrome: comparison of cognitive profiles between metabolic imaging - matched groups.

BACKGROUND: Corticobasal syndrome (CBS) is typically asymmetric. Case reports suggest that left-hemisphere CBS (lhCBS) is associated with major language impairment, and right-hemisphere CBS (rhCBS) is associated with major visuospatial deficits, but no group study has ever verified these observations. In our study, we enrolled 49 patients with CBS, classified them as lhCBS or rhCBS based on asymmetry of hypometabolism on brain FDG-PET and compared their cognitive and behavioural profiles. METHODS: We defined asymmetry of hypometabolism upon visual inspection of qualitative PET images and confirmed it through paired comparison of left- and right-hemisphere FDG uptake values. The two groups were also matched for severity of hypometabolism within the more affected and more preserved hemispheres, to unravel differences in the cognitive profiles ascribable specifically to each hemisphere's functional specializations. All patients were assessed for memory, language, executive and visuospatial deficits, apraxia, neglect, dyscalculia, agraphia and behavioural disturbances. RESULTS: LhCBS (n. 26) and rhCBS (n. 23) patients did not differ for demographics, disease duration and severity of global cognitive impairment. The two cognitive profiles were largely overlapping, with two exceptions: Digit span forward was poorer in lhCBS, and visual neglect was more frequent in rhCBS. CONCLUSIONS: After balancing out patients for hemispheric hypometabolism, we did not confirm worse language or visuospatial deficits in, respectively, lhCBS and rhCBS. However, verbal short-term memory was more impaired in lhCBS, and spatial attention was more impaired in rhCBS. Both of these functions reflect the functional specialization of the left and right fronto-parietal pathways, i.e. of the main loci of neurodegeneration in CBS.

Mobile Applications to Support Multiple Sclerosis Communities: The Post-COVID-19 Scenario.

Introduction: The increase in the use of mobile apps since the COVID-19 pandemic, even among people with multiple sclerosis (PwMS) and health care providers (HCPs), has enabled access to reliable information, symptoms monitoring and management, and social connections. The pandemic has undoubtedly contributed to the acceleration of the "digital revolution." But how far has it progressed for the MS communities? Methods: Italian Google Play and App Store were queried, selecting MS-specific apps in English or Italian language and usable by a wide public. Results: Fifty-four (n = 54) MS-specific apps were identified; most were PwMS-oriented (83%), free of charge (94%), and in English language (76%). The 45 PwMS-oriented apps focused on increasing MS knowledge (71%), tracking symptoms (33%), and promoting networking with peers or HCPs (38%). The 13 HCPs-oriented tools addressed education and updates on MS (62%), disease assessment and management (54%), and research (15%). Google Search tool was also queried to find non-MS-specific apps to fulfill some unmet domains (as sleep, pain, sexual or mental health). Twenty-four additional apps were listed to provide a valuable contribution. Conclusion: The "digital revolution" led to increasingly customized tools for PwMS, especially as m-health or social-networking apps. However, apps to support other specific MS-relevant domains, appealing HCPs-oriented apps, and specific mobile tools for MS caregivers are still lacking. The absence of data assessing the usability and quality of MS apps in ecologically contexts leads to not reliable conclusions about potential benefits. A strong dialogue between MS communities and the digital industry is encouraged to fill this gap.

Head down tilt 15° to preserve salvageable brain tissue in acute ischemic stroke: A pre-clinical pooled analysis, with focus on cerebral hemodynamics.

Neurological outcome after ischemic stroke depends on residual salvageable brain tissue at the time of recanalization. Head down tilt 15° (HDT15) was proven effective in reducing infarct size and improving functional outcome in rats with transient middle cerebral artery occlusion (t-MCAO) by increasing cerebral perfusion within the ischemic penumbra. In this pooled analysis, individual animal-level data from three experimental series were combined in a study population of 104 t-MCAO rats (45 in HDT15 group and 59 in flat position group). Co-primary outcomes were infarct size and functional outcome at 24 h in both groups. The secondary outcome was hemodynamic change induced by HDT15 in ischemic and non-ischemic hemispheres in a subgroup of animals. Infarct size at 24 h was smaller in HDT15 group than in flat position group (absolute mean difference 31.69 mm3 , 95% CI 9.1-54.2, Cohen's d 0.56, p = 0.006). Functional outcome at 24 h was better in HDT15 group than in flat position group (median [IQR]: 13[10-16] vs. 11), with a shift in the distribution of the neurobehavioural scores in favour of HDT15. Mean cerebral perfusion in the ischemic hemisphere was higher during HDT15 than before its application (Perfusion Unit [P.U.], mean ± SD: 52.5 ± 19.52 P.U. vs. 41.25 ± 14.54 P.U., mean of differences 13.36, 95% CI 7.5-19.18, p = 0.0002). Mean cerebral perfusion in the non-ischemic hemisphere before and during HDT15 was unchanged (P.U., mean ± SD: 94.1 ± 33.8 P.U. vs. 100.25 ± 25.34 P.U., mean of differences 3.95, 95%, CI -1.9 to 9.6, p = 0.1576). This study confirmed that HDT15 improves the outcome in t-MCAO rats by promoting cerebral perfusion in the ischemic territory, without disrupting hemodynamics in non-ischemic areas.

Epilepsy in cerebral amyloid angiopathy: an observational retrospective study of a large population.

OBJECTIVE: Cerebral amyloid angiopathy (CAA) is a major cause of spontaneous intracranial hemorrhage in older adults. Epilepsy represents a possible sequela of the disease. To date, studies on epilepsy in CAA are lacking, and the few data available mainly focus on CAA-related inflammation (CAA-ri), the inflammatory form of the disease. METHODS: In this retrospective observational study, we consecutively recruited CAA patients observed over a time span of 10 years, collecting demographic, clinical, and instrumental data. Significant baseline characteristics were evaluated as potential risk factors for the development of epilepsy in the CAA population, and in the subgroups of CAA-ri and CAA without inflammatory reaction (CAA-nri). The effect of potential risk factors for epilepsy was measured as odds ratio with 95% confidence interval. RESULTS: Within 96 recruited CAA cases, 33 (34.4%) developed epilepsy during follow-up (median = 13.5 months). The prevalent type of seizure was focal (81.3%); 12.1% of the epileptic patients presented status epilepticus, and 6.1% developed drug-resistant epilepsy. Electroencephalographic traces revealed slow and epileptic discharge activity in the majority of epileptic patients, but also in those without epilepsy. The presence of focal or disseminated cortical superficial siderosis (cSS) was associated with an increased risk of epilepsy in the CAA-nri group, and the association with CAA-ri and epilepsy was present in the overall population. SIGNIFICANCE: Epilepsy is a common manifestation during the course of CAA, where CAA-ri and cSS represent predisposing factors for the development of seizures. These data suggest the importance of a deep characterization of CAA patients, to better select those more prone to develop epilepsy.

A multidisciplinary approach to screen the post-COVID-19 conditions.

BACKGROUND: Post-COronaVIrus Disease 2019 (COVID-19) conditions (PCC) include multiple symptoms afflicting different organs and systems. To evaluate the frequency and type of them, we described our multidisciplinary approach with preliminary results of the first enrolled patients. METHODS: We included patients aged ≥ 18 years with hospital admission for confirmed SARS-CoV-2 infection. Symptoms were grouped in five macro groups hereafter referred to as "Symptoms Category" (SC): respiratory SC (dyspnoea or cough), neurological SC (peripheral neuropathies, headache, impaired mobility, behavioural disorders), psychological SC (sleep disorders, mood disorders), muscular SC (arthromyalgia, asthenia), other SC (fever, alopecia, diarrhoea, weight loss, smell and taste alterations, sexual dysfunctions). SC were evaluated at discharge and at follow-up. Association between patients' characteristics and presence of SC at follow up was estimated by a logistic multivariable regression model. RESULTS: From June 2020 to July 2021, we followed up 361 patients: 128 (35.5%) who were previously admitted to Intensive Care Unit (ICU) and 233 patients to ordinary department. The median length of hospital stay was 20 days (Inter-Quartile-Range 13-32). Most patients (317/361, 87.8%) were still symptomatic at discharge, with one third referring three or more SC. At follow up, 67.3% (243/361) of patients still complained at least one SC. Moreover, 159 patients (44%) developed at least one new involved SC during follow up: 116 (72.9%) one SC, 39 (24.5%) two SC, 4 (2.5%) three or more SC. At follow up visit 130 of 361 (36%) were still with SC developed during follow up. At multivariable analysis presence of any SC at follow-up was associated with male gender (Odds Ratio [OR] 3.23, Confidence Interval [CI] 95% 1.46-7.15), ICU admission (OR 2.78, CI 95% 1.29-5.96) and presence of SC at discharge (OR 14.39, CI 95% 6.41-32.32). CONCLUSIONS: In our sample of patients with severe COVID-19, we found that PCC are highly variable and fluctuating over time; in particular, in about 50% of our patients new SC appear during follow up. Moreover, presence of PCC also in patients without SC at discharge and the variability of symptoms underlining the advisability of our multidisciplinary approach. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT04424992, registered on 28 February 2020 https://www. CLINICALTRIALS: gov/ct2/results?recrs=ab&cond=&term=NCT04424992&cntry=&state=&city=&dist The current version of protocol is version 1.0 enrolling since June 2020. The enrollment is still ongoing.

An updated overview of recent and ongoing deep brain stimulation (DBS) trials in patients with dementia: a systematic review.

BACKGROUND: Dementia affects more than 55 million people worldwide. Several technologies have been developed to slow cognitive decline: deep brain stimulation (DBS) of network targets in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) have been recently investigated. OBJECTIVE: This study aimed to review the characteristics of the populations, protocols, and outcomes of patients with dementia enrolled in clinical trials investigating the feasibility and efficacy of DBS. MATERIALS AND METHODS: A systematic search of all registered RCTs was performed on Clinicaltrials.gov and EudraCT, while a systematic literature review was conducted on PubMed, Scopus, Cochrane, and APA PsycInfo to identify published trials. RESULTS: The literature search yielded 2122 records, and the clinical trial search 15 records. Overall, 17 studies were included. Two of 17 studies were open-label studies reporting no NCT/EUCT code and were analysed separately. Of 12 studies investigating the role of DBS in AD, we included 5 published RCTs, 2 unregistered open-label (OL) studies, 3 recruiting studies, and 2 unpublished trials with no evidence of completion. The overall risk of bias was assessed as moderate-high. Our review showed significant heterogeneity in the recruited populations regarding age, disease severity, informed consent availability, inclusion, and exclusion criteria. Notably, the standard mean of overall severe adverse events was moderately high (SAEs: 9.10 ± 7.10%). CONCLUSION: The population investigated is small and heterogeneous, published results from clinical trials are under-represented, severe adverse events not negligible, and cognitive outcomes uncertain. Overall, the validity of these studies requires confirmation based on forthcoming higher-quality clinical trials.

COVID-19-associated Guillain-Barré syndrome in the early pandemic experience in Lombardia (Italy).

OBJECTIVE: To estimate the incidence and describe clinical characteristics and outcome of GBS in COVID-19 patients (COVID19-GBS) in one of the most hit regions during the first pandemic wave, Lombardia. METHODS: Adult patients admitted to 20 Neurological Units between 1/3-30/4/2020 with COVID19-GBS were included as part of a multi-center study organized by the Italian society of Hospital Neuroscience (SNO). RESULTS: Thirty-eight COVID19-GBS patients had a mean age of 60.7 years and male frequency of 86.8%. CSF albuminocytological dissociation was detected in 71.4%, and PCR for SARS-CoV-2 was negative in 19 tested patients. Based on neurophysiology, 81.8% of patients had a diagnosis of AIDP, 12.1% of AMSAN, and 6.1% of AMAN. The course was favorable in 76.3% of patients, stable in 10.5%, while 13.2% worsened, of which 3 died. The estimated occurrence rate in Lombardia ranges from 0.5 to 0.05 GBS cases per 1000 COVID-19 infections depending on whether you consider positive cases or estimated seropositive cases. When we compared GBS cases with the pre-pandemic period, we found a reduction of cases from 165 to 135 cases in the 2-month study period in Lombardia. CONCLUSIONS: We detected an increased incidence of GBS in COVID-19 patients which can reflect a higher risk of GBS in COVID-19 patients and a reduction of GBS events during the pandemic period possibly due to a lower spread of more common respiratory infectious diseases determined by an increased use of preventive measures.

The Interaction between HLA-DRB1 and Smoking in Parkinson's Disease Revisited.

BACKGROUND: Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions. OBJECTIVE: To perform a large-scale independent replication of the HLA-DRB1 × smoking interaction. METHODS: We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA-DRB1. RESULTS: At the amino acid level, a valine at position 11 (V11) in HLA-DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59-0.93, PInteraction  = 0.028). In silico predictions of the influence of V11 and smoking-induced modifications of α-synuclein on binding affinity showed findings consistent with this interaction pattern. CONCLUSIONS: Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study.

BACKGROUND: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. OBJECTIVE: The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). METHODS: We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). RESULTS: Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12-2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37-4.56], P = 0.003; P-difference with women = 0.029). CONCLUSIONS: Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society.

Clinical and metabolic imaging features of late-onset and early-onset posterior cortical atrophy.

BACKGROUND AND PURPOSE: Late-onset (LO) and early-onset (EO) dementia show neurobiological and clinical differences. Clinical and 18 fluoro-deoxy-glucose positron emission tomography (FDG-PET) features of LO and EO posterior cortical atrophy (LO_PCA, EO_PCA), the visual variant of Alzheimer's disease (AD), were compared. LO_PCA patients were also compared with a group of patients with LO typical AD (tAD). METHODS: Thirty-seven LO_PCA patients (onset age ≥ 65 years), 29 EO_PCA patients and 40 tAD patients who all underwent a standard neuropsychological battery were recruited; PCA patients were also assessed for the presence of posterior signs and symptoms. Brain FDG-PET was available in 32 LO_PCA cases, 23 EO_PCA cases and all tAD cases, and their scans were compared with scans from 30 healthy elderly controls. Within the entire PCA sample FDG uptake was also correlated with age at onset as a continuous variable. RESULTS: The main difference between the two PCA groups was a higher prevalence of Bálint-Holmes symptoms in EO cases, which was associated with the presence of severe bilateral occipito-temporo-parietal hypometabolism, whilst LO_PCA patients showed reduction of FDG uptake mainly in the right posterior regions. The latter group also showed mesial temporal hypometabolism, similarly to the tAD group, although with a right rather than left lateralization. Correlation analysis confirmed the association between older age and decreased limbic metabolism and between younger age and decreased left parietal metabolism. CONCLUSIONS: The major involvement of the temporal cortex in LO cases and of the parietal cortex in EO cases reported previously within the AD spectrum holds true also for the visual variant of AD.

Tics: neurological disorders determined by a deficit in sensorimotor gating processes.

Tic related disorders affect 4-20% of the population, mostly idiopathic, can be grouped in a wide spectrum of severity, where the most severe end is Tourette Syndrome (TS). Tics are arrhythmic hyperkinesias to whom execution the subject is forced by a "premonitory urge" that can be classified as sensory tic, just-right experience or urge without obsession. If an intact volitional inhibition allows patients to temporarily suppress tics, a lack or deficit in automatic inhibition is involved in the genesis of the disorder. Studies have assessed the presence of intrinsic microscopic and macroscopic anomalies in striatal circuits and relative cortical areas in association with a hyperdopaminergic state in the basal forebrain. Prepulse inhibition (PPI) of the startle reflex is a measure of inhibitory functions by which a weak sensory stimulus inhibits the elicitation of a startle response determined by a sudden intense stimulus. It is considered an operation measure of sensorimotor gating, a neural process by which unnecessary stimuli are eliminated from awareness. Evidence points out that the limbic domain of the CSTC loops, dopamine and GABA receptors within the striatum play an important role in PPI modulation. It is conceivable that a sensorimotor gating deficit may be involved in the genesis of premonitory urge and symptoms. Therefore, correcting the sensorimotor gating deficit may be considered a target for tic-related disorders therapies; in such case PPI (as well as other indirect estimators of sensorimotor gating) could represent therapeutic impact predictors.

Neurological soft signs are increased in migraine without aura: relationship with the affective status.

INTRODUCTION: Neurological soft signs (NSS) are subtle non-localizing sensorimotor abnormalities initially reported as increased in primary headache patients. The aims of this study were confirming with full power NSS increased expression in migraine and, collaterally, determining if psychiatric traits or white matter lesions at brain imaging could influence this result. METHODS: Forty drug-free episodic migraine outpatients (MH) were recruited with 40 matched controls. NSS were determined by the 16-item Heidelberg scale; depression, anxiety and QoL by the HAM-D; the STAI-X1/X2; and the SF36, respectively. The Fazekas scale on brain MR studies was applied in n = 32 MH, unravelling deep white matter signal alterations (DWM). MH characteristics, including the headache disability inventory (HDI), were recorded. RESULTS: NSS were 46% increased in MH vs. controls (p = 0.0001). HAM-D and STAI-X1/X2 were increased in MH, while SF36 was unchanged, but they all failed to influence NSS, just as MH characteristics. NSS scores were increased in MH-DWM + (n = 11, + 85%) vs. MH-DWM - (n = 21, + 27%) vs. controls (p < 0.0001). NSS increased expression in MH was influenced by DWM, while psychiatric traits and headache characteristics failed to do so. DISCUSSION/CONCLUSIONS: NSS are increased in MH and probably not influenced by the affective status, possibly marking a dysfunction within the cerebellar-thalamic-prefrontal circuit that may deserve further attention from the prognostic point of view.

Neurovascular and infectious disease phenotype of acute stroke patients with and without COVID-19.

BACKGROUND: The infectious disease phenotype of acute stroke associated with COVID-19 has been poorly characterized. OBJECTIVE: We investigated the neurovascular and infectious disease phenotype of stroke patients with and without COVID-19 infection, and their effect on in-hospital mortality. METHODS: This is a retrospective cohort study of consecutive patients with acute stroke, admitted to any ward of a hub hospital for stroke in Lombardy, Italy, during the first wave of COVID-19. Demographic, neurovascular, infectious disease, and respiratory characteristics were collected. The effect of clinical variables on survival was evaluated using logistic regression models. RESULTS: One hundred thirty-seven patients with acute stroke were recruited; 30 (21.9%) patients had COVID-19 and represented 2.5% of the 1218 COVID-19 patients hospitalized in the study period. Demographics, comorbidities, stroke type, stroke severity, and etiology did not differ between COVID + stroke patients and non-COVID stroke patients, except for an excess of multi-embolic ischemic stroke in the COVID + group. Most COVID + stroke patients had symptomatic infection (60%) and interstitial pneumonia (70%). COVID + stroke patients required more frequently respiratory support (77% versus 29%; p < 0.0001) and had higher in-hospital mortality (40% versus 12%; p = 0.0005) than non-COVID stroke patients. Mortality was independently associated with symptomatic interstitial pneumonia (aOR 6.7; 95% CI 2.0-22.5; p = 0.002) and, to a lesser extent, with NIHSS on admission (aOR 1.1; 95% CI 1.03-1.2; p = 0.007) and recanalization therapies (aOR 0.2; 95% CI 0.04-0.98; p = 0.046). CONCLUSION: Symptomatic interstitial pneumonia was the major driver of in-hospital mortality in COVID + stroke patients.

New-onset myasthenia gravis after mRNA SARS-CoV-2 vaccination: a case series.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease that targets acetylcholine receptor (AChR) of the neuromuscular junction. New-onset MG after SARS-CoV-2 vaccination has rarely been reported. CASE PRESENTATION: We report about three patients who presented new-onset myasthenia gravis after receiving mRNA SARS-CoV-2 vaccination. The patients were all males and older than 55 years. All the patients presented with ocular and bulbar symptoms. The interval between vaccine administration and MG onset ranged from 3 days after the first dose to 10 days after the second dose. All the patients had elevated serum AChR antibodies and responded to pyridostigmine. Two out of three patients were successfully treated with IVIG or plasma exchange and with long-term immunosuppression. CONCLUSIONS: MG is a rare disease; clinicians should be aware of possible new-onset MG after SARS-CoV-2 vaccination, especially with the current recommendation of booster doses. The hyperstimulation of the innate immune system or the exacerbation of a subclinical pre-existing MG could be possible explanations.

Brand new norms for a good old test: Northern Italy normative study of MiniMental State Examination.

AIM: Mini-Mental State Examination (MMSE) is one of the most used tests for the screening of global cognition in patients with neurological and medical disorders. Norms for the Italian version of the test were published in the 90 s; more recent norms were published in 2020 for Southern Italy only. In the present study, we computed novel adjustment coefficients, equivalent scores and cut-off value for Northern Italy (Lombardia and Veneto) and Italian speaking Switzerland. METHODS: We recruited 361 healthy young and old (range: 20-95 years) individuals of both sexes (men: 156, women: 205) and from different educational levels (range: 4-22 years). Neuropsychiatric disorders and severe medical conditions were excluded with a questionnaire and cognitive deficits and were ruled out with standardized neuropsychological tests assessing the main cognitive domains. We used a slightly modified version of MMSE: the word 'fiore' was replaced with 'pane' in verbal recalls to reduce the common interference error 'casa, cane, gatto'. The effect of socio-demographic features on performance at MMSE was assessed via multiple linear regression, with test raw score as dependent variable and sex, logarithm of 101-age and square root of schooling as predictors. RESULTS: Mean raw MMSE score was 28.8 ± 1.7 (range: 23-30). Multiple linear regression showed a significant effect of all socio-demographic variables and reported a value of R2 = 0.26. The new cut off was ≥ 26 /30. CONCLUSION: We provide here updated norms for a putatively more accurate version of Italian MMSE, produced in a Northern population but potentially valid all over Italy.

Neuroprotection and Non-Invasive Brain Stimulation: Facts or Fiction?

Non-Invasive Brain Stimulation (NIBS) techniques, such as transcranial Direct Current Stimulation (tDCS) and repetitive Magnetic Transcranial Stimulation (rTMS), are well-known non-pharmacological approaches to improve both motor and non-motor symptoms in patients with neurodegenerative disorders. Their use is of particular interest especially for the treatment of cognitive impairment in Alzheimer's Disease (AD), as well as axial disturbances in Parkinson's (PD), where conventional pharmacological therapies show very mild and short-lasting effects. However, their ability to interfere with disease progression over time is not well understood; recent evidence suggests that NIBS may have a neuroprotective effect, thus slowing disease progression and modulating the aggregation state of pathological proteins. In this narrative review, we gather current knowledge about neuroprotection and NIBS in neurodegenerative diseases (i.e., PD and AD), just mentioning the few results related to stroke. As further matter of debate, we discuss similarities and differences with Deep Brain Stimulation (DBS)-induced neuroprotective effects, and highlight possible future directions for ongoing clinical studies.

Comorbidities in patients with epilepsy: Frequency, mechanisms and effects on long-term outcome.

OBJECTIVE: To assess frequency, types, and mechanisms of comorbidities in people with epilepsy and verify their association with disease features and outcome. METHODS: This cohort study was performed in 13 Italian epilepsy centers with nationwide distribution and accurate records. Eligible patients were children and adults diagnosed before December 31, 2005, and followed for a minimum of 10 years. Two pairs of raters independently reviewed patients' records and classified each comorbidity. In case of disagreement, a third reviewer made the final decision. Comorbidities were classified according to type (organ/system) and underlying mechanism (causal, shared risk factors, chance association). Comorbidity types and mechanisms were described in the entire sample and according to epilepsy prognostic patterns (sustained remission, relapsing-remitting course, no remission). RESULTS: Of 1006 included patients, 266 (26.4%) had at least one comorbidity. The most common were developmental/perinatal (7.5% of cases), psychiatric (6.2%), cardiovascular (5.3%), and endocrine/metabolic (3.8%). Among 408 reported comorbidities, the underlying mechanisms were, in decreasing order, chance association (42.2%), shared risk factors (31.1%), and causal (26.7%). Psychiatric diseases were present in 13.3% of patients with no remission, 5.9% of patients with relapsing-remitting course, and 4.8% of patients with sustained remission (p = .016). The corresponding numbers for endocrine/metabolic diseases were respectively, 9.6%, 3.4%, and 2.9% (p = .013); for respiratory diseases were 3.6%, .3%, and .3% (p = .001), and for urogenital diseases were 3.6%, .7%, and 1.6% (p = .048). The association of endocrine/metabolic, psychiatric, and respiratory comorbidities with epilepsy prognosis was confirmed by multivariable analysis adjusted for the main demographic and clinical variables, with patients with these comorbidities showing a lower probability of achieving remission. SIGNIFICANCE: Comorbidities in epilepsy are not uncommon and reflect differing underlying mechanisms. Psychiatric, endocrine/metabolic, and respiratory disorders are associated with a worse long-term epileptological outcome.

Discontinuation of antiseizure medications in seizure-free patients with long-term follow-up: Patients' profile, seizure recurrence, and risk factors.

OBJECTIVE: To compare withdrawal of antiseizure medications (ASM) to continued treatment in newly diagnosed individuals achieving seizure freedom, and assess the risk of relapse and factors associated with relapse. METHODS: This is a multicenter retrospective cohort study with long-term follow-up. Patients with newly diagnosed epilepsy were identified from the medical records of 13 Italian epilepsy centers and followed up until the most recent visit or death. Seizure-free patients discontinuing treatment were compared to patients who maintained treatment for baseline characteristics. Treatment was stopped upon clinical judgment. The probability of relapse was calculated with the Kaplan-Meier method. Demographic, clinical, and instrumental variables associated with relapse were assessed with Cox proportional hazards models. RESULTS: One thousand and six patients aged 1 month to 72 years at diagnosis were enrolled and followed up for 17,892 person-years (median follow-up, 9.9 years). Three hundred and twenty patients (31.8%) underwent one or more treatment discontinuations. Factors associated with ASM withdrawal were younger age at remission and normal psychiatric examination. The probability of relapse after the first withdrawal was 16% at six months, 24% at 12 months, and 36%, 45%, and 53% at three, five, and ten years, respectively. The probability of remission after the first relapse was 59% at one month, 67%, 72, and 76% at three, six, and 12 months, respectively. Variables associated with relapse were age 14+ years, structural etiology, abnormal neuroimaging, ASM initiation after a single seizure, and symptomatic/cryptogenic epilepsy. CONCLUSIONS: About one half of seizure-free patients stopping ASM relapse in 10 years. However, the possibility of remission after relapse is high, particularly in children and patients with idiopathic/cryptogenic epilepsy. Treatment deprescription might be encouraged at least in these patients.