A "glympse" into neurodegeneration: Diffusion MRI and cerebrospinal fluid aquaporin-4 for the assessment of glymphatic system in Alzheimer's disease and other dementias.

The glymphatic system (GS) is a whole-brain perivascular network, consisting of three compartments: the periarterial and perivenous spaces and the interposed brain parenchyma. GS dysfunction has been implicated in neurodegenerative diseases, particularly Alzheimer's disease (AD). So far, comprehensive research on GS in humans has been limited by the absence of easily accessible biomarkers. Recently, promising non-invasive methods based on magnetic resonance imaging (MRI) along with aquaporin-4 (AQP4) quantification in the cerebrospinal fluid (CSF) were introduced for an indirect assessment of each of the three GS compartments. We recruited 111 consecutive subjects presenting with symptoms suggestive of degenerative cognitive decline, who underwent 3 T MRI scanning including multi-shell diffusion-weighted images. Forty nine out of 111 also underwent CSF examination with quantification of CSF-AQP4. CSF-AQP4 levels and MRI measures-including perivascular spaces (PVS) counts and volume fraction (PVSVF), white matter free water fraction (FW-WM) and mean kurtosis (MK-WM), diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) (mean, left and right)-were compared among patients with AD (n = 47) and other neurodegenerative diseases (nAD = 24), patients with stable mild cognitive impairment (MCI = 17) and cognitively unimpaired (CU = 23) elderly people. Two runs of analysis were conducted, the first including all patients; the second after dividing both nAD and AD patients into two subgroups based on gray matter atrophy as a proxy of disease stage. Age, sex, years of education, and scanning time were included as confounding factors in the analyses. Considering the whole cohort, patients with AD showed significantly higher levels of CSF-AQP4 (exp(b) = 2.05, p = .005) and FW-WM FW-WM (exp(b) = 1.06, p = .043) than CU. AQP4 levels were also significantly higher in nAD in respect to CU (exp(b) = 2.98, p < .001). CSF-AQP4 and FW-WM were significantly higher in both less atrophic AD (exp(b) = 2.20, p = .006; exp(b) = 1.08, p = .019, respectively) and nAD patients (exp(b) = 2.66, p = .002; exp(b) = 1.10, p = .019, respectively) compared to CU subjects. Higher total (exp(b) = 1.59, p = .013) and centrum semiovale PVS counts (exp(b) = 1.89, p = .016), total (exp(b) = 1.50, p = .036) and WM PVSVF (exp(b) = 1.89, p = .005) together with lower MK-WM (exp(b) = 0.94, p = .006), mean and left ALPS (exp(b) = 0.91, p = .043; exp(b) = 0.88, p = .010 respectively) were observed in more atrophic AD patients in respect to CU. In addition, more atrophic nAD patients exhibited higher levels of AQP4 (exp(b) = 3.39, p = .002) than CU. Our results indicate significant changes in putative MRI biomarkers of GS and CSF-AQP4 levels in AD and in other neurodegenerative dementias, suggesting a close interaction between glymphatic dysfunction and neurodegeneration, particularly in the case of AD. However, the usefulness of some of these biomarkers as indirect and standalone indices of glymphatic activity may be hindered by their dependence on disease stage and structural brain damage.

Are patients with GBA-Parkinson disease good candidates for deep brain stimulation? A longitudinal multicentric study on a large Italian cohort.

BACKGROUND: GBA variants increase the risk of developing Parkinson disease (PD) and influence its outcome. Deep brain stimulation (DBS) is a recognised therapeutic option for advanced PD. Data on DBS long-term outcome in GBA carriers are scarce. OBJECTIVE: To elucidate the impact of GBA variants on long-term DBS outcome in a large Italian cohort. METHODS: We retrospectively recruited a multicentric Italian DBS-PD cohort and assessed: (1) GBA prevalence; (2) pre-DBS clinical features; and (3) outcomes of motor, cognitive and other non-motor features up to 5 years post-DBS. RESULTS: We included 365 patients with PD, of whom 73 (20%) carried GBA variants. 5-year follow-up data were available for 173 PD, including 32 mutated subjects. GBA-PD had an earlier onset and were younger at DBS than non-GBA-PD. They also had shorter disease duration, higher occurrence of dyskinesias and orthostatic hypotension symptoms.At post-DBS, both groups showed marked motor improvement, a significant reduction of fluctuations, dyskinesias and impulsive-compulsive disorders (ICD) and low occurrence of most complications. Only cognitive scores worsened significantly faster in GBA-PD after 3 years. Overt dementia was diagnosed in 11% non-GBA-PD and 25% GBA-PD at 5-year follow-up. CONCLUSIONS: Evaluation of long-term impact of GBA variants in a large Italian DBS-PD cohort supported the role of DBS surgery as a valid therapeutic strategy in GBA-PD, with long-term benefit on motor performance and ICD. Despite the selective worsening of cognitive scores since 3 years post-DBS, the majority of GBA-PD had not developed dementia at 5-year follow-up.

Are we social enough? Use of social media among members of the Italian Society of Neurology for the study of dementia.

BACKGROUND: Clinical researchers increasingly embrace social media in their professional lives. The digital revolution has provided new routes for sharing data, disseminating results, and promoting the impact of scientific findings. In this study, we explored the attitude of the members of the Italian Society of Neurology for the study of dementia (SINdem) to use social media with the aim to set up possible corrective actions to maximize digitalization benefits at the individual and community levels. METHOD: An ad hoc designed survey was implemented and distributed to the SINdem and SINdem4Juniors communities. It explored the different use of social media taking into account frequency, type of social media use (active vs passive; professional vs private). Descriptive statistical analyses were performed alongside statistical comparisons to highlight possible differences in the use. RESULTS: We collected 133 answers showing a prominent use of social media in private life (t(132) = 21.1, p < 0.001), with SINdem4Juniors members showing a higher private use compared to the older SINdem colleagues. Professional use was mainly limited to passive activities such as following others' social profiles (t(132) = 11.9, p < 0.001). DISCUSSION: Overall scenario suggests that professional use of social media is very limited in both SINdem and SINdem4juniors communities. This evidence points to an urgent need for training interventions and top-down strategies aimed at improving collaboration, dissemination, and sharing through social media among individuals belonging to the same scientific-professional community.

Precuneus magnetic stimulation for Alzheimer's disease: a randomized, sham-controlled trial.

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.

15-Year Subthalamic Deep Brain Stimulation outcome in a Parkinson's disease patient with Parkin gene mutation: a case report.

INTRODUCTION: Parkinson's Disease (PD) patients with Parkin gene (PRKN) mutations show good response to subthalamic deep brain stimulation (STN-DBS). Currently, the longest follow-up available of these patients is 6 years. We report a very long-term outcome (more than 15 years) of a STN-DBS-treated patient with a compound heterozygous deletion of exons 3 and 11 of the PRKN gene. CASE REPORT: In 1993, a 39-year-old male was diagnosed with PD after the onset of resting tremor. Levodopa was started, and during the following 10 years, he reported good motor symptoms control, with only mild modification of levodopa intake and pramipexole introduction. In 2005, he developed disabling motor fluctuations and dyskinesia. In 2007, he underwent bilateral STN-DBS, with a marked improvement of motor symptoms and fluctuations during the following years. After 6 years, he reported mild motor fluctuations, improved after stimulation and treatment modifications. After 10 years he showed diphasic dyskinesias, feet dystonia, postural instability, and gambling (resolved after pramipexole discontinuation). In 2018, he developed a non-amnestic single-domain mild cognitive impairment (MCI). In 2023, after more than 15 years of STN-DBS, motor symptoms and fluctuations are still well controlled. He reports mild dysphagia, mild depression, and multiple-domain MCI. His quality of life is better than before surgery, and he still reports a subjective significant improvement from STN-DBS. CONCLUSION: Confirming the very long-term efficacy of STN-DBS in PRKN-mutated patients, our case report underlines their peculiar suitability for surgical treatment.

Aberrant Cerebello-Cerebral Connectivity in Remitted Bipolar Patients 1 and 2: New Insight into Understanding the Cerebellar Role in Mania and Hypomania.

Bipolar disorder (BD) is a major mental illness characterized by periods of (hypo) mania and depression with inter-episode remission periods. Functional studies in BD have consistently implicated a set of linked cortical and subcortical limbic regions in the pathophysiology of the disorder, also including the cerebellum. However, the cerebellar role in the neurobiology of BD still needs to be clarified. Seventeen euthymic patients with BD type1 (BD1) (mean age/SD, 38.64/13.48; M/F, 9/8) and 13 euthymic patients with BD type 2 (BD2) (mean age/SD, 41.42/14.38; M/F, 6/7) were compared with 37 sex- and age-matched healthy subjects (HS) (mean age/SD, 45.65/14.15; M/F, 15/22). T1 weighted and resting-state functional connectivity (FC) scans were acquired. The left and right dentate nucleus were used as seed regions for the seed based analysis. FC between each seed and the rest of the brain was compared between patients and HS. Correlations between altered cerebello-cerebral connectivity and clinical scores were then investigated. Different patterns of altered dentate-cerebral connectivity were found in BD1 and BD2. Overall, impaired dentate-cerebral connectivity involved regions of the anterior limbic network specifically related to the (hypo)manic states of BD. Cerebello-cerebral connectivity is altered in BD1 and BD2. Interestingly, the fact that these altered FC patterns persist during euthymia, supports the hypothesis that cerebello-cerebral FC changes reflect the neural correlate of subthreshold symptoms, as trait-based pathophysiology and/or compensatory mechanism to maintain a state of euthymia.

Relapsing-remitting and secondary-progressive multiple sclerosis patients differ in decoding others' emotions by their eyes.

BACKGROUND AND PURPOSE: Difficulties in emotion processing and social cognition identified in multiple sclerosis (MS) patients have a potential impact on their adaptation to the social environment. We aimed to explore the neural correlates of emotion recognition in MS and possible differences between relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) patients by the Reading the Mind in the Eyes test (RMEt). METHODS: A total of 43 MS patients (27 RRMS, 16 SPMS) and 25 matched healthy controls (HC) underwent clinical assessments, RMEt, and a high-resolution T1-weighted 3-T magnetic resonance imaging (MRI) scan. The number of correct answers on the RMEt was compared between groups. T1-weighted volumes were processed according to an optimized voxel-based morphometry (VBM) protocol to obtain gray matter (GM) maps. Voxelwise analyses were run to assess potential associations between RMEt performance and regional GM volumes. RESULTS: Taken altogether, MS patients reported significantly lower performance on the RMEt compared to HC. When dividing the patients into those with RRMS and those with SPMS, only the latter group was found to perform significantly worse than HC on the RMEt. VBM analysis revealed significant association between RMEt scores and GM volumes in several cortical (temporoparieto-occipital cortex) and subcortical (hippocampus, parahippocampus, and basal ganglia) brain regions, and in the cerebellum in SPMS patients only. CONCLUSIONS: Results suggest that, in addition to other clinical differences between RRMS and SPMS, the ability to recognize others' emotional states may be affected in SPMS more significantly than RRMS patients. This is supported by both behavioral and MRI data.

Burden of caregiving for cardiovascular dysautonomia in Parkinson's disease.

PURPOSE: We sought to estimate the impact of cardiovascular autonomic neuropathy (cAN) on informal caregivers of patients with Parkinson's disease (PD), defined as individuals providing regular care to a friend, partner, or family member with PD, and to evaluate the mutual relationship between caregiver burden and patient health-related quality of life (HRQoL). METHODS: We enrolled 36 consecutive patients with PD and their informal caregivers. Patients underwent a detailed motor, autonomic, cognitive, and functional assessment. Caregivers were assessed using the Zarit Burden Interview (ZBI). Differences in caregiver burden, expressed by the ZBI score, and strength of association between caregiver burden, cAN, and HRQoL were assessed using analysis of covariance (ANCOVA), logistic regression, and linear regression analyses. Analyses were adjusted for patients' age, PD duration, and motor and cognitive disability, as well as caregivers' age. RESULTS: Moderate-severe caregiver burden was reported in 41.7% of PDcAN+ versus 8.7% of PDcAN- (p < 0.001). The ZBI score was increased in PDcAN+ versus PDcAN- (31.5 ± 3.4 versus 15.2 ± 2.3; p < 0.001), with tenfold higher odds (p = 0.012) of moderate-severe caregiver burden in PDcAN+, even after adjusting for potential confounders. The ZBI score correlated with cAN severity (p = 0.005), global autonomic impairment (p = 0.012), and HRQoL impairment (p < 0.001). CONCLUSION: These results highlight the significant impact of cAN on PD caregivers and the need for targeted interventions addressing this frequently overlooked and insufficiently treated source of nonmotor disability in PD.

Anxiety, depression, and worries in advanced Parkinson disease during COVID-19 pandemic.

BACKGROUND: The psychological impact of the COVID-19 outbreak and lockdown on frail populations with advanced Parkinson disease (APD) and their caregivers may present with peculiar features and require specific interventions. METHODS: We enrolled here 100 APD patients and 60 caregivers. Seventy-four patients were treated with device-aided therapies (DAT) and 26 with standard medical treatment (SMT). Through a telephonic interview, subjects underwent the Hospital Anxiety and Depression Scale (HADS-A; HADS-D), and an ad hoc questionnaire to explore thoughts and emotions related to the pandemic. RESULTS: Depression was observed in 35% of APD patients and anxiety in 39%, with a significant reduction of the latter after the lockdown (p= 0.023). We found a significant correlation between the type of therapy and the HADS-A score (p= 0.004). Patients' main worries were as follows: a possible higher risk of COVID-19 infection (25%), interruption of non-pharmacological treatments (35%), interruption of outpatient clinics (38%), PD complications related to COVID-19 (47%). Patients treated with DAT manifested worries about device-related issues and risk for caregivers' infection. The 40% of caregivers showed anxiety, while the 21.7% of them showed depression. CONCLUSION: Our study reveals a higher prevalence of anxiety and the presence of peculiar worries and needs in APD patients during the pandemic alongside psychological sequelae of their caregivers. These findings are important for neurologists and healthcare services to foster strategies for the management of psychological distress in both patients and caregivers.

Accuracy of the clinical diagnosis of dementia with Lewy bodies (DLB) among the Italian Dementia Centers: a study by the Italian DLB study group (DLB-SINdem).

INTRODUCTION: Dementia with Lewy bodies (DLB) may represent a diagnostic challenge, since its clinical picture overlaps with other dementia. Two toolkits have been developed to aid the clinician to diagnose DLB: the Lewy Body Composite Risk Score (LBCRS) and the Assessment Toolkit for DLB (AT-DLB). We aim to evaluate the reliability of these two questionnaires, and their ability to enhance the interpretation of the international consensus diagnostic criteria. METHODS: LBCRS and AT-DLB were distributed to 135 Italian Neurological Centers for Cognitive Decline and Dementia (CDCDs), with the indication to administer them to all patients with dementia referred within the subsequent 3 months. We asked to subsequently apply consensus criteria for DLB diagnosis, to validate the diagnostic accuracy of the two toolkits. RESULTS: A total of 23 Centers joined the study; 1854 patients were enrolled. We found a prevalence of possible or probable DLB of 13% each (26% total), according to the consensus criteria. LBCRS toolkit showed good reliability, with a Cronbach alpha of 0.77, stable even after removing variables from the construct. AT-DLB toolkit Cronbach alpha was 0.52 and, after the subtraction of the "cognitive fluctuation" criterion, was only 0.31. Accuracy, sensitivity, and specificity were higher for LBCRS vs. AT-DLB. However, when simultaneously considered in the logistic models, AT-DLB showed a better performance (p < 0.001). Overall, the concordance between LBCRS positive and AT-DLB possible/probable was of 78.02% CONCLUSIONS: In a clinical setting, the LBCRS and AT-DLB questionnaires have good accuracy for DLB diagnosis.

Detection of Alzheimer's Disease using cortical diffusion tensor imaging.

The aim of this research was to test a novel in-vivo brain MRI analysis method that could be used in clinical cohorts to investigate cortical architecture changes in patients with Alzheimer's Disease (AD). Three cohorts of patients with probable AD and healthy volunteers were used to assess the results of the method. The first group was used as the "Discovery" cohort, the second as the "Test" cohort and the last "ATN" (Amyloid, Tau, Neurodegeneration) cohort was used to test the method in an ADNI 3 cohort, comparing to amyloid and Tau PET. The method can detect altered quality of cortical grey matter in AD patients, providing an additional tool to assess AD, distinguishing between these and healthy controls with an accuracy range between good and excellent. These new measurements could be used within the "ATN" framework as an index of cortical microstructure quality and a marker of Neurodegeneration. Further development may aid diagnosis, patient selection, and quantification of the "Neurodegeneration" component in response to therapies in clinical trials.

Evidence for interhemispheric imbalance in stroke patients as revealed by combining transcranial magnetic stimulation and electroencephalography.

Interhemispheric interactions in stroke patients are frequently characterized by abnormalities, in terms of balance and inhibition. Previous results showed an impressive variability, mostly given to the instability of motor-evoked potentials when evoked from the affected hemisphere. We aim to find reliable interhemispheric measures in stroke patients with a not-evocable motor-evoked potential from the affected hemisphere, by combining transcranial magnetic stimulation (TMS) and electroencephalography. Ninteen stroke patients (seven females; 61.26 ± 9.8 years) were studied for 6 months after a first-ever stroke in the middle cerebral artery territory. Patients underwent four evaluations: clinical, cortical, corticospinal, and structural. To test the reliability of our measures, the evaluations were repeated after 3 weeks. To test the sensitivity, 14 age-matched healthy controls were compared to stroke patients. In stroke patients, stimulation of the affected hemisphere did not result in any inhibition onto the unaffected. The stimulation of the unaffected hemisphere revealed a preservation of the inhibition mechanism onto the affected. This resulted in a remarkable interhemispheric imbalance, whereas this mechanism was steadily symmetric in healthy controls. This result was stable when cortical evaluation was repeated after 3 weeks. Importantly, patients with a better recovery of the affected hand strength were the ones with a more stable interhemispheric balance. Finally, we found an association between microstructural integrity of callosal fibers, suppression of interhemispheric TMS-evoked activity and interhemispheric connectivity. We provide direct and sensitive cortical measures of interhemispheric imbalance in stroke patients. These measures offer a reliable means of distinguishing healthy and pathological interhemispheric dynamics.

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.

Focal seizures with impaired awareness as long-term neurological complication of COVID-19: a case report.

We report here the first case of a young individual otherwise healthy, who presented with frequent focal seizures with impaired awareness as a possible long-term complication of severe acute respiratory syndrome coronavirus-2 infection. Seizures were documented by electroencephalography and responded clinically and neuro-physiologically to antiseizure therapy. The patient underwent an extensive investigation including cerebrospinal fluid examination, conventional and quantitative brain magnetic resonance imaging, and 18-FDG positron emission tomography. Beyond the clinical interest, this case contributes to clarify the possible pathways by which SARS-CoV-2 may enter the central nervous system and cause long-term neurological complications.

Myasthenia gravis and telemedicine: a lesson from COVID-19 pandemic.

COVID-19 pandemic has induced an urgent reorganization of the healthcare system to ensure continuity of care for patients affected by chronic neurological diseases including myasthenia gravis (MG). Due to the fluctuating nature of the disease, early detection of disease worsening, adverse events, and possibly life-threatening complications is mandatory. This work analyzes the main unresolved issues in the management of the myasthenic patient, the possibilities offered so far by digital technologies, and proposes an online evaluation protocol based on 4 simple tests to improve MG management. Telemedicine and Digital Technology might help neurologists in the clinical decision-making process of MG management, avoiding unnecessary in presence consultations and allowing a rational use of the time and space reduced by the pandemic.

Early reversible leukoencephalopathy and unilateral sixth cranial nerve palsy in mild COVID-19 infection.

OBJECTIVES: To provide new insights into neurological manifestations of COVID-19. We describe a patient with mild COVID-19 associated with diplopia from right sixth cranial nerve palsy and early diffuse leukoencephalopathy, successfully treated with intravenous methylprednisolone. METHODS: The patient was evaluated for diplopia that occurred 1 day after the onset of fever, myalgia, and headache. A complete neurological workup, including neurological examination, cerebrospinal fluid (CSF) analysis with viral polymerase chain reaction (PCR), serum autoimmune encephalitis, and anti-nerve antibodies and brain magnetic resonance imaging (MRI), was performed. RESULTS: Clinical examination revealed incomplete right sixth cranial nerve palsy. Brain MRI showed diffuse confluent fluid-attenuated inversion recovery (FLAIR) hyperintense white matter abnormalities, while CSF analysis showed mild hyperproteinorrachia (61 mg/dL) without pleocytosis. The patients were treated with high-dose intravenous methylprednisolone with rapid improvement of neurological symptoms and resolution of CSF and MRI abnormalities. DISCUSSION: Our report shows that COVID-19 may predominantly present with neurological symptoms; furthermore, it argues the notion of leukoencephalopathy as a typical feature of a severe case of the disease. Mechanisms underpinning neurological symptoms in COVID-19 still need to be elucidated; nonetheless, early recognition and prompt management may ensure their improvement or even complete recovery and are therefore recommended.

Comparison of Cerebellar Grey Matter Alterations in Bipolar and Cerebellar Patients: Evidence from Voxel-Based Analysis.

The aim of this study was to compare the patterns of cerebellar alterations associated with bipolar disease with those induced by the presence of cerebellar neurodegenerative pathologies to clarify the potential cerebellar contribution to bipolar affective disturbance. Twenty-nine patients affected by bipolar disorder, 32 subjects affected by cerebellar neurodegenerative pathologies, and 37 age-matched healthy subjects underwent a 3T MRI protocol. A voxel-based morphometry analysis was used to show similarities and differences in cerebellar grey matter (GM) loss between the groups. We found a pattern of GM cerebellar alterations in both bipolar and cerebellar groups that involved the anterior and posterior cerebellar regions (p = 0.05). The direct comparison between bipolar and cerebellar patients demonstrated a significant difference in GM loss in cerebellar neurodegenerative patients in the bilateral anterior and posterior motor cerebellar regions, such as lobules I-IV, V, VI, VIIIa, VIIIb, IX, VIIb and vermis VI, while a pattern of overlapping GM loss was evident in right lobule V, right crus I and bilateral crus II. Our findings showed, for the first time, common and different alteration patterns of specific cerebellar lobules in bipolar and neurodegenerative cerebellar patients, which allowed us to hypothesize a cerebellar role in the cognitive and mood dysregulation symptoms that characterize bipolar disorder.

Changes in functional connectivity in people with HIV switching antiretroviral therapy.

We assessed changes in functional connectivity by fMRI (functional magnetic resonance imaging) and cognitive measures in otherwise neurologically asymptomatic people with HIV (PWH) switching combination antiretroviral therapy (cART). In a prospective study (baseline and follow-up after at least 4 months), virologically suppressed PWH switched non-nuclease reverse-transcriptase inhibitors (NNRTI; tenofovir-DF/emtricitabine with efavirenz to rilpivirine) and integrase-strand-transfer inhibitors (INSTI; tenofovir-DF/emtricitabine with raltegravir to dolutegravir). PWH were assessed by resting-state fMRI and stop-signal reaction time (SSRT) task fMRI as well as with a cognitive battery (CogState™) at baseline and follow-up. Switching from efavirenz to rilpivirine (n = 10) was associated with increased functional connectivity in the dorsal attention network (DAN) and a reduction in SSRTs (p = 0.025) that positively correlated with the time previously on efavirenz (mean = 4.8 years, p = 0.02). Switching from raltegravir to dolutegravir (n = 12) was associated with increased connectivity in the left DAN and bilateral sensory-motor and associative visual networks. In the NNRTI study, significant improvements in the cognitive domains of executive function, working memory and speed of visual processing were observed, whereas no significant changes in cognitive function were observed in the INSTI study. Changes in fMRI are evident in PWH without perceived neuropsychiatric complaints switching cART. fMRI may be a useful tool in assisting to elucidate the underlying pathogenic mechanisms of cART-related neuropsychiatric effects.

Evolutionary modifications in human brain connectivity associated with schizophrenia.

The genetic basis and human-specific character of schizophrenia has led to the hypothesis that human brain evolution may have played a role in the development of the disorder. We examined schizophrenia-related changes in brain connectivity in the context of evolutionary changes in human brain wiring by comparing in vivo neuroimaging data from humans and chimpanzees, one of our closest living evolutionary relatives and a species with which we share a very recent common ancestor. We contrasted the connectome layout between the chimpanzee and human brain and compared differences with the pattern of schizophrenia-related changes in brain connectivity as observed in patients. We show evidence of evolutionary modifications of human brain connectivity to significantly overlap with the cortical pattern of schizophrenia-related dysconnectivity (P < 0.001, permutation testing). We validated these effects in three additional, independent schizophrenia datasets. We further assessed the specificity of effects by examining brain dysconnectivity patterns in seven other psychiatric and neurological brain disorders (including, among others, major depressive disorder and obsessive-compulsive disorder, arguably characterized by behavioural symptoms that are less specific to humans), which showed no such associations with modifications of human brain connectivity. Comparisons of brain connectivity across humans, chimpanzee and macaques further suggest that features of connectivity that evolved in the human lineage showed the strongest association to the disorder, that is, brain circuits potentially related to human evolutionary specializations. Taken together, our findings suggest that human-specific features of connectome organization may be enriched for changes in brain connectivity related to schizophrenia. Modifications in human brain connectivity in service of higher order brain functions may have potentially also rendered the brain vulnerable to brain dysfunction.

The impact of lacosamide on mood disorders in adult patients with epilepsy: A systematic review.

Mood disorders such as depression and anxiety have a high prevalence in adult patients with epilepsy, and their evaluation is crucial in choosing the most appropriate antiepileptic drug (AED) with regard to side effects, which can account for long-term discontinuation, poor compliance, and ultimately, failure of seizure control. While more evidence is provided for older AEDs on their effect on mood changes, newer AEDs such as lacosamide have not yet been extensively studied. We performed a systematic review of the literature available on the impact of lacosamide on mood in adult patients with epilepsy. A literature search on MEDLINE, COCHRANE, Scielo, and Clinicaltrials.gov databases was performed, and articles where mood scales where specifically reported as primary or secondary outcome measures were included. Articles differed greatly in terms of inclusion criteria, concomitant AEDs, seizure reduction control, and outcome measures. If lacosamide is used as add-on, two studies point towards a beneficial effect on depressive and anxiety symptoms, two studies claim no effects on mood, and one reports a positive effect only in patients with major depressive symptoms at baseline. Additional evidence from either retrospective or comparative drug studies indicates no effects of lacosamide on mood. Even though presently, a negative effect on mood seems unlikely, whether lacosamide could exert a beneficial impact on mood remains controversial. Multicenter, randomized, controlled, double-blind studies are needed to assess the impact on lacosamide on mood disorders, given the low evidence level (Class III and IV) of currently available studies.