The dynamics of cyclic-periodic phenomena during non-rapid and rapid eye movement sleep.

Sleep is a complex physiological state characterized by distinct stages, each exhibiting unique electroencephalographic patterns and physiological phenomena. Sleep research has unveiled the presence of intricate cyclic-periodic phenomena during both non-rapid eye movement and rapid eye movement sleep stages. These phenomena encompass a spectrum of rhythmic oscillations and periodic events, including cyclic alternating pattern, periodic leg movements during sleep, respiratory-related events such as apneas, and heart rate variability. This narrative review synthesizes empirical findings and theoretical frameworks to elucidate the dynamics, interplay and implications of cyclic-periodic phenomena within the context of sleep physiology. Furthermore, it invokes the clinical relevance of these phenomena in the diagnosis and management of sleep disorders.

Sex-based disparities in dopamine agonist response in patients with restless legs syndrome.

This study aimed to investigate sex-related differences in the response to ropinirole and pramipexole in patients with restless legs syndrome (RLS). By analysing clinical parameters and polysomnographic (PSG) findings, we sought to elucidate the potential factors related to sex disparities modulating treatment responses and sleep quality in RLS. A total of 41 drug-free patients with RLS, aged ≥18 years, underwent two consecutive nocturnal PSG recordings, without medication at baseline; before the second night, 26 patients received an oral dose of 0.25 mg pramipexole whereas 15 received 0.5 mg ropinirole. After each PSG recording, patients self-evaluated the severity of their previous night symptoms by means of an ad hoc visual analogue scale (VAS). At baseline, sleep efficiency and percentage of Stage N2 tended to be higher in females while wakefulness after sleep onset was significantly higher in males. After treatment, total leg movements during sleep (LMS), periodic LMS (PLMS), and periodicity indexes were significantly lower in females than in males. The VAS score was lower after treatment in all patients, without differences between the two sexes. This study demonstrates a higher acute responsiveness of PLMS to dopamine agonists (pramipexole and ropinirole) in females than in males with RLS. These findings might be explained by differential sex-related expression of dopamine receptors, especially D3, within the central nervous system. In addition, our findings provide translational hints toward a better tailored and sex-specific approach to the treatment of RLS associated with PLMS, with dopamine agonist possibly associated with a better outcome in females than in males.

COVID-19 and Mental Health: A "Pandemic Within a Pandemic".

The COVID-19 pandemic has brought significant changes in daily life for humanity and has had a profound impact on mental health. As widely acknowledged, the pandemic has led to notable increases in rates of anxiety, depression, distress, and other mental health-related issues, affecting both infected patients and non-infected individuals. COVID-19 patients and survivors face heightened risks for various neurological and psychiatric disorders and complications. Vulnerable populations, including those with pre-existing mental health conditions and individuals living in poverty or frailty, may encounter additional challenges. Tragically, suicide rates have also risen, particularly among young people, due to factors such as unemployment, financial crises, domestic violence, substance abuse, and social isolation. Efforts are underway to address these mental health issues, with healthcare professionals urged to regularly screen both COVID-19 and post-COVID-19 patients and survivors for psychological distress, ensuring rapid and appropriate interventions. Ongoing periodic follow-up and multidimensional, interdisciplinary approaches are essential for individuals experiencing long-term psychiatric sequelae. Preventive strategies must be developed to mitigate mental health problems during both the acute and recovery phases of COVID-19 infection. Vaccination efforts continue to prioritize vulnerable populations, including those with mental health conditions, to prevent future complications. Given the profound implications of mental health problems, including shorter life expectancy, diminished quality of life, heightened distress among caregivers, and substantial economic burden, it is imperative that political and health authorities prioritize the mental well-being of all individuals affected by COVID-19, including infected individuals, non-infected individuals, survivors, and caregivers.

Gene Expression Profiling of Post Mortem Midbrain of Parkinson's Disease Patients and Healthy Controls.

Parkinson's disease (PD) stands as the most prevalent degenerative movement disorder, marked by the degeneration of dopaminergic neurons in the substantia nigra of the midbrain. In this study, we conducted a transcriptome analysis utilizing post mortem mRNA extracted from the substantia nigra of both PD patients and healthy control (CTRL) individuals. Specifically, we acquired eight samples from individuals with PD and six samples from CTRL individuals, with no discernible pathology detected in the latter group. RNA sequencing was conducted using the TapeStation 4200 system from Agilent Technologies. A total of 16,148 transcripts were identified, with 92 mRNAs displaying differential expression between the PD and control groups. Specifically, 33 mRNAs were significantly up-regulated, while 59 mRNAs were down-regulated in PD compared to the controls. The identification of statistically significant signaling pathways, with an adjusted p-value threshold of 0.05, unveiled noteworthy insights. Specifically, the enriched categories included cardiac muscle contraction (involving genes such as ATPase Na+/K+ transporting subunit beta 2 (ATP1B2), solute carrier family 8 member A1 (SLC8A1), and cytochrome c oxidase subunit II (COX2)), GABAergic synapse (involving GABA type A receptor-associated protein-like 1 (GABARAPL1), G protein subunit beta 5 (GNB5), and solute carrier family 38 member 2 (SLC38A2), autophagy (involving GABARAPL1 and tumor protein p53-inducible nuclear protein 2 (TP53INP2)), and Fc gamma receptor (FcγR) mediated phagocytosis (involving amphiphysin (AMPH)). These findings uncover new pathophysiological dimensions underlying PD, implicating genes associated with heart muscle contraction. This knowledge enhances diagnostic accuracy and contributes to the advancement of targeted therapies.

Neurobiology and Applications of Inositol in Psychiatry: A Narrative Review.

Inositol is a natural sugar-like compound, commonly present in many plants and foods. It is involved in several biochemical pathways, most of them controlling vital cellular mechanisms, such as cell development, signaling and nuclear processes, metabolic and endocrine modulation, cell growth, signal transduction, etc. In this narrative review, we focused on the role of inositol in human brain physiology and pathology, with the aim of providing an update on both potential applications and current limits in its use in psychiatric disorders. Overall, imaging and biomolecular studies have shown the role of inositol levels in the pathogenesis of mood disorders. However, when administered as monotherapy or in addition to conventional drugs, inositol did not seem to influence clinical outcomes in both mood and psychotic disorders. Conversely, more encouraging results have emerged for the treatment of panic disorders. We concluded that, despite its multifaceted neurobiological activities and some positive findings, to date, data on the efficacy of inositol in the treatment of psychiatric disorders are still controversial, partly due to the heterogeneity of supporting studies. Therefore, systematic use of inositol in routine clinical practice cannot be recommended yet, although further basic and translational research should be encouraged.

Severity of REM sleep without atonia correlates with measures of cognitive impairment and depressive symptoms in REM sleep behaviour disorder.

This study aimed to correlate REM sleep without atonia (RSWA) and neuropsychological data in patients with idiopathic/isolated REM sleep behaviour disorder (iRBD) and those with RBD associated with Parkinson's disease (PDRBD), in order to assess whether higher degrees of RSWA are related to poorer cognitive performance. A total of 142 subjects were enrolled: 48 with iRBD, 55 with PDRBD, and 39 PD without RBD (PDnoRBD). All participants underwent video-polysomnographic recording, clinical and neuropsychological assessment. RSWA was quantified according to two manual scoring methods (Montréal, SINBAR) and one automated (REM atonia index, RAI). Mild cognitive impairment (MCI) was diagnosed according to diagnostic criteria for MCI in Parkinson's disease. The relationship between neuropsychological scores and RSWA metrics was explored by multiple linear regression analysis and logistic regression models. Patients with iRBD showed significantly lower visuospatial functions and working memory, compared with the others. More severe RSWA was associated with a higher risk of reduced visuospatial abilities (OR 0.15), working memory (OR 2.48), attention (OR 2.53), and semantic fluency (OR 0.15) in the iRBD. In the whole group, a greater RSWA was associated with an increased risk for depressive symptoms (OR 3.6). A total of 57(40%) MCI subjects were found (17 iRBD, 26 PDRBD, and 14 PDnoRBD). Preserved REM-atonia was associated with a reduced odds of multi-domain MCI in the whole study population (OR 0.54). In conclusion, a greater severity of RSWA was associated with an increased risk for poor cognitive performance and depressive mood in patients with RBD. Moreover, higher RAI was associated with a lower risk of multi-domain MCI.

Central and Peripheral Nervous System Complications of Vasculitis Syndromes from Pathology to Bedside: Part 2-Peripheral Nervous System.

PURPOSE OF REVIEW: Peripheral nervous system vasculitides (PNSV) are a heterogeneous group of disorders with a clinical subset that may differ in prognosis and therapy. We provide a comprehensive update on the clinical assessment, diagnosis, complications, treatment, and follow-up of PNSV. RECENT FINDINGS: Progress in neuroimaging, molecular testing, and peripheral nerve biopsy has improved clinical assessment and decision-making of PNSV, also providing novel insights on how to prevent misdiagnosis and increase diagnostic certainty. Advances in imaging techniques, allowing to clearly display the vessel walls, have also enhanced the possibility to differentiate inflammatory from non-inflammatory vascular lesions, while recent histopathology data have identified the main morphological criteria for more accurate diagnosis and differential diagnoses. Overall, the identification of peculiar morphological findings tends to improve diagnostic accuracy by defining a clearer boundary between systemic and non-systemic neuropathies. Therefore, the definition of epineurium vessel wall damage, type of vascular lesion, characterization of lymphocyte populations, antibodies, and inflammatory factors, as well as the identification of direct nerve damage or degeneration, are the common goals for pathologists and clinicians, who will both benefit for data integration and findings translation. Nevertheless, to date, treatment is still largely empiric and, in some cases, unsatisfactory, thus often precluding precise prognostic prediction. In this context, new diagnostic techniques and multidisciplinary management will be essential in the proper diagnosis and prompt management of PNSV, as highlighted in the present review. Thirty to fifty percent of all patients with vasculitis have signs of polyneuropathy. Neuropathies associated with systemic vasculitis are best managed according to the guidelines of the underlying disease because appropriate workup and initiation of treatment can reduce morbidity. Steroids, or in severe or progressive cases, cyclophosphamide pulse therapy is the standard therapy in non-systemic vasculitic neuropathies. Some patients need long-term immunosuppression. The use of novel technologies for high-throughput genotyping will permit to determine the genetic influence of related phenotypes in patients with PNSV.

Water model for hydrophobic cavities: structure and energy from quantum-chemical calculations.

This ab initio study aims to design a series of large water clusters having a hollow clathrate-like cage able to host hydrophobic solutes of various sizes. Starting from the (H2O)n (n = 18, 20, 24 and 28) hollow cages, water layers have been added in a stepwise manner in order to model the configuration of water molecules beyond the primary shell. The large (H2O)100, (H2O)120 and (H2O)140 clusters complete the hydrogen bonding network of the cage with optimal and regular tiling of the do-, tetra-decahedron and hexa-decahedron, respectively. This study is corroborated by an investigation of dense water clusters up to the (H2O)123 one, being highly consistent with experimental data on ice concerning the electronic and zero-point energies for aggregate formation at 0 K and enthalpy and entropy at 273 K. The cavity creation profoundly alters the orientation of water molecules compared with those found in dense clusters. Nevertheless, such a large reorganization is necessary to maximize the water-water attraction by making it similar to the one found in dense clusters. The cage formation is an endothermic process; however, the computed values are large compared with previous reports for hydrocarbon aqueous solutions. Larger clusters are required for a more fruitful comparison.

Transcranial Magnetic Stimulation for the Treatment of Gambling Disorder: A Systematic Review.

BACKGROUND: Gambling Disorder (GD) is a behavioral addiction listed within the diagnostic category of substance-related and addictive disorders. Recently, transcranial magnetic stimulation (TMS), which non-invasively stimulates the brain and has neuromodulatory properties, has emerged as an innovative treatment tool for GD, thus offering a new option for the management of this complex disorder. The present review explored the efficacy of TMS as a possible non-pharmacological treatment for GD. METHODS: An exhaustive search was performed across the MEDLINE, Web of Science, and EMBASE databases using a specific search string related to GD and TMS. A total of 20 papers were selected for full-text examination, out of which eight fulfilled the inclusion criteria and were therefore systematically analyzed in the present review. RESULTS: This review included eight studies: three randomized-controlled trials (RCTs), three non-controlled studies, one case series, and one case report. Two cross-over RCTs described a decrease in craving after high-frequency (excitatory), repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) and the medial prefrontal cortex (PFC), respectively; another study applying low-frequency (inhibitory) rTMS on the right DLPFC did not find any positive effect on craving. Among uncontrolled studies, one demonstrated the beneficial effect of high-frequency rTMS over the left DLPFC, while another showed the efficacy of a continuous theta burst stimulation protocol directed over the pre-supplementary motor area, bilaterally. CONCLUSION: The included studies showed the promising effect of excitatory stimulation over the left PFC. However, further investigation is needed, particularly in terms of standardizing stimulation protocols and psychometric assessments.

A Systematic Review on the Effect of Nutraceuticals on Antidepressant-Induced Sexual Dysfunctions: From Basic Principles to Clinical Applications.

Sexual dysfunctions are common side effects reported by patients during antidepressant treatment. When they occur, patients often discontinue psychopharmacological therapy, with a negative impact on the underlying psychiatric disease. Recently, great attention has been paid to the use of nutraceuticals in the management of psychiatric disorders, although a systematic review on their effects as a treatment option for antidepressant-induced sexual dysfunctions (AISD) is lacking. Here, we conducted a systematic search in the following databases: MEDLINE (through PubMed), EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, and Web of Science. We searched eligible studies among parallel or crossover randomized controlled trials (RCTs) in adult populations. After this process, a total of 10 articles that evaluated the effect of six different nutraceuticals versus placebo were included: Maca Root, S-adenosyl-L-methionine (SAMe), Rosa Damascena, Ginkgo Biloba, Saffron, and Yohimbine. Overall, a high dose of Maca Root and the use of SAMe or Saffron may improve AISD. Additionally, the administration of Rosa Damascena seemed to be more effective in men than in women, whereas no evidence of effects emerged for Gingko Biloba and Yohimbine. Given the mixed results still available, future RCTs should consider larger samples and confounding factors, such as depressive status and individual vulnerability.

Central and Peripheral Nervous System Complications of Vasculitis Syndromes From Pathology to Bedside: Part 1-Central Nervous System.

PURPOSE OF REVIEW: The aim of this review is to provide a comprehensive update on the clinical assessment, diagnosis, complications, and treatment of primary central nervous system vasculitis (PCNSV). RECENT FINDINGS: The developments in neuroimaging, molecular testing, and cerebral biopsy have enhanced clinical assessment and decision making, providing novel insights to prevent misdiagnosis increasing diagnostic certainty. Advances in imaging techniques visualizing the wall of intracranial vessels have improved the possibility to distinguish inflammatory from non-inflammatory vascular lesions. Large recent studies have revealed a more varied histopathological pictures and disclosed an association with amyloid angiopathy. Unfortunately, therapy remains largely empiric. PCNSV is a heterogeneous group of disorders encompassing different clinical subsets that may differ in terms of prognosis and therapy. Recent evidence has described a more benign course, with good response to therapy. New diagnostic techniques will play soon a pivotal role in the appropriate diagnosis and prompt management of PCNSV.

Post-stroke aphasia at the time of COVID-19 pandemic: a telerehabilitation perspective.

We report on our remote speech therapy experience in post-stroke aphasia. The aim was to test the feasibility and utility of telerehabilitation to support future randomized controlled trials. Post-stroke aphasia is a common and disabling speech disorder, which significantly affects patients' and caregivers' health and quality of life. Due to COVID-19 pandemic, most of the conventional speech therapy approaches had to stop or "switch" into telerehabilitation procedures to ensure the safety of patients and operators but, concomitantly, the best rehabilitation level possible. Here, we planned a 5-month telespeech therapy programme, twice per week, of a patient with non-fluent aphasia following an intracerebral haemorrhage. Overall, treatment adherence based on the operator's assessments was high, and incomplete adherence for technical problems occurred very rarely. In line with the patient's feedback, acceptability was also positive, since he was constantly motivated during the sessions and the exercises performed autonomously, as confirmed by the speech therapist and caregiver, respectively. Moreover, despite the sequelae from the cerebrovascular event, evident in some writing tests due to the motor deficits in his right arm and the disadvantages typical of all telepractices, more relevant results were achieved during the telerehabilitation period compared to those of the "face-to-face" therapy before the COVID-19 outbreak. The telespeech therapy performed can be considered successful and the patient was able to return to work. Concluding, we support it as a feasible approach offering patients and their families the opportunity to continue the speech and language rehabilitation pathway, even at the time of pandemic.

Daily mocha coffee intake and psycho-cognitive status in non-demented non-smokers subjects with subcortical ischaemic vascular disease.

Coffee intake has been recently associated with better cognition and mood in mild vascular cognitive impairment (mVCI). As tobacco can reduce the caffeine half-life, we excluded smokers from the original sample. Hamilton Depression Rating Scale (HDRS), mini-mental state examination (MMSE), Stroop Colour-Word Interference Test (Stroop), activities of daily living (ADL0) and instrumental ADL were the outcome measures. Significant differences were observed in higher consumption groups (moderate intake for HDRS; high intake for MMSE and Stroop) compared to the other groups, as well as in age and education. With age, education and coffee used as independent predictors, and HDRS, Stroop and MMSE as dependent variables, a correlation was found between age and both MMSE and Stroop, as well as between education and MMSE and between HDRS and Stroop; coffee intake negatively correlated with HDRS and Stroop. Higher coffee consumption was associated with better psycho-cognitive status among non-smokers with mVCI.

Celiac Disease and Neurological Manifestations: From Gluten to Neuroinflammation.

Celiac disease (CD) is a complex multi-organ disease with a high prevalence of extra-intestinal involvement, including neurological and psychiatric manifestations, such as cerebellar ataxia, peripheral neuropathy, epilepsy, headache, cognitive impairment, and depression. However, the mechanisms behind the neurological involvement in CD remain controversial. Recent evidence shows these can be related to gluten-mediated pathogenesis, including antibody cross-reaction, deposition of immune-complex, direct neurotoxicity, and in severe cases, vitamins or nutrients deficiency. Here, we have summarized new evidence related to gut microbiota and the so-called "gut-liver-brain axis" involved in CD-related neurological manifestations. Additionally, there has yet to be an agreement on whether serological or neurophysiological findings can effectively early diagnose and properly monitor CD-associated neurological involvement; notably, most of them can revert to normal with a rigorous gluten-free diet. Moving from a molecular level to a symptom-based approach, clinical, serological, and neurophysiology data might help to disentangle the many-faceted interactions between the gut and brain in CD. Eventually, the identification of multimodal biomarkers might help diagnose, monitor, and improve the quality of life of patients with "neuroCD".

Role and Dysregulation of miRNA in Patients with Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative synucleinopathy that has a not yet fully understood molecular pathomechanism behind it. The role of risk genes regulated by small non-coding RNAs, or microRNAs (miRNAs), has also been highlighted in PD, where they may influence disease progression and comorbidities. In this case-control study, we analyzed miRNAs on peripheral blood mononuclear cells by means of RNA-seq in 30 participants, with the aim of identifying miRNAs differentially expressed in PD compared to age-matched healthy controls. Additionally, we investigated the pathways influenced by differentially expressed miRNAs and assessed whether a specific pathway could potentially be associated with PD susceptibility (enrichment analyses performed using the Ingenuity Pathway Analysis tools). Overall, considering that the upregulation of miRNAs might be related with the downregulation of their messenger RNA targets, and vice versa, we found several putative targets of dysregulated miRNAs (i.e., upregulated: hsa-miR-1275, hsa-miR-23a-5p, hsa-miR-432-5p, hsa-miR-4433b-3p, and hsa-miR-4443; downregulated: hsa-miR-142-5p, hsa-miR-143-3p, hsa-miR-374a-3p, hsa-miR-542-3p, and hsa-miR-99a-5p). An inverse connection between cancer and neurodegeneration, called "inverse comorbidity", has also been noted, showing that some genes or miRNAs may be expressed oppositely in neurodegenerative disorders and in some cancers. Therefore, it may be reasonable to consider these miRNAs as potential diagnostic markers and outcome measures.

A Transcriptome Analysis of mRNAs and Long Non-Coding RNAs in Patients with Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. The number of cases of PD is expected to double by 2030, representing a heavy burden on the healthcare system. Clinical symptoms include the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain, which leads to striatal dopamine deficiency and, subsequently, causes motor dysfunction. Certainly, the study of the transcriptome of the various RNAs plays a crucial role in the study of this neurodegenerative disease. In fact, the aim of this study was to evaluate the transcriptome in a cohort of subjects with PD compared with a control cohort. In particular we focused on mRNAs and long non-coding RNAs (lncRNA), using the Illumina NextSeq 550 DX System. Differential expression analysis revealed 716 transcripts with padj ≤ 0.05; among these, 630 were mRNA (coding protein), lncRNA, and MT_tRNA. Ingenuity pathway analysis (IPA, Qiagen) was used to perform the functional and pathway analysis. The highest statistically significant pathways were: IL-15 signaling, B cell receptor signaling, systemic lupus erythematosus in B cell signaling pathway, communication between innate and adaptive immune cells, and melatonin degradation II. Our findings further reinforce the important roles of mitochondria and lncRNA in PD and, in parallel, further support the concept of inverse comorbidity between PD and some cancers.

On the size, shape and energetics of the hydration shell around alkanes.

A large number of clathrate-like cages have been proposed as the very first hydration shell of alkanes. The cages include canonical structures commonly found in clathrate hydrates and many others, not previously reported, derived from the carbon fullerene cavities. These structures have a rich and variegated form, which can adapt to the shape and conformation of the solute. They avoid "wasting" hydrogen bonds, while minimizing the volume cage and maximizing the solute-solvent van der Waals interactions. DFT/M06-2X and MP2 ab initio calculations give comparable structural and energetic results although the latter predicts slightly larger cages for a given solute. It is shown that the van der Waals interactions are substantial and the large exoenergetic values found for isobutane and cyclopentane provide an explanation for the surprising high melting points of related hydrates at room pressure. The encaging enthalpy for various hydrocarbons is similar to the enthalpy of solution measured at a temperature just above the melting point of aqueous hydrocarbon solutions, thus indicating that water molecules should not deviate too much from the configuration with O-H bonds tangentially oriented with respect to the solute surface. The computed trend differs from the enthalpy of solution measured at room temperature, thus the very first hydration shell departs, up to a certain degree, from the clathrate-like structures.

Late-onset oro-facial dyskinesia in Spinocerebellar Ataxia type 2: a case report.

BACKGROUND: Genetic familiar causes of oro-facial dyskinesia are usually restricted to Huntington's disease, whereas other causes are often missed or underestimated. Here, we report the case of late-onset oro-facial dyskinesia in an elderly patient with a genetic diagnosis of Spinocerebellar Ataxia type 2 (SCA2). CASE PRESENTATION: A 75-year-old man complained of progressive balance difficulty since the age of 60 years, associated with involuntary movements of the mouth and tongue over the last 3 months. No exposure to anti-dopaminergic agents, other neuroleptics, antidepressants, or other drugs was reported. Family history was positive for SCA2 (brother and the son of the brother). At rest, involuntary movements of the mouth and tongue were noted; they appeared partially suppressible and became more evident during stress and voluntary movements. Cognitive examination revealed frontal-executive dysfunction, memory impairment, and attention deficit. Brain magnetic resonance imaging (MRI) disclosed signs of posterior periventricular chronic cerebrovascular disease and a marked ponto-cerebellar atrophy, as confirmed by volumetric MRI analysis. A dopamine transporter imaging scan demonstrated a bilaterally reduced putamen and caudate nucleus uptake. Ataxin-2 (ATXN2) gene analysis revealed a 36 cytosine-adenine-guanine (CAG) repeat expansion, confirming the diagnosis of SCA2. CONCLUSIONS: SCA2 should be considered among the possible causes of adult-onset oro-facial dyskinesia, especially when the family history suggests an inherited cerebellar disorder. Additional clinical features, including parkinsonism and motor neuron disease, may represent relevant cues for an early diagnosis and adequate management.

Evaluation and Treatment of Vascular Cognitive Impairment by Transcranial Magnetic Stimulation.

The exact relationship between cognitive functioning, cortical excitability, and synaptic plasticity in dementia is not completely understood. Vascular cognitive impairment (VCI) is deemed to be the most common cognitive disorder in the elderly since it encompasses any degree of vascular-based cognitive decline. In different cognitive disorders, including VCI, transcranial magnetic stimulation (TMS) can be exploited as a noninvasive tool able to evaluate in vivo the cortical excitability, the propension to undergo neural plastic phenomena, and the underlying transmission pathways. Overall, TMS in VCI revealed enhanced cortical excitability and synaptic plasticity that seem to correlate with the disease process and progression. In some patients, such plasticity may be considered as an adaptive response to disease progression, thus allowing the preservation of motor programming and execution. Recent findings also point out the possibility to employ TMS to predict cognitive deterioration in the so-called "brains at risk" for dementia, which may be those patients who benefit more of disease-modifying drugs and rehabilitative or neuromodulatory approaches, such as those based on repetitive TMS (rTMS). Finally, TMS can be exploited to select the responders to specific drugs in the attempt to maximize the response and to restore maladaptive plasticity. While no single TMS index owns enough specificity, a panel of TMS-derived measures can support VCI diagnosis and identify early markers of progression into dementia. This work reviews all TMS and rTMS studies on VCI. The aim is to evaluate how cortical excitability, plasticity, and connectivity interact in the pathophysiology of the impairment and to provide a translational perspective towards novel treatments of these patients. Current pitfalls and limitations of both studies and techniques are also discussed, together with possible solutions and future research agenda.

A Customized Next-Generation Sequencing-Based Panel to Identify Novel Genetic Variants in Dementing Disorders: A Pilot Study.

Purpose: The advancements in the next-generation sequencing (NGS) techniques have allowed for rapid, efficient, and cost-time-effective genetic variant detection. However, in both clinical practice and research setting, sequencing is still often limited to the use of gene panels clinically targeted on the genes underlying the disease of interest. Methods: We performed a neurogenetic study through an ad hoc NGS-based custom sequencing gene panel in order to screen 16 genes in 8 patients with different types of degenerative cognitive disorders (Alzheimer's disease, mild cognitive impairment, frontotemporal dementia, and dementia associated with Parkinson's disease). The study protocol was based on previous evidence showing a high sensitivity and specificity of the technique even when the panel is limited to some hotspot exons. Results: We found variants of the TREM2 and APP genes in three patients; these have been previously identified as pathogenic or likely pathogenic and, therefore, considered "disease causing." In the remaining subjects, the pathogenicity was evaluated according to the guidelines of the American College of Medical Genetics (ACMG). In one patient, the p.R205W variant in the CHMP2B gene was found to be likely pathogenic of the disease. A variant in the CSF1R and SERPINI1 genes found in two patients was classified as benign, whereas the other two (in the GRN and APP genes) were classified as likely pathogenic according to the ACMG. Conclusions: Notwithstanding the preliminary value of this study, some rare genetic variants with a probable disease association were detected. Although future application of NGS-based sensors and further replication of these experimental data are needed, this approach seems to offer promising translational perspectives in the diagnosis and management of a wide range of neurodegenerative disorders.