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Mineralizing lenticulostriate vasculopathy is a well-recognized risk factor for basal ganglia stroke after minor head trauma in infants and young children; it is diagnosed on head computed tomography by the presence of basal ganglia calcification, seen as punctate hyperdensities on axial and linear hyperdensities on reconstructed coronal and sagittal images. In children with anterior fontanel window, its presence is suggested by branching hyperechogenic stripes in the basal ganglia region on cranial ultrasound. Brain magnetic resonance imaging, including susceptibility-weighted sequences and brain magnetic resonance angiography, fail to detect calcification or vascular abnormalities. Although its etiology remains unknown, mineralizing lenticulostriate vasculopathy is considered to represent end-stage pathology of lenticulostriate vasculopathy, a neonatal radiographic condition detected during routine neonatal cranial ultrasonographic examination and represents nonspecific finding associated with a multitude of etiologies. The significance of mineralizing lenticulostriate vasculopathy lies in the fact that it has emerged as one of the most common risk factors for basal ganglia stroke in Indian children, accounting for one-fourth to one-half of all causes of stroke in some studies. The outcome of stroke in children with mineralizing lenticulostriate vasculopathy appears to be favorable with the majority achieving complete or nearly complete recovery of their motor functions. Stroke recurrence following repeat head trauma is seen in a small proportion of children despite aspirin treatment. [ABSTRACT FROM AUTHOR]

Background: Leigh syndrome (LS) is a progressive neurodegenerative mitochondrial disease characterized by necrotizing lesions affecting different parts of the central nervous system, especially in the brainstem and basal ganglia. Lesions in this area may involve respiratory and sleep centers, resulting in the clinically significant disturbances seen-but poorly characterized-in LS. The purpose of the present study is to characterize and compare the physiologic responses to respiratory disturbances quantified by polysomnography metrics of children with LS with age-sex- and apnea-hypopnea index (AHI)-matched patients with obstructive sleep apnea (OSA), a common clinical population with similar burden of sleep-disordered breathing.Methods: Retrospective comparative study of polysomnographic data from six patients with LS were reviewed and compared with 18 age-sex-AHI-matched patients with OSA, with particular attention to cardiorespiratory and sleep architecture metrics.Results: Sleep architecture and stage duration were conserved in LS and OSA groups, but increased wake after sleep onset was seen among the first group. The LS group exhibited both obstructive and central sleep apnea. The group also had significantly greater values of heart rate, ≥3% oxygen desaturation index, and lower values of sleep efficiency, respiratory arousal index, and total sleep time when compared with the OSA group.Conclusions: Patients with LS exhibited significantly more sleep-related cardiorespiratory disturbances and sleep fragmentation when compared with neurotypical children with OSA. Given that these findings are plausibly detrimental to health and development, sleep evaluation in patients with similar conditions should be encouraged for early management. [ABSTRACT FROM AUTHOR]

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a treatable neurometabolic disease caused by variants in SLC19A3. Typical imaging features include symmetrical involvement of the caudate nuclei and putamina. The study sought to explore classical BTBGD without caudate nucleus involvement, to highlight the importance of recognizing this new pattern early in the disease. Individuals with genetically confirmed BTBGD who harbored the same homozygous variant: NM_025243.4 (SLC19A3): c.1264A > G (p.Thr422Ala) and had atypical neuroimaging were recruited. Nine patients with BTBGD had atypical neuroimaging findings on the first MRI scan. The median age at symptom onset was 3 years. All patients presented with classical clinical features of subacute encephalopathy, dystonia, ataxia, and seizures. During the acute crisis, MRI revealed bilateral and symmetric involvement of the putamina in all patients; one showed small caudate nuclei involvement. In addition, the thalami, cerebellum, and brain stem were involved in six patients, seven patients, and three patients, respectively. Treatment included a combination of high doses of thiamine and biotin. One patient died; he did not receive any vitamin supplementation. Two patients who were treated late had severe neurological sequelae, including generalized dystonia and quadriplegia. Six patients treated early had good outcomes with minimal sequelae, including mild dystonia and dysarthria. Two patients showed the classical chronic atrophic and necrotic changes already described. The early atypical neuroimaging pattern of BTBGD described here, particularly the lack of caudate nucleus involvement, should not dissuade the clinician and radiologist from considering a diagnosis of BTBGD. [ABSTRACT FROM AUTHOR]

Parkinsons disease (PD) is a chronic fast growing neurodegenerative disorder of Central Nervous System (CNS) characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and formation of Lewy bodies (LBs) which causes dopamine deficiency within basal ganglia leading to motor and non-motor manifestation. According to reports, many factors are responsible for pathogenesis of PD which includes environmental factors, genetic factors, and aging factors. Whereas death of dopaminergic neurons is also caused by oxidative stress, neuroinflammation, and autophagy disorder. Molecular chaperones/co-chaperones are proteins that binds to an unstable conformer of another protein and stabilizes it. Chaperones prevent incorrect interaction between non-native polypeptides which increases the yield but not the rate of reaction. The Bcl-2-associated athanogene (BAG) is a multifunctional group of proteins belonging to BAG family of co-chaperones. Recent studies demonstrates that chaperones interact with PD-related proteins. Co-chaperones like BAG family proteins regulate the function of chaperones. Molecular chaperones regulate the mitochondrial functions by interacting with the PD-related proteins associated with it. This review studies the contribution of chaperones and PD-related proteins in pathogenesis of PD aiming to provide an alternate molecular target for preventing the disease progression. [Display omitted] [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the brain. Despite existing treatments, there remains an unmet need for therapies that can halt or reverse disease progression. Gene therapy has been tried and tested for a variety of illnesses, including PD. The goal of this systematic review is to assess gene therapy techniques' safety and effectiveness in PD clinical trials. Online databases PubMed/Medline, and Cochrane were used to screen the studies for this systematic review. The risk of bias of the included studies was assessed using standard tools. Gene therapy can repair damaged dopaminergic neurons from the illness or deal with circuit anomalies in the basal ganglia connected to Parkinson's disease symptoms. Rather than only treating symptoms, this neuroprotective approach alters the illness itself. Medication for gene therapy is currently administered at the patient's bedside. It can hyperactivate specific brain circuits associated with motor dysfunction. PD therapies are developing quickly, and there aren't enough head-to-head trials evaluating the safety and effectiveness of available treatments. When choosing an advanced therapy, patient-specific factors should be considered in addition to the effectiveness and safety of each treatment option. In comparison to conventional therapies, gene therapy may be advantageous for PD. It may minimize side effects, relieve symptoms, and offer dependable dopamine replacement. [ABSTRACT FROM AUTHOR]

The clinical treatment and prognosis of major depressive disorder (MDD) are limited by the high degree of disease heterogeneity. It is unclear whether there is a potential network mechanism for age-related heterogeneity. We aimed to uncover the heterogeneity of the white matter (WM) network at different ages of onset and its correlation with different symptom characteristics. 85 first-episode MDD patients and 84 corresponding healthy controls (HCs) were recruited and underwent diffusion tensor imaging scans. Structural network characteristics were analyzed using graph theory methods. We observed an accelerated age-related decline of the WM network in MDD patients compared with HCs. Distinct symptom-related networks were identified in three MDD groups with different onset-age. For early-onset MDD (18-29 years; EOD), higher guilt and loss of interest were correlated with the insula, and inferior parietal lobe which in default mode network and salience network. For mid-term-onset MDD (30-44 years; MOD), higher somatic symptoms were correlated with thalamus which in cortico-striatal-thalamic-cortical circuit. For later-onset MDD (45-60 years; LOD), poor sleep symptoms were correlated with the caudate in the basal ganglia, which suggests the cingulate operculum network in the control of sleep. These results supported a circuit-based heterogeneity associated with the age of onset in MDD. Understanding this circuit-based heterogeneity might help to develop a new target for clinical treatment strategies. [ABSTRACT FROM AUTHOR]

• Basal ganglia dynamics are modeled by push-pull systems to explain hypokinesia or hyperkinesia. • Push-pull systems cannot explain the complex orchestration of motor units in health and disease. • We raise awareness that non-linear sciences could benefit the modeling of the BG-Th-Ctx circuitry. Current theories on the basal ganglia-thalamic-cortical circuitry address the phenomena of hypokinesia and hyperkinesia. In this Perspective, we question whether the current models can address the orchestration of the motor units which is the common final pathway of the motor system. We conclude that the current theories do not to address this orchestration in health and disease. One alternative approach worthy of consideration is nonmonotonic nonlinear dynamics that contrast with a fundamentally linear or monotonic nonlinear approach that are presumed by current theories of basal ganglia-thalamic-cortical system. The purpose here is to make the case that current theories do presuppose a linear or monotonic nonlinear perspective which will be demonstrated as failing to adequately explicate the complex orchestration of motor unit activities in normal movement and in movement disorders. The notion of nonlinear dynamics is not new to neurophysiology; however, it is argued that it is new to the concepts of the physiology and pathophysiology of the basal ganglia-thalamic-cortical system. Providing a wholesale reconceptualization of the basal ganglia-thalamic-cortical system is beyond the scope of this effort. Rather, the contribution of the essay is convincing that there is a need to reconceptualize theories as nonlinear dynamical systems and there are metaphors and analogies from nonlinear science that can be productive in the reconsideration. [ABSTRACT FROM AUTHOR]

Biotin-thiamine-responsive basal ganglia disease (BTRBGD) is a rare treatable autosomal recessive neurometabolic disorder characterized by progressive encephalopathy that eventually leads to severe disability and death if not treated with biotin and thiamine. BTRBGD is caused by mutations in the SLC19A3 gene on chromosome 2q36.6, encoding human thiamine transporter 2 (hTHTR2). Episodes of BTRBGD are often triggered by febrile illness. The patient was 2 years 10 months old male child presented with fever and progressive acute encephalopathy associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus infection. MRI revealed bilateral symmetrical high signal involving both basal ganglia and medial thalami which is swollen with central necrosis, initially diagnosed as acute necrotizing encephalomyelitis with increased severity. Genetic analysis revealed BTRBGD. BTRBGD requires high index of suspicion in any patient presenting with acute encephalopathy, characteristic MRI findings (that are difficult to differentiate from necrotizing encephalopathy), regardless of the existence of a proven viral infection. [ABSTRACT FROM AUTHOR]

Leigh syndrome (LS) is a neurodegenerative disease characterized by bilaterally symmetric brainstem or basal ganglia lesions. More than 80 genes, largely impacting mitochondrial energy metabolism, can underlie LS, and no approved medicines exist. Described 70 years ago, LS was initially diagnosed by the characteristic, necrotic lesions on autopsy. It has been broadly assumed that antemortem neuroimaging abnormalities in these regions correspond to end-stage histopathology. However, clinical observations and animal studies suggest that neuroimaging findings may represent an intermediate state, that is more dynamic than previously appreciated, and even reversible. We review this literature, discuss related conditions that are treatable, and present two new LS cases with radiographic improvement. We review studies in which hypoxia reverses advanced LS in a mouse model. The fluctuating and potentially reversible nature of radiographic LS lesions will be important in clinical trial design. Better understanding of this plasticity could lead to new therapies. [ABSTRACT FROM AUTHOR]

Introduction: Levodopa has become the main therapy for motor symptoms of Parkinson's disease (PD). This study aimed to test whether the amplitude of low-frequency fluctuation (ALFF) computed by fMRI could predict individual patient's response to levodopa treatment.Methods: We included 40 patients. Treatment efficacy was defined based on motor symptoms improvement from the state of medication off to medication on, as assessed by the Unified Parkinson's Disease Rating Scale score III. Two machine learning models were constructed to test the prediction ability of ALFF. First, the ensemble method was implemented to predict individual treatment responses. Second, the categorical boosting (CatBoost) classification was used to predict individual levodopa responses in patients classified as moderate and superior responders, according to the 50% threshold of improvement. The age, disease duration and treatment dose were controlled as covariates.Results: No significant difference in clinical data were observed between moderate and superior responders. Using the ensemble method, the regression model showed a significant correlation between the predicted and the observed motor symptoms improvement (r = 0.61, p < 0.01, mean absolute error = 0.11 ± 0.02), measured as a continuous variable. The use of the Catboost algorithm revealed that ALFF was able to differentiate between moderate and superior responders (area under the curve = 0.90). The mainly contributed regions for both models included the bilateral primary motor cortex, the occipital cortex, the cerebellum, and the basal ganglia.Conclusion: Both continuous and binary ALFF values have the potential to serve as promising predictive markers of dopaminergic therapy response in patients with PD. [ABSTRACT FROM AUTHOR]

Gait impairment and its etiologic correlate has not previously been subject of special attention in Batten disease. In the present review, the clinical picture of gait phenotype during Batten disease course accompanied by descriptions of the known concomitant patho-anatomical changes is presented. In CLN1 a non-rhythmic gait is seen around 1-1½ years of age. Shortly after, postural hypotonia and exaggerated tendon reflexes develop. The disease reaches a burnt-out stage during the third year of age and subsequently the children are almost without voluntary movements. The existing literature indicates that gait phenotype in CLN1 is caused by early involvement of the spinal interneurons followed by impact of the cortex and the cortico-spinal tracts. The earliest walking abnormality in children with CLN2 is a clumsy, ataxic, and spastic gait, which is in accordance with the existing imaging and histologic studies showing early involvement of the cerebellum and the cortico-spinal pathways. In CLN3, a reduction in walking speed is present at the age of 7–8 years. It occurs simultaneously with a reduction in the white matter microstructure and brain connectivity networks. Functional impairment of the basal ganglia contributing to a parkinsonian gait phenotype occurs in the mid-teens. In the late teens and early twenties involvement of the peripheral nerves, neurogenic musculoskeletal atrophy, loss of tendon reflexes and postural control are seen. The progressively impaired gait function in Batten disease is related to timing of damage of distinct areas of the nervous system depending on subtype and is a powerful marker of disease progression. • Gait impairment in Batten disease manifests itself in different ways depending on subtype • In CLN1 truncal ataxia and a non-rhythmic gait is seen between 1 and 1½ years of age • Impairment of the cerebellum has an early impact on locomotion in CLN2 • Initial motor symptom of CLN3 is slowing of walking speed, later extrapyramidal symptoms dominate • Gait phenotype may be a powerful and distinct marker for CLN disease progression [ABSTRACT FROM AUTHOR]

Introduction: Several reports have shown that neuromelanin-sensitive magnetic resonance imaging (NMI) using 3T magnetic resonance imaging is useful for the differential diagnosis of Parkinson's disease (PD), progressive supranuclear palsy (PSP), and other neurological diseases. However, the number of cases in previous studies has been insufficient. We aimed to determine the relationship between NMI and severity of PD and related disorders, and thereby establish the diagnostic utility of NMI for diagnosing neurological diseases.Methods: We enrolled 591 patients (531 subjects after removal of duplicates) with parkinsonism who underwent NMI. The contrast ratio of the locus coeruleus (LC-CR) and the area of the substantia nigra pars compacta (SNc) were analyzed in each patient.Results: The patients' clinical diagnoses were as follows: 11 patients in the disease control group (DCG), 244 patients with PD, 49 patients with PSP, and 19 patients with multiple system atrophy with predominant parkinsonism. Additionally, some patients were diagnosed with dementia with Lewy bodies, vascular parkinsonism, and drug-induced parkinsonism. SNc in the patients with PD and PSP was significantly smaller than that in DCG. LC-CR in the patients with PD was lower than that in DCG; furthermore, LC-CR in the patients with PD was significantly lower than that in the patients with PSP. We found that an area under the receiver-operating characteristic curve, indicating diagnostic efficacy, of 0.85 for LC-CR is a promising biomarker for differentiating PD from PSP.Conclusion: NMI effectively contributes to differentiating neurodegenerative diseases, such as PD and PSP. [ABSTRACT FROM AUTHOR]

Introduction: Parkinson's disease (PD) disrupts the control and coordination of grasping forces, likely due to a disruption in basal ganglia circuitry and diminished activity within the supplementary motor area (SMA). High intensity aerobic exercise has been shown to enhance connectivity between basal ganglia nuclei and cortical areas, including the SMA. The aim of this project was to determine the effects of high intensity lower extremity exercise on motor control patterns underlying a manual dexterity task.Methods: PD participants completed eight weeks of high intensity aerobic exercise under forced or voluntary exercise (FE or VE) modalities. Grasping forces for each limb were quantified during a functional bimanual dexterity task. Data were collected while OFF antiparkinsonian medication at baseline, end of treatment (EOT), and eight weeks after exercise cessation (EOT+8).Results: Eight weeks of high intensity exercise improved MDS-UPDRS Motor III clinical ratings by more than 4 points (~15%) for the FE and VE groups. Time to complete the task decreased nearly 30% across both groups as well. The control and coordination of grasping forces, simultaneity of force initiation, and rate of grip and load force exhibited significant improvements following exercise. In general, improvements in biomechanical outcomes were sustained following exercise cessation.Conclusion: High intensity aerobic exercise, achieved via a forced or voluntary mode, improved PD symptoms and bimanual dexterity. Sustained improvement of upper extremity motor control following exercise cessation indicates high intensity exercise enhances CNS functioning and suggests exercise may be a candidate for altering PD progression. [ABSTRACT FROM AUTHOR]

Neurofeedback (NF) techniques support individuals to self-regulate specific features of brain activity, which has been shown to impact behavior and potentially ameliorate clinical symptoms. Electrophysiological NF (epNF) may be particularly impactful for patients with Parkinson's disease (PD), as evidence mounts to suggest a central role of pathological neural oscillations underlying symptoms in PD. Exaggerated beta oscillations (12–30 Hz) in the basal ganglia-cortical network are linked to motor symptoms (e.g., bradykinesia, rigidity), and beta is reduced by successful therapy with dopaminergic medication and Deep Brain Stimulation (DBS). PD patients also experience non-motor symptoms related to sleep, mood, motivation, and cognitive control. Although less is known about the mechanisms of non-motor symptoms in PD and how to successfully treat them, low frequency neural oscillations (1–12 Hz) in the basal ganglia-cortical network are particularly implicated in non-motor symptoms. Here, we review how cortical and subcortical epNF could be used to target motor and non-motor specific oscillations, and potentially serve as an adjunct therapy that enables PD patients to endogenously control their own pathological neural activities. Recent studies have demonstrated that epNF protocols can successfully support volitional control of cortical and subcortical beta rhythms. Importantly, this endogenous control of beta has been linked to changes in motor behavior. epNF for PD, as a casual intervention on neural signals, has the potential to increase understanding of the neurophysiology of movement, mood, and cognition and to identify new therapeutic approaches for motor and non-motor symptoms. • Parkinson's disease (PD) is characterized by motor and non-motor oscillatory cortico-basal ganglia signals. • Electrophysiological neurofeedback (epNF) presents a method for voluntary modulation of neural oscillations. • epNF has shown promise for modulation of cortical and basal ganglia signals in PD. • epNF requires high quality and robust trial designs to move towards translation. [ABSTRACT FROM AUTHOR]

Background: Neuroleptics are commonly prescribed drugs to treat acute conditions (e.g., migraines) in the emergency department, but can cause serious adverse effects. Using diphenhydramine to prevent these adverse effects is very common but remains controversial.Objective: We performed a systematic review to determine whether prophylactic administration of diphenhydramine reduces the incidence of neuroleptic adverse effects in patients with acute conditions.Methods: Medline, Embase, Cochrane, PsycInfo, and Web of Science were searched for randomized controlled trials evaluating any neuroleptic with diphenhydramine vs. the same neuroleptic with any inactive agent. Primary outcome was incidence of any extrapyramidal adverse effect. Secondary outcomes were akathisia, rescue medication, subjective restlessness, neuroleptic malignant syndrome, and sedation. Independent reviewers scanned identified citations, extracted data, and assessed risk of bias. Meta-analysis was performed using random effect models.Results: Of 1566 identified citations, nine studies (n = 1648 patients) met eligibility criteria. Four studies were specifically designed to compare the incidence of neuroleptic adverse effects with and without co-administration of diphenhydramine. Four studies were at high risk of bias. In primary analysis, diphenhydramine had no effect on the incidence of extrapyramidal symptoms (7 studies, n = 1393, risk ratio [RR] 0.75; 95% confidence interval [CI] 0.44-1.31) or akathisia (5 studies, n = 1094; RR 0.78; 95% CI 0.33-1.82) or any of the secondary outcomes. In subgroup analysis, diphenhydramine was associated with a significant decrease in extrapyramidal adverse effects compared with placebo (4 studies, n = 705; RR 0.61; 95% CI 0.41-0.90). Dosage analysis yielded no further information.Conclusions: When compared with placebo, diphenhydramine was associated with a significant reduction of extrapyramidal adverse effects. Overall quality of evidence is low. Further studies are warranted. [ABSTRACT FROM AUTHOR]

Introduction: Total tau (τT), phosphorylated tau (τP-181) and amyloid beta (Aβ42) are cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD). There is no consensus on the interpretation criteria of these biomarkers. The aim of this study was to apply three different sets of criteria for CSF AD biomarker interpretation in a cohort of corticobasal degeneration (CBD) patients.Method: SForty patients fulfilling diagnostic criteria for "probable CBD" were included. The AT(N), BIOMARKAPD/ABSI and the τP-181/Aβ42 ratio criteria were applied.Results: The AT(N) criteria categorized 50% of "probable CBD" patients as AD, and 62.5% as harboring amyloid pathology. The BIOMARKAPD/ABSI and τP- 181/Aβ42 criteria categorized ~40% of "probable CBD" patients as AD.Discussion: Use of different interpretation criteria for CSF AD biomarkers produces diverse results. AD pathology is common in patients fulfilling "probable" CBD criteria. CBD diagnostic criteria may have suboptimal positive predictive value. A consensus regarding interpretation criteria of CSF AD biomarkers is pivotal. [ABSTRACT FROM AUTHOR]

Hydranencephaly is a congenital central nervous system disorder characterized by the complete or near-complete absence of the cerebral cortex and basal ganglia. Because of its rarity, data on the clinical features and survivorship remain sparse. We aim to determine the clinical features and survivorship of a cohort of patients with hydranencephaly. We performed a retrospective cohort study of all patients diagnosed with hydranencephaly at our institution from 2008 to 2018. Data on demographics, clinical features, presence of comorbidities, surgical operations performed, and status on last follow-up were collected. Survival curves were generated using Kaplan-Meier analysis. Fifty patients were included in the cohort, who had a median age at diagnosis of 4 months and a female predilection. The most common clinical manifestations were macrocephaly (92%) and seizures or myoclonic movements. Infection was present in 36% of cases, endocrinopathies in 22%, dysmorphisms in 20%, and cardiac disease in 8%. Twenty patients underwent shunt insertion, with half developing a postoperative complication at a mean follow-up of 14.9 months. The median survival of the cohort was not reached at 7.5 years. Among the patients with follow-up, characteristics were similar between the surgical and nonsurgical groups, except for the greater incidence of infections in the nonsurgical group. The survival curves among the groups were significantly different, with a hazard ratio of 3.731 in the nonsurgical group. In this large single-center retrospective cohort of patients with hydranencephaly, novel findings are presented regarding the clinical manifestations and survivorship of this condition. [ABSTRACT FROM AUTHOR]

Idiopathic Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterised by the progressive loss of dopaminergic nigrostriatal terminals. Currently, in early idiopathic PD, dopamine transporter (DAT)-specific imaging assesses the extent of striatal dopaminergic deficits, and conventional magnetic resonance imaging (MRI) of the brain excludes the presence of significant ischaemic load in the basal ganglia as well as signs indicative of other forms of Parkinsonism. In this article, we discuss the use of multimodal DAT-specific and MRI protocols for insight into the early pathological features of idiopathic PD, including: structural MRI, diffusion tensor imaging, nigrosomal iron imaging and neuromelanin-sensitive MRI sequences. These measures may be acquired serially or simultaneously in a hybrid scanner. From current evidence, it appears that both nigrosomal iron imaging and neuromelanin-sensitive MRI combined with DAT-specific imaging are useful to assist clinicians in diagnosing PD, while conventional structural MRI and diffusion tensor imaging protocols are better suited to a research context focused on characterising early PD pathology. We believe that in the future multimodal imaging will be able to characterise prodromal PD and stratify the clinical stages of PD progression. [ABSTRACT FROM AUTHOR]

Delusional disorder is an uncommon psychotic disorder. The first-line treatments for this chronic and resistant condition are antipsychotic medications, usually associated with several side effects that can exacerbate poor adherence. Conversely, aripiprazole is a well-tolerated antipsychotic drug that is effective in the treatment of other psychotic disorders. Here, we aimed to systematically review and summarize the currently available literature to evaluate the effectiveness and tolerability of aripiprazole in delusional disorders. A comprehensive literature search from inception until February 2020 was performed in PubMed, Cochrane Database of Systematic Reviews, and Scopus databases using The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We identified 21 single cases of delusional disorders, mostly somatic type, treated with aripiprazole. All studies reported patient clinical improvements after the beginning of the treatment with aripiprazole. The average dose of aripiprazole was 11.1 mg/day, and the average time to achieve a clinical response was 5.7 weeks. Few adverse effects were reported, including asthenia, extrapyramidal symptoms, hyperprolactinemia, and insomnia. Our findings suggest that aripiprazole may be an effective treatment for delusional disorders with good tolerability. Further studies comparing aripiprazole with other antipsychotics in the treatment of delusional disorders are needed. [ABSTRACT FROM AUTHOR]

Introduction: To identify areas of brain activity associated with involuntary muscle contractions in patients with blepharospasm using functional MRI.Methods: 15 patients with blepharospasm underwent 8-min resting state scans with spontaneous orbicularis oculi muscle contractions simultaneously recorded using MRI-compatible surface electromyography. Spasm severity and spasm onset/offset were modeled using the amplitude of the electromyography signal (EMG-Amp) and its first temporal derivative (EMG-Onset), respectively, and included in a multiple regression functional MRI analysis using SPM12. Primary outcome was within-group blood-oxygen-level dependent activations that co-varied with EMG-Amp and EMG-Onset following correction for multiple comparisons for an overall cluster corrected p < 0.05. Secondary analyses included testing for correlations between imaging findings and symptom severity, as measured by clinical dystonia rating scales, using an uncorrected voxel-level threshold of p < 0.001.Results: Imaging data from one subject were excluded due to excessive movement. EMG-Amp co-activated within the left sensorimotor cortex and cerebellum, as well as right lingual gyrus and superior temporal gyrus. EMG-Onset co-activated within the left posterior putamen/pallidum and a frontal eye field region in the left superior frontal gyrus. Symptom severity and EMG-Amp significantly co-varied in a small cluster within the left cerebellum.Conclusion: Our preliminary findings here suggest that cerebello-cortical circuits in blepharospasm could drive the intensity of eyelid spasms while basal ganglia circuits are associated with the triggering of spasms. This supports the network model for dystonia and identifies specific areas of involvement consistent with known brain regions responsible for control of movement. [ABSTRACT FROM AUTHOR]

To present seven new genetically confirmed cases of biotin–thiamin-responsive basal ganglia disease (BTBGD) with different clinical and brain magnetic resonance imaging (MRI) characteristics. Genetic variants, clinical presentations, brain MRI findings, treatment response, and prognosis of seven selected patients with BTBGD, diagnosed with SLC19A3 mutations were described. Among seven patients diagnosed with BTBGD, two had early infantile form, four had classic childhood form, and one was asymptomatic. Four different homozygous variants were found in the SLC19A3. Two patients with early infantile form presented with encephalopathy, dystonia, and refractory seizure in the neonatal period and have different variants. Their MRI findings were similar and pathognomonic for the early infantile form. Three siblings had same variants: one presented seizure and encephalopathy at the age of 4 months, one presented seizure at 14 years, and another was asymptomatic at 20 years. Only one of them had normal MRI findings, and the others MRI findings were similar and suggestive of the classic form. Other two siblings; one of them presented with developmental delay, seizure, and dystonia at 18 months and the other presented with subacute encephalopathy and ataxia at 20 months. Their MRI findings were also similar and suggestive of the classic form. BTBGD may present with dissimilar clinical characteristics or remain asymptomatic for a long time period even in a family or patients with same variants. Brain MRI patterns may be important for the early diagnosis of BTBGD that would save children's lives. [ABSTRACT FROM AUTHOR]

Intermittent explosive outbursts (IEO), manifesting as sudden episodes of verbal or physical aggression, are frequently present in patients with Tourette disorder (TD) and considered as one of the most disabling symptoms by patients and families. The neuronal correlates of these behaviours are poorly understood, and this was the primary objective of the present study. We assessed the presence of IEO in 55 patients with TD and then compared the subgroup of the patients with IEO to those without these manifestations using a multimodal neuroimaging approach. 47% of TD patients presented IEO, which was frequently associated with attention deficit hyperactivity disorder (ADHD). TD patients (without ADHD) with IEO compared to TD without IEO, showed structural changes in the right supplementary motor area as well as in the right hippocampus (increased fractional anisotropy), and in the left orbitofrontal cortex (decreased mean diffusivity). Using these three nodes as seeds for resting state functional connectivity, we showed a lower connectivity within the sensori-motor cortico-basal ganglia network, and an altered connectivity pattern among the orbito-frontal cortex, amygdala and hippocampus. Overall, our results indicate that TD with IEO is associated with brain dysfunction related to a less efficient top-down control on action selection, and impairments related to emotional regulation, impulse control and aggressive behaviours. [ABSTRACT FROM AUTHOR]

In the trials, a substantial proportion of newborns who underwent therapeutic hypothermia (TH) had an adverse outcome after hypoxic-ischaemic encephalopathy (HIE). Cooled babies were noted to have fewer cerebral lesions on MRI but when present lesions were predictive of adverse outcome. We investigate the predictive value of cerebral MRI in babies who undergo cooling in the clinical setting outside of the clinical trials in a prospective UK cohort. Of 75 babies recruited from four centres, neurodevelopment was available for 69 (92%) with 29% (20/69) being abnormal. The unfavourable MRI group (n = 22) had significantly lower motor (p < 0.001), language (p < 0.001) and cognition (p < 0.001) scores on Bayley-III assessment, compared to the favourable MRI group (n = 47). On multiple regression there was a significant relationship between basal ganglia and thalami abnormality and motor (p = 0.002), cognition (p = 0.011) and language (p = 0.013) outcomes. Half of the babies who had an MRI predictive of adverse outcome (11/22) had highest grade cerebral palsy. Cerebral MRI had 95% sensitivity, 94% specificity, 91% PPV and 98% NPV in predicting neurodevelopment. In this clinical cohort, fewer children had adverse neurodevelopment after TH compared to the TH trials. However, half the children who had an MRI predictive of adverse ND outcome had the most severe form of cerebral palsy. In this cohort, cerebral MRI was found to be highly predictive of neurodevelopmental outcome. • In this cohort, conventional cerebral MRI is highly predictive of neurodevelopmental outcome. • 73% of babies with cerebral MRI predictive of adverse outcome developed cerebral palsy. • Conventional cerebral MRI provides useful prognostic information for counselling families. [ABSTRACT FROM AUTHOR]

Background: Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive disease with characteristic neuro-endocrine manifestations. WSS encompasses heterogeneous phenotypes and disease course.Objective: We aimed to characterize neurological involvement of the disease through subgrouping of core neurological manifestations.Methods: A single-institution retrospective analysis of patients with clinically and genetically confirmed diagnosis of WSS.Results: A total of 38 individuals belonging to 17 families were identified to have WSS. The mean age at enrollment was 30.1 years (range 16-53 years). Neurological involvement was noted in 31 patients (81.5%). Dystonia was the most common neurological manifestation (67%), followed by intellectual disability (45%) and sensorineural hearing loss (30%). Based on the Neurological Impairment Scale (NIS), the disease was recognized to have two distinct patterns. A disabling, rapidly progressive pattern (NIS of 3-4; Type 1) was noted in eighteen patients (12 males, 6 females; 47.4%) with severe disability that occurs within a mean duration of 7.4 ± 3.6 years. Type 2 WSS was identified in twenty patients (8 males, 12 females; 52.6%), and showed either absent or mild neurological involvement with preserved activities of daily living (NIS of 0-1). The mean age of onset for neurological manifestations was earlier in type 1 (12.6 ± 4.5 years) compared to type 2 (18.1 ± 4.3 years). Type 1 WSS has a significantly higher rate of intellectual disability (p= <0.001).Conclusions: In this pleiotropic syndrome, we identified two distinct phenotypes with variable prognosis. A high Interfamilial and intrafamilial phenotypic variability despite having a similar gene mutation suggests a possible role of genetic or environmental modifying factor. [ABSTRACT FROM AUTHOR]

Background: The corticobasal syndrome (CBS) is heterogeneous in terms of postmortem neuropathology. While it has been previously studied with antemortem neuroimaging, clinicopathologic features of corticobasal syndrome associated with cerebrovascular pathology (vascular CBS) have yet to be reported.Methods: To identify vascular CBS, we searched the database of the CurePSP Brain Bank for patients with a clinical diagnosis of CBS who failed to meet neuropathologic criteria for corticobasal degeneration (CBD) or other neurodegenerative disease processes, but who had significant cerebrovascular pathology. Hemibrains were assessed macroscopically and processed for histological assessment. Medical records were reviewed to characterize clinical features of vascular CBS.Results: Of 217 patients with an antemortem diagnosis of CBS, we identified three patients with vascular CBS. Multiple infarcts in the watershed regions (frontal lobe and motor cortex), periventricular white matter, thalamus, and basal ganglia were observed in two patients. One patient had no cortical infarcts, but had multiple white matter infarcts and corticospinal tract degeneration. All were clinically thought to have CBS based on progressive asymmetric motor symptoms, including rigidity and apraxia, as well as cognitive impairment. Antemortem imaging studies showed findings of chronic cerebrovascular disease, with infarcts or white matter pathology.Conclusions: This autopsy study of vascular CBS shows that, while rare, cerebrovascular pathology involving the frontal lobe, white matter tracts, basal ganglia, thalamus, and corticospinal tract can underlie clinical features suggestive of CBS. When neuroimaging suggests an alternative explanation, including chronic infarcts in critical regions, caution is merited in considering CBD as the underlying pathology. [ABSTRACT FROM AUTHOR]

Introduction: Spinocerebellar ataxia 48 has recently been described as an adult onset ataxia associated with a cerebellar cognitive affective syndrome, caused by a heterozygous mutation in the STUB1 gene.Methods: We characterized the clinical and neuroimaging phenotype of eight patients from two autosomal dominant ataxia multigenerational Italian families, in whom we conducted whole exome sequencing, targeted multigene sequencing, and Sanger sequencing studies.Results: We describe a complex syndrome characterized by ataxia and cognitive-psychiatric disorder in all cases, variably associated with chorea, parkinsonism, dystonia, urinary symptoms, and epilepsy. MRI showed a significant cerebellar atrophy, coupled to a T2-weighted hyperintensity affecting the dentate nuclei and extending to the middle cerebellar peduncles, whereas FDG-PET studies revealed glucose hypometabolism in cerebellum, striatum, and cerebral cortex. We identified two different novel STUB1 mutations segregating in the two families. One of the two mutations, p.(Gly33Ser), occurs in the TRP domain, whereas p.(Pro228Ser) is located in the ubiquitin ligase region.Discussion: We emphasize the similarity of the described clinical picture with that of SCAR16, an autosomal recessive ataxia caused by biallelic mutations in the same gene, and of spinocerebellar ataxia type 17, which is considered the main Huntington's disease-like syndrome. The pathogenesis of the disease and the relationship between SCA48 and SCAR16 remain to be clarified. [ABSTRACT FROM AUTHOR]

Abstract Striatal medium spiny neurons (MSNs) control motor function. Hyper- or hypo-activity of MSNs coincides with basal ganglia-related movement disorders. Based on the assumption that lasting alterations in neuronal activity lead to structural changes in the brain, understanding these structural alterations may be used to infer MSN functional abnormalities. To infer MSN function from structural data, understanding how long-lasting alterations in MSN activity affect brain morphology is essential. To address this, we utilized a simplified model of functional induction by stimulating MSNs expressing channelrhodopsin 2 (ChR2). Subsequent structural alterations which induced long-term activity changes in these MSNs were investigated in the striatal pathway and its associated regions by diffusion tensor imaging (DTI) and histological assessment with super-resolution microscopy. DTI detected changes in the striatum, substantia nigra, and motor cortex. Histological assessment found a reduction in the diameter of myelinated cortical axons as well as MSN dendrites and axons. The structural changes showed a high correlation between DTI parameters and histological data. These results demonstrated that long-term neural activation in the MSNs alters the diameter of MSN and cortical neurons fibers. This study provides a tool for understanding the causal relationship between functional and structural alterations. Highlights • Long-term optogenetic stimulation in MSNs induced motor dysfunction. • DTI found changes in DTI parameters in the striatal pathway. • Super-resolution microscopy confirmed structural changes described by DTI. • Long activation in MSNs alters the diameter of MSN fibers and cortical fibers. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Quantified impact of tissue iron levels on high field magnetic resonance imaging. • Validation with post-mortem synchrotron X-ray imaging of regional brain iron. • Influence of iron content on magnetic resonance signal matches empirical predictions. • Quantified relationships apply equally to Alzheimer's cases and healthy controls. Abstract Background Chemical imaging of the human brain has great potential for diagnostic and monitoring purposes. The heterogeneity of human brain iron distribution, and alterations to this distribution in Alzheimer's disease, indicate iron as a potential endogenous marker. The influence of iron on certain magnetic resonance imaging (MRI) parameters increases with magnetic field, but is under-explored in human brain tissues above 7 T. New Method Magnetic resonance microscopy at 9.4 T is used to calculate parametric images of chemically-unfixed post-mortem tissue from Alzheimer's cases (n = 3) and healthy controls (n = 2). Iron-rich regions including caudate nucleus, putamen, globus pallidus and substantia nigra are analysed prior to imaging of total iron distribution with synchrotron X-ray fluorescence mapping. Iron fluorescence calibration is achieved with adjacent tissue blocks, analysed by inductively coupled plasma mass spectrometry or graphite furnace atomic absorption spectroscopy. Results Correlated MR images and fluorescence maps indicate linear dependence of R 2 , R 2 * and R 2 ' on iron at 9.4 T, for both disease and control, as follows: [R 2 (s−1) = 0.072[Fe] + 20]; [R 2 *(s−1) = 0.34[Fe] + 37]; [R 2 '(s−1) = 0.26[Fe] + 16] for Fe in μg/g tissue (wet weight). Comparison with Existing Methods This method permits simultaneous non-destructive imaging of most bioavailable elements. Iron is the focus of the present study as it offers strong scope for clinical evaluation; the approach may be used more widely to evaluate the impact of chemical elements on clinical imaging parameters. Conclusion The results at 9.4 T are in excellent quantitative agreement with predictions from experiments performed at lower magnetic fields. [ABSTRACT FROM AUTHOR]

Summary Parkinson's disease (PD) is known to have a long prodromal stage due to the degeneration of dopaminergic neurons of the substantia nigra pars compacta over the course of many years without clinical manifestations of PD. When the diagnosis is made, the neuropathological process is already well entrenched. Consequently, identifying individuals during this prodromal period could be very helpful for future trials of neuroprotective or disease-modifying therapies, which might slow or prevent the degeneration of dopaminergic neurons. Thus, efforts are needed to determine appropriate early markers of PD. Gait and balance disorders are frequent during the early stages of PD. This systematic review aims to determine if gait and balance disorders occur before the diagnosis of PD and if so, whether they could be used as markers of preclinical PD. Findings reveal that, at the presymptomatic stage of PD, impaired basal ganglia function leads to disorders in gait and balance. Both clinical and instrumental assessments allow early detection of these disorders, particularly when performed under challenging conditions (e.g. dual-task). Among all studied parameters, temporal gait variability and arm kinematics appear to be promising markers of preclinical PD. [ABSTRACT FROM AUTHOR]

Abstract The deposition of amyloid-β (Aβ) aggregates in the brain is a hallmark of the Alzheimer's disease (AD)-affected brain. Various aggregated Aβ species, including oligomers and fibrils, are generated upon the aggregation process, and these Aβ aggregates have distinct biological properties. To non-invasively monitor the aggregation pathways of Aβ and identify the existence of certain Aβ species in biological environments, an effective strategy to detect Aβ species is necessary. Herein, we report a turn-on near-infrared (near-IR) fluorescent probe, 1 , for Aβ aggregates, which consists of a donor-π-acceptor system with an Aβ-interacting moiety. Our probe, 1 , shows a noticeable increase in near-IR fluorescence at ca. 710 nm in the presence of Aβ aggregates in aqueous media. In addition, the fluorescent response of 1 was altered depending on the degree of Aβ aggregation. Moreover, 1 indicates turn-on fluorescence with Aβ aggregates in living cells and is nontoxic under the condition used for live-cell imaging. Graphical abstract Image 1 Highlights • A near-IR fluorescent probe for detecting Aβ species was developed. • 1 monitors Aβ aggregation with a change in fluorescence in aqueous media. • 1 shows turn-on fluorescence with Aβ species in living cells. [ABSTRACT FROM AUTHOR]

We hypothesize that Parkinson's disease (PD) pathogenesis can be divided into three temporal phases. During the first phase, 'triggers', such as viral infections or environmental toxins, spark the disease process in the brain and/or peripheral tissues. Triggers alone, however, may be insufficient, requiring 'facilitators' like peripheral inflammation for PD pathology to develop. Once the disease manifests, 'aggravators' spur further neurodegeneration and exacerbate symptoms. Aggravators are proposed to include impaired autophagy and cell-to-cell propagation of α-synuclein pathology. We believe clinical trials need to consider these three phases and target potential therapies at the appropriate stage of the disease process in order to be effective. Highlights We propose a new conceptual model for PD pathogenesis, in which disease-associated factors are divided into three categories: triggers, facilitators, and aggravators. Triggers are agents or events that begin the disease process; these factors are necessary but insufficient for PD to develop. Facilitators are factors that allow the disease to spread to, and significantly impact, the central nervous system. Aggravators directly promote the neurodegenerative process and often have a snowballing effect that exacerbates pathology and spreads the disease beyond the basal ganglia. We propose that clinical therapies aimed at slowing or arresting PD progression should not only be given to patients enriched for the appropriate target (i.e., administered to the appropriate subpopulation), but also be applied during the appropriate temporal phase at which the relevant factor is most active. [ABSTRACT FROM AUTHOR]

Parkinson's disease is a neurodegenerative disorder in which dopamine (a specific type of neurotransmitter) production by neurons is destroyed in the brain. Therefore, there is less or no production of dopamine in the human brain and the patient has motor and non-motor complications. The main reason for Parkinson's disease is the basal ganglia (BG) system imbalance. Therefore, it is imperative to find effective control methods to stabilize and regulate the BG system. To control the BG system within the normal oscillating performance, the opinion of closed-loop deep brain stimulation (DBS) system is used as the most innovative surgical treatment. In this paper, a quasi-linear parameter-varying (LPV) model is extracted from two known nonlinear models (the RT model and the modified RT model with 19 dynamics as the state variables of the BG system) as a comprehensive model to result in a more accurate control for the DBS system. The theoretical contributions in this paper are novel because this model is considered as a positive system and the related theories and properties are discussed. In view of this, quasi-LPV positive observer-based control method is designed for two situations; when all parameters are available for estimation (exact observer) and when all accurate parameters cannot be easily accessed (inexact observer). By designing such controllers, the provided algorithm does not need the availability of the scheduling parameters of the model, which is the novel challenge of this paper. The positivity and asymptotic stability of the proposed controllers have been studied based on linear matrix inequalities. The feasibility of the proposed closed-loop system and the effectiveness of the controllers are verified by numerical simulation. The designed controllers make the closed-loop DBS system stable and positive in both situations. It is while, without this controller, there is no such oscillating performance for Parkinsonian patients. • A quasi-linear parameter-varying (quasi-LPV) model is extracted from two nonlinear models of the basal ganglia system (the RT and modified RT models). It will be a comprehensive model with 19 dynamics of the state variables for the closed-loop Deep brain stimulation (DBS) system. • The DBS system is considered as a positive system and the related theories and properties are discussed. The previous methods have all designed the controller without considering that the system is positive, while we are controlling it based on positive system theories. • Positive observer is different from the general observer. The main opinion of the positive observer is to guarantee that all the estimates and also, the estimation error never become negative at any time. • The novel observer-based control approach is used to solve the problem of when the state variables are not available. Therefore, observation is an important point for the brain system in which state variables cannot be easily accessed. Moreover, these observations may not be exact in many cases and we have an inexact observer. It is possible that during the surgery and the DBS system implementation, the parameters are measured with a little difference from their actual value. Therefore, two scenarios are considered for the observation problem; exact observer and inexact observer. • The presented theorems guarantee that the closed-loop DBS system is both positive and stable by solvinbg a set of feasible linear matrix inequalities (LMIs). Therefore, the obtained approach can control the basal ganglia system within the normal oscillating performance and then, and the PD patient is protected from Parkinsons' symptoms and complications. [ABSTRACT FROM AUTHOR]

The product of thiamine phosphokinase is the cofactor for many enzymes, including the dehydrogenases of pyruvate, 2-ketoglutarate and branched chain ketoacids. Its deficiency has recently been described in a small number of patients, some of whom had a Leigh syndrome phenotype. The patient who also had a Leigh phenotype was initially found to have a low concentration of biotin in plasma and massive urinary excretion of biotin. Despite treatment with biotin and thiamine, her disease was progressive. Mutations c.311delG and c.426G > C were found in the TPK1 gene. • Thiamine Phosphokinase Deficiency. • Mutation in the TPK1 gene. • Biotin Responsive Basal Ganglia Disease. • Leigh phenotype. • Leigh syndrome. [ABSTRACT FROM AUTHOR]

Abstract The possible hemispheric specialization of the basal ganglia during emotional prosody (i.e., vocal emotion) processing has still to be elucidated. Coupled with affective measures and neuroimaging, Parkinson's disease offers a unique opportunity to study this question, on account of its characteristically asymmetric striatal dysfunction, which translates into predominantly contralateral motor symptoms. We investigated the cerebral metabolic bases of emotional prosody recognition in patients with Parkinson's disease with left- versus right-lateralized motor symptoms, postulating that patients with greater right hemispheric brain dysfunction have a specific impairment that correlates with the metabolic modification of a brain network known to be involved in emotional prosody. A total of 38 patients performed a validated emotional prosody recognition task and underwent a resting-state F-18 fluorodeoxyglucose PET scan, as well as clinical, motor, neuropsychological, and psychiatric assessments. Patients' performances were compared with those of 45 healthy controls. As expected, vocal emotion recognition was significantly poorer among patients with left-sided motor symptoms than among both right-sided patients and controls. There was no significant difference between right-sided patients and controls. This effect was observed for both the total score and the happiness subscore. Interestingly, regressions showed that the greater the emotional misattribution, the greater the patients' age and asymmetric motor symptom severity. Finally, at the metabolic level, positive correlations were found between the happiness recognition subscore and the metabolism of the right orbitofrontal cortex in patients with left-sided motor symptoms. A right orbitofrontal-basal ganglia coupling seems to be specifically involved in the vocal emotion recognition deficit observed in Parkinson's disease. The asymmetry of motor symptoms is thus an important clinical factor, in that it may influence the presence or severity of affective disorders in Parkinson's disease. Graphical abstract fx1 Highlights • We explored the impact of lateralized motor symptoms on vocal emotion in PD. • Only left -lateralized PD patients presented a vocal emotion deficit. • This deficit correlated with glucose metabolism in the right orbito-frontal cortex. • This suggests a specific role of right fronto-striatal network in vocal emotion. • Brain hemispheric specialization in emotional prosody is discussed. [ABSTRACT FROM AUTHOR]

Striatal-direct and -indirect Pathway Neurons showed different vulnerability in basal ganglia disorders. Therefore, present study aimed to examine and compare characteristic changes of densities, protein and mRNA levels of soma, dendrites, and spines between striatal-direct and -indirect pathway neurons after DA depletion by using immunohistochemistry, Western blotting, real-time PCR and immunoelectron microscopy techniques. Experimental results showed that: 1) 6OHDA-induced DA depletion decreased the soma density of striatal-direct pathway neurons (SP+), but no significant changes for striatal-indirect pathway neurons (ENK+). 2) DA depletion resulted in a decline of dendrite density for both striatal-direct (D1+) and -indirect (D2+) pathway neurons, and D2+ dendritic density declined more obviously. At the ultrastructure level, the densities of D1+ and D2+ dendritic spines reduced in the 6OHDA groups compared with their control groups, but the density of D2+ dendritic spines reduced more significant than that of D1. 3) Striatal DA depletion down-regulated protein and mRNA expression levels of SP and D1, on the contrary, ENK and D2 protein and mRNA levels of indirect pathway neurons were up-regulated significantly. Present results suggested that indirect pathway neurons be more sensitive to 6OHDA-induced DA depletion. [ABSTRACT FROM AUTHOR]

A series of multifunctional 3-piperazinecarboxylate sarsasapogenin derivatives were designed and synthesized against Alzheimer's disease (AD). The protection against H 2 O 2 -triggered oxidative stress in PC12 cells, and inhibition on LPS-induced NO production in RAW264.7 cell lines in vitro by these derivatives were firstly evaluated. Most of the compounds showed better antioxidant and antiinflammatory activities compared with sarsasapogenin, especially AA34 and AA36 . Structure-activity relationships revealed that benzyl group, electron-donating group and intramolecular hydrogen bond might be beneficial to enhancing their neuroprotective activities. Moreover, Aβ42 was the optimum predicted target based on the high 3D molecular similarity between compound AA36 and caprospinol. In the following experiments, AA36 significantly protected PC12 cells from Aβ-induced damage and improved learning and memory impairments in Aβ-injected mice. Thus AA36 is regarded as a potent anti-AD agent and N-substituted piperazinecarboxylate can be served as a promising structural unit for anti-AD drug design. [ABSTRACT FROM AUTHOR]

Introduction Idiopathic basal ganglia calcification (IBGC), also called Fahr's disease or recently primary familial brain calcification (PFBC), is characterized by abnormal deposits of minerals including calcium mainly and phosphate in the brain. Mutations in SLC20A2 (IBGC1 (merged with former IBGC2 and IBGC3)), which encodes PiT-2, a phosphate transporter, is the major cause of IBGC. Recently, Slc20a2 -KO mice have been showed to have elevated levels of inorganic phosphorus (Pi) in cerebrospinal fluid (CSF); however, CSF Pi levels in patients with IBGC have not been fully examined. Methods We investigated the cases of 29 patients with IBGC including six patients with SLC20A2 mutation and three patients with PDGFB mutation, and 13 controls. The levels of sodium (Na), potassium (K), chloride (Cl), calcium (Ca), and Pi in sera and CSF were determined by potentiometry and colorimetry. Moreover, clinical manifestations were investigated in the IBGC patients with high Pi levels in CSF. Results The study revealed that the average level of Pi in the CSF of the total group of patients with IBGC is significantly higher than that of the control group, and the levels of Pi in CSF of the IBGC patients with SLC20A2 mutations are significantly higher than those of the IBGC patients with PDGFB mutations, the other IBGC patients and controls. Conclusion Results of this study suggest that the levels of CSF Pi will be a good biomarker for IBGC1. [ABSTRACT FROM AUTHOR]

Background: Studies of individual biomarkers for depression have shown insufficient sensitivity and specificity for clinical use, and most likely combinations of biomarkers may provide a better signature. The sorting-related receptor with A-type repeats (SorLA) is a well-studied pathogenic factor for Alzheimer's. SorLA belongs to the Vps10p domain receptor family, which also encompasses sortilin and SorCS1-3. All family members have been implicated in neurological and mental disorders. Notably, the SORCS3 gene is genome-wide significantly associated with depression and serum protein levels of sortilin are reduced in depressed individuals. SorLA regulates the activity of neurotrophic factors and cytokines and we hence speculated that SorLA might be implicated in depression.Methods: Serum SorLA levels were measured in two well-defined clinical samples using ELISA. Generalized linear models were used in the statistical analyses.Results: We identified a multivariate model to discriminate depressed individuals from healthy controls. Interestingly, the model consisted of serum SorLA levels and additional four predictors: previous depressive episode, stressful life events, serum levels of sortilin and VEGF. However, as an isolated factor, we observed no significant difference in SorLA levels between 140 depressed individuals and 140 healthy controls. Nevertheless, we observed a significant increase in SorLA levels following 12 weeks of treatment with nortriptyline, but not escitalopram.Limitations: The number of biomarkers included in the multivariate model for depression and lack of replication limit our study.Conclusions: Our results suggest SorLA as one of five factors that in combination may support the depression diagnosis, but not as an individual biomarker for depression or treatment response. [ABSTRACT FROM AUTHOR]

Background: The management of acute agitation in the emergency department often requires the administration of rapid-acting antipsychotic agents. However, there are few comparative studies and little guidance regarding the risks associated with use of such drugs in the acute setting.Objective: This structured evidence-based review compared the safety of antipsychotic pharmacotherapies for acute agitation using data from randomized controlled trials identified by a literature search of the PubMed database.Results: Based on findings from 34 blinded, randomized controlled trials, common acute adverse effects of second-generation antipsychotics and haloperidol were headache, dizziness, insomnia, and somnolence. There were some differences in incidence of extrapyramidal symptoms (EPS), degree of sedation, and acute QTc prolongations between agents.Conclusions: The results of this review demonstrate the improved safety (particularly regarding EPS and over-sedation) of certain newer-generation antipsychotic agents compared with haloperidol and benzodiazepines for the treatment of acutely agitated patients. The risk of prolonged QT interval and torsade de pointes needs to be considered with haloperidol and some of the second-generation antipsychotics. [ABSTRACT FROM AUTHOR]

Background: Enlarged perivascular spaces (EPVS), markers of cerebral small vessel disease, are associated with unfavorable prognosis of stroke. This study explored the relationship between EPVS and poststroke depression (PSD).Methods: A total of 725 patients with acute ischemic stroke were recruited from the Stroke Unit of a university-affiliated hospital in Hong Kong. PSD was defined as a Geriatric Depression Scale score of ≥ 7 assessed at three months after stroke. The extent of EPVS in the basal ganglia (BG) and the centrum semiovale (CS) was assessed on axial T2 weighted magnetic resonance imaging using a validated scale. Patients' EPVS status was categorized as either mild or moderate to severe degree. The association between EPVS and PSD was examined with logistic regression.Results: One hundred and fifty-three (21.1%) of the study sample had PSD three month after stroke. 55.6% of the study sample were classified as having a minor stroke. The median scores of CS- and BG-EPVS were 1 (1-2) and 1 (0-2), respectively. After adjusting for demographic, clinical and imaging characteristics in multivariate logistic regression analyses, the CS-EPVS continuous score remained an independent predictor of PSD [odds ratio (OR) = 1.27; 95% confidence interval (CI) = 1.03-1.57]. After dichotomized, moderate to severe CS-EPVS was independently associated with PSD with an OR of 1.68 (95%CI = 1.10-2.57).Limitations: The diagnosis of PSD was based on GDS score rather than a standardized clinical examination. The study favored the patients with milder stroke.Conclusion: CS-EPVS were associated with PSD identified at three months after mild to moderate acute ischemic stroke. [ABSTRACT FROM AUTHOR]

Background and Purpose The idiopathic basal ganglia calcification (Fahr syndrome) may occur due to senility. Fetuin-A is a negative acute phase reactant which inhibits calcium-phosphorus precipitation and vascular calcification. In this study, we aimed to evaluate whether serum fetuin-A levels correlate with bilateral basal ganglia calcification. Method Forty-five patients who had bilateral basal ganglia calcification on brain CT were selected according to the inclusion and exclusion criteria, and 45 age and gender-matched subjects without basal ganglia calcification were included for the control group. Serum fetuin-A levels were measured from venous blood samples. All participants were divided into two groups; with and without basal ganglia calcification. These groups were divided into subgroups regarding age (18–32 and 33–45 years of age) and gender (male, female). Results We detected lower levels of serum fetuin-A in patients with basal ganglia calcification compared with the subjects without basal ganglia calcification. In all subgroups (female, male, 18–32 years and 33–45 years), mean fetuin-A levels were significantly lower in patients with basal ganglia calcification (p = 0.017, p = 0.014, p = 0.024, p = 0.026, p = 0.01 respectively). And statistically significantly lower levels of fetuin-A was found to be correlated with the increasing densities of calcification in the calcified basal ganglia group (p-value: <0.001). Conclusion Considering the role of fetuin-A in tissue calcification and inflammation, higher serum fetuin-A levels should be measured in patients with basal ganglia calcification. We believe that the measurement of serum fetuin-A may play a role in the prediction of basal ganglia calcification as a biomarker. [ABSTRACT FROM AUTHOR]

Background: Intracranial arteriopathies are frequent causes of pediatric stroke and important risk factors for stroke recurrence. Without tissue diagnosis, vascular imaging is relied upon to identify the underlying etiology and prognosis. We hypothesized that children with unilateral intracranial arteriopathy with lenticulostriate collaterals would demonstrate distinct vascular outcomes compared with children without collaterals.Methods: We retrospectively identified children with unilateral intracranial arteriopathy from two institutions. Two blinded raters from each institution reviewed magnetic resonance or digital subtraction angiography at baseline and ≥12 months. Patients were grouped according to presence or absence of lenticulostriate collaterals. Clinical features and vascular imaging outcomes were compared using univariate analysis and multivariate logistic regression.Results: Forty-four children were included: 22 males, median age 8.2 years (range two to 16.9 years), and further stratified into the collateral group (n = 20) and non-collateral group (n = 24), with median follow-up of 25.5 months and 23 months, respectively. Both groups demonstrated similar rates of progression on vascular imaging at ≥12 months, 50% in the collateral group versus 37.5% in the non-collateral group (P > 0.05). The collateral group was associated with asymptomatic clinical presentation, normal brain MRI, border zone infarcts, and either vascular stabilization or new contralateral disease. The non-collateral group demonstrated either vascular improvement or discordant progression (combination of improved and progressive lesions). Using a multivariate model, collaterals continued to be an independent predictor of vascular outcome.Conclusions: This study suggests that lenticulostriate collaterals in children with unilateral intracranial arteriopathy may serve as a useful neuroimaging biomarker that helps to stratify patients with distinct clinical features and patterns of vascular evolution. [ABSTRACT FROM AUTHOR]

Background and aims Enlarged basal ganglia perivascular spaces (BG-PVS) are a marker of cerebral small vessel disease (SVD). The association between enlarged BG-PVS and atherosclerosis has been explored, but knowledge is limited to extracranial vessels. We aimed to assess whether enlarged BG-PVS correlate with carotid siphon calcifications (CSC), used as a surrogate of intracranial atherosclerosis. Methods Atahualpa residents aged ≥60 years underwent head computed tomography (CT) for assessment of CSC, and brain magnetic resonance imaging (MRI) for evaluation of BG-PVS and other imaging markers of SVD. We evaluated the association between BG-PVS and CSC severity (dependent variable) using regression models adjusted for demographics and cardiovascular risk factors. Results Of 437 candidates, 354 (81%) were included. Grade 1 CSC were observed in 131 (37%), Grade 2 in 99 (28%), Grade 3 in 92 (26%), and Grade 4 in 32 (9%) subjects. MRI showed >10 enlarged BG-PVS in 97 (27%) participants, moderate-to-severe white matter hyperintensities in 81 (23%), lacunar infarcts in 39 (11%), and deep microbleeds in 28 (8%). Fully-adjusted models showed a significant association between enlarged BG-PVS and CSC severity. Individuals with Grade 4 CSC have 3 times de odds of having enlarged BG-PVS than those with Grade 1 CSC. Enlarged BG-PVS were observed in 20% versus 41% of individuals with Grade 1 and Grade 4 CSC, respectively. Conclusions Enlarged BG-PVS often coexist with CSC, suggesting that a common pathogenetic mechanism may explain the occurrence of both conditions. [ABSTRACT FROM AUTHOR]

The cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) is the rate-limiting step in beta amyloid generation during Alzheimer's disease (AD) pathogenesis. In AD brains, BACE1 is abnormally accumulated in endocytic compartments, where the acidic pH is optimal for its activity. However, mechanisms regulating the endosome-to-trans-Golgi network (TGN) retrieval of BACE1 remain unclear. Here, we show that partitioning defective 3 (Par3) facilitates BACE1 retrograde trafficking from endosomes to the TGN. Par3 functions through aPKC-mediated phosphorylation of BACE1 on Ser498, which in turn promotes the interaction between BACE1 and phosphofurin acidic cluster sorting protein 1 and facilitates the retrograde trafficking of BACE1 to the TGN. In human AD brains, there is a significant decrease in Ser498 phosphorylation of BACE1 suggesting that defective phosphorylation-dependent retrograde transport of BACE1 is important in AD pathogenesis. Together, our studies provide mechanistic insight into a novel role for Par3 and aPKC in regulating the retrograde endosome-to-TGN trafficking of BACE1 and shed light on the mechanisms of AD pathogenesis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) patients display hippocampal atrophy, memory impairment, and cognitive decline. New neurons are generated throughout adulthood in 2 regions of the brain implicated in AD, the dentate gyrus of the hippocampus and the subventricular zone of the olfactory bulb. Disruption of this process contributes to neurodegenerative diseases including AD, and many of the molecular players in AD are also modulators of adult neurogenesis. However, the genetic mechanisms underlying adult neurogenesis in AD have been underexplored. To address this gap, we performed a gene-based association analysis in cognitively normal and impaired participants using neurogenesis pathway-related candidate genes curated from existing databases, literature mining, and large-scale genome-wide association study findings. A gene-based association analysis identified adenosine A2a receptor ( ADORA2A ) as significantly associated with hippocampal volume and the association between rs9608282 within ADORA2A and hippocampal volume was replicated in the meta-analysis after multiple comparison adjustments ( p = 7.88 × 10 −6 ). The minor allele of rs9608282 in ADORA2A is associated with larger hippocampal volumes and better memory. [ABSTRACT FROM AUTHOR]

Background: RAB39B pathogenic variants cause X-linked Parkinsonism associated with Intellectual Disability, known as Waisman syndrome, a very rare disorder that has been mainly identified through exome sequencing in large Parkinson's disease cohorts. In this study we searched for pathogenic variants in RAB39B in two Italian families affected by X-linked early-onset Parkinsonism and Intellectual Disability.Methods: Three patients received neurological evaluation and underwent RAB39B sequencing.Results: Two novel RAB39B frameshift variants were found to result in the absence of RAB39B protein (family 1: c.137dupT; family 2: c.371delA). Patients showed unilateral rest tremor and bradykinesia; one of them also displayed an early-onset postural tremor. Paramagnetic substance deposition in the substantia nigra, globus pallidi, red nucleus, putamen and pulvinar was assessed by brain imaging. Two patients also showed moderate calcification of globus pallidi.Conclusion: In this study we highlight the evidence that X-linked early-onset Parkinsonism associated with Intellectual Disability occurs as a pattern of clinical and neuroimaging features attributable to RAB39B pathogenic variants. [ABSTRACT FROM AUTHOR]