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Abstract The relationship between reduced serum uric acid (UA) levels and Parkinson’s disease (PD), particularly purine metabolic pathways, is not fully understood. Our study compared serum and cerebrospinal fluid (CSF) levels of inosine, hypoxanthine, xanthine, and UA in PD patients and healthy controls. We analyzed 132 samples (serum, 45 PD, and 29 age- and sex-matched healthy controls; CSF, 39 PD, and 19 age- and sex-matched healthy controls) using liquid chromatography-tandem mass spectrometry. Results showed significantly lower serum and CSF UA levels in PD patients than in controls (p

Although dietary behaviors are affected by neuropsychiatric disorders, various environmental conditions can have strong effects as well. We found that mice under multiple stresses, including social isolation, intermittent high-fat diet, and physical restraint, developed feeding behavior patterns characterized by a deviated bait approach (fixated feeding). All the tested stressors affected dopamine release at the nucleus accumbens (NAcc) shell and dopamine normalization reversed the feeding defects. Moreover, inhibition of dopaminergic activity in the ventral tegmental area that projects into the NAcc shell caused similar feeding pattern aberrations. Given that the deviations were not consistently accompanied by changes in the amount consumed or metabolic factors, the alterations in feeding behaviors likely reflect perturbations to a critical stress-associated pathway in the mesolimbic dopamine system. Thus, deviations in feeding behavior patterns that reflect reward system abnormalities can be sensitive biomarkers of psychosocial and physical stress.

Abstract Objective Recent studies have revealed an association between Parkinson's disease (PD) and Fabry disease, a lysosomal storage disorder; however, the underlying mechanisms remain to be elucidated. This study aimed to investigate the enzymatic properties of serum alpha‐galactosidase A (GLA) and compared them with the clinical parameters of PD. Methods The study participants consisted of 66 sporadic PD patients and 52 controls. We measured serum GLA activity and calculated the apparent Michaelis constant (Km) and maximal velocity (Vmax) by Lineweaver–Burk plot analysis. Serum GLA protein concentration was measured by enzyme‐linked immunosorbent assay. We examined the potential correlations between serum GLA activity and GLA protein concentration and clinical features and the plasma neurofilament light chain (NfL) level. Results Compared to controls, PD patients showed significantly lower serum GLA activity (P

In patients with Parkinson’s disease (PD), dopamine replacement therapy with dopamine D2/D3 receptor agonists induces impairments in decision-making, including pathological gambling. The neurobiological mechanisms underlying these adverse effects remain elusive. Here, in a mouse model of PD, we investigated the effects of the dopamine D3 receptor (D3R)-preferring agonist pramipexole (PPX) on decision-making. PD model mice were generated using a bilateral injection of the toxin 6-hydroxydopamine into the dorsolateral striatum. Subsequent treatment with PPX increased disadvantageous choices characterized by a high-risk/high-reward in the touchscreen-based Iowa Gambling Task. This effect was blocked by treatment with the selective D3R antagonist PG-01037. In model mice treated with PPX, the number of c-Fos-positive cells was increased in the external globus pallidus (GPe), indicating dysregulation of the indirect pathway in the corticothalamic-basal ganglia circuitry. In accordance, chemogenetic inhibition of the GPe restored normal c-Fos activation and rescued PPX-induced disadvantageous choices. These findings demonstrate that the hyperactivation of GPe neurons in the indirect pathway impairs decision-making in PD model mice. The results provide a candidate mechanism and therapeutic target for pathological gambling observed during D2/D3 receptor pharmacotherapy in PD patients.

Abstract Background Distinguishing between central nervous system lymphoma (CNSL) and CNS infectious and/or demyelinating diseases, although clinically important, is sometimes difficult even using imaging strategies and conventional cerebrospinal fluid (CSF) analyses. To determine whether detection of genetic mutations enables differentiation between these diseases and the early detection of CNSL, we performed mutational analysis using CSF liquid biopsy technique. Methods In this study, we extracted cell‐free DNA from the CSF (CSF‐cfDNA) of CNSL (N = 10), CNS infectious disease (N = 10), and demyelinating disease (N = 10) patients, and performed quantitative mutational analysis by droplet‐digital PCR. Conventional analyses were also performed using peripheral blood and CSF to confirm the characteristics of each disease. Results Blood hemoglobin and albumin levels were significantly lower in CNSL than CNS infectious and demyelinating diseases, CSF cell counts were significantly higher in infectious diseases than CNSL and demyelinating diseases, and CSF‐cfDNA concentrations were significantly higher in infectious diseases than CNSL and demyelinating diseases. Mutation analysis using CSF‐cfDNA detected MYD88L265P and CD79Y196 mutations in 60% of CNSLs each, with either mutation detected in 80% of cases. Mutual existence of both mutations was identified in 40% of cases. These mutations were not detected in either infectious or demyelinating diseases, and the sensitivity and specificity of detecting either MYD88/CD79B mutations in CNSL were 80% and 100%, respectively. In the four cases biopsied, the median time from collecting CSF with the detected mutations to definitive diagnosis by conventional methods was 22.5 days (range, 18–93 days). Conclusions These results suggest that mutation analysis using CSF‐cfDNA might be useful for differentiating CNSL from CNS infectious/demyelinating diseases and for early detection of CNSL, even in cases where brain biopsy is difficult to perform.

Tardive dyskinesia (TD) is a movement disorder that can arise as a side effect of treatment with dopamine receptor-blocking agents (DRBAs), including antipsychotic drugs (APDs) used to manage psychotic illnesses. Second-generation APDs (SGAs) are often preferred to first-generation drugs due to their lower propensity to cause TD, however many SGAs-treated patients still develop the condition. Although TD is a global health concern, evidence regarding the occurrence of TD and how it is managed in Asian countries is currently limited. This article reports the results of a systematic review of the published literature on TD focusing on its prevalence, types of patients, knowledge of the condition, causative factors, and usual treatment pathways in clinical practice in Asian countries. Epidemiological data suggest that the prevalence of TD is increasing globally due to an overall rise in APD use, contributing factors being polypharmacy with multiple APDs, the use of higher than necessary doses, and off-label use for non-psychotic indications. Although exact prevalence figures for TD in Asian countries are difficult to define, there is a similar pattern of rising APD use which will result in increasing numbers of TD patients in this region. These issues need to be addressed and strategies developed to minimize TD risk and manage this disabling condition which impacts patients' quality of life and daily functioning. To date, both research into TD has been predominantly psychiatry focused and the perspectives from neurologists regarding the clinical management of this challenging condition are scarce. However, neurologists have an essential role in managing the movement disorders manifestations that characterize TD. Optimum management of TD, therefore, should ideally involve collaboration between psychiatrists and neurologists in joint care pathways, wherever practical. Collaborative pathways are proposed in this article, and the challenges that will need to be addressed in Asian countries to improve the care of people with TD are highlighted, with a focus on the neurologist's viewpoint and the implications for the management of TD globally.

BackgroundNon-motor symptoms (NMS) are important factors when selecting treatments for patients with advanced Parkinson's disease (PD). We sought to elucidate the prescribing practices for advanced PD patients with NMS in Japanese clinical practice.MethodsWe examined the prescription rates and doses of anti-PD drugs, and the use of non-steroidal anti-inflammatory drugs (NSAIDs) in post hoc analyses of a 52-week observational study of 996 PD patients with wearing-off on levodopa-containing therapy and ≥1 NMS.ResultsDopamine agonists were the most frequently prescribed drugs combined with levodopa-containing drugs, followed by entacapone, zonisamide, istradefylline, selegiline, and amantadine. The daily dose of levodopa-containing drugs, rotigotine, entacapone, istradefylline, and droxidopa, and the levodopa-equivalent dose increased during the observation period. In a subgroup analysis of patients stratified by NMS status (improved/unchanged/deteriorated), the deteriorated group had higher prescription rates of entacapone and istradefylline, whereas the improved group had higher prescription rates of NSAIDs and zonisamide at Week 52. Prescriptions varied by geographical region for anti-PD drugs and by NMS status for NSAIDs.ConclusionsThere were significant changes in the prescriptions and dosing of selected anti-PD drugs, especially newer drugs. Anti-PD drug and NSAID prescriptions also varied by changes in NMS status and geographic region.

Objective: In this study, we aimed to clarify the relationship between initial treatment response, prednisolone (PSL) dosage, clinical type, and recurrence in patients with hypertrophic pachymeningitis (HP). Methods: The study cohort comprised eight patients with HP who had been admitted to our hospital from April 2015 to June 2020. Diagnostic criteria for HP included neurological abnormalities and dural thickening on magnetic resonance gadolinium-enhanced T1-weighted images. Results: Relevant characteristics of the eight study patients are as follows. There were two men and six women. The average age at onset was 58.3 (range: 29–79) years. Three of them had myeloperoxidase-antineutrophil cytoplasmic antibody-related vasculitis, one immunoglobulin G4-related disease, and one ulcerative colitis. The remaining three patients had idiopathic HP. The average maximum dosage of PSL was 0.79 mg/kg/day, and the average daily maintenance dosage 0.18 mg/kg/day. Three patients needed additional immunosuppressive drugs. Both idiopathic and secondary HP initially responded well to PSL, with improvement in activities of daily living. Six patients had some sequelae related to cranial nerve involvement. No relapses occurred while the patients were taking moderate doses of PSL; however, all patients with idiopathic HP had recurrences when their PSL dosage was reduced. Conclusions: Patients with idiopathic HP and HP associated with immune disorders respond to steroids and immunosuppressive drugs and recover well. However, there is a high rate of relapse after reduction of PSL dosage, mainly in those with idiopathic HP.

Background: No studies have examined the associations between adult height and ischemic stroke subtypes. Methods: We conducted a population-based case-control study that included 2,451 thrombotic and 687 embolic stroke cases, as well as 1,623 intracerebral and 768 subarachnoid hemorrhage cases without history of stroke aged 40–79 years, and the same number of sex- and age-matched controls. Cases and controls were grouped according to the quintile cut-off values of height in controls, and the third quintile, which was approximately the average height group, was used as the reference group. Height divided by one standard deviation of height in controls was also examined as a continuous variable. The analyses were carried out separately for participants aged 40–59 years and 60–79 years. Results: In both younger and older men, height was linearly inversely associated with total and thrombotic strokes, and the shortest quintile compared to the reference group was associated with increased risks of these strokes. Although height was linearly inversely associated with embolic stroke and intracerebral hemorrhage in younger men, the shortest quintile did not show increased risks of these strokes. Height did not seem to be associated with total stroke and any stroke subtypes in younger women. In contrast, the tallest quintile was significantly associated with increased risks of total stroke and intracerebral hemorrhage, and height tended to be positively associated with these strokes in older women. Conclusion: We reported the associations between adult height and ischemic stroke subtypes for the first time, which differed according to sex and age group.

The core pathological event in Parkinson’s disease (PD) is the specific dying of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). The reasons why SNc DA neurons are especially vulnerable and why idiopathic PD has only been found in humans are still puzzling. The two main underlying factors of SNc DA neuron vulnerability appear related to high DA production, namely (i) the toxic effects of cytoplasmic DA metabolism and (ii) continuous cytosolic Ca2+ oscillations in the absence of the Ca2+-buffer protein calbindin. Both factors cause oxidative stress by producing highly reactive quinones and increasing intra-mitochondrial Ca2+ concentrations, respectively. High DA expression in human SNc DA neuron cell bodies is suggested by the abundant presence of the DA-derived pigment neuromelanin, which is not found in such abundance in other species and has been associated with toxicity at higher levels. The oxidative stress created by their DA production system, despite the fact that the SN does not use unusually high amounts of energy, explains why SNc DA neurons are sensitive to various genetic and environmental factors that create mitochondrial damage and thereby promote PD. Aging increases multiple risk factors for PD, and, to a large extent, PD is accelerated aging. To prevent PD neurodegeneration, possible approaches that are discussed here are (1) reducing cytoplasmic DA accumulation, (2) blocking cytoplasmic Ca2+ oscillations, and (3) providing bioenergetic support.

Accumulating evidence from anatomical and neuroimaging studies suggests that the cerebellum is engaged in a variety of motor and cognitive tasks. Given its various functions, a key question is whether the cerebellum also plays an important role in the brain's integrative functions. Here, we hypothesize the existence of connector regions, also known as connector hubs, where multiple resting state networks converged in the cerebellum. To verify this, we employed a recently developed voxel-level network measure called functional connectivity overlap ratio (FCOR), which could be used to quantify the spatial extent of a region's connection to several large-scale cortical networks. Using resting state functional MRI data from 101 healthy participants, cerebellar FCOR maps were constructed and used to identify the locations of connector hubs in the cerebellum. Results showed that a number of cerebellar regions exhibited strong connectivity with multiple functional networks, verifying our hypothesis. These highly connected regions were located in the posterior cerebellum, especially in lobules VI, VII, and IX, and mainly connected to the core neurocognitive networks such as default mode and executive control networks. Regions associated with the sensorimotor network were also localized in lobule V, VI, and VIII, albeit in small clusters. These cerebellar connector hubs may play an essential role in the processing of information across the core neurocognitive networks.

Abstract Objective Amyotrophic lateral sclerosis (ALS) is a multisystem disorder associated with motor impairment and behavioral/cognitive involvement. We examined decision‐making features and changes in the neural hub network in patients with ALS using a probabilistic reversal learning task and resting‐state network analysis, respectively. Methods Ninety ALS patients and 127 cognitively normal participants performed this task. Data from 62 ALS patients and 63 control participants were fitted to a Q‐learning model. Results ALS patients had anomalous decision‐making features with little shift in choice until they thought the value of the two alternatives had become equal. The quantified parameters (Pαβ) calculated by logistic regression analysis with learning rate and inverse temperature well represented the unique choice pattern of ALS patients. Resting‐state network analysis demonstrated a strong correlation between Pαβ and decreased degree centrality in the anterior cingulate gyrus and frontal pole. Interpretation Altered decision‐making in ALS patients may be related to the decreased hub function of medial prefrontal areas.

Abstract Parkinson’s disease (PD) is a debilitating neurodegenerative disorder in which nonmotor symptoms, such as constipation and hyposmia, precede the onset of motor symptoms by 20 years. The aim of this study was to identify biomarkers at the premotor stage of PD. We assessed the differences in longitudinal changes in anthropometric and serological indices obtained from health check-up data before and after the onset of motor symptoms between male and female PD patients and healthy subjects. We enrolled 22 male and 23 female PD patients and 60 male and 60 female healthy controls. A mixed-effects model was used to estimate the trajectory of each clinical marker over the years before and after motor symptoms onset in the PD subjects, which were then compared with the trajectories of the healthy controls. The results showed a premotor blood pressure increase in female PD patients and premotor decreases in haematocrit, total cholesterol and low-density lipoprotein cholesterol in the male patients. Our results indicated that blood pressure, haematocrit and serum cholesterol levels are potential premotor markers of PD. Additionally, the changes in anthropometric and serological indices before PD motor symptoms onset were sex specific.

Purpose: Maintenance of cognitive performance is important for healthy aging. This study aims to elucidate the relationship between brain networks and cognitive function in subjects maintaining relatively good cognitive performance.Methods: A total of 120 subjects, with equal number of participants from each age group between 20 and 70 years, were included in this study. Only participants with Addenbrooke’s Cognitive Examination – Revised (ACE-R) total score greater than 83 were included. Anatomical T1-weighted MR images and resting-state functional MR images (rsfMRIs) were taken from all participants using a 3-tesla MRI scanner. After preprocessing, several factors associated with age including the ACE-R total score, scores of five domains, sub-scores of ACE-R, and brain volumes were tested. Morphometric changes associated with age were analyzed using voxel based morphometry (VBM) and changes in resting state networks (RSNs) were examined using dual regression analysis.Results: Significant negative correlations with age were seen in the total gray matter volume (GMV, r = −0.58), and in the memory, attention, and visuospatial domains. Among the different sub-scores, the score of the delayed recall (DR) showed the highest negative correlation with age (r = −0.55, p < 0.001). In VBM analysis, widespread regions demonstrated negative correlation with age, but none with any of the cognitive scores. Quadratic approximations of cognitive scores as functions of age showed relatively delayed decline compared to total GMV loss. In dual regression analysis, some cognitive networks, including the dorsal default mode network, the lateral dorsal attention network, the right / left executive control network, the posterior salience network, and the language network, did not demonstrate negative correlation with age. Some regions in the sensorimotor networks showed positive correlation with the DR, memory, and fluency scores.Conclusion: Some domains of the cognitive test did not correlate with age, and even the highly correlated sub-scores such as the DR score, showed delayed decline compared to the loss of total GMV. Some RSNs, especially involving cognitive control regions, were relatively maintained with age. Furthermore, the scores of memory, fluency, and the DR were correlated with the within-network functional connectivity values of the sensorimotor network, which supported the importance of exercise for maintenance of cognition.

To understand the mechanisms underlying preserved and impaired cognitive function in healthy aging and dementia, respectively, the spatial relationships of brain networks and mechanisms of their resilience should be understood. The hub regions of the brain, such as the multisensory integration and default mode networks, are critical for within- and between-network communication, remain well-preserved during aging, and play an essential role in compensatory processes. On the other hand, these brain hubs are the preferred sites for lesions in neurodegenerative dementias, such as Alzheimer’s disease. Disrupted primary information processing networks, such as the auditory, visual, and sensorimotor networks, may lead to overactivity of the multisensory integration networks and accumulation of pathological proteins that cause dementia. At the cellular level, the brain hub regions contain many synapses and require a large amount of energy. These regions are rich in ATP-related gene expression and had high glucose metabolism as demonstrated on positron emission tomography (PET). Importantly, the number and function of mitochondria, which are the center of ATP production, decline by about 8% every 10 years. Dementia patients often have dysfunction of the ubiquitin-proteasome and autophagy-lysosome systems, which require large amounts of ATP. If there is low energy supply but the demand is high, the risk of disease can be high. Imbalance between energy supply and demand may cause accumulation of pathological proteins and play an important role in the development of dementia. This energy imbalance may explain why brain hub regions are vulnerable to damage in different dementias. Here, we review (1) the characteristics of gray matter network, white matter network, and resting state functional network changes related to resilience in healthy aging, (2) the mode of resting state functional network disruption in neurodegenerative dementia, and (3) the cellular mechanisms associated with the disruption.

Summary: The thalamus is critical for the brain's integrative hub functions; however, the localization and characterization of the different thalamic hubs remain unclear. Using a voxel-level network measure called functional connectivity overlap ratio (FCOR), we examined the thalamus' association with large-scale resting-state networks (RSNs) to elucidate its connector hub roles. Connections to the core-neurocognitive networks were localized in the anterior and medial parts, such as the anteroventral and mediodorsal nuclei areas. Regions functionally connected to the sensorimotor network were distinctively located around the lateral pulvinar nucleus but to a limited extent. Prominent connector hubs include the anteroventral, ventral lateral, and mediodorsal nuclei with functional connections to multiple RSNs. These findings suggest that the thalamus, with extensive connections to most of the RSNs, is well placed as a critical integrative functional hub and could play an important role for functional integration facilitating brain functions associated with primary processing and higher cognition.

Background: The clinicopathological continuity between amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is well known. Although ALS demonstrates language symptoms similar to FTLD, including semantic dementia, word reading impairments in ALS have not been well studied. “Jukujikun” are Kanji-written words with irregular pronunciation comparable to “exception words” and useful for detecting semantic deficits in Japan. We conducted a cross-sectional study to investigate Jukujikun reading impairments and related network changes in ALS. Methods: We enrolled 71 ALS patients and 69 healthy controls (HCs). Age-, sex-, and education matched HCs were recruited from another cohort study concurrently with patient registration. We examined neuropsychological factors including low frequency Jukujikun reading. We performed resting-state functional magnetic resonance imaging with voxel-based graph analysis on a subset of participants who agreed. Findings: Low frequency Jukujikun score was decreased in ALS (15·0[11·0–19·0](median[25–75 percentile])) compared with HCs (19·0[17·3–20·0]) (p

Abstract Healthy aging is associated with structural and functional changes in the brain even in individuals who are free of neurodegenerative diseases. Using resting state functional magnetic resonance imaging data from a carefully selected cohort of participants, we examined cross sectional changes in the functional organization of several large-scale brain networks over the adult lifespan and its potential association with general cognitive performance. Converging results from multiple analyses at the voxel, node, and network levels showed widespread reorganization of functional brain networks with increasing age. Specifically, the primary processing (visual and sensorimotor) and visuospatial (dorsal attention) networks showed diminished network integrity, while the so-called core neurocognitive (executive control, salience, and default mode) and basal ganglia networks exhibited relatively preserved between-network connections. The visuospatial and precuneus networks also showed significantly more widespread increased connectivity with other networks. Graph analysis suggested that this reorganization progressed towards a more integrated network topology. General cognitive performance, assessed by Addenbrooke’s Cognitive Examination-Revised total score, was positively correlated with between-network connectivity among the core neurocognitive and basal ganglia networks and the integrity of the primary processing and visuospatial networks. Mediation analyses further indicated that the observed association between aging and relative decline in cognitive performance could be mediated by changes in relevant functional connectivity measures. Overall, these findings provided further evidence supporting widespread age-related brain network reorganization and its potential association with general cognitive performance during healthy aging.

Parkinson’s disease (PD) is an aging-related disease and the second most common neurodegenerative disease after Alzheimer’s disease. The main symptoms of PD are movement disorders accompanied with deficiency of neurotransmitter dopamine (DA) in the striatum due to cell death of the nigrostriatal DA neurons. Two main histopathological hallmarks exist in PD: cytosolic inclusion bodies termed Lewy bodies that mainly consist of α-synuclein protein, the oligomers of which produced by misfolding are regarded to be neurotoxic, causing DA cell death; and black pigments termed neuromelanin (NM) that are contained in DA neurons and markedly decrease in PD. The synthesis of human NM is regarded to be similar to that of melanin in melanocytes; melanin synthesis in skin is via DOPAquinone (DQ) by tyrosinase, whereas NM synthesis in DA neurons is via DAquinone (DAQ) by tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC). DA in cytoplasm is highly reactive and is assumed to be oxidized spontaneously or by an unidentified tyrosinase to DAQ and then, synthesized to NM. Intracellular NM accumulation above a specific threshold has been reported to be associated with DA neuron death and PD phenotypes. This review reports recent progress in the biosynthesis and pathophysiology of NM in PD.

Neuroimaging studies have shown that the brain is functionally organized into several large-scale brain networks. Within these networks are regions that are widely connected to several other regions within and/or outside the network. Regions that connect to several other networks, known as connector hubs, are believed to be crucial for information transfer and between-network communication within the brain. To identify regions with high between-network connectivity at the voxel level, we introduced a novel metric called functional connectivity overlap ratio (FCOR), which quantifies the spatial extent of a region's connection to a given network. Using resting state functional magnetic resonance imaging data, FCOR maps were generated for several well-known large-scale resting state networks (RSNs) and used to examine the relevant associations among different RSNs, identify connector hub regions in the cerebral cortex, and elucidate the hierarchical functional organization of the brain. Constructed FCOR maps revealed a strong association among the core neurocognitive networks (default mode, salience, and executive control) as well as among primary processing networks (sensorimotor, auditory, and visual). Prominent connector hubs were identified in the bilateral middle frontal gyrus, posterior cingulate, lateral parietal, middle temporal, dorsal anterior cingulate, and anterior insula, among others, regions mostly associated with the core neurocognitive networks. Finally, clustering the whole brain using FCOR features yielded a topological organization that arranges brain regions into a hierarchy of information processing systems with the primary processing systems at one end and the heteromodal systems comprising connector hubs at the other end.

Recent studies have demonstrated that connector hubs, regions considered critical for the flow of information across neural systems, are mostly involved in neurodegenerative dementia. Considering that aging can significantly affect the brain’s intrinsic connectivity, identifying aging’s impact on these regions’ overall connection strength is important to differentiate changes associated with healthy aging from neurodegenerative disorders. Using resting state functional magnetic resonance imaging data from a carefully selected cohort of 175 healthy volunteers aging from 21 to 86 years old, we computed an intrinsic connectivity contrast (ICC) metric, which quantifies a region’s overall connectivity strength, for whole brain, short-range, and long-range connections and examined age-related changes of this metric over the adult lifespan. We have identified a limited number of hub regions with ICC values that showed significant negative relationship with age. These include the medial precentral/midcingulate gyri and insula with both their short-range and long-range (and thus whole-brain) ICC values negatively associated with age, and the angular, middle frontal, and posterior cingulate gyri with their long-range ICC values mainly involved. Seed-based connectivity analyses further confirmed that these regions are connector hubs with connectivity profile that strongly overlapped with multiple large-scale brain networks. General cognitive performance was not associated with these hubs’ ICC values. These findings suggest that even healthy aging could negatively impact the efficiency of regions critical for facilitating information transfer among different functional brain networks. The extent of the regions involved, however, was limited.

Introduction: Parkinson's disease (PD) shows a variety of visual deficits including visuoperceptual disturbances, however, the neural basis remains unclear. We aimed to clarify clinical and neural features of visuoperceptual disturbances in PD. Methods: The visuospatial/perceptual abilities of ninety-six participants (48 patients with PD and 48 healthy controls) were evaluated using the subtest part 1 and 5–8 of the Visual Object and Space Perception battery (VOSP), cube/pentagon copying and clock drawing tasks. Resting-state fMRI images were acquired and analyzed the differences between PD with incomplete letters below the cut-off and above for intranetwork (primary/medial/higher visual networks) and interregional functional connectivity changes, and spectral dynamic causal modeling was performed to examine the causality. Results: In the PD group, position discrimination and incomplete letter scores were significantly decreased among VOSP subtests, the latter having the largest effect size. The incomplete letter scores correlated with the position discrimination while not with the dot counting, number location and cube analysis, cube/pentagon copying or clock drawing. The group with the incomplete letter scores below the cut-off had regions with decreased functional connectivity surrounding the calcarine sulcus in the primary visual network. These regions had decreased interregional functional connectivity with bilateral lingual gyri and cunei but increased with the thalamus. In this group, effective connectivity from the lingual gyrus to the calcarine sulcus was significantly decreased. Conclusion: The incomplete letters may be sensitive to detect visuoperceptual disturbances in PD. Decreased connectivity in the ventral visual feedback pathway may contribute to these deficits.

Multiple system atrophy (MSA) is an adult-onset, progressive neurodegenerative disorder. Patients with MSA show various phenotypes during the course of their illness, including parkinsonism, cerebellar ataxia, autonomic failure, and pyramidal signs. Patients with MSA sometimes present with isolated autonomic failure or motor symptoms/ signs. The median duration from onset to the concomitant appearance of motor and autonomic symptoms is approximately 2 years but can range up to 14 years. As the presence of both motor and autonomic symptoms is essential for the current diagnostic criteria, early diagnosis is difficult when patients present with isolated autonomic failure or motor symptoms/signs. In contrast, patients with MSA may show severe autonomic failure and die before the presentation of motor symptoms/signs, which are currently required for the diagnosis of MSA. Recent studies have also revealed that patients with MSA may show nonsupporting features of MSA such as dementia, hallucinations, and vertical gaze palsy. To establish early diagnostic criteria and clinically definitive categorization for the successful development of disease-modifying therapy or symptomatic interventions for MSA, research should focus on the isolated phase and atypical symptoms to develop specific clinical, imaging, and fluid biomarkers that satisfy the requirements for objectivity, for semi- or quantitative measurements, and for uncomplicated, worldwide availability. Several novel techniques, such as automated compartmentalization of the brain into multiple parcels for the quantification of gray and white matter volumes on an individual basis and the visualization of α-synuclein and other candidate serum and cerebrospinal fluid biomarkers, may be promising for the early and clinically definitive diagnosis of MSA.

FUS is an RNA-binding protein associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Previous reports have demonstrated intrinsic roles of FUS in synaptic function. However, the mechanism underlying FUS’s regulation of synaptic morphology has remained unclear. We found that reduced mature spines after FUS depletion were associated with the internalization of PSD-95 within the dendritic shaft. Mass spectrometry of PSD-95-interacting proteins identified SynGAP, whose expression decreased after FUS depletion. Moreover, FUS and the ELAV-like proteins ELAVL4 and ELAVL1 control SynGAP mRNA stability in a 3′UTR length-dependent manner, resulting in the stable expression of the alternatively spliced SynGAP isoform α2. Finally, abnormal spine maturation and FTLD-like behavioral deficits in FUS-knockout mice were ameliorated by SynGAP α2. Our findings establish an important link between FUS and ELAVL proteins for mRNA stability control and indicate that this mechanism is crucial for the maintenance of synaptic morphology and cognitive function.

Fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) are RNA binding proteins that regulate RNA metabolism. We found that alternative splicing of the Mapt gene at exon 10, which generates 4-repeat tau (4R-T) and 3-repeat tau (3R-T), is regulated by interactions between FUS and SFPQ in the nuclei of neurons. Hippocampus-specific FUS- or SFPQ-knockdown mice exhibit frontotemporal lobar degeneration (FTLD)-like behaviors, reduced adult neurogenesis, accumulation of phosphorylated tau, and hippocampal atrophy with neuronal loss through an increased 4R-T/3R-T ratio. Normalization of this increased ratio by 4R-T-specific silencing results in recovery of the normal phenotype. These findings suggest a biological link among FUS/SFPQ, tau isoform alteration, and phenotypic expression, which may function in the early pathomechanism of FTLD.

Background: Imaging studies in Alzheimer’s disease (AD) have yet to answer the underlying questions concerning the relationship among tau retention, neuroinflammation, network disruption and cognitive decline. We compared the spatial retention patterns of 18F-THK5351 and resting state network (RSN) disruption in patients with early AD and healthy controls.Methods: We enrolled 23 11C-Pittsburgh compound B (PiB)-positive patients with early AD and 24 11C-PiB-negative participants as healthy controls. All participants underwent resting state functional MRI and 18F-THK5351 PET scans. We used scaled subprofile modeling/principal component analysis (SSM/PCA) to reduce the complexity of multivariate data and to identify patterns that exhibited the largest statistical effects (variances) in THK5351 concentration in AD and healthy controls.Findings: SSM/PCA identified a significant spatial THK5351 pattern composed by mainly three clusters including precuneus/posterior cingulate cortex (PCC), right and left dorsolateral prefrontal cortex (DLPFC) which accounted for 23.6% of the total subject voxel variance of the data and had 82.6% sensitivity and 79.1% specificity in discriminating AD from healthy controls. There was a significant relationship between the intensity of the 18F-THK5351 covariation pattern and cognitive scores in AD. The spatial patterns of 18F-THK5351 uptake showed significant similarity with intrinsic functional connectivity, especially in the PCC network. Seed-based connectivity analysis from the PCC showed significant decrease in connectivity over widespread brain regions in AD patients. An evaluation of an autopsied AD patient with Braak V showed that 18F-THK5351 retention corresponded to tau deposition, monoamine oxidase-B (MAO-B) and astrogliosis in the precuneus/PCC.Interpretation: We identified an AD-specific spatial pattern of 18F-THK5351 retention in the precuneus/PCC, an important connectivity hub region in the brain. Disruption of the functional connections of this important network hub may play an important role in developing dementia in AD.

Frontotemporal lobar degeneration (FTLD) is a group of clinically, pathologically and genetically heterogeneous neurodegenerative disorders that involve the frontal and temporal lobes. Behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA) are three major clinical syndromes. TDP-43, FUS, and tau are three major pathogenetic proteins. In this review, we first discuss the loss-of-function mechanism of FTLD. We focus on FUS-associated pathogenesis in which FUS is linked to tau by regulating its alternative splicing machinery. Moreover, FUS is associated with abnormalities in post-synaptic formation, which can be an early disease marker of FTLD. Second, we discuss clinical and pathological aspects of FTLD. Recently, FTLD and amyotrophic lateral sclerosis (ALS) have been recognized as the same disease entity; indeed, nearly all sporadic ALS cases show TDP-43 pathology irrespective of FTD phenotype. Thus, investigating early structural and network changes in the FTLD/ALS continuum can be useful for developing early diagnostic markers of FTLD. MRI studies have revealed the involvement of the caudate nucleus and its anatomical networks in association with the early phase of behavioral/cognitive decline in FTLD/ALS. In particular, even ALS patients with normal cognition have shown a significant decrease in structural connectivity between the caudate head networks. In pathological studies, FTLD/ALS has shown striatal involvement of both efferent system components and glutamatergic inputs from the cerebral cortices even in ALS patients. Thus, the caudate nucleus may be primarily associated with behavioral abnormality and cognitive involvement in FTLD/ALS. Although several clinical trials have been conducted, there is still no therapy that can change the disease course in patients with FTLD. Therefore, there is an urgent need to establish a strategy for predominant sporadic FTLD cases.

The stability of the MRI scanner throughout a given study is critical in minimizing hardware-induced variability in the acquired imaging data set. However, MRI scanners do malfunction at times, which could generate image artifacts and would require the replacement of a major component such as its gradient coil. In this article, we examined the effect of low intensity, randomly occurring hardware-related noise due to a faulty gradient coil on brain morphometric measures derived from T1-weighted images and resting state networks (RSNs) constructed from resting state functional MRI. We also introduced a method to detect and minimize the effect of the noise associated with a faulty gradient coil. Finally, we assessed the reproducibility of these morphometric measures and RSNs before and after gradient coil replacement. Our results showed that gradient coil noise, even at relatively low intensities, could introduce a large number of voxels exhibiting spurious significant connectivity changes in several RSNs. However, censoring the affected volumes during the analysis could minimize, if not completely eliminate, these spurious connectivity changes and could lead to reproducible RSNs even after gradient coil replacement.

Severe hyposmia is a risk factor of dementia in Parkinson's disease (PD), while the underlying functional connectivity (FC) and brain volume alterations in PD patients with severe hyposmia (PD-SH) are unclear.We examined voxel-based morphometric and resting state functional magnetic resonance imaging findings in 15 cognitively normal PD-SH, 15 cognitively normal patients with PD with no/mild hyposmia (PD-N/MH), and 15 healthy controls (HCs).Decreased gray matter volume (GMV) was observed in the bilateral cuneus, right associative visual area, precuneus, and some areas in anterior temporal lobes in PD-SH group compared to HCs. Both the PD-SH and PD-N/MH groups showed increased GMV in the bilateral posterior insula and its surrounding regions. A widespread significant decrease in amygdala FC beyond the decreased GMV areas and olfactory cortices were found in the PD-SH group compared with the HCs. Above all, decreased amygdala FC with the inferior parietal lobule, lingual gyrus, and fusiform gyrus was significantly correlated with both reduction of Addenbrooke's Cognitive Examination-Revised scores and severity of hyposmia in all participants. Canonical resting state networks exhibited decreased FC in the precuneus and left executive control networks but increased FC in the primary and high visual networks of patients with PD compared with HCs. Canonical network FC to other brain regions was enhanced in the executive control, salience, primary visual, and visuospatial networks of the PD-SH.PD-SH showed extensive decreased amygdala FC. Particularly, decreased FC between the amygdala and inferior parietal lobule, lingual gyrus, and fusiform gyrus were associated with the severity of hyposmia and cognitive performance. In contrast, relatively preserved canonical networks in combination with increased FC to brain regions outside of canonical networks may be related to compensatory mechanisms, and preservation of brain function.

In this study, we investigated changes in resting state networks (RSNs) in patients with gliomas located in the left hemisphere and its relation to cognitive function. We hypothesized that long distance connection, especially between hemispheres, would be affected by the presence of the tumor. We further hypothesized that these changes would correlate with, or reflect cognitive changes observed in patients with gliomas. Resting state functional MRI datasets from 12 patients and 12 healthy controls were used in the analysis. The tumor's effect on three well-known RSNs including the default mode network (DMN), executive control network (ECN), and salience network (SN) identified using independent component analysis were investigated using dual regression analysis. Scores of neuropsychometric testing (WAIS-III and WMS-R) were also compared. Compared to the healthy control group, the patient group showed significant decrease in functional connectivity in the right angular gyrus/inferior parietal lobe of the ventral DMN and in the dorsolateral prefrontal cortex of the left ECN, whereas a significant increase in connectivity in the right ECN was observed in the right parietal lobe. Changes in connectivity in the right ECN correlated with spatial memory, while that on the left ECN correlated with attention. Connectivity changes in the ventral DMN correlated with attention, working memory, full IQ, and verbal IQ measures. Although the tumors were localized in the left side of the brain, changes in connectivity were observed in the contralateral side. Moreover, these changes correlated with some aspects of cognitive function indicating that patients with gliomas may undergo cognitive changes even in the absence of or before the onset of major symptoms. Evaluation of resting state networks could be helpful in advancing our hodological understanding of brain function in glioma cases.

Phosphorylated and truncated TAR DNA-binding protein-43 (TDP-43) is a major component of ubiquitinated cytoplasmic inclusions in neuronal and glial cells of two TDP-43 proteinopathies, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Modifications of TDP-43 are thus considered to play an important role in the pathogenesis of TDP-43 proteinopathies. However, both the initial cause of these abnormal modifications and the TDP-43 region responsible for its aggregation remain uncertain. Here we report that the 32 kDa C-terminal fragment of TDP-43, which lacks the RNP2 motif of RNA binding motif 1 (RRM1), formed aggregates in cultured cells, and that similar phenotypes were obtained when the RNP2 motif was either deleted from or mutated in full-length TDP-43. These aggregations were ubiquitinated, phosphorylated and truncated, and sequestered the 25 kDa C-terminal TDP-43 fragment seen in the neurons of TDP-43 proteinopathy patients. In addition, incubation with RNase decreased the solubility of TDP-43 in cell lysates. These findings suggest that the RNP2 motif of RRM1 plays a substantial role in pathological TDP-43 modifications and that it is possible that disruption of RNA binding may underlie the process of TDP-43 aggregation.

Tardive dyskinesia (TD) is a movement disorder that can arise as a side efect of treatment with dopamine receptor-blocking agents (DRBAs), including antipsychotic drugs (APDs) used to manage psychotic illnesses. Second-generation APDs (SGAs) are often preferred to first-generation drugs due to their lower propensity to cause TD, however many SGAs-treated patients still develop the condition. Although TD is a global health concern, evidence regarding the occurrence of TD and how it is managed in Asian countries is currently limited. This article reports the results of a systematic review of the published literature on TD focusing on its prevalence, types of patients, knowledge of the condition, causative factors, and usual treatment pathways in clinical practice in Asian countries. Epidemiological data suggest that the prevalence of TD is increasing globally due to an overall rise in APD use, contributing factors being polypharmacy with multiple APDs, the use of higher than necessary doses, and off-label use for non-psychotic indications. Although exact prevalence figures for TD in Asian countries are difficult to define, there is a similar pattern of rising APD use which will result in increasing numbers of TD patients in this region. These issues need to be addressed and strategies developed to minimize TD risk and manage this disabling condition which impacts patients' quality of life and daily functioning. To date, both research into TD has been predominantly psychiatry focused and the perspectives from neurologists regarding the clinicalmanagement of this challenging condition are scarce. However, neurologists have an essential role inmanaging themovement disorders manifestations that characterize TD. Optimum management of TD, therefore, should ideally involve collaboration between psychiatrists and neurologists in joint care pathways, wherever practical. Collaborative pathways are proposed in this article, and the challenges that will need to be addressed in Asian countries to improve the care of people with TD are highlighted, with a focus on the neurologist's viewpoint and the implications for the management of TD globally. [ABSTRACT FROM AUTHOR]

We aimed to elucidate the distribution pattern of the positron emission tomography probe [18F]THK 5351, a marker for astrogliosis and tau accumulation, in healthy aging. We also assessed the relationship between THK5351 retention and resting state networks. We enrolled 62 healthy participants in this study. All participants underwent magnetic resonance imaging/positron emission tomography scanning consisting of T1-weighted images, resting state functional magnetic resonance imaging, Pittsburgh Compound-B and THK positron emission tomography. The preprocessed THK images were entered into a scaled subprofile modeling/principal component analysis to extract THK distribution patterns. Using the most significant THK pattern, we generated regions of interest, and performed seed-based functional connectivity analyses. We also evaluated the functional connectivity overlap ratio to identify regions with high between-network connectivity. The most significant THK distributions were observed in the medial prefrontal cortex and bilateral putamen. The seed regions of interest in the medial prefrontal cortex had a functional connectivity map that significantly overlapped with regions of the dorsal default mode network. The seed regions of interest in the putamen showed strong overlap with the basal ganglia and anterior salience networks. The functional connectivity overlap ratio also showed that three peak regions had the characteristics of connector hubs. We have identified an age-related spatial distribution of THK in the medial prefrontal cortex and basal ganglia in normal aging. Interestingly, the distribution’s peaks are located in regions of connector hubs that are strongly connected to large-scale resting state networks associated with higher cognitive function. [ABSTRACT FROM AUTHOR]