Background Parkinson's disease with subjective cognitive decline (PD-SCD), defined as self-perceived cognitive decline in the absence of objective impairment, is associated with an increased risk of progression to mild cognitive impairment (PD-MCI) and dementia. Cerebral blood flow (CBF) imaging may provide insight into functional alterations preceding measurable cognitive decline. Objective To characterize regional CBF patterns in PD-SCD and compare them with those in PD with normal cognition (PD-NC) and PD-MCI. Methods A total of 140 patients with PD were classified as PD-NC (n = 32), PD-SCD (n = 31), or PD-MCI (n = 77) using Movement Disorder Society (MDS) Task Force PD-MCI Level II criteria in conjunction with commonly used assessments of SCD. All participants underwent clinical evaluation, depression assessment, MRI, and 123I-iodoamphetamine single-photon emission computed tomography (SPECT). Whole-brain voxel-wise comparisons of tracer uptake ratios were performed using statistical parametric mapping, adjusting for age, sex, SPECT scanner, and depressive symptom scores. Results Compared with PD-NC, PD-SCD demonstrated significantly increased CBF in bilateral frontal and temporal regions (p < 0.01, family - wise error [FWE] corrected) and the left cerebellum (p < 0.05, FWE corrected), despite preserved cognition. PD-MCI exhibited bilateral frontal and temporal hypo-perfusion relative to PD-SCD (p < 0.01, FWE corrected). Conclusion PD-SCD is associated with frontal and temporal hyper-perfusion relative to PD-NC and PD-MCI. These regions partially overlap with cortical areas vulnerable to thinning in PD dementia, supporting the hypothesis that hyper-perfusions may reflect compensatory network responses in regions susceptible to structural degeneration.

Multiple cortical hypointense lesions on T2*-weighted images and ischemic lesions are one of the radiological manifestations of cardiac myxoma, while the mechanism of the hypointense lesions is inconclusive. We describe a 60-year-old woman with a cardiac myxoma who presented with multiple ischemic lesions and cortical hypointense lesions revealed by T2*-weighted images. A gadolinium-enhanced T1-weighted image revealed micro-aneurysmal lesions, which corresponded to the hypointense lesions. Previous pathological studies have revealed that aneurysmal lesions could be caused by cardiac myxoma. Our findings suggest a potential association between cortical microbleeds and microaneurysmal changes in patients with cardiac myxoma.

BACKGROUND:A dual-syndrome hypothesis, which states the cognitive impairments in Parkinson's disease (PD) are attributable to frontostriatal dopaminergic dysregulation and cortical disturbance-each associated with attention/executive and memory/visuospatial dysfunction, respectively-has been widely accepted. This multisystem contribution also underlies highly heterogeneous progression rate to dementia. METHODS:Nondemented PD patients who underwent [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane ([123I]FP-CIT) SPECT and neuropsychological examinations were enrolled. Patients who agreed to participate and age- and sex-matched healthy controls (HCs) also underwent 7-T MRI. Patients were classified as cognitively normal (PD-CN) or mild cognitive impairment (PD-MCI) following the level II criteria of Movement Disorder Society Guideline. RESULTS:A total of 155 patients (PD-CN/PD-MCI 74/81) were enrolled, whereas 76 patients (PD-CN/PD-MCI 35/41) and 56 HCs underwent 7 T-MRI. The caudate [123I]FP-CIT uptake in PD was correlated with the performance of attention/working memory (trail-making test [TMT]-A and symbol digit modality test) and executive (TMT-B) domains. In contrast, the regional cortical thickness in the left frontotemporal and right frontal lobes in PD was correlated with performance of memory (Hopkins verbal learning test-revised delayed recall) and visuospatial (judgment of line orientation) domains. Moreover, compared to 37 HCs with a Montreal Cognitive Assessment score of >25, PD-CN patients showed broad occipitoparietal cortical thinning. CONCLUSIONS:We demonstrated distinctive impairments of dopaminergic frontostriatal deficits and cortical degeneration as neural bases for the dual-syndrome hypothesis. Our findings suggest that occipitoparietal lobe thinning occurs at a cognitively normal stage, and additional frontotemporal lobe thinning underlies impairments in the memory and visuospatial domains at the PD-MCI stage.

Introduction:Pharmacological control of the motor symptoms of Parkinson's disease (PD) is challenging with disease progression. Device-aided therapies help relieve these symptoms but are invasive and require specific management. Induced pluripotent stem (iPS) cells avoid ethical concerns and may prevent immune rejection in autologous transplants. Allogeneic iPS cells are considerably more practical, despite potential concerns regarding tumor formation post-transplantation. The present study aimed to clarify the perceptions and acceptance of patients with PD regarding regenerative medicine, invasive surgical treatments (deep brain stimulation, levodopa-carbidopa intestinal gel), and cell transplantation (iPS cells, embryonic stem cells, fetal-derived cells). Methods:This prospective cross-sectional survey of 102 patients with PD applied a new questionnaire based on a previous survey of the general public's perception of regenerative medicine. Results:Cell-based therapies were the most popular choice, with 86.1 % of responders choosing it, mainly due to "improvement in quality of life" (69.1 %), "the possibility of slowing the disease progression" (66.2 %), and "treatment effectiveness" (51.5 %). Among these patients, 47.1 % expected regenerative medicine to become the standard therapy within several years and 82.4 % believed that regenerative medicine was safe. Autologous iPS cells were accepted by 83.8 % of the patients, while 52.5 % accepted allogeneic iPS cells. Conclusions:Patients had high expectations for the therapeutic effects of cell-based therapies and were optimistic about its early implementation and safety in regenerative medicine, with iPS cells being the most accepted for transplantation. The present findings should be confirmed in a larger cohort, as these findings are based on a limited sample.

BACKGROUND AND OBJECTIVES:Neural computations underlying gait disorders in Parkinson disease (PD) are multifactorial and involve impaired expression of stereotactic locomotor patterns and compensatory recruitment of cognitive functions. This study aimed to clarify the network mechanisms of cognitive contribution to gait control and its breakdown in patients with PD. METHODS:Patients with PD were instructed to walk at a comfortable pace on a mat with pressure sensors. The characterization of cognitive-motor interplay was enhanced by using a gait with a secondary cognitive task (dual-task condition) and a gait without additional tasks (single-task condition). Participants were scanned using 3-T MRI and 123I-ioflupane SPECT. RESULTS:According to gait characteristics, cluster analysis assisted by a nonlinear dimensionality reduction technique, t-distributed stochastic neighbor embedding, categorized 56 patients with PD into 3 subpopulations. The preserved gait (PG) subgroup (n = 23) showed preserved speed and variability during gait, both with and without additional cognitive load. Compared with the PG subgroup, the mildly impaired gait (MIG) subgroup (n = 16) demonstrated deteriorated gait variability with additional cognitive load and impaired speed and gait variability without additional cognitive load. The severely impaired gait (SIG) subgroup (n = 17) revealed the slowest speed and highest gait variability. In addition, group differences were found in attention/working memory and executive function domains, with the lowest performance in the SIG subgroup than in the PG and MIG subgroups. Using resting-state functional MRI, the SIG subgroup demonstrated lower functional connectivity of the left and right frontoparietal network (FPN) with the caudate than the PG subgroup did (left FPN, d = 1.21, p < 0.001; right FPN, d = 1.05, p = 0.004). Cortical thickness in the FPN and 123I-ioflupane uptake in the striatum did not differ among the 3 subgroups. By contrast, the severity of Ch4 density loss was significantly correlated with the level of functional connectivity degradation of the FPN and caudate (left FPN-caudate, r = 0.27, p = 0.04). DISCUSSION:These findings suggest that the functional connectivity of the FPN with the caudate, as mediated by the cholinergic Ch4 projection system, underlies the compensatory recruitment of attention and executive function for damaged automaticity in gait in patients with PD.

INTRODUCTION:Magnetic resonance imaging (MRI)-determined atrophy of the nucleus basalis of Meynert (Ch4) predicts cognitive decline in Parkinson's disease (PD). However, interactions with other brain regions causing the decline remain unclear. This study aimed to describe how MRI-determined Ch4 atrophy leads to cognitive decline in patients with PD. METHODS:We evaluated 137 patients with PD and 39 healthy controls using neuropsychological examinations, MRI, and 123I-ioflupane single-photon emission computed tomography. First, we explored brain areas with regional gray matter loss correlated with Ch4 volume reduction using voxel-based morphometry (VBM). We then assessed the correlation between Ch4 volume reduction and cognitive impairments in PD using partial correlation coefficients (rpar). Finally, we examined whether the regional gray matter loss mediated the association between Ch4 volume reduction and cognitive impairments using mediation analysis. RESULTS:Our PD cohort was "advanced-stage enriched." VBM analyses revealed that Ch4 volume loss was correlated with volume reduction in the medial temporal lobe in PD (P < 0.05, family-wise error corrected, >29 voxels). Ch4 volume reduction was significantly correlated with verbal memory deficits in PD when adjusted for age, sex, total brain volume, and 123I-ioflupane uptake in the caudate (rpar = 0.28, P < 0.001). The mediation analysis revealed that the hippocampus mediated the effects of Ch4 volumes on verbal memory (average causal mediation effect = 0.013, 95 % CI = 0.006-0.020, P < 0.001). CONCLUSION:Particularly in advanced-stage PD, Ch4 atrophy was associated with medial temporal lobe atrophy, which played an intermediary role in the relationship between Ch4 atrophy and verbal memory impairments.

Objectives:The causes of intellectual disability (ID) are varied, with as many as 1,400 causative genes. We attempted to identify the causative gene in a patient with long-standing undiagnosed ID.Methods:Although this was an isolated case with no family history, we searched for the causative gene using trio-based whole-exome sequencing (trio-WES), because severe ID is often caused by genetic variations, and inherited metabolic disorders (IMDs) are assumed to be the cause when regression and epilepsy occur.Results:We identified homozygous donor splice-site variants in the AGA gene (aspartylglucosaminidase; NM_000027.4) Chr4(GRCh38):g. 177436275C>A, c.698+1G>T. This gene is implicated in aspartylglucosaminuria (AGU; OMIM #208400) and originated from both of the patient's parents. We confirmed the pathogenicity of the variant by detecting the splicing defect in cDNA from the patient's blood and accumulation of aberrant metabolites in the patient's urine.Discussion:We discuss how to more readily achieve an accurate diagnosis for patients with undiagnosed intellectual disabilities. Medical practitioners' awareness of the characteristics of the disease leading to clinical suspicion in patients with matching presentations, and the performance of newborn screening when possible, is important for the diagnosis of ID. In addition, the characteristic symptoms and course of the disease give rise to suspicion of IMDs. Given our results, we consider trio-WES to be a powerful method for identifying the causative genes in cases of ID with genetic causes.

The clinical manifestation of Parkinson's disease exhibits significant heterogeneity in the prevalence of non-motor symptoms and the rate of progression of motor symptoms, suggesting that Parkinson's disease can be classified into distinct subtypes. In this study, we aimed to explore this heterogeneity by identifying a set of subtypes with distinct patterns of spatiotemporal trajectories of neurodegeneration. We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning algorithm that combined disease progression modelling with clustering methods, to cortical and subcortical neurodegeneration visible on 3 T structural MRI of a large cross-sectional sample of 504 patients and 279 healthy controls. Serial longitudinal data were available for a subset of 178 patients at the 2-year follow-up and for 140 patients at the 4-year follow-up. In a subset of 210 patients, concomitant Alzheimer's disease pathology was assessed by evaluating amyloid-beta concentrations in the CSF or via the amyloid-specific radiotracer F-18-flutemetamol with PET. The SuStaIn analysis revealed three distinct subtypes, each characterized by unique patterns of spatiotemporal evolution of brain atrophy: neocortical, limbic and brainstem. In the neocortical subtype, a reduction in brain volume occurred in the frontal and parietal cortices in the earliest disease stage and progressed across the entire neocortex during the early stage, although with relative sparing of the striatum, pallidum, accumbens area and brainstem. The limbic subtype represented comparative regional vulnerability, which was characterized by early volume loss in the amygdala, accumbens area, striatum and temporal cortex, subsequently spreading to the parietal and frontal cortices across disease stage. The brainstem subtype showed gradual rostral progression from the brainstem extending to the amygdala and hippocampus, followed by the temporal and other cortices. Longitudinal MRI data confirmed that 77.8% of participants at the 2-year follow-up and 84.0% at the 4-year follow-up were assigned to subtypes consistent with estimates from the cross-sectional data. This three-subtype model aligned with empirically proposed subtypes based on age at onset, because the neocortical subtype demonstrated characteristics similar to those found in the old-onset phenotype, including older onset and cognitive decline symptoms (P < 0.05). Moreover, the subtypes correspond to the three categories of the neuropathological consensus criteria for symptomatic patients with Lewy pathology, proposing neocortex-, limbic- and brainstem-predominant patterns as different subgroups of alpha-synuclein distributions. Among the subtypes, the prevalence of biomarker evidence of amyloid-beta pathology was comparable. Upon validation, the subtype model might be applied to individual cases, potentially serving as a biomarker to track disease progression and predict temporal evolution.

Objective The motor severity in Parkinson disease (PD) is believed to parallel dopaminergic terminal degeneration in the striatum, although the terminal was reported to be virtually absent by 4 years postdiagnosis. Meanwhile, neuromelanin‐laden dopamine neuron loss in the substantia nigra (SN) elucidated a variability at early stages and gradual loss with less variability 10 years postdiagnosis. Here, we aimed to clarify the correlation between motor impairments and striatal dopaminergic terminal degeneration and nigral neuromelanin‐laden dopamine neuron loss at early to advanced stages of PD. Methods Ninety‐three PD patients were divided into early and advanced subgroups based on motor symptom duration and whether motor fluctuation was present. Striatal dopaminergic terminal degeneration was evaluated using a presynaptic dopamine transporter tracer, 123 I‐ioflupane single photon emission computed tomography (SPECT). Nigral neuromelanin‐laden dopamine neuron density was assessed by neuromelanin‐sensitive magnetic resonance imaging (NM‐MRI). Results In patients with early stage PD (motor symptoms for ≤8 or 10 years), motor dysfunction during the drug‐off state was paralleled by a decline in 123 I‐ioflupane uptake in the striatum despite the absence of a correlation with reductions in NM‐MRI signals in SN. Meanwhile, in patients with advanced stage PD (motor symptoms for >8 or 10 years and with fluctuation), the degree of motor deficits during the drug‐off state was not correlated with 123 I‐ioflupane uptake in the striatum, despite its significant negative correlation with NM‐MRI signals in SN. Interpretation We propose striatal dopaminergic terminal loss measured using 123 I‐ioflupane SPECT and nigral dopamine neuron loss assessed with NM‐MRI as early stage and advanced stage motor impairment biomarkers, respectively. ANN NEUROL 2022;92:110–121

Tremor associated with encephalitis is usually transient and rarely becomes chronic and refractory. Treatment for such tremor using deep brain stimulation (DBS) has not yet been reported. We report an uncommon case of chronic tremor after encephalitis of unknown etiology and its outcome treated with thalamic DBS. A 47-year-old man presented with a 6-month history of medically refractory tremor after non-infectious and probable autoimmune encephalitis. The patient showed an atypical mixture of resting, postural, kinetic, and intention tremor. The tremor significantly disabled the patient’s activities of daily life (ADL). The patient underwent bilateral thalamic DBS surgery. DBS leads were placed to cross the border between the ventralis oralis posterior (Vop) nucleus and ventralis intermedius (Vim) nucleus of the thalamus. Stimulation of both the Vop and Vim using the bipolar contacts controlled the mixed occurrence of tremor. The ADL and performance scores on The Essential Tremor Rating Assessment Scale (TETRAS) improved from 47 to 0 and from 44 to 9, respectively. The therapeutic effects have lasted for 24 months. Administration of combined Vop and Vim DBS may control uncommon tremor of atypical etiology and phenomenology.

This article reviews the stereotactic targets in the posterior subthalamic area(PSA), fields H1/H2 of Forel(pallidothalamic tract), and the pedunculopontine nucleus(PPN)to complement the preceding articles on stereotactic and functional neurosurgery for movement disorders in the present issue of No Shinkei Geka. Two regions within the subthalamus, the PSA and fields H1/H2 of Forel, are the revisited stereotactic targets to treat movement disorders. Currently, the PSA is often utilized to treat essential tremor and various types of tremor. Fields H1/H2 of Forel are investigated as a target for magnetic resonance-guided focused ultrasound to treat motor symptoms and motor complications in patients with Parkinson's disease. For the past twenty years, the PPN has been investigated to treat refractory gait freezing and fall in patients with Parkinson's disease. These revisited and novel targets may be utilized as substitutes and complements for the present standard stereotactic targets.

Dopamine-containing neurons in Parkinson's disease (PD) degenerate in different parts of substantia nigra (SN) to different degrees. The maximal neuron loss occurs in nigrosome-1, which is considered as a diagnostic biomarker in PD with iron-sensitive MRI techniques. However, clinical correlates of iron accumulation in nigrosome-1 remain unknown. Here, we measured quantitative susceptibility mapping (QSM) of nigrsome-1 using a 7 Tesla MRI and computed correlation with motor symptoms and with striatal dopamine terminal degeneration using 123I-ioflupane SPECT, to identify the clinical parameter that reflects nigrosome-1 degeneration.

A 53-year-old woman was admitted to the department of neurology in Tenri Hospital because of progressive thoracic myelitis a month after she had eaten uncooked bovine liver. A previous episode of right optic neuritis and a positive test for serum anti-aquaporin-4 antibodies indicated a diagnosis of neuromyelitis optica spectrum disorders. Although the patient initially recovered with the reduction of anti-aquaporin-4 antibodies during treatment with intravenous methylprednisolone infusion and plasma exchange, her neurological symptoms deteriorated soon after the completion of plasma exchange. Western blotting analysis detected anti-Toxocara canis antibodies in the serum; thus, the patient underwent oral albendazole treatment. This resulted in the alleviation of her symptoms. We therefore consider that rigorous investigation should be encouraged to detect rare pathogens including parasites in cases of treatment-resistant neuromyelitis optica spectrum disorders.

Objective: The aim of this study is to evaluate the efficacy and the complications associated with prophylaxis using cyclosporine A (CsA) and prednisone in patients with neuromyelitis optica spectrum disorders (NMOSD). Background: The efficacy of calcineurin inhibitors, such as CsA or tacrolimus, in the prophylaxis of NMOSD has been underestimated because of the limited number of published studies, even though these drugs are frequently used for NMOSD patients in Japan. Methods: We reviewed the clinical records of 11 patients with NMOSD, who were treated with CsA and prednisone. Results: Treatment of 10 patients was started with prednisone monotherapy followed by the addition of CsA and that of the other patient was started with CsA monotherapy followed by the addition of prednisone. The median duration of combination treatment was 51 (range, 37-55) months. The annual relapse rate in patients with relapsing-remitting disease course decreased from 2.1 (1.3-3.4) to 0.22 (0-0.45) after initiating CsA treatment (P = 0.008). The median expanded disability severity scale scores of all patients before and after CsA treatment were 4 (2-6.5) and 2 (1.8-5), respectively (P = 0.375). The median doses of concomitant prednisone decreased from 17.5 (range, 10-28.8) mg/day to 7 (range, 5-10) mg/day (P = 0.007) in 10 patients. One patient developed malignant lymphoma, and another patient planned to start tocilizumab because of inefficacy at the end of the study. Although the renal function in all patients was minimally impaired, they all tolerated the treatment well. Conclusions: Prophylaxis using a combination of CsA with prednisone is effective and well tolerable in patients with NMOSD when the dose of CsA is optimized based on the strict monitoring of the renal function.

A 67-year-old woman developed dropped head. Her neck was severely flexed, with prominent cervical paraspinal muscles, although no parkinsonism was observed. Brain MRI showed no significant findings. We considered dystonia as the cause of the dropped head and administered trihexyphenidyl, an anticholinergic. After 10 years of follow-up, remarkable psychotic symptoms, including hallucinations regarding insects, appeared. Following the discontinuation of trihexyphenidyl, the psychotic symptoms decreased but still remained. (123)I-N-isopropyl-p-iodoamphetamine single-photon emission computed tomography ((123)I-IMP SPECT) revealed hypoperfusion in the bilateral occipital lobes. We diagnosed the patient with dementia with Lewy bodies (DLB). This case suggests that dropped head syndrome may precede the onset of DLB.

A 78-year-old man presented to the emergency department at Tenri Hospital, for acute left limb weakness 3 h and 20 min after its onset. He had experienced severe neck pain 30 min before the development of limb weakness. On examination, left hemiplegia was noted without facial weakness (Fig. 1a,b). There was no ptosis or anisocoria. Sensation to pinpricks and light touch was intact. He had urinary retention. Computed tomography and magnetic resonance imaging (MRI) of the head showed no causative abnormality. MRI of the neck showed an epidural hematoma extending from vertebral levels C2 to C5 (Fig. 1c,d). Because the hemiplegia persisted, the patient underwent decompressive surgery 13 h after its onset (Fig. 1e,f). He recovered without any residual symptoms (Fig. 1g). Spontaneous spinal epidural hematoma is an important stroke mimic, because intravenous thrombolysis might worsen bleeding. Hemiparesis is a common presentation of cervical spontaneous spinal epidural hematoma according to a literature review.1 Neurologists should consider spontaneous spinal epidural hematoma in patients with acute hemiparesis not affecting the face, particularly in those with severe neck pain.

We report a case of lymphocytic primary angiitis of the central nervous system (PACNS) with a characteristic gadolinium-enhancement pattern on magnetic resonance imaging (MRI). A 48-year-old, right-handed man presented with a 3-month history of tremor and progressing dementia. Neurologic examination revealed cognitive decline with anterograde amnesia and postural tremor of the fingers. Except for the positive result of serum antinuclear antibody, intense investigations for infectious, rheumatic and neoplastic diseases were negative. Analysis of cerebrospinal fluid showed mild pleocytosis (14 cells/μl). Brain MRI revealed diffuse hyperintense areas in the deep cerebral white matter on T2-weighted images. Gadolinium-enhanced T1-weighted images demonstrated fan-shaped multiple linear enhancements converging to the body of the lateral ventricles. Brain biopsy showed intense infiltration of small lymphocytes without atypia or granuloma mainly within the vessel walls and perivascular spaces. The diagnosis of lymphocytic PACNS was made. Administration of corticosteroid markedly improved the tremor and cognitive dysfunction. MRI after the treatment showed resolution of the abnormal fan-shaped linear enhancement. He returned to his previous occupation. PACNS should be included in the differential diagnosis for fan-shaped linear enhancement converging to the lateral ventricles on MRI in patients with unexplained progressing dementia.