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Multiple sclerosis (MS) causes gait and cognitive impairments that are partially normalized by compensatory mechanisms. We aimed to identify the gait tasks that unmask gait disturbance and the underlying neural correlates in MS. We included 25 patients with MS (Expanded Disability Status Scale score: median 2.0, interquartile range 1.0-2.5) and 19 healthy controls. Fast-paced gait examinations with inertial measurement units were conducted, including straight or circular walking with or without cognitive/motor tasks, and the timed up and go test (TUG). Receiver operating characteristic curve analysis was performed to distinguish both groups by the gait parameters. The correlation between gait parameters and cortical thickness or fractional anisotropy values was examined by using three-dimensional T1-weighted imaging and diffusion tensor imaging, respectively (corrected p .05). Total TUG duration (6.0 s, sensitivity 88.0%, specificity 84.2%) and stride velocity during cognitive dual-task circular walking (1.12 m/s, 84.0%, 84.2%) had the highest discriminative power of the two groups. Deterioration of these gait parameters was correlated with thinner cortical thickness in regional areas, including the left precuneus and left temporoparietal junction, overlapped with parts of the default mode network, ventral attention network, and frontoparietal network. Total TUG duration was negatively correlated with fractional anisotropy values in the deep cerebral white matter areas. Turning and multitask gait may be optimal to unveil partially compensated gait disturbance in patients with mild-to-moderate MS through dynamic balance control and multitask processing, based on the structural damage in functional networks.

We recently developed a positron emission tomography (PET) probe, [sup18/supF]PM-PBB3, to detect tau lesions in diverse tauopathies, including mixed three-repeat and four-repeat (3R + 4R) tau fibrils in Alzheimer's disease (AD) and 4R tau aggregates in progressive supranuclear palsy (PSP). For wider availability of this technology for clinical settings, bias-free quantitative evaluation of tau images without a priori disease information is needed.We aimed to establish tau PET pathology indices to characterize PSP and AD using a machine learning approach and test their validity and tracer capabilities.Data were obtained from 50 healthy control subjects, 46 patients with PSP Richardson syndrome, and 37 patients on the AD continuum. Tau PET data from 114 regions of interest were subjected to Elastic Net cross-validation linear classification analysis with a one-versus-the-rest multiclass strategy to obtain a linear function that discriminates diseases by maximizing the area under the receiver operating characteristic curve. We defined PSP- and AD-tau scores for each participant as values of the functions optimized for differentiating PSP (4R) and AD (3R + 4R), respectively, from others.The discriminatory ability of PSP- and AD-tau scores assessed as the area under the receiver operating characteristic curve was 0.98 and 1.00, respectively. PSP-tau scores correlated with the PSP rating scale in patients with PSP, and AD-tau scores correlated with Mini-Mental State Examination scores in healthy control-AD continuum patients. The globus pallidus and amygdala were highlighted as regions with high weight coefficients for determining PSP- and AD-tau scores, respectively.These findings highlight our technology's unbiased capability to identify topologies of 3R + 4R versus 4R tau deposits. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundAccumulating evidence indicated decreased levels of glutamate (Glu) and N-acetylaspartate (NAA) in the posterior cingulate cortex (PCC) in Alzheimer’s disease (AD) brains. However, the levels of these metabolites in the other brain regions and the associations with abnormal protein of AD remain to be elucidated.MethodsWe enrolled 19 patients with AD and 26 healthy controls (HC). We performed magnetic resonance spectroscopic imaging (MRSI) to evaluate Glu/creatine (Cr) and NAA/Cr ratios and measure plasma neurofilament light chain (NfL) levels. We examined tau and amyloid-β depositions with standardized uptake value ratios (SUVRs) of florzolotau (18F) and11C-PiB positron emission tomography, respectively. Heatmaps were created to visualize Z scores of Glu/Cr and NAA/Cr ratios using HC data.ResultsIn the AD brains, Z-score maps demonstrated reduced Glu/Cr and NAA/Cr ratios in the gray matter, including the right dorsolateral prefrontal cortex (DLPFC) and PCC; Glu/Cr ratios negatively correlated with florzolotau (18F) SUVRs in the PCC; mini-mental state examination total scores correlated with Glu/Cr (P < 0.001, r = 0.72) and NAA/Cr ratios (P < 0.001, r = 0.75) in the right DLPFC; and blood NfL levels were increased and negatively correlated with the Glu/Cr (P = 0.040, r = −0.50) and NAA/Cr ratios (P = 0.003, r = −0.68) in the right DLPFC.ConclusionsOur findings indicated that decreased Glu/Cr levels correlated with tau pathologies of AD in the PCC. MRSI is capable of providing spatial information on neural function, enabling the identification of vulnerabilities in the right DLPFC in AD pathology.

ObjectiveIncreasing evidence suggests that reactive astrocytes are associated with Alzheimer’s disease (AD). However, its underlying pathogenesis remains unknown. Given the role of astrocytes in energy metabolism, reactive astrocytes may contribute to altered energy metabolism. It is hypothesized that lactate, a glucose metabolite, is produced in astrocytes and subsequently shuttled to neurons as an energy substrate. This study aimed to examine alterations in brain lactate levels and their association with astrocytic activities in AD.Methods30 AD and 30 cognitively unimpaired (CU) subjects were enrolled. For AD subjects, amyloid and tau depositions were confirmed by positron emission tomography using [11C]PiB and [18F]florzolotau, respectively. Lactate and myo-inositol, an astroglial marker, in the posterior cingulate cortex (PCC) were quantified by magnetic resonance spectroscopy (MRS). These MRS metabolites were compared with plasma biomarkers, including glial fibrillary acidic protein (GFAP) as another astrocytic marker.ResultsLactate and myo-inositol levels were higher in AD than in CU (p< 0.05). Lactate levels correlated with myo-inositol levels (r= 0.272,p= 0.047). Lactate and myo-inositol levels were positively associated with the Clinical Dementia Rating sum-of-boxes scores (p< 0.05). Significant correlations were noted between myo-inositol levels and plasma GFAP and tau phosphorylated at threonine 181 levels (p< 0.05).InterpretationWe found high lactate levels accompanied by an increased astrocytic marker in the PCC in AD. Thus, impaired lactate shuttle of reactive astrocytes may disrupt energy regulation, resulting in surplus lactate levels. Myo-inositol and plasma GFAP may reflect similar astrocytic changes.

Glutamatergic neurons and cingulate cortices have crucial roles in the cognitive dysfunction of Alzheimer's disease (AD). This study aimed to evaluate regional vulnerabilities of the glutamatergic system in AD at the level of the cingulate gyrus in relation to tau and amyloid-β (Aβ) depositions. Combining MRSI and PET, we found that the glutamatergic system in the posterior cingulate cortex (PCC) is vulnerable to tau deposits but not Aβ from the early stage of AD, and glutamate in the PCC region may be a marker of disease progression in AD., 2022 Joint Annual Meeting ISMRM-ESMRMB

Background Gait automaticity, which is impaired in patients with Parkinson's disease (PD), can be quantified by gait variability analysis. Among the 3 regions of the striatum (sensorimotor, executive, and limbic), the sensorimotor region may play a crucial role in motor automaticity in healthy individuals. However, neural correlates of impaired gait automaticity are poorly investigated in PD. Objective We aimed to examine the relationship between gait automaticity and striatal dopaminergic depletion in drug-naive PD patients. Methods A total of 21 drug-naive PD patients and 12 healthy controls were enrolled. Gait parameters were measured via wearable inertial sensors under fast-paced gait or cognitive dual-task conditions, and their respective coefficient of variation (CV) and dual-task cost were calculated. The extent of striatal dopaminergic depletion was evaluated by dopamine transporter (DAT) imaging with single-photon emission computed tomography using N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-[123 I]iodophenyl)nortropane. Correlation between DAT uptake and gait variables was analyzed using the region-of-interest analysis for the 3 right or left striatal regions and voxel-based analysis. Results PD had higher mean bilateral CV and dual-task cost of stride length than healthy controls. The mean bilateral CV of stride length was negatively correlated with DAT uptake in the bilateral executive regions of the striatum. Voxel-based analysis revealed a negative correlation between the mean bilateral CV of stride length and DAT uptake in the anteromedial striatum. Conclusions Dopaminergic denervation in the anteromedial striatum, a part of the executive region, is associated with impaired gait automaticity in drug-naive PD patients. This region may compensate for the posterior sensorimotor striatum, maintaining gait automaticity. © 2020 International Parkinson and Movement Disorder Society.

Objective: Despite accumulating evidence for impaired glutamatergic neurotransmission in Alzheimer’s disease (AD) brains, its significance in neurofunctional and neuropathological alterations remains elusive. The aim of this study is to evaluate the associations between glutamatergic dysfunctions and tau depositions across cortical regions in AD patients using magnetic resonance spectroscopic imaging (MRSI). Methods: We enrolled 16 patients with AD, consisting of cases with mild cognitive impairment due to AD and AD dementia, and 15 healthy controls (HCs). We performed tau and amyloid-β (Aβ) PET with 18F-PM-PBB3 and 11C-PiB, respectively, and single-plane MRSI for evaluating a glutamate/creatine (Glu/Cr) ratio at the level of the cingulate gyrus. PET probe retentions were quantified as standardized uptake value ratio (SUVR) using the cerebellar cortex as a reference region. Results: Z-score maps of the AD group compared to the HC group showed marked tau and Aβ depositions in extensive cortical gray matter regions, and reduced glutamate levels in more confined areas (Figures 1-3). Glutamate levels were correlated with tau but not Aβ burdens in some regions, including the posterior cingulate cortex (PCC) (Figures 4). In an analysis of combined voxels covering PCC, Glu/Cr ratios were correlated negatively with tau deposits in the AD group (r = -0.53, p < 0.05) and positively with mini-mental state examination scores (r = 0.74, p < 0.05) in AD dementia cases. Conclusions: MRSI revealed the regionally variable vulnerability of the glutamatergic system to tau depositions in AD brains. In PCC, tau accumulations are likely to induce disrupted glutamine transmissions, aggravating cognitive functions., AD/PD 2022

【目的】タッチパネルを用いた認知機能検査バッテリーであるUser eXperience-Trail Making Test: UX-TMTの，パーキンソン病(PD)と進行性核上性麻痺(PSP)の認知および運動機能障害検出における有用性を評価する． 【方法】健常者(HC)9例: 75.7(8.0)歳[平均(SD)]，女性56%，PD患者5例: 70.2(8.7)歳，女性60%，PSP患者6例: 70.5(7.1)歳，女性67%を対象とした．PD重症度評価にはHoehn-Yahrステージを，その他の評価にはMini-Mental State Examination (MMSE)と従来型TMT，UX-TMTを用いた．UX-TMTは認知症スクリーニングスコアの他，TMTにおけるタップダウンからタップアップまでの時間(Contact Duration:CD)を評価に用いた． 【結果】PD群のYahrは平均2.0[1-4]であった．MMSEではHC群28.4(1.1)とPD群29.0(1.0)，PSP群27.5(1.6)に有意差(Kruskal-Wallis)はなかったが，UX-TMT_part BのCD(msec)ではPD群241.8(69.3)がHC群100.6(27.6)(p=.010)とPSP群164.9(96.8) (p=.021)より有意に遅延しており，従来型TMT_part B所要時間(sec)ではPSP群178.8(49.4)がHC群87.2(14.0)(p=.000)とPD群 102.4(25.1)(p=.002)より有意に遅延していた．PDのYahrステージとUX-TMTに相関は認めなかった(Spearman)． 【結論】UX-TMTは従来型より視野範囲が狭く筆記動作がない反面，線で結ばない等認知負荷は高い為，従来型と異なる病状を捉える可能性があり，PDの前駆・潜在的認知機能障害検出に有用であることが示唆された．, 第40回日本認知症学会学術集会

【目的】非アルツハイマー型認知症のタウオパチーである進行性核上性麻痺(PSP)において，18F-PM-PBB3をプローブとするタウ病変PET画像による客観的な自動診断法を開発する．【方法】対象は健常高齢者(HC) 43例 (69.2 ± 7.0 [平均 ± 標準偏差]歳，女性 48.8%)，PSP 42例 (71.5 ± 7.1歳，女性 35.7%，MDS-PSP診断基準でprobable)，疾患対照としてパーキンソン病患者(PD) 8例 (70.6 ± 6.4歳，女性 12.5%) で，機械学習訓練用(75%)と診断能評価用(25%)に分けて解析した(stratified shuffle splitで10セット分作成)．マルチアトラス法を用いて脳実質112カ所の関心領域(ROI)を同定し，病変が少ない小脳皮質とのプローブ集積比(SUVR)を算出した．値は年齢，性別で補正し標準化した．各領域のSUVRと重み係数の積の総和(PSP tauスコア)によるPSP群対，HC+PD群の弁別能が最も高くなるように，機械学習(elastic net CV)により重み係数の最適化を行った．得られたスコアと重症度の相関も解析した．【結果】淡蒼球，中脳，被殻などが重み係数の高い弁別に重要なROIであった．評価用10セットデータのPSP tauスコアを平均化して解析した診断能は正確度 96.7%, 感度 95.1%, 特異度 98.0%であった．PSP tauスコアと重症度(PSP rating scale)は有意な相関を認めた(Spearman’s rs = 0.4, p = 0.009).【結論】18F-PM-PBB3 PETを用いてPSPの自動診断および重症度の予測に有望な手法を開発した．, 第40回日本認知症学会学術集会

【目的】近年の死後脳研究やtau PET (positron emission tomography)による検討により、老年期に発症する気分障害の背景病態として脳内に病的蛋白が蓄積する神経変性疾患の関与が示されている。今回、高齢で発症した双極性障害患者に対して神経心理検査、臨床症状、MRIによる脳構造評価、tau、amyloid PETを縦断的に実施し得た３例のケースを経験したため報告する。【方法】50歳以上発症の双極性障害患者3名に対し、MRI検査、18F-PM-PBB3（tau）、11C-PiB（amyloid）を用いたPET検査、神経心理検査を1年以上空けて2回行った。ligand蓄積量は、小脳皮質を参照領域とするSUVR(standardized uptake value ratio)法にて算出した。【結果】1例目は72歳時に躁状態で発症し、1回目のPETでは18F-PM-PBB3の側頭葉前部への局所的集積を認め、前頭側頭葉変性症であることが示唆された。その後、脱抑制、反社会的行動、食行動の変化を認めるようになり、２回目のPETでは18F-PM-PBB3集積分布の増加を認めた。2例目は72歳時に躁状態を呈した症例であり、1回目のPETで11C-PiB陽性であったことからAlzheimer病が示唆された。その後、風呂とトイレを間違える、歯磨きの仕方が分からくなる等の認知機能低下を認め、2回目のPETでは11C-PiB 、18F-PM-PBB3集積の増加を認めた。3例目は50代後半からうつ状態、躁状態を呈し、1回目のPETでは左下側頭葉に18F-PM-PBB3の局所的集積を認めた。病歴から脳震盪への長期暴露が明らかとなり慢性外傷性脳症が示唆された。その後、認知機能低下および社会行動障害を呈するようになり、2回目のPETでは18F-PM-PBB3の集積増加を認めた。【考察】高齢発症の双極性障害においては、amyloid蓄積の有無、tau蓄積の分布、経時的変化から、背景に複数の神経変性疾患が存在することが示唆された。明らかな認知機能低下や行動異常が出現する前にamyloid、tau PETを行うことは治療方針を定める上で参考になると考える。, 第45回日本神経心理学会学術集会

《背景》役に立たず不要に思われるが患者にとっては意味のある物を収集する行動は病的収集活動と呼ばれ、前頭側頭葉変性症や前頭葉損傷で引き起こされることが知られている。われわれは、重度頭部外傷から遅発性に病的収集活動を呈した症例を経験し、過去に本学会で報告した。近年、頭部への受傷から長期間が経過した後に引き起こされる精神神経症状は遅発性脳障害と呼ばれており、その代表的な病態が慢性外傷性脳症である。慢性外傷性脳症は脳内にタウ凝集体が蓄積する神経変性疾患であり、その脳内タウ蓄積はポジトロン断層撮影（PET）により画像化が可能である。今回、[18F]PM-PBB3および[11C]PiBをプローブとするPETによって、それぞれ脳内タウおよびアミロイド病変を評価しため、本症例の脳画像所見について報告する。《症例》症例は48歳の右利き男性。33歳時、自動車事故によるびまん性軸索損傷にて約3週間の意識障害が遷延した。神経学的な後遺症はなかったが、自発性低下のため無為な日々を送った。41歳時、病的収集活動（同一機種の型番を全て揃えたカメラなどで家は寝床もないほどだった）が始まった。46歳時に精査加療目的で当院初診。各種神経心理学検査で、処理速度で顕著な低下を認めるが知能は正常、記憶障害、遂行機能障害、保続を認めず、ギャンブリング課題ではハイリスクの山を引き続け、-125000円で終了した。頭部MRIでは、脳挫傷や脳表ヘモジデリン沈着を認めず、SWI（susceptibility-weighted imaging）で左頭頂葉白質、脳梁体部、左側頭葉白質、左小脳半球に微小出血を認め、びまん性軸索損傷に矛盾しなかった。[11C]PiB PETは陰性、[18F]PM-PBB3 PETは右前頭葉の脳溝深部に近い灰白質白質境界部および後頭葉白質に局所的集積を認めた。《考察》本症例では、頭部外傷から遅発性に病的収集活動を呈し、PETにより慢性外傷性脳症に特徴的な分布様式のタウ蓄積を認めたことから、頭部外傷によって引き起こされた脳内タウ蓄積が遅発性の症候に関与している可能性が示唆された。, 第45回日本神経心理学会学術集会

A 26-year-old woman with relapsing-remitting multiple sclerosis (MS) underwent F-THK5351 PET during a remission period. PET imaging showed that small regions with elevated uptake of F-THK5351 were scattered in the brain and that the foci of F-THK5351 accumulations corresponded anatomically to MS plaques identified by MRI. Because F-THK5351 binds to monoamine oxidase B highly expressed in astrocytes, F-THK5351 accumulates in lesions undergoing astrogliosis. Hence, elevated uptake of F-THK5351 in the present case can represent ongoing astrogliosis in inactive MS lesions (plaques).

Autosomal-dominant striatal degeneration is a rare autosomal-dominant neurodegenerative movement disorder characterized by slowly progressive parkinsonism. Recently, a mutation of the cyclic nucleotide phosphodiesterase 8B gene was reported to be a causal gene mutation of this disease.We report on the clinical characteristics of 2 patients of a Japanese family with autosomal-dominant striatal degeneration and the result of gene mutation analysis of this family.Clinical features of the patients are slowly progressive parkinsonism and brain MRI showing high signal intensity in T2-weighted images in the striatum. We found a heterozygous nonsense mutation in the first exon of cyclic nucleotide phosphodiesterase 8B gene, which is predicted to disrupt all important functional domains of the cyclic nucleotide phosphodiesterase 8B protein.This family is the second family with autosomal-dominant striatal degeneration after the first German family, confirming that cyclic nucleotide phosphodiesterase 8B gene is the causative gene for this disease.