Contribution of amyloid and putative Lewy body pathologies in neuropsychiatric symptoms.

OBJECTIVES: Neuropsychiatric symptom could be useful for detecting patients with prodromal dementia. Similarities and differences in the NPSs between preclinical/prodromal Alzheimer's disease (AD) and prodromal Parkinson's disease dementia (PDD)/Dementia with Lewy bodies (DLB) may exist. This study aimed to compare the NPSs between preclinical/prodromal AD and prodromal PDD/DLB. METHODS: One hundred and three participants without dementia aged ≥50 years were included in this study. The mild behavioral impairment (MBI) total score and the MBI scores for each domain were calculated using the neuropsychiatric inventory questionnaire score. Participants were divided into five groups based on the clinical diagnosis by neurologists or psychiatrists in each institution based on the results of the amyloid positron emission tomography and dopamine transporter single photon emission computed tomography (DAT-SPECT): Group 1: amyloid-positive and abnormal DAT-SPECT, Group 2: amyloid-negative and abnormal DAT-SPECT, Group 3: amyloid-positive and normal DAT-SPECT, Group 4: mild cognitive impairment unlikely due to AD with normal DAT-SPECT, and Group 5: cognitively normal with amyloid-negative and normal DAT-SPECT. RESULTS: The MBI abnormal perception or thought content scores were significantly higher in Group 1 than Group 5 (Bonferroni-corrected p = 0.012). The MBI total score (Bonferroni-corrected p = 0.011) and MBI impulse dyscontrol score (Bonferroni-corrected p = 0.033) in Group 4 were significantly higher than those in Group 5. CONCLUSION: The presence of both amyloid and putative Lewy body pathologies may be associated with psychotic symptoms.

The Motor Network Reduces Multisensory Illusory Perception.

Observing mouth movements has strikingly effects on the perception of speech. Any mismatch between sound and mouth movements will result in listeners perceiving illusory consonants (McGurk effect), whereas matching mouth movements assist with the correct recognition of speech sounds. Recent neuroimaging studies have yielded evidence that the motor areas are involved in speech processing, yet their contributions to multisensory illusion remain unclear. Using functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) in an event-related design, we aimed to identify the functional roles of the motor network in the occurrence of multisensory illusion in female and male brains. fMRI showed bilateral activation of the inferior frontal gyrus (IFG) in audiovisually incongruent trials. Activity in the left IFG was negatively correlated with occurrence of the McGurk effect. The effective connectivity between the left IFG and the bilateral precentral gyri was stronger in incongruent than in congruent trials. The McGurk effect was reduced in incongruent trials by applying single-pulse TMS to motor cortex (M1) lip areas, indicating that TMS facilitates the left IFG-precentral motor network to reduce the McGurk effect. TMS of the M1 lip areas was effective in reducing the McGurk effect within the specific temporal range from 100 ms before to 200 ms after the auditory onset, and TMS of the M1 foot area did not influence the McGurk effect, suggesting topographical specificity. These results provide direct evidence that the motor network makes specific temporal and topographical contributions to the processing of multisensory integration of speech to avoid illusion.SIGNIFICANCE STATEMENT The human motor network, including the inferior frontal gyrus and primary motor cortex lip area, appears to be involved in speech perception, but the functional contribution to the McGurk effect is unknown. Functional magnetic resonance imaging revealed that activity in these areas of the motor network increased when the audiovisual stimuli were incongruent, and that the increased activity was negatively correlated with perception of the McGurk effect. Furthermore, applying transcranial magnetic stimulation to the motor areas reduced the McGurk effect. These two observations provide evidence that the motor network contributes to the avoidance of multisensory illusory perception.

A patient with McLeod syndrome showing involvement of the central sensorimotor tracts for the legs.

BACKGROUND: McLeod syndrome is a rare X-linked recessive acanthocytosis associated with neurological manifestations including progressive chorea, cognitive impairment, psychiatric disturbances, seizures, and sensorimotor axonal polyneuropathy. However, no studies have investigated the functioning of central sensorimotor tracts in patients with McLeod syndrome. CASE PRESENTATION: A 66-year-old man had experienced slowly progressive chorea and gait disturbance due to lower limb muscle weakness since his early fifties. Blood examinations showed erythrocyte acanthocytosis and the reduction of Kell antigens in red blood cells. Brain magnetic resonance imaging showed atrophy of the bilateral caudate nuclei and putamen. The diagnosis of McLeod syndrome was confirmed by the presence of a mutation of the XK gene on the X chromosome. Somatosensory-evoked potential and transcranial magnetic stimulation studies demonstrated that the central sensory and motor conduction times were abnormally prolonged for the lower extremity but normal for the upper extremity. CONCLUSIONS: This is the first report of the involvement of the central sensorimotor tracts for the legs in a patient with McLeod syndrome. The clinical neurophysiological technique revealed the central sensorimotor tracts involvements clinically masked by neuropathy.

Frequency-dependent current perception threshold in healthy Japanese adults.

The purpose of the study involves measuring the threshold for electric currents (i.e., current perception threshold or CPT) under several stimulating current frequencies. Specifically, current perception threshold (CPT) was measured in 53 healthy volunteers between the ages of 21 and 67. The stimulation currents were applied on the right index finger with stimulus frequencies in the range of 50 Hz - 300 kHz. The method of limits and method of constant stimuli were combined to measure the CPT. In a manner consistent with the findings obtained by previous studies, the results indicated that CPT was higher in men than in women and in older individuals than in young subjects. Bioelectromagnetics. 9999:XX-XX, 2019. © 2019 Bioelectromagnetics Society.

The effect of age on the homotopic motor cortical long-term potentiation-like effect induced by quadripulse stimulation.

The reduction of plasticity with age has been shown by many previous papers in animal experiments. This issue can be studied in humans because several non-invasive brain stimulation techniques induce synaptic plasticity in the human brain. We investigated the influence of individuals' age on the responder rate of the long-term potentiation (LTP)-like effect induced by quadripulse magnetic stimulation (QPS). The participants were 107 healthy volunteers: 53 older participants (Mean ± SD 65.0 ± 1.5 years) and 54 younger participants (37.2 ± 8.7). The quadripulse stimulation with 5-ms inter-pulse interval (QPS5) was applied over the primary motor cortex (M1). We measured motor evoked potentials (MEPs) before QPS, and at five time points after QPS for up to 25 min. In each participant, average MEP amplitude (size) ratios were quantified. We first classified participants as responders and non-responders simply by comparing the size ratio with 1.0 for consistency with previous studies, then as "significant responders", "non-responders", and "opposite responders" for more detailed analysis by comparing the size ratio with the mean and standard deviation of the MEP size ratios of the sham condition. The degree of LTP-like effects induced by QPS5 was significantly smaller in the older group compared to the younger group. Also, the rates of responders and significant responders were lower in the older group (58 and 47%, respectively) compared to the younger group (80 and 76%, respectively). The age of the participants significantly affected the LTP-like effect induced by QPS5, which suggests that brain plasticity decreases with age.

Water diffusion reveals networks that modulate multiregional morphological plasticity after repetitive brain stimulation.

Repetitive brain stimulation protocols induce plasticity in the stimulated site in brain slice models. Recent evidence from network models has indicated that additional plasticity-related changes occur in nonstimulated remote regions. Despite increasing use of brain stimulation protocols in experimental and clinical settings, the neural substrates underlying the additional effects in remote regions are unknown. Diffusion-weighted MRI (DWI) probes water diffusion and can be used to estimate morphological changes in cortical tissue that occur with the induction of plasticity. Using DWI techniques, we estimated morphological changes induced by application of repetitive transcranial magnetic stimulation (rTMS) over the left primary motor cortex (M1). We found that rTMS altered water diffusion in multiple regions including the left M1. Notably, the change in water diffusion was retained longest in the left M1 and remote regions that had a correlation of baseline fluctuations in water diffusion before rTMS. We conclude that synchronization of water diffusion at rest between stimulated and remote regions ensures retention of rTMS-induced changes in water diffusion in remote regions. Synchronized fluctuations in the morphology of cortical microstructures between stimulated and remote regions might identify networks that allow retention of plasticity-related morphological changes in multiple regions after brain stimulation protocols. These results increase our understanding of the effects of brain stimulation-induced plasticity on multiregional brain networks. DWI techniques could provide a tool to evaluate treatment effects of brain stimulation protocols in patients with brain disorders.

Harmonizing multisite data with the ComBat method for enhanced Parkinson's disease diagnosis via DAT-SPECT.

Background: Dopamine transporter single-photon emission computed tomography (DAT-SPECT) is a crucial tool for evaluating patients with Parkinson's disease (PD). However, its implication is limited by inter-site variability in large multisite clinical trials. To overcome the limitation, a conventional prospective correction method employs linear regression with phantom scanning, which is effective yet available only in a prospective manner. An alternative, although relatively underexplored, involves retrospective modeling using a statistical method known as "combatting batch effects when combining batches of gene expression microarray data" (ComBat). Methods: We analyzed DAT-SPECT-specific binding ratios (SBRs) derived from 72 healthy older adults and 81 patients with PD registered in four clinical sites. We applied both the prospective correction and the retrospective ComBat correction to the original SBRs. Next, we compared the performance of the original and two corrected SBRs to differentiate the PD patients from the healthy controls. Diagnostic accuracy was assessed using the area under the receiver operating characteristic curve (AUC-ROC). Results: The original SBRs were 6.13 ± 1.54 (mean ± standard deviation) and 2.03 ± 1.41 in the control and PD groups, respectively. After the prospective correction, the mean SBRs were 6.52 ± 1.06 and 2.40 ± 0.99 in the control and PD groups, respectively. After the retrospective ComBat correction, the SBRs were 5.25 ± 0.89 and 2.01 ± 0.73 in the control and PD groups, respectively, resulting in substantial changes in mean values with fewer variances. The original SBRs demonstrated fair performance in differentiating PD from controls (Hedges's g = 2.76; AUC-ROC = 0.936). Both correction methods improved discrimination performance. The ComBat-corrected SBR demonstrated comparable performance (g = 3.99 and AUC-ROC = 0.987) to the prospectively corrected SBR (g = 4.32 and AUC-ROC = 0.992) for discrimination. Conclusion: Although we confirmed that SBRs fairly discriminated PD from healthy older adults without any correction, the correction methods improved their discrimination performance in a multisite setting. Our results support the utility of harmonization methods with ComBat for consolidating SBR-based diagnosis or stratification of PD in multisite studies. Nonetheless, given the substantial changes in the mean values of ComBat-corrected SBRs, caution is advised when interpreting them.

Abnormal motor cortical plasticity as a useful neurophysiological biomarker for Alzheimer's disease pathology.

OBJECTIVE: Amyloid-beta (Aß) and tau accumulations impair long-term potentiation (LTP) induction in animal hippocampi. We investigated relationships between motor-cortical plasticity and biomarkers for Alzheimer's disease (AD) diagnosis in subjects with cognitive decline. METHODS: Twenty-six consecutive subjects who complained of memory problems participated in this study. We applied transcranial quadripuse stimulation with an interstimulus interval of 5 ms (QPS5) to induce LTP-like plasticity. Motor-evoked potentials were recorded from the right first-dorsal interosseous muscle before and after QPS5. Cognitive functions, Aß42 and tau levels in the cerebrospinal fluid (CSF) were measured. Amyloid positron-emission tomography (PET) with11C-Pittsburg compound-B was also conducted. We studied correlations of QPS5-induced plasticity with cognitive functions or AD-related biomarkers. RESULTS: QPS5-induced LTP-like plasticity positively correlated with cognitive scores. The degree of LTP-like plasticity negatively correlated with levels of CSF-tau, and the amount of amyloid-PET accumulation at the precuneus, and correlated with the CSF-Aß42 level positively. In the amyloid-PET positive subjects, non-responder rate of QPS5 was higher than the CSF-tau positive rate. CONCLUSIONS: Findings suggest that QPS5-induced LTP-like plasticity is a functional biomarker of AD. QPS5 could detect abnormality at earlier stages than CSF-tau in the amyloid-PET positive subjects. SIGNIFICANCE: Assessing motor-cortical plasticity could be a useful neurophysiological biomarker for AD pathology.

Differential centiloid scale normalization techniques: comparison between hybrid PET/MRI and independently acquired MRI.

OBJECTIVE: Centiloid (CL) scales play an important role in semiquantitative analyses of amyloid-ß (Aß) PET. CLs are derived from the standardized uptake value ratio (SUVR), which needs Aß positron emission tomography (PET) normalization processing. There are two methods to collect the T1-weighted imaging (T1WI) for normalization: (i) anatomical standardization using simultaneously acquired T1WI (PET/MRI), usually adapted to PET images from PET/MRI scanners, and (ii) T1WI from a separate examination (PET + MRI), usually adapted to PET images from PET/CT scanners. This study aimed to elucidate the correlations and differences in CLs between when using the above two T1WI collection methods. METHODS: Among patients who underwent Aß PET/MRI (using 11C-Pittuberg compound B (11C-PiB) or 18F-flutemetamol (18F-FMM)) at our institution from 2015 to 2023, we selected 49 patients who also underwent other additional MRI examinations, including T1WI for anatomic standardization within 3 years. Thirty-one of them underwent 11C-PiB PET/MRI, and 18 participants underwent 18F-FMM PET/MRI. Twenty-five of them, additional MRI acquisition parameters were identical to simultaneous MRI during PET, and 24 participants were different. After normalization using PET/MRI or PET + MRI method each, SUVR was measured using the Global Alzheimer's Association Initiative Network cerebral cortical and striatum Volume of Interest templates (VOI) and whole cerebellum VOI. Subsequently, CLs were calculated using the previously established equations for each Aß PET tracer. RESULTS: Between PET/MRI and PET + MRI methods, CLs correlated linearly in 11C-PiB PET (y = 1.00x - 0.11, R2 = 0.999), 18F-FMM PET (y = 0.97x - 0.12, 0.997), identical additional MRI acquisition (y = 1.00x + 0.33, 0.999), different acquisition (y = 0.98x - 0.43, 0.997), and entire study group (y = 1.00x - 0.24, 0.999). Wilcoxon signed-rank test revealed no significant differences: 11C-PiB (p = 0.49), 18F-FMM (0.08), and whole PET (0.46). However, significant differences were identified in identical acquisition (p = 0.04) and different acquisition (p = 0.02). Bland-Altman analysis documented only a small bias between PET/MRI and PET + MRI in 11C-PiB PET, 18F-FMM PET, identical additional MRI acquisition, different acquisition, and whole PET (- 0.05, 0.67, - 0.30, 0.78, and 0.21, respectively). CONCLUSIONS: Anatomical standardizations using PET/MRI and using PET + MRI can lead to almost equivalent CL. The CL values obtained using PET/MRI or PET + MRI normalization methods are consistent and comparable in clinical studies.

Analysis of the Relationship Between Muscle Tones and Abnormal Postures in a Computational Model.

Patients with Parkinson's disease (PD), a neurodegenerative disorder, exhibit a characteristic posture known as a forward flexed posture. Increased muscle tone is suggested as a possible cause of this abnormal posture. For further analysis, it is necessary to measure muscle tone, but the experimental measurement of muscle tone during standing is challenging. The aim of this study was to examine the hypothesis that "In patients with PD, abnormal postures are those with a small sway at increased muscle tones" using a computational model. The muscle tones of various magnitudes were estimated using the computational model and standing data of patients with PD. The postures with small sway at the estimated muscle tones were then calculated through an optimization method. The postures and sway calculated using the computational model were compared to those of patients with PD. The results showed that the differences in posture and sway between the simulation and experimental results were small at higher muscle tones compared to those considered plausible in healthy subjects by the simulations. This simulation result indicates that the reproduced sway at high muscle tones is similar to that of actual patients with PD and that the reproduced postures with small sway locally at high muscle tones in the simulations are similar to those of patients with PD. The result is consistent with the hypothesis, reinforcing the hypothesis.Clinical relevance- This study implies that improving the increased muscle tone in patients with PD may lead to an improved abnormal posture.

Analysis of abnormal posture in patients with Parkinson's disease using a computational model considering muscle tones.

Patients with Parkinson's disease (PD) exhibit distinct abnormal postures, including neck-down, stooped postures, and Pisa syndrome, collectively termed "abnormal posture" henceforth. In the previous study, when assuming an upright stance, patients with PD exhibit heightened instability in contrast to healthy individuals with disturbance, implying that abnormal postures serve as compensatory mechanisms to mitigate sway during static standing. However, limited studies have explored the relationship between abnormal posture and sway in the context of static standing. Increased muscle tone (i.e., constant muscle activity against the gravity) has been proposed as an underlying reason for abnormal postures. Therefore, this study aimed to investigate the following hypothesis: abnormal posture with increased muscle tone leads to a smaller sway compared with that in other postures, including normal upright standing, under the sway minimization criterion. To investigate the hypothesis, we assessed the sway in multiple postures, which is determined by joint angles, including cases with bended hip joints. Our approach involved conducting forward dynamics simulations using a computational model comprising a musculoskeletal model and a neural controller model. The neural controller model proposed integrates two types of control mechanisms: feedforward control (representing muscle tone as a vector) and feedback control using proprioceptive and vestibular sensory information. An optimization was performed to determine the posture of the musculoskeletal model and the accompanied parameters of the neural controller model for each of the given muscle tone vector to minimize sway. The optimized postures to minimize sway for the optimal muscle tone vector of patients with PD were compared to the actual postures observed in these patients. The results revealed that on average, the joint-angle differences between these postures was <4°, which was less than one-tenth of the typical joint range of motion. These results suggest that patients with PD exhibit less sway in the abnormal posture than in other postures. Thus, adopting an abnormal posture with increased muscle tone can potentially serve as a valid strategy for minimizing sway in patients with PD.

Correction: Hoshi et al. High Correlation among Brain-Derived Major Protein Levels in Cerebrospinal Fluid: Implication for Amyloid-Beta and Tau Protein Changes in Alzheimer's Disease. Metabolites 2022, 12, 355.

In the original publication [...].

Quadripulse transcranial magnetic stimulation inducing long-term depression in healthy subjects may increase seizure risk in some patients with intractable epilepsy.

Objective: This study aimed to assess the efficacy and safety of quadripulse transcranial magnetic stimulation-50 (QPS-50) in patients with intractable epilepsy. Methods: Four patients were included in the study. QPS-50, which induces long-term depression in healthy subjects, was administered for 30 min on a weekly basis for 12 weeks. Patients' clinical symptoms and physiological parameters were evaluated before, during, and after the repeated QPS-50 period. We performed two control experiments: the effect in MEP (Motor evoked potential) size after a single QPS-50 session with a round coil in nine healthy volunteers, and a follow-up study of physiological parameters by repeated QPS-50 sessions in four other healthy participants. Results: Motor threshold (MT) decreased during the repeated QPS-50 sessions in all patients. Epileptic symptoms worsened in two patients, whereas no clinical worsening was observed in the other two patients. In contrast, MT remained unaffected for 12 weeks in all healthy volunteers. Conclusions: QPS-50 may not be effective as a treatment for intractable epilepsy. Significance: In intractable epilepsy patients, administering repeated QPS-50 may paradoxically render the motor cortex more excitable, probably because of abnormal inhibitory control within the epileptic cortex. The possibility of clinical aggravation should be seriously considered when treating intractable epilepsy patients with non-invasive stimulation methods.

Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study: Rationale, Design, and Background.

The Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study (TMM Brain MRI Study) was established to collect multimodal information through neuroimaging and neuropsychological assessments to evaluate the cognitive function and mental health of residents who experienced the Great East Japan Earthquake (GEJE) and associated tsunami. The study also aimed to promote advances in personalized healthcare and medicine related to mental health and cognitive function among the general population. We recruited participants for the first (baseline) survey starting in July 2014, enrolling individuals who were participating in either the TMM Community-Based Cohort Study (TMM CommCohort Study) or the TMM Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study). We collected multiple magnetic resonance imaging (MRI) sequences, including 3D T1-weighted sequences, magnetic resonance angiography (MRA), diffusion tensor imaging (DTI), pseudo-continuous arterial spin labeling (pCASL), and three-dimensional fluid-attenuated inversion recovery (FLAIR) sequences. To assess neuropsychological status, we used both questionnaire- and interview-based rating scales. The former assessments included the Tri-axial Coping Scale, Impact of Event Scale in Japanese, Profile of Mood States, and 15-item Depression, Anxiety, and Stress Scale, whereas the latter assessments included the Mini-Mental State Examination, Japanese version. A total of 12,164 individuals were recruited for the first (baseline) survey, including those unable to complete all assessments. In parallel, we returned the MRI results to the participants and subsequently shared the MRI data through the TMM Biobank. At present, the second (first follow-up) survey of the study started in October 2019 is underway. In this study, we established a large and comprehensive database that included robust neuroimaging data as well as psychological and cognitive assessment data. In combination with genomic and omics data already contained in the TMM Biobank database, these data could provide new insights into the relationships of pathological processes with neuropsychological disorders, including age-related cognitive impairment.

A computational model based on corticospinal functional MRI revealed asymmetrically organized motor corticospinal networks in humans.

Evolution of the direct, monosynaptic connection from the primary motor cortex to the spinal cord parallels acquisition of hand dexterity and lateralization of hand preference. In non-human mammals, the indirect, multi-synaptic connections between the bilateral primary motor cortices and the spinal cord also participates in controlling dexterous hand movement. However, it remains unknown how the direct and indirect corticospinal pathways work in concert to control unilateral hand movement with lateralized preference in humans. Here we demonstrated the asymmetric functional organization of the two corticospinal networks, by combining network modelling and simultaneous functional magnetic resonance imaging techniques of the brain and the spinal cord. Moreover, we also found that the degree of the involvement of the two corticospinal networks paralleled lateralization of hand preference. The present results pointed to the functionally lateralized motor nervous system that underlies the behavioral asymmetry of handedness in humans.

High Correlation among Brain-Derived Major Protein Levels in Cerebrospinal Fluid: Implication for Amyloid-Beta and Tau Protein Changes in Alzheimer's Disease.

The cerebrospinal fluid (CSF) plays an important role in homeostasis of the brain. We previously demonstrated that major CSF proteins such as lipocalin-type prostaglandin D2 synthase (L-PGDS) and transferrin (Tf) that are biosynthesized in the brain could be biomarkers of altered CSF production. Here we report that the levels of these brain-derived CSF proteins correlated well with each other across various neurodegenerative diseases, including Alzheimer's disease (AD). In addition, protein levels tended to be increased in the CSF samples of AD patients compared with the other diseases. Patients at memory clinics were classified into three categories, consisting of AD (n = 61), mild cognitive impairment (MCI) (n = 42), and cognitively normal (CN) (n = 23), with MMSE scores of 20.4 ± 4.2, 26.9 ± 1.7, and 29.0 ± 1.6, respectively. In each category, CSF protein levels were highly correlated with each other. In CN subjects, increased CSF protein levels correlated well with those of AD markers, including amyloid-ß and tau protein, whereas in MCI and AD subjects, correlations declined with AD markers except p-tau. Future follow-up on each clinical subject may provide a clue that the CSF proteins would be AD-related biomarkers.

Probing for hemispheric specialization for motor skill learning: a transcranial direct current stimulation study.

Convergent findings point to a left-sided specialization for the representation of learned actions in right-handed humans, but it is unknown whether analogous hemispheric specialization exists for motor skill learning. In the present study, we explored this question by comparing the effects of anodal transcranial direct current stimulation (tDCS) over either left or right motor cortex (M1) on motor skill learning in either hand, using a tDCS montage to better isolate stimulation to one hemisphere. Results were compared with those previously found with a montage more commonly used in the field. Six groups trained for three sessions on a visually guided sequential pinch force modulation task with their right or left hand and received right M1, left M1, or sham tDCS. A linear mixed-model analysis for motor skill showed a significant main effect for stimulation group (left M1, right M1, sham) but not for hand (right, left) or their interaction. Left M1 tDCS induced significantly greater skill learning than sham when hand data were combined, a result consistent not only with the hypothesized left hemisphere specialization for motor skill learning but also with possible increased left M1 responsiveness to tDCS. The unihemispheric montage effect size was one-half that of the more common montage, and subsequent power analysis indicated that 75 subjects per group would be needed to detect differences seen with only 12 subjects with the customary bihemispheric montage.

Transferrin Biosynthesized in the Brain Is a Novel Biomarker for Alzheimer's Disease.

Glycosylation is a cell type-specific post-translational modification that can be used for biomarker identification in various diseases. Aim of this study is to explore glycan-biomarkers on transferrin (Tf) for Alzheimer's disease (AD) in cerebrospinal fluid (CSF). Glycan structures of CSF Tf were analyzed by ultra-performance liquid chromatography followed by mass spectrometry. We found that a unique mannosylated-glycan is carried by a Tf isoform in CSF (Man-Tf). The cerebral cortex contained Man-Tf as a major isofom, suggesting that CSF Man-Tf is, at least partly, derived from the cortex. Man-Tf levels were analyzed in CSF of patients with neurological diseases. Concentrations of Man-Tf were significantly increased in AD and mild cognitive impairment (MCI) comparing with other neurological diseases, and the levels correlated well with those of phosphorylated-tau (p-tau), a representative AD marker. Consistent with the observation, p-tau and Tf were co-expressed in hippocampal neurons of AD, leading to the notion that a combined p-tau and Man-Tf measure could be a biomarker for AD. Indeed, levels of p-tau x Man-Tf showed high diagnostic accuracy for MCI and AD; 84% sensitivities and 90% specificities for MCI and 94% sensitivities and 89% specificities for AD. Thus Man-Tf could be a new biomarker for AD.

Stimulus-response profile during single-pulse transcranial magnetic stimulation to the primary motor cortex.

We examined the stimulus-response profile during single-pulse transcranial magnetic stimulation (TMS) by measuring motor-evoked potentials (MEPs) with electromyographic monitoring and hemodynamic responses with functional magnetic resonance imaging (fMRI) at 3 Tesla. In 16 healthy subjects, single TMS pulses were irregularly delivered to the left primary motor cortex at a mean frequency of 0.15 Hz with a wide range of stimulus intensities. The measurement of MEP proved a typical relationship between stimulus intensity and MEP amplitude in the concurrent TMS-fMRI environment. In the population-level analysis of the suprathreshold stimulation conditions, significant increases in hemodynamic responses were detected in the motor/somatosensory network, reflecting both direct and remote effects of TMS, and also the auditory/cognitive areas, perhaps related to detection of clicks. The stimulus-response profile showed both linear and nonlinear components in the direct and remote motor/somatosensory network. A detailed analysis suggested that the nonlinear components of the motor/somatosensory network activity might be induced by nonlinear recruitment of neurons in addition to sensory afferents resulting from movement. These findings expand our basic knowledge of the quantitative relationship between TMS-induced neural activations and hemodynamic signals measured by neuroimaging techniques.