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.

Repeated Acute Exacerbations of Chronic Inflammatory Demyelinating Polyradiculoneuropathy Accompanied by Pain and Swelling in Distal Extremities.

An 81-year-old man experienced acute progression of weakness in the extremities accompanied by a fever, tenderness, and swelling in distal parts of the extremities. He had flaccid tetraparesis with fasciculations and general hyporeflexia. Nerve conduction studies indicated demyelinating sensorimotor neuropathy. A cerebrospinal fluid examination revealed elevated proteins without pleocytosis. Immunological treatments were effective, but his symptoms exhibited repeated relapse and remission phases. He was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with an acute onset. The highlight of this case is pain with inflammatory reaction recognized as red flags of CIDP, with the clinical course and electrophysiological findings compatible with CIDP.

Impaired long-term potentiation-like motor cortical plasticity in progressive supranuclear palsy.

OBJECTIVE: To elucidate long-term potentiation (LTP)-like effects on the primary motor cortical (M1) in progressive supranuclear palsy (PSP) and its relationships with clinical features. METHODS: Participants were 18 probable/possible PSP Richardson syndrome (PSP-RS) patients and 17 healthy controls (HC). We used quadripulse stimulation (QPS) over the M1 with an interstimulus interval of 5 ms (QPS-5) to induce LTP-like effect and analyzed the correlations between the degree of LTP-like effect and clinical features. We also evaluated cortical excitability using short interval intracortical inhibition (SICI), intracortical facilitation (ICF) and short interval intracortical facilitation (SICF) in 15 PSP patients and 17 HC. RESULTS: LTP-like effect after QPS in PSP was smaller than HC and negatively correlated with Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) score, especially bradykinesia, but not with either age or any scores of cognitive functions. The SICI was abnormally reduced in PSP, but neither ICF nor SICF differed from those of normal subjects. None of these cortical excitability parameters correlated with any clinical features. CONCLUSIONS: LTP induction was impaired in PSP. The degree of LTP could reflect the severity of bradykinesia. The bradykinesia may partly relate with the motor cortical dysfunction. SIGNIFICANCE: The degree of motor cortical LTP could relate with the severity of motor symptoms in PSP.

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.

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 [...].

[An autopsy case of polyarteritis nodosa accompanied with multiple immune-specific autoantibodies and rhabdomyolysis].

A 72-year-old male complained of fever lasting 1 month and developed muscle weakness and paresthesia in the legs. He presented with muscle weakness, grasping pain, decreased deep tendon reflexes in the extremities, and reduction of tactile sensation in the distal parts of the left leg muscles. Blood tests revealed leukocytosis and inflammatory reactions. Collagen-disease-specific autoantibodies including anti-double-stranded DNA and anti-Scl-70 antibodies were positive, but antineutrophil cytoplastic antibodies were negative. Nerve conduction studies revealed asymmetric axonal degeneration, indicating multiple mononeuropathy. We started intravenous methylprednisolone pulse and plasma exchange therapies. However, the patient developed intestinal necrosis and perforation, and he died 44 days after the onset of fever. An autopsy revealed vasculitis in small- to medium-sized vessels in multiple organs as well as myoglobin casts in the renal tubules, which were suggestive polyarteritis nodosa (PAN) accompanied with rhabdomyolysis. Positivity for collagen-disease-specific autoantibodies and accompanying rhabdomyolysis are atypical findings with PAN. This patient was not clinically diagnosed as PAN, and so promptly starting immunotherapies should be considered when a case presents with evidence of vasculitis.

[Unilateral asterixis after hemiballism in a patient with acute cerebral infarction].

An-88-year-old right-handed female complained of repeated intermittent hemiballism in the right upper and lower extremities. She presented to our hospital with monoparesis and asterixis of the right arm, but not hemiballism. Brain MRI revealed acute disseminated cerebral infarctions in the middle cerebral artery watershed area of the left hemisphere, including the striatum and cortical areas. Occlusion of the left internal carotid artery was also detected. She was diagnosed as acute cerebral infarction and received intravenous infusion, after which her neurological symptoms gradually improved. We presumed that the intermittent hemiballism was related to dysfunction of the motor loop induced by circulatory insufficiency in the left striatum, and that unilateral asterixis might be induced by hemodynamic hypoperfusion in the left frontal lobe. The hemodynamic changes induced by occlusion of the left internal carotid artery might be associated with pathogenesis of these involuntary movements.

Expression of Transferrin Protein and Messenger RNA in Neural Cells from Mouse and Human Brain Tissue.

Iron is an essential nutrient in the body. However, iron generates oxidative stress and hence needs to be bound to carrier proteins such as the glycoprotein transferrin (Tf) in body fluids. We previously reported that cerebrospinal fluid contains Tf glycan-isoforms that are derived from the brain, but their origins at the cellular level in the brain have not yet been elucidated. In the present report, we described the localization of Tf protein and mRNA in mouse and human brain tissue. In situ hybridization of mouse brain tissue revealed that Tf mRNA is expressed by different cell types such as epithelial cells in the choroid plexus, oligodendrocyte-like cells in the medulla, and neurons in the cortex, hippocampus, and basal ganglia. In contrast, Tf protein was barely detected by immunohistochemistry in hippocampal and some cortical neurons, but it was detected in other types of cells such as oligodendrocyte-like cells and choroid plexus epithelial cells. The results showed that Tf mRNA is expressed by neural cells, while Tf protein is expressed in different brain regions, though at very low levels in hippocampal neurons. Low Tf level in the hippocampus may increases susceptibility to iron-induced oxidative stress, and account for neuron death in neurodegenerative diseases.

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.

Enhancement of LTD-like plasticity by associative pairing of quadripulse magnetic stimulation with peripheral nerve stimulation.

OBJECTIVE: Quadripulse magnetic stimulation (QPS) is useful for changing corticospinal excitability, but the long-term depression (LTD)-like effect considerably has low responder rate. To solve this problem, we modified inhibitory QPS (QPSLTD) by pairing it with the application of an electrical stimulus (ES) to peripheral nerves (paired-associative QPS [PA-QPSLTD]), and investigated the effects of PA-QPSLTD on motor-evoked potentials (MEPs). METHODS: The peripheral-nerve ES was applied at two timings with a synchrony to transcranial magnetic stimulation (TMS) over the primary motor cortex (M1). The intrapair interval between ES and TMS was the N20-peak latency plus 2 ms for PALTP-QPSLTD, and N20-peak latency minus 5 ms for PALTD-QPSLTD. MEPs elicited by TMS over the left M1 were recorded from the right abductor pollicis brevis muscle before and after the interventions. The responder rates of PALTD-QPSLTD and QPSLTD was also studied. RESULTS: The PALTD-QPSLTD induced larger LTD-like effect than QPSLTD, and the PALTP-QPSLTD induced smaller aftereffect than QPSLTD. The responder rates were significantly higher for PALTD-QPSLTD than for QPSLTD. CONCLUSIONS: The new protocol, PALTD-QPSLTD, induces powerful and consistent LTD-like aftereffects in the corticospinal tract neurons. SIGNIFICANCE: PALTD-QPSLTD is suitable for use in physiological evaluations and therapeutic approaches in various neurological disorders.

Intensity dependency of peripheral nerve stimulation in spinal LTP induced by paired associative corticospinal-motoneuronal stimulation (PCMS).

Paired associative corticospinal-motoneuronal stimulation (PCMS) induces plasticity at synapses between corticospinal tracts (CSTs) and spinal motoneurons (SMs). We investigated the effects of peripheral nerve electrical stimulation (PNS) intensity on PCMS-induced plasticity. PCMS consisted of 180 paired stimuli of transcranial magnetic stimulation (TMS) over the left primary motor cortex with PNS on the right ulnar nerve at the wrist. We compared effects induced by different PNS intensities: supramaximal, twice and three times sensory threshold intensities. For evaluating efficacy of the synapse between CSTs and SMs, single-pulse TMS was delivered at cervicomedullary junction level, and cervicomedullary motor-evoked potentials (CMEPs) were recorded from the right first-dorsal interosseous muscle before and after PCMS. PCMS with the supramaximal PNS intensity increased CMEP amplitude. The facilitatory effect of PCMS with the supramaximal PNS was larger than those of PCMS with weaker PNS intensities. Sham TMS with the supramaximal PNS showed no CMEP changes after the intervention. PNS intensity of PCMS influences the magnitude of synaptic plasticity induction between the CSTs and SMs at the spinal level, and the supramaximal intensity is the best for induction of long-term potentiation-like effects. The PNS intensity may influence the number of activated SMs by axonal backpropagating pulses with PNS which must overlap with descending volleys induced by TMS.

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.

Bilateral asterixis in a patient with bilateral anterior cerebral artery infarction.

A 83-year-old woman complained of muscular weakness in the left leg and trembling in all extremities. She was apathetic and had left leg paresis and asterixis in all extremities. Magnetic resonance imaging revealed acute cerebral infarctions in the bilateral frontal lobes perfused by the anterior cerebral artery (ACA). Anticoagulant treatments improved ischemia-induced damage of the frontal lobes, and then her neurological symptoms including asterixis gradually disappeared. A unique point of this case is that acute stroke in the bilateral ACA territory induced bilateral asterixis resembling metabolic encephalopathy. Occurrence of the bilateral ACA territory infarction is extremely rare, but it should be considered in patients presenting with bilateral asterixis.

[Hemichorea in a patient with acute cerebral infarction of the somatosensory cortex].

A 86-year-old woman with left hemiparesis was admitted to our hospital. When visiting to our hospital, hemichorea appeared on her left extremities in an ambulance. She also had mild disturbance of consciousness, spatial disorientation, and sensory disturbance. Blood biochemical studies revealed mild renal failure. DWI MRI showed hyperintensities in the postcentral gyrus and a posterior part of the insula in the right hemisphere, but no signal changes in FLAIR. No lesions were detected in the basal ganglia. The DWI-FLAIR mismatch suggested acute cerebral infarction, and we performed intravenous thrombolysis therapy. Her neurological symptoms including hemichorea gradually improved, and she was finally discharged on foot. Two conspicuous points of the present patient are the sensory cortical infarction and an association with renal failure. In this patient, the sensory cortical infarction must produce chorea even though sensory cortical lesions rarely caused chorea. The associated renal dysfunction may play some role in the production of chorea. The double-crash of cerebral infarction and metabolic abnormality (renal dysfunction) may cause hemichorea which is rarely seen in patients with cerebral infarction of the sensory cortex and insula with no metabolic abnormalities.

Direct comparison of efficacy of the motor cortical plasticity induction and the interindividual variability between TBS and QPS.

BACKGROUND: Theta burst stimulation (TBS) and quadripulse stimulation (QPS) are known to induce synaptic plasticity in humans. There have been no head-to-head comparisons of the efficacy and variability between TBS and QPS. OBJECTIVE: To compare the efficacy and interindividual variability between the original TBS and QPS protocols. We hypothesized that QPS would be more effective and less variable than TBS. METHODS: Forty-six healthy subjects participated in this study. Thirty subjects participated in the main comparison experiment, and the other sixteen subjects participated in the experiment to obtain natural variation in motor-evoked potentials. The facilitatory effects were compared between intermittent TBS (iTBS) and QPS5, and the inhibitory effects were compared between continuous TBS (cTBS) and QPS50. The motor-evoked potential amplitudes elicited by transcranial magnetic stimulation over the primary motor cortex were measured before the intervention and every 5 min after the intervention for 1 h. To investigate the interindividual variability, the responder/nonresponder/opposite-responder rates were also analyzed. RESULTS: The facilitatory effects of QPS5 were greater than those of iTBS, and the inhibitory effects of QPS50 were much stronger than those of cTBS. The responder rate of QPS was significantly higher than that of TBS. QPS had a smaller number of opposite responders than TBS. CONCLUSION: QPS is more effective and stable for synaptic plasticity induction than TBS.

Inter-individual variations in electric fields induced in the brain by exposure to uniform magnetic fields at 50 Hz.

The International Commission on Non-Ionizing Radiation Protection (ICNIRP) guidelines and the Institute of Electrical and Electronics Engineers (IEEE) standard establish safety limits for human exposure to electromagnetic fields. At low frequencies, only a limited number of computational body models or simplified geometrical shapes are used to relate the internal induced electric fields and the external magnetic fields. As a consequence, both standard/guidelines derive the exposure reference levels for the external magnetic field without considering the variability between individuals. Here we provide quantitative data on the variation of the maximum electric field strengths induced in the brain of 118 individuals when exposed to uniform magnetic fields at 50 Hz. We found that individual characteristics, such as age and skull volume, as well as incident magnetic field direction, have a systematic effect on the peak electric field values. Older individuals show higher induced electric field strengths, possibly due to age-related anatomical changes in brain. Peak electric field strengths are found to increase for larger skull volumes, as well as for incident magnetic fields directed along the lateral direction. Moreover, the maximum electric fields provided by the anatomical models used by ICNIRP for deriving exposure limits are considerably higher than those obtained here. On the contrary, the IEEE elliptical exposure model produces a weaker peak electric field strength. Our findings are useful for the revision and harmonization of the current exposure standard and guidelines. The present investigation reduces the dosimetric uncertainty of the induced electric field among different anatomical induction models. The obtained results can be used as a basis for the selection of appropriate reduction factors when deriving exposure reference levels for human protection to low-frequency electromagnetic exposure.

[Successful early treatment with acyclovir and corticosteroids for acute myelitis associated with zoster sine herpete: a case report].

A 79-year-old man presented with chest and back pain on the right side but with no cutaneous lesions. He had received oral corticosteroids and immunosuppressants for systemic lupus erythematosus. He had spastic paraplegia, sensory disturbance in the lower limbs, and dysfunction of the bladder and bowel. He showed mononuclear-dominant pleocytosis and elevated proteins in the cerebrospinal fluid (CSF), and a decreased CSF/blood glucose ratio. Although polymerase chain reaction techniques found no varicella-zoster virus (VZV) DNA, VZV IgG antibodies were elevated in both the serum and CSF, and the VZV IgG index was dramatically elevated. MRI revealed no lesions in the brain or spine. However, somatosensory evoked potentials in the tibial nerve showed abnormal prolongation of the central sensory conduction time. We diagnosed the patient with acute myelitis associated with zoster sine herpete (ZSH). He received acyclovir and intravenous methylprednisolone pulse therapy in the early stage, and his symptoms and CSF findings completely recovered. We conclude that acute myelitis associated with ZSH should be treated as soon as possible because VZV infection may induce necrotizing myelitis if the treatment is delayed.

Central motor conduction time reveals upper motor neuron involvement masked by lower motor neuron impairment in a significant portion of patients with amyotrophic lateral sclerosis.

OBJECTIVE: We retrospectively investigated the utility of the central motor conduction time (CMCT) in detecting upper motor neuron (UMN) involvements in patients with amyotrophic lateral sclerosis (ALS). METHODS: Fifty-two ALS patients and 12 disease control patients participated in this study. Surface electromyograms were recorded from the first dorsal interosseous (FDI) and tibialis anterior (TA) muscles. We stimulated the motor cortex, brainstem, and spinal nerve using transcranial magnetic stimulation (TMS) in order to measure the cortical, brainstem, and spinal latencies. We divided the ALS patients into 2 subgroups (with UMN impairment vs. without UMN impairment) and calculated the rates of abnormal CMCT prolongation judged by their comparison with the normal ranges obtained by the measurement in the control patients. RESULTS: The CMCTs in the FDI and TA were abnormally prolonged in over 40% of the ALS patients with UMN impairment and in nearly 30% of those without UMN impairment. CONCLUSIONS: CMCT shows UMN dysfunction in ALS patients without clinical UMN impairment. SIGNIFICANCE: TMS still has diagnostic utility in a significant portion of ALS patients.

TMS activation site estimation using multiscale realistic head models.

OBJECTIVE: Transcranial magnetic stimulation (TMS) activates brain structures non-invasively. Computational models can be used to elucidate the activation site; however, the exact activation site is controversial. The aim is to present an imaging technique of the TMS activation cortical site estimation using individualized multi-scale realistic head models based on experimentally-derived TMS fields. APPROACH: The induced electric field (EF) was computed using subject-specific head models and experimental-specific TMS coil configuration during suprathreshold stimulation for relaxed muscles. The experimentally-derived EFs were used to calculate the activation of pyramidal tract model embedded in the head models to derive the activation site on the cortical surface at the macroscopic level. MAIN RESULTS: The TMS activation site was located at the anterior wall of the central sulcus, which agreed with a concurrent TMS/fMRI study. In contrast, the EF strength was not entirely consistent with TMS/fMRI studies. Multiscale physical modelling is a feasible imaging technique to investigate the activation site for TMS. SIGNIFICANCE: By combining subject-specific multiscale modelling with experimental TMS measurements, we showed that this method could serve as a TMS imaging technique at suprathreshold condition.