High pulse wave velocity is associated with enlarged perivascular spaces in dementia with Lewy bodies.

Previous studies have demonstrated associations between enlarged perivascular spaces (EPVS) and dementias such as Alzheimer's disease. However, an association between EPVS and dementia with Lewy bodies (DLB) has not yet been clarified. We performed a cross-sectional analysis of our prospective study cohort of 109 participants (16 with DLB). We assessed cognitive function, pulse wave velocity (PWV), and brain magnetic resonance imaging features. The relationships between EPVS and DLB were evaluated using multivariable logistic regression analyses. Compared with the non-dementia group, the DLB group was more likely to have EPVS in the basal ganglia. Compared with participants without EPVS, those with EPVS were older and had cognitive impairment and high PWV. In multivariable analyses, EPVS in the basal ganglia was independently associated with DLB. High PWV was also independently associated with EPVS in both the basal ganglia and centrum semiovale. High PWV may cause cerebrovascular pulsatility, leading to accelerated EPVS in DLB participants.

Trait-anxiety and glial-related neuroinflammation of the amygdala and its associated regions in Alzheimer's disease: A significant correlation.

Background: Positron emission tomography, which assesses the binding of translocator protein radiotracers, 11C-DPA-713, may be a sensitive method for determining glial-mediated neuroinflammation levels. This study investigated the relationship between regional 11C-DPA713 binding potential (BPND) and anxiety in patients with Alzheimer's disease (AD) continuum. Methods: Nineteen patients with AD continuum determined to be amyloid-/p-tau 181-positive via cerebrospinal fluid analysis were included in this cross-sectional study (mild cognitive impairment [MCI, n = 5] and AD [n = 14]). Anxiety was evaluated using the State-Trait Anxiety Inventory (STAI). A whole-brain voxel-based analysis was performed to examine the relationship between 11C-DPA-713-BPND values at each voxel and the STAI score. Stepwise multiple regression analysis was performed to determine the predictors of STAI scores using independent variables, including 11C-DPA-713-BPND values within significant clusters. 11C-DPA-713-BPND values were compared between patients with AD continuum with low-to-moderate and high STAI scores. Results: Voxel-based analysis revealed a positive correlation between trait anxiety severity and 11C-DPA713-BPND values in the centromedial amygdala and the left inferior occipital area [P < 0.001 (uncorrected) at the voxel-level]. 11C-DPA713-BPND values in these regions were a strong predictor of the STAI trait anxiety score. Specifically, patients with AD continuum and high trait anxiety had increased 11C-DPA713-BPND values in these regions. Conclusions: The amygdala-occipital lobe circuit influences the control of emotional generation, and disruption of this network by AD pathology-induced inflammation may contribute to the expression of anxiety. Our findings suggest that suppression of inflammation can help effectively treat anxiety by attenuating damage to the amygdala and its associated areas.

Comparison of consistency in centiloid scale among different analytical methods in amyloid PET: the CapAIBL, VIZCalc, and Amyquant methods.

OBJECTIVE: The Centiloid (CL) scale is a standardized measure for quantifying amyloid deposition in amyloid positron emission tomography (PET) imaging. We aimed to assess the agreement among 3 CL calculation methods: CapAIBL, VIZCalc, and Amyquant. METHODS: This study included 192 participants (mean age: 71.5 years, range: 50-87 years), comprising 55 with Alzheimer's disease, 65 with mild cognitive impairment, 13 with non-Alzheimer's dementia, and 59 cognitively normal participants. All the participants were assessed using the three CL calculation methods. Spearman's rank correlation, linear regression, Friedman tests, Wilcoxon signed-rank tests, and Bland-Altman analysis were employed to assess data correlations, linear associations, method differences, and systematic bias, respectively. RESULTS: Strong correlations (rho = 0.99, p < .001) were observed among the CL values calculated using the three methods. Scatter plots and regression lines visually confirmed these strong correlations and met the validation criteria. Despite the robust correlations, a significant difference in CL value between CapAIBL and Amyquant was observed (36.1 ± 39.7 vs. 34.9 ± 39.4; p < .001). In contrast, no significant differences were found between CapAIBL and VIZCalc or between VIZCalc and Amyquant. The Bland-Altman analysis showed no observable systematic bias between the methods. CONCLUSIONS: The study demonstrated strong agreement among the three methods for calculating CL values. Despite minor variations in the absolute values of the Centiloid scores obtained using these methods, the overall agreement suggests that they are interchangeable.

A Case of Tinea Faciei due to Trichophyton indotineae with Steroid Rosacea Related to Topical Over-The-Counter Drugs Purchased Outside of Japan.

A Filipino woman in her forties had facial erythema that was being self-treated with over-the-counter (OTC) drugs purchased outside of Japan. The drugs included clobetasol propionate, antibiotic, and antifungal components. Her facial erythema symptoms were worse during summertime. KOH direct examination of annular erythema was positive for fungal hyphae and negative for Demodex folliculorum. Fungal culture revealed Trichophyton indotineae based on internal transcribed spacer sequence analysis. Minimal inhibitory concentration for terbinafine was 0.06 µg/mL. We made a diagnosis of tinea faciei with steroid rosacea. We treated the patient with oral itraconazole. Physicians should be aware of increasing T. indotineae infections and increasing self-medication using topical OTC steroids combined with antifungals and antibiotics not only in India but also among foreign people living in other countries such as Japan.

Cross-Sectional Analysis of Periodontal Disease and Cognitive Impairment Conducted in a Memory Clinic: The Pearl Study.

BACKGROUND: Periodontal disease (PeD) is a risk factor of Alzheimer's disease and is associated with cognitive decline in older adults. However, the relationships between subitems of neuropsychological tests and PeD have not been fully clarified. OBJECTIVE: To evaluate associations between PeD and subitems of neuropsychological tests. METHODS: We performed a cross-sectional analysis of data of 183 participants (women: 50%, mean age: 79 years) from a clinical study. We enrolled patients who visited our memory clinic and assessed demographics, dementia-related risk factors, neuropsychological tests, brain magnetic resonance images, and a dental screening check. We evaluated the relationships between cognitive function and PeD using multivariable logistic regression analyses. RESULTS: Participants with dementia were less likely to make periodical visits to the dentist, had fewer teeth, had less frequent tooth brushing habits, and were more likely to have PeD. Impaired cognitive function was significantly associated with an increasing degree of PeD. In multivariable logistic regression analyses, impaired visuospatial function and attention were associated with twice the risk of moderate or severe PeD compared with individuals with preserved visuospatial function and attention (odds ratio: 2.11, 95% confidence interval: 1.04-4.29, p = 0.037). Impaired word recall and recognition and following commands were associated with increased risk of PeD (odds ratio: 2.80, 95% confidence interval: 1.41-5.32, p = 0.003). CONCLUSIONS: Cognitive decline, such as impaired visuospatial function, attention, word recall and recognition, and inability to follow commands were independently and strongly associated with PeD. These items can be assessed easily on a daily basis.

Neuroimaging biomarkers of glial activation for predicting the annual cognitive function decline in patients with Alzheimer's disease.

BACKGROUND: Glial activation is central to the pathogenesis of Alzheimer's disease (AD). However, researchers have not demonstrated its relationship to longitudinal cognitive deterioration. We aimed to compare the prognostic effects of baseline positron emission tomography (PET) imaging of glial activation and amyloid/tau pathology on the successive annual cognitive decline in patients with AD. METHODS: We selected 17 patients diagnosed with mild cognitive impairment or AD. We assessed the annual changes in global cognition and memory. Furthermore, we assessed the predictive effects of baseline amyloid and tau pathology indicated by cerebrospinal fluid (CSF) concentrations and PET imaging of glial activation (11C-DPA-713-binding potential in the area of Braak 1-3 [11C-DPA-713-BPND]) on global cognition and memory using a stepwise regression analysis. RESULTS: The final multiple regression model of annual changes in global cognition and memory scores included 11C-DPA-713-BPND as the predictor. The CSF Aß42/40 ratios and p-tau concentrations were removed from the final model. In stepwise Bayesian regression analysis, the Bayes factor-based model comparison suggested that the best model included 11C-DPA-713-BPND as the predictor of decline in global cognition and memory. CONCLUSIONS: Translocator protein-PET imaging of glial activation is a stronger predictor of AD clinical progression than the amount of amyloid/tau pathology measured using CSF concentrations. Glial activation is the primary cause of tau-induced neuronal toxicity and cognitive deterioration, thereby highlighting the potential of blocking maladaptive microglial responses as a therapeutic strategy for AD treatment.

Early-onset Alzheimer Disease Associated With Neuromyelitis Optica Spectrum Disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease of the central nervous system. Although recent reports have noted that cognitive impairment is common in NMOSD, little longitudinal information is available on the trajectories of cognitive function in the disease. Here, we report a case of a 55-year-old woman with an 11-year history of NMOSD who visited our memory clinic for progressive memory loss. She was diagnosed with early-onset Alzheimer disease based on amyloid and tau positron emission tomography imaging biomarkers. This is the first report of early-onset Alzheimer disease in a patient with NMOSD. Complications of Alzheimer disease should be considered when patients with NMOSD exhibit rapid cognitive decline. More longitudinal studies of NMOSD with cognitive impairment are needed.

Involvement of inflammation in the medial temporal region in the development of agitation in Alzheimer's disease: an in vivo positron emission tomography study.

BACKGROUND: The evaluation of 11 C-DPA-713 binding using positron emission tomography for quantifying the translocator protein can be a sensitive approach in determining the level of glial activation induced by neuroinflammation. Herein, we aimed to investigate the relationship between regional 11 C-DPA713-binding potential (BPND ) and neuropsychiatric symptoms (NPS) in amyloid-positive Alzheimer's disease (AD) patients. METHODS: Fifteen AD patients were enrolled in this study. Correlations were evaluated between the 11 C-DPA713-BPND and Neuropsychiatric Inventory Questionnaire (NPI-Q) scores, including scores in its four domains: agitation, psychosis, affective, and apathy. 11 C-DPA713-BPND values were compared between groups with and without the neuropsychiatric symptoms for which a relationship was observed in the abovementioned correlation analysis. RESULTS: A positive correlation was found between the severity of agitation and 11 C-DPA713-BPND in the Braak 1-3 area, including the amygdala, hippocampal and parahippocampal regions, and lingual and fusiform areas. An increase in the 11 C-DPA713-BPND was observed in AD patients with agitation. We did not find any significant effects of possible confounding factors, such as age, duration of illness, education, gender, Mini-Mental State Examination score, cerebrospinal fluid amyloid ß 42/40 ratio, and apolipoprotein E4 positivity, on either the 11 C-DPA713-BPND or agitation score. CONCLUSIONS: Neuroinflammation in the medial temporal region and its neighbouring area was shown to be associated with the development of agitation symptoms in AD patients. Our findings extend those of previous studies showing an association between some NPS and inflammation, suggesting that immunologically based interventions for agitation can serve as an alternative treatment for dementia.

Estimation of blood-based biomarkers of glial activation related to neuroinflammation.

Background: Neuroinflammation is a well-known feature of Alzheimer's disease (AD), and a blood-based test for estimating the levels of neuroinflammation would be expected. In this study, we examined and validated a model using blood-based biomarkers to predict the level of glial activation due to neuroinflammation, as estimated by 11C-DPA-713 positron emission tomography (PET) imaging. Methods: We included 15 patients with AD and 10 cognitively normal (CN) subjects. Stepwise backward deletion multiple regression analysis was used to determine the predictors of the TSPO-binding potential (BPND) estimated by PET imaging. The independent variables were age, sex, diagnosis, apolipoprotein E4 positivity, body mass index and the serum concentration of blood-based biomarkers, including monocyte chemotactic protein 1 (MCP-1), fractalkine, chitinase 3-like protein-1 (CHI3L1), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and clusterin. Results: Sex, diagnosis, and serum concentrations of MCP1 and sTREM2 were determined as predictors of TSPO-BPND in the Braak1-3 area. The serum concentrations of MCP1 and sTREM2 correlated positively with TSPO-BPND. In a leave one out (LOO) cross-validation (CV) analysis, the model gave a LOO CV R2 of 0.424, which indicated that this model can account for approximately 42.4% of the variance of brain TSPO-BPND. Conclusions: We found that the model including serum MCP-1 and sTREM2 concentration and covariates of sex and diagnosis was the best for predicting brain TSPO-BPND. The detection of neuroinflammation in AD patients by blood-based biomarkers should be a sensitive and useful tool for making an early diagnosis and monitoring disease progression and treatment effectiveness.

Pressure ulcer induced by discontinuation of levodopa: Case report of an older patient with Parkinson's disease.

We report the case of a pressure ulcer that developed consequent to the discontinuation of levodopa (L-3,4-dihydroxyphenylalanine) administration. The 86-year-old female patient had a 5-year history of Parkinson's disease treated with levodopa. She developed a sacral pressure ulcer due to unanticipated immobilization induced by the discontinuation of levodopa. Discontinuation of mandatory drugs is therefore a risk factor for the development of pressure ulcers in patients with Parkinson's disease.

Differentiating Dementia with Lewy Bodies from Alzheimer's Disease Using the Fall Risk Evaluation Questionnaire.

Objective Dementia with Lewy bodies (DLB) is the second-most common form of neurodegenerative dementia after Alzheimer's disease (AD). Falls are a vital prognostic factor in patients with dementia and are a characteristic feature of DLB. This study investigated the screening potential of the fall risk evaluation for DLB and compared it with that of AD to facilitate an accurate diagnosis. Methods We enrolled patients diagnosed with DLB (n=410) and AD (n=2,683) and categorized the participants into 3 groups depending on their physical ability, age, cognitive function, and fall events. Using the Fall Risk Index-21 (FRI-21) questionnaire, we evaluated and comparatively analyzed the fall risk between DLB and AD patients in three defined groups of participants. Results The FRI-21 score was significantly higher in DLB patients than in AD patients in every group. Using this score, we were able to distinguish between DLB and AD patients in each group. Among the three groups, the group with a young age, relatively mild cognitive dysfunction, and no fall events exhibited the best specificity for DLB (0.895). Conclusions The FRI-21 is a useful tool for screening for DLB and differentiating it from AD. This questionnaire can be used at a relatively early stage of the disease in young patients with mild cognitive dysfunction and no history of falling. These preliminary results need to be validated in an interventional study to evaluate the effectiveness of rehabilitative measures and daily environmental changes carried out to prevent falls using this tool.

Patterns of Distribution of 18F-THK5351 Positron Emission Tomography in Alzheimer's Disease Continuum.

BACKGROUND: Alzheimer's disease (AD) is conceptualized as a biological continuum encompassing the preclinical (clinically asymptomatic but with evidence of AD pathology) and clinical (symptomatic) phases. OBJECTIVE: Using 18F-THK5351 as a tracer that binds to both tau and monoamine oxidase B (MAO-B), we investigated the changes in 18F-THK5351 accumulation patterns in AD continuum individuals with positive amyloid PET consisting of cognitively normal individuals (CNp), amnestic mild cognitive impairment (aMCI), and AD and cognitively normal individuals (CNn) with negative amyloid PET. METHODS: We studied 69 individuals (32 CNn, 11 CNp, 9 aMCI, and 17 AD) with structural magnetic resonance imaging, 11C-Pittsburgh compound-B (PIB) and 18F-THK5351 PET, and neuropsychological assessment. 18F-THK5351 accumulation was evaluated with visual analysis, voxel-based analysis and combined region of interest (ROI)-based analysis corresponding to Braak neurofibrillary tangle stage. RESULTS: On visual analysis, 18F-THK5351 accumulation was increased with stage progression in the AD continuum. On voxel-based analysis, there was no statistical difference in 18F-THK5351 accumulation between CNp and CNn. However, a slight increase of the bilateral posterior cingulate gyrus in aMCI and definite increase of the bilateral parietal temporal association area and posterior cingulate gyrus/precuneus in AD were detected compared with CNn. On ROI-based analyses, 18F-THK5351 accumulation correlated positively with supratentorial 11C-PIB accumulation and negatively with the hippocampal volume and neuropsychological assessment. CONCLUSION: The AD continuum showed an increase in 18F-THK5351 with stage progression, suggesting that 18F-THK5351 has the potential to visualize the severity of tau deposition and neurodegeneration in accordance with the AD continuum.

Phase-dependent modulation of the vestibular-cerebellar network via combined alternating current stimulation influences human locomotion and posture.

Background: Human locomotion induces rhythmic movements of the trunk and head. Vestibular signaling is relayed to multiple regions in the brainstem and cerebellum, and plays an essential role in maintaining head stability. However, how the vestibular-cerebellar network contributes to the rhythmic locomotor pattern in humans is unclear. Transcranial alternating current stimulation (tACS) has been used to investigate the effects of the task-related network between stimulation regions in a phase-dependent manner. Here, we investigated the relationship between the vestibular system and the cerebellum during walking imagery using combined tACS over the left cerebellum and alternating current galvanic vestibular stimulation (AC-GVS). Methods: In Experiment 1, we tested the effects of AC-GVS alone at around individual gait stride frequencies. In Experiment 2, we then determined the phase-specificity of combined stimulation at the gait frequency. Combined stimulation was applied at in-phase (0° phase lag) or anti-phase (180° phase lag) between the left vestibular and left cerebellar stimulation, and the sham stimulation. We evaluated the AC-GVS-induced periodic postural response during walking imagery or no-imagery using the peak oscillatory power on the angular velocity signals of the head in both experiments. In Experiment 2, we also examined the phase-locking value (PLV) between the periodic postural responses and the left AC-GVS signals to estimate entrainment of the postural response by AC-GVS. Results: AC-GVS alone induced the periodic postural response in the yaw and roll axes, but no interactions with imagery walking were observed in Experiment 1 (p > 0.05). By contrast, combined in-phase stimulation increased yaw motion (0.345 ± 0.23) compared with sham (-0.044 ± 0.19) and anti-phase stimulation (-0.066 ± 0.18) during imaginary walking (in-phase vs. other conditions, imagery: p < 0.05; no-imagery: p ≥ 0.125). Furthermore, there was a positive correlation between the yaw peak power of actual locomotion and in-phase stimulation in the imagery session (imagery: p = 0.041; no-imagery: p = 0.177). Meanwhile, we found no imagery-dependent effects in roll peak power or PLV, although in-phase stimulation enhanced roll motion and PLV in Experiment 2. Conclusion: These findings suggest that combined stimulation can influence vestibular-cerebellar network activity, and modulate postural control and locomotion systems in a temporally sensitive manner. This novel combined tACS/AC-GVS stimulation approach may advance development of therapeutic applications.

Lesion Area in the Cerebral Cortex Determines the Patterns of Axon Rewiring of Motor and Sensory Corticospinal Tracts After Stroke.

The corticospinal tract (CST) is an essential neural pathway for reorganization that recovers motor functions after brain injuries such as stroke. CST comprises multiple pathways derived from different sensorimotor areas of the cerebral cortex; however, the patterns of reorganization in such complex pathways postinjury are largely unknown. Here we comprehensively examined the rewiring patterns of the CST pathways of multiple cerebral origins in a mouse stroke model that varied in size and location in the sensorimotor cortex. We found that spared contralesional motor and sensory CST axons crossed the midline and sprouted into the denervated side of the cervical spinal cord after stroke in a large cortical area. In contrast, the contralesional CST fibers did not sprout in a small stroke, whereas the ipsilesional axons from the spared motor area grew on the denervated side. We further showed that motor and sensory CST axons did not innervate the projecting areas mutually when either one was injured. The present results reveal the basic principles that generate the patterns of CST rewiring, which depend on stroke location and CST subtype. Our data indicate the importance of targeting different neural substrates to restore function among the types of injury.

Data-point-wise spatiotemporal mapping of human ventral visual areas: Use of spatial frequency/luminance-modulated chromatic faces.

Visual information involving facial identity and expression is crucial for social communication. Although the influence of facial features such as spatial frequency (SF) and luminance on face processing in visual areas has been studied extensively using grayscale stimuli, the combined effects of other features in this process have not been characterized. To determine the combined effects of different SFs and color, we created chromatic stimuli with low, high or no SF components, which bring distinct SF and color information into the ventral stream simultaneously. To obtain neural activity data with high spatiotemporal resolution we recorded face-selective responses (M170) using magnetoencephalography. We used a permutation test procedure with threshold-free cluster enhancement to assess statistical significance while resolving problems related to multiple comparisons and arbitrariness found in traditional statistical methods. We found that time windows with statistically significant threshold levels were distributed differently among the stimulus conditions. Face stimuli containing any SF components evoked M170 in the fusiform gyrus (FG), whereas a significant emotional effect on M170 was only observed with the original images. Low SF faces elicited larger activation of the FG and the inferior occipital gyrus than the original images, suggesting an interaction between low and high SF information processing. Interestingly, chromatic face stimuli without SF first activated color-selective regions and then the FG, indicating that facial color was processed according to a hierarchy in the ventral stream. These findings suggest complex effects of SFs in the presence of color information, reflected in M170, and unveil the detailed spatiotemporal dynamics of face processing in the human brain.

A specific phase of transcranial alternating current stimulation at the ß frequency boosts repetitive paired-pulse TMS-induced plasticity.

Transcranial alternating current stimulation (tACS) at 20 Hz (ß) has been shown to modulate motor evoked potentials (MEPs) when paired with transcranial magnetic stimulation (TMS) in a phase-dependent manner. Repetitive paired-pulse TMS (rPPS) with I-wave periodicity (1.5 ms) induced short-lived facilitation of MEPs. We hypothesized that tACS would modulate the facilitatory effects of rPPS in a frequency- and phase-dependent manner. To test our hypothesis, we investigated the effects of combined tACS and rPPS. We applied rPPS in combination with peak or trough phase tACS at 10 Hz (α) or ß, or sham tACS (rPPS alone). The facilitatory effects of rPPS in the sham condition were temporary and variable among participants. In the ß tACS peak condition, significant increases in single-pulse MEPs persisted for over 30 min after the stimulation, and this effect was stable across participants. In contrast, ß tACS in the trough condition did not modulate MEPs. Further, α tACS parameters did not affect single-pulse MEPs after the intervention. These results suggest that a rPPS-induced increase in trans-synaptic efficacy could be strengthened depending on the ß tACS phase, and that this technique could produce long-lasting plasticity with respect to cortical excitability.

Efficacy of group-based multi-component psycho-education for caregivers of people with dementia: A randomized controlled study.

AIM: The aim of this study was to examine the ability of a group-based multi-component psycho-educational intervention (GMC-PEI) to reduce depression, and improve caregiving appraisals, coping skills of informal caregivers and the condition of people with dementia. METHODS: In this randomized controlled and blinded trial, we enrolled 54 informal caregivers of people with dementia visiting the Japan National Center of Geriatrics and Gerontology, and divided them into GMC-PEI and control groups. The intervention group received a 12-week GMC-PEI program that included six 2-h structured sessions to enhance their knowledge of dementia, caregiving skills and coping skills. The control group received leaflets containing information about dementia. We evaluated caregivers' depression, caregiving time, subjective burden, caregiving appraisal and care coping skills. We also evaluated people with dementia at baseline and 12 weeks, and reassessed 20 participants from the intervention group at 24 and 48 weeks. RESULTS: The GMC-PEI significantly improved depression, positive appraisals of fulfillment in caregiving, affection for care recipients, self-growth and coping skills, such as seeking formal support. Depression, fulfillment and affection for people with dementia showed a peak improvement at 24 weeks; formal support-seeking showed a linear improvement throughout the 48-week follow-up period. CONCLUSIONS: The group-based multi-component psycho-educational intervention reduced depression, improved self-appraisal and enhanced coping skills in caregivers. However, emotional enhancements dissipated sooner than support-seeking skills, suggesting that caregivers should be reviewed every 12-24 weeks. Geriatr Gerontol Int 2021; 21: 561-567.

Unclassified four-repeat tauopathy associated with familial parkinsonism and progressive respiratory failure.

We describe an autopsied patient with familial parkinsonism and unclassified four repeat-tau (4R-tau) aggregation. She presented with bradykinesia, truncal dystonia, and mild amnesia at the age of 61 and then exhibited body weight loss (15 kg over 8 months), sleep disturbances, and progressive respiratory failure with CO2 narcosis. She died of respiratory failure at the age of 62, 14 months after disease onset. Her brother also showed parkinsonism at the age of 58 and suddenly died 6 months later. Postmortem examination revealed 4R-tau aggregation, which was characterized by neuronal globose-type tangles or pretangles, bush-like or miscellaneous astrocytic inclusions, and coiled bodies. The temporal tip, the striatum, the substantia nigra, the tegmentum of the midbrain, the medullary reticular formation, and the spinal cord were severely involved with tau aggregation. Argyrophilic grains and ballooned neurons were also found in the medial temporal structures, however, extensions of the 4R-aggregations in the case were clearly broader than those of the argyrophilic grains. Western blot analysis of sarkosyl-insoluble fractions from brain lysates revealed prominent bands of tau at both 33 kDa and 37 kDa. Genetic examinations did not reveal any known pathogenic mutations in MAPT, DCTN-1, PSEN-1, or familial or young-onset parkinsonism-related genes. The clinical manifestations, pathologic findings, and biochemical properties of aggregated tau in our patient cannot be explained by argyrophilic grain disease or other known 4R-tauopathies alone. Our results further extend the clinical and neuropathologic spectra of 4R-tauopathy.

Transcranial alternating current stimulation of α but not ß frequency sharpens multiple visual functions.

BACKGROUND: Transcranial alternating current stimulation (tACS) can entrain and enhance cortical oscillatory activity in a frequency-dependent manner. In our previous study (Nakazono et al., 2016), 20 Hz (ß) tACS significantly increased excitability of primary motor cortex compared with 10 Hz (α) tACS. α oscillations are a prominent feature of the primary visual cortex (V1) in a resting electroencephalogram. Hence, we investigated whether α and ß tACS can differentially influence multiple visual functions. METHODS: Firstly, we evaluated the after-effects of α and ß tACS on pattern-reversal (PR) and focal-flash (FF) visual evoked potentials (VEPs). Secondly, we determined the relationship between resting α oscillations and PR-VEPs modulated by tACS. Thirdly, the behavioral effects of tACS were assessed by contrast sensitivity. RESULTS: α tACS modulated the amplitudes of PR-VEPs, compared with ß tACS, but did not modulate the FF-VEPs. Time-frequency analysis revealed that α tACS facilitated event-related α phase synchronizations without increasing power, which consequently increased the PR-VEP amplitudes. There was a significant positive correlation between PR-VEP amplitudes and resting α oscillations. These findings suggested that α tACS modulated α oscillations, and affected visual functions of contrast and spatial frequency. Indeed, α tACS also improved subjects' contrast sensitivity at the behavioral level. Conversely, ß tACS increased posterior α activity, but did not change VEP amplitudes. CONCLUSIONS: α tACS can influence different neuronal populations from those influenced by ß tACS. Thus, our results provide evidence that α tACS sharpens multiple visual functions by modulating α oscillations in V1.

Electromagnetic signatures of the preclinical and prodromal stages of Alzheimer's disease.

Biomarkers useful for the predementia stages of Alzheimer's disease are needed. Electroencephalography and magnetoencephalography (MEG) are expected to provide potential biomarker candidates for evaluating the predementia stages of Alzheimer's disease. However, the physiological relevance of EEG/MEG signal changes and their role in pathophysiological processes such as amyloid-ß deposition and neurodegeneration need to be elucidated. We evaluated 28 individuals with mild cognitive impairment and 38 cognitively normal individuals, all of whom were further classified into amyloid-ß-positive mild cognitive impairment (n = 17, mean age 74.7 ± 5.4 years, nine males), amyloid-ß-negative mild cognitive impairment (n = 11, mean age 73.8 ± 8.8 years, eight males), amyloid-ß-positive cognitively normal (n = 13, mean age 71.8 ± 4.4 years, seven males), and amyloid-ß-negative cognitively normal (n = 25, mean age 72.5 ± 3.4 years, 11 males) individuals using Pittsburgh compound B-PET. We measured resting state MEG for 5 min with the eyes closed, and investigated regional spectral patterns of MEG signals using atlas-based region of interest analysis. Then, the relevance of the regional spectral patterns and their associations with pathophysiological backgrounds were analysed by integrating information from Pittsburgh compound B-PET, fluorodeoxyglucose-PET, structural MRI, and cognitive tests. The results demonstrated that regional spectral patterns of resting state activity could be separated into several types of MEG signatures as follows: (i) the effects of amyloid-ß deposition were expressed as the alpha band power augmentation in medial frontal areas; (ii) the delta band power increase in the same region was associated with disease progression within the Alzheimer's disease continuum and was correlated with entorhinal atrophy and an Alzheimer's disease-like regional decrease in glucose metabolism; and (iii) the global theta power augmentation, which was previously considered to be an Alzheimer's disease-related EEG/MEG signature, was associated with general cognitive decline and hippocampal atrophy, but was not specific to Alzheimer's disease because these changes could be observed in the absence of amyloid-ß deposition. The results suggest that these MEG signatures may be useful as unique biomarkers for the predementia stages of Alzheimer's disease.