Interactive effects of hearing aid use and cognitive function in patients with hearing loss.

BACKGROUND: There has been a significant increase in scientific investigations of the hearing-dementia association among the research on potentially modifiable risk factors for cognitive impairment. We tested two clinical questions. Analysis 1: does persistent hearing aid (HA) use decrease the decline in cognitive function caused by ageing? Analysis 2: does cognitive function at the time of HA fitting predict future persistent HA use? METHODS: This case-control study performed at two referral centres reported data obtained over a 4.5-year period. We recruited a group of patients with cognitive decline, aged 65 or older with or without hearing loss. The intervention consisted of the use of HAs. The primary outcome measures were adherence to continuous HA use and cognitive function measured using the Japanese version of the Mini-Mental State Examination Test and the Reading Cognitive Test Kyoto. RESULTS: Eighteen HA users and 18 controls were included in the first analysis. HA use was associated with a deceleration of cognitive decline 12 months later. In the second analysis, 11 participants with good adherence to HA use were compared with 12 participants who showed poor adherence to HA use. Among the variables employed in this study, cognitive function measured using the Reading Cognitive Test Kyoto was significantly lower in participants with poor adherence to HA. CONCLUSIONS: HA use in cognitively impaired individuals with hearing loss can slow age-related cognitive decline. Cognitively impaired people with hearing loss who fail to commit to HA use tend to have lower cognitive measurement scores before HA fitting. HA use is generally more challenging as people age and their cognitive abilities decline. Therefore, it is desirable that HAs be used when hearing loss and dementia are in their early stages.

Acute inhibition of AMPA receptors by perampanel reduces amyloid ß-protein levels by suppressing ß-cleavage of APP in Alzheimer's disease models.

Hippocampal hyperexcitability is a promising therapeutic target to prevent Aß deposition in AD since enhanced neuronal activity promotes presynaptic Aß production and release. This article highlights the potential application of perampanel (PER), an AMPA receptor (AMPAR) antagonist approved for partial seizures, as a therapeutic agent for AD. Using transgenic AD mice combined with in vivo brain microdialysis and primary neurons under oligomeric Aß-evoked neuronal hyperexcitability, the acute effects of PER on Aß metabolism were investigated. A single oral administration of PER rapidly decreased ISF Aß40 and Aß42 levels in the hippocampus of J20, APP transgenic mice, without affecting the Aß40 /Aß42 ratio; 5 mg/kg PER resulted in declines of 20% and 31%, respectively. Moreover, PER-treated J20 manifested a marked decrease in hippocampal APP ßCTF levels with increased FL-APP levels. Consistently, acute treatment of PER reduced sAPPß levels, a direct byproduct of ß-cleavage of APP, released to the medium in primary neuronal cultures under oligomeric Aß-induced neuronal hyperexcitability. To further evaluate the effect of PER on ISF Aß clearance, a γ-secretase inhibitor was administered to J20 1 h after PER treatment. PER did not influence the elimination of ISF Aß, indicating that the acute effect of PER is predominantly on Aß production. In conclusion, acute treatment of PER reduces Aß production by suppressing ß-cleavage of amyloid-ß precursor protein effectively, indicating a potential effect of PER against Aß pathology in AD.

[Non-convulsive status epilepticus manifesting as ictal catatonia: a case report].

A 66 year-old right-handed female was admitted to our hospital presenting with recurrent episodes of catatonic symptoms consisting of stupor, waxy flexibility, and catalepsy lasting about 5-20 minutes. A brain MRI showed no significant abnormalities. An scalp-electroencephalography (EEG) concurrent with the symptoms showed ictal EEG activities arising from the left fronto-central area, which evolved into the bilateral frontal and bilateral parietal areas together. An 18F-fluorodeoxy glucose positron emission tomography (18F-FDG-PET) 4 days after improvement of the symptoms showed hypermetabolism in the bilateral frontal and parietal lobes. Her catatonic symptoms are assumed to be due to non-convulsive status epilepticus (NCSE), namely ictal catatonia. The introduction of several anti-epileptic drugs improved the symptoms and normalized the EEG and FDG-PET findings. NCSE must be considered as one of the underlying state of catatonic symptoms because the treatment plan for acute and chronic state is different from that of catatonic syndrome due to psychiatric disorders.

Synaptic Vesicle Protein 2B Negatively Regulates the Amyloidogenic Processing of AßPP as a Novel Interaction Partner of BACE1.

BACKGROUND: Given that amyloid-ß (Aß) peptide is produced and released at synapses, synaptic Aß is one of the promising therapeutic targets to prevent synaptic dysfunction in Alzheimer's disease (AD). Although Aß production begins with the cleavage of the amyloid-ß protein precursor (AßPP) by ß-site AßPP cleaving enzyme 1 (BACE1), the mechanism on how BACE1 is involved in AßPP processing at synapses remains unclear. OBJECTIVE: This study aimed to identify novel BACE1 interacting proteins regulating Aß production at the synapse. METHODS: BACE1 interacting proteins were pulled down using a mass spectrometry-based proteomics of wild-type (WT) rat brain synaptoneurosome lysates utilizing anti-BACE1 antibody. Then, a novel BACE1 interactor was identified and characterized using experimental systems that utilized transfected cells and knockout (KO) mice. RESULTS: Synaptic vesicle protein 2B (SV2B) was identified as a novel presynaptic interaction partner of BACE1. In HEK293 cells, co-overexpression of SV2B with BACE1 significantly reduced the sAßPPß and Aß levels released in the media; thus, SV2B overexpression negatively affected the AßPP cleavage by BACE1. Compared with those of WT mice, the hippocampal lysates of SV2B knockout mice had significantly elevated Aß levels, whereas the ß-secretase activity and the AßPP and BACE1 protein levels remained unchanged. Finally, a fractionation assay revealed that BACE1 was mislocalized in SV2B KO mice; hence, SV2B may be involved in BACE1 trafficking downregulating the amyloidogenic pathway of AßPP. CONCLUSION: SV2B has a novel role of negatively regulating the amyloidogenic processing of AßPP at the presynapses.

Development of the Reading Cognitive Test Kyoto (ReaCT Kyoto) for Early Detection of Cognitive Decline in Patients with Hearing Loss.

BACKGROUND: Early detection of cognitive decline allows timely intervention to delay progression of dementia. However, current cognitive evaluation tools often include items delivered via verbal forms of instruction, which can cause poor performance in patients with hearing loss. OBJECTIVE: To develop and validate a cognitive screening battery, the Reading Cognitive Test Kyoto (ReaCT Kyoto), comprising test items given through non-verbal instruction. METHODS: A cross-sectional and multi-center study was conducted in the three medical institutes. ReaCT Kyoto was designed to evaluate domains of "registration," "repetition," "delayed recall," "visuospatial recognition," "orientation in time and place," and "executive function." The Japanese version of the Mini-Mental State Examination Test (MMSE-J) and ReaCT Kyoto were applied by experienced psychotherapists. Concurrent validity was evaluated between the ReaCT Kyoto Test and MMSE-J and between the ReaCT Kyoto Test and physician-diagnosed dementia. RESULTS: ReaCT Kyoto was validated in a sample of 115 participants. The mean age of subjects was 81.0±6.4 years, and the sample comprised 53.0% females. The area under the receiver operating curves was 0.95 for detecting physician-diagnosed dementia. When classifying patients in accordance with presence or absence of hearing loss, the AUCs were 0.93 and 0.97 for those with and without hearing loss, respectively. With a cut-off score of < 29 points for suspected dementia, ReaCT Kyoto correctly classified 90.4% of the subjects as belonging to the group with or without physician-diagnosed dementia. CONCLUSION: ReaCT Kyoto provides an appropriate solution for detection of cognitive impairment in persons with or without hearing loss.

Two-Point Dynamic Observation of Alzheimer's Disease Cerebrospinal Fluid Biomarkers in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Extensive research into cerebrospinal fluid (CSF) biomarkers was performed in patients with idiopathic normal pressure hydrocephalus (iNPH). Most prior research into CSF biomarkers has been one-point observation. OBJECTIVE: To investigate dynamic changes in CSF biomarkers during routine tap test in iNPH patients. METHODS: We analyzed CSF concentrations of tau, amyloid-ß (Aß) 42 and 40, and leucine rich α-2-glycoprotein (LRG) in 88 consecutive potential iNPH patients who received a tap test. We collected two-point lumbar CSF separately at the first 1 ml (First Drip (FD)) and at the last 1 ml (Last Drip (LD)) during the tap test and 9 patients who went on to receive ventriculo-peritoneal shunt surgery each provided 1 ml of ventricular CSF (VCSF). RESULTS: Tau concentrations were significantly elevated in LD and VCSF compared to FD (LD/FD = 1.22, p = 0.003, VCSF/FD = 2.76, p = 0.02). Conversely, Aß42 (LD/FD = 0.80, p < 0.001, VCSF/FD = 0.38, p = 0.03) and LRG (LD/FD = 0.74, p < 0.001, VCSF/FD = 0.09, p = 0.002) concentrations were significantly reduced in LD and VCSF compared to FD. Gait responses to the tap test and changes in cognitive function in response to shunt were closely associated with LD concentrations of tau (p = 0.02) and LRG (p = 0.04), respectively. CONCLUSIONS: Dynamic changes were different among the measured CSF biomarkers, suggesting that LD of CSF as sampled during the tap test reflects an aspect of VCSF contributing to the pathophysiology of iNPH and could be used to predict shunt effectiveness.

Increase in direct social care costs of Alzheimer's disease in Japan depending on dementia severity.

AIM: With the aging population, costs of direct social support for patients with Alzheimer's disease have grown and will continue to increase. The purpose of the present study was to estimate the cost of direct social support for Alzheimer's disease under long-term care insurance in Japan. METHODS: This cross-sectional study included 169 patients with Alzheimer's disease or mild cognitive impairment who visited a memory clinic and were followed over time. Dementia severity, use of care services and costs were analyzed. RESULTS: The use of direct social support and costs increased significantly between patients with mild, moderate and severe dementia (P < 0.001). In particular, the use of day services and short stay services increased with the severity of dementia (P < 0.001). Similar findings were obtained when participants were stratified by long-term care insurance care levels. Of 169 participants, 49 had not applied for long-term care insurance, although their dementia severity was not different from support-need level 1 and care-need level 1. Logistic regression analysis of "did not apply" and "applied and certified" groups showed significant differences not only in dementia severity, but also in age (odds ratio 1.112, 95% confidence interval 1.037-1.193, P = 0.003) and living arrangements (odds ratio 0.257, 95% confidence interval 0.076-0.862, P = 0.028). CONCLUSIONS: As the number of patients with Alzheimer's disease increases, direct social costs will increase. The findings of this study might help standardize the type of direct social support provided after diagnosis of Alzheimer's disease and contribute to the development of cost-effective care for these patients. Geriatr Gerontol Int 2019; 19: 1023-1029.

Hashimoto's Encephalopathy Presenting with Smoldering Limbic Encephalitis.

Hashimoto's encephalopathy (HE) is a steroid-responsive autoimmune encephalopathy associated with Hashimoto thyroiditis. We herein report a case of HE manifesting "smoldering" limbic encephalitis with persisting symptoms and abnormalities on examinations. Although our patient experienced partial clinical remission after treatment, hippocampal hypermetabolism on [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) and subclinical seizures on video electroencephalography persisted. Hypermetabolism on FDG-PET was improved by additional prednisolone therapy. Thus, as with other autoimmune limbic encephalitis cases, HE can take a course of "smoldering" encephalitis. FDG-PET and electroencephalogram findings can reflect the disease activity degree in such patients, although with certain neurophysiological and biochemical distinctions.

[An adult female with proline-rich transmembrane protein 2 related paroxysmal disorders manifesting paroxysmal kinesigenic choreoathetosis and epileptic seizures].

A 21-year-old woman presented with a chief complaint of generalized tonic-clonic seizures occurring once a month at night since the age of 14. The patient was treated with clonazepam plus levetiracetam, but seizure frequency was not reduced. After the detailed re-examination of her history of illness, it was revealed that she has been suffering from transient and recurrent choreoathetoid attacks triggered by sudden voluntary movements since she was a junior high school student, and it recently increased in frequency. Neither she nor her family recognize that it was significant to describe to the doctors. She was diagnosed as a complex of paroxysmal kinesigenic choreoathetosis (PKC) and its related conditions. Direct sequencing of proline-rich transmembrane protein 2 (PRRT2) revealed the most frequently described gene mutation, (NM_145239.2:c.649dupC), among PRRT2-related paroxysmal disorders. PKC and seizures were readily controlled with small dose of carbamazepine. Given the broad spectrum of PRRT2-related paroxysmal disorders, assessment of potential clinical complication of paroxysmal disorders including PKC might therefore be critical.

A comparative study: visual rating scores and the voxel-based specific regional analysis system for Alzheimer's disease on magnetic resonance imaging among subjects with Alzheimer's disease, mild cognitive impairment, and normal cognition.

AIM: Hippocampal atrophy shown on magnetic resonance imaging can differentiate Alzheimer's disease (AD) patients from subjects with normal cognition (NC). Simplified automated methods that use volumetric analysis, such as as the voxel-based specific regional analysis system for AD, have become widely used in Japan. However, the diagnostic value of the voxel-based specific regional analysis system compared with visual rating scores for clinical diagnosis is unclear. METHODS: Study participants consisted of 37 AD patients, 29 mild cognitive impairment (MCI) patients, and 21 NC subjects. All participants underwent neuropsychological testing and magnetic resonance imaging. The imaging was scored visually for regional brain atrophy by two raters based on a newly developed visual rating score. The voxel-based specific regional analysis system for AD scores were calculated with the analysis system's advanced software. We analyzed whether these scores aid in discriminating among AD, MCI, and NC. RESULTS: The AD group had significantly different visual rating scores, regional analysis scores, and all neuropsychological test scores than the NC group. The AD group had significantly different visual rating scores than the MCI group, and a significant difference was observed between the MCI and NC groups on regional analysis scores. Both the visual rating and regional analysis scores showed equivalent correlations with the neuropsychological test scores. CONCLUSIONS: Both the visual rating and regional analysis scores are clinically useful tools for differentiating among AD, MCI, and NC.

Fibronectin type III domain-containing protein 5 interacts with APP and decreases amyloid ß production in Alzheimer's disease.

The deposition of Amyloid-beta peptides (Aß) is detected at an earlier stage in Alzheimer's disease (AD) pathology. Thus, the approach toward Aß metabolism is considered to play a critical role in the onset and progression of AD. Mounting evidence suggests that lifestyle-related diseases are closely associated with AD, and exercise is especially linked to the prevention and the delayed progression of AD. We previously showed that exercise is more effective than diet control against Aß pathology and cognitive deficit in AD mice fed a high-fat diet; however, the underlying molecular mechanisms remain poorly understood. On the other hand, a report suggested that exercise induced expression of fibronectin type III domain-containing protein 5 (FNDC5) in the hippocampus of mice through PGC1α pathway. Thus, in the current study, we investigated a possibility that FNDC5 interacts with amyloid precursor protein (APP) and affects Aß metabolism. As a result, for the first time ever, we found the interaction between FNDC5 and APP, and forced expression of FNDC5 significantly decreased levels of both Aß40 and Aß42 secreted in the media. Taken together, our results indicate that FNDC5 significantly affects ß-cleavage of APP via the interaction with APP, finally regulating Aß levels. A deeper understanding of the mechanisms by which the interaction between APP and FNDC5 may affect Aß production in an exercise-dependent manner would provide new preventive strategies against the development of AD.

Degradation of amyloid ß peptide by neprilysin expressed from Borna disease virus vector.

Accumulation of amyloid ß (Aß40 and Aß42) in the brain is a characteristic of Alzheimer's disease (AD). Because neprilysin (NEP) is a major Aß-degrading enzyme, NEP delivery in the brain is a promising gene therapy for AD. Borna disease virus (BoDV) vector enables long-term transduction of foreign genes in the central nerve system. Here, we evaluated the proteolytic ability of NEP transduced by the BoDV vector and found that the amounts of Aß40 and Aß42 significantly decreased, which suggests that NEP expressed from the BoDV vector is functional to degrade Aß.

An acute functional screen identifies an effective antibody targeting amyloid-ß oligomers based on calcium imaging.

Soluble amyloid ß oligomers (AßOs) are widely recognized neurotoxins that trigger aberrant signaling in specific subsets of neurons, leading to accumulated neuronal damage and memory disorders in Alzheimer's disease (AD). One of the profound downstream consequences of AßO-triggered events is dysregulation of cytosolic calcium concentration ([Ca2+]i), which has been implicated in synaptic failure, cytoskeletal abnormalities, and eventually neuronal death. We have developed an in vitro/in vivo drug screening assay to evaluate putative AßO-blocking candidates by measuring AßO-induced real-time changes in [Ca2+]i. Our screening assay demonstrated that the anti-AßO monoclonal antibody ACU3B3 exhibits potent blocking capability against a broad size range of AßOs. We showed that picomolar concentrations of AßOs were capable of increasing [Ca2+]i in primary neuronal cultures, an effect prevented by ACU3B3. Topical application of 5 nM AßOs onto exposed cortical surfaces also elicited significant calcium elevations in vivo, which was completely abolished by pre-treatment of the brain with 1 ng/mL (6.67 pM) ACU3B3. Our results provide strong support for the utility of this functional screening assay in identifying and confirming the efficacy of AßO-blocking drug candidates such as the human homolog of ACU3B3, which may emerge as the first experimental AD therapeutic to validate the amyloid oligomer hypothesis.

Identification of the novel activity-driven interaction between synaptotagmin 1 and presenilin 1 links calcium, synapse, and amyloid beta.

BACKGROUND: Synaptic loss strongly correlates with memory deterioration. Local accumulation of amyloid ß (Aß) peptide, and neurotoxic Aß42 in particular, due to abnormal neuronal activity may underlie synaptic dysfunction, neurodegeneration, and memory impairments. To gain an insight into molecular events underlying neuronal activity-regulated Aß production at the synapse, we explored functional outcomes of the newly discovered calcium-dependent interaction between Alzheimer's disease-associated presenilin 1 (PS1)/γ-secretase and synaptic vesicle proteins. RESULTS: Mass spectrometry screen of mouse brain lysates identified synaptotagmin 1 (Syt1) as a novel synapse-specific PS1-binding partner that shows Ca(2+)-dependent PS1 binding profiles in vitro and in vivo. We found that Aß level, and more critically, conformation of the PS1 and the Aß42/40 ratio, are affected by Syt1 overexpression or knockdown, indicating that Syt1 and its interaction with PS1 might regulate Aß production at the synapse. Moreover, ß-secretase 1 (BACE1) stability, ß- and γ-secretase activity, as well as intracellular compartmentalization of PS1 and BACE1, but not of amyloid precursor protein (APP), nicastrin (Nct), presenilin enhancer 2 (Pen-2), or synaptophysin (Syp) were altered in the absence of Syt1, suggesting a selective effect of Syt1 on PS1 and BACE1 trafficking. CONCLUSIONS: Our findings identify Syt1 as a novel Ca(2+)-sensitive PS1 modulator that could regulate synaptic Aß, opening avenues for novel and selective synapse targeting therapeutic strategies.

Exercise is more effective than diet control in preventing high fat diet-induced ß-amyloid deposition and memory deficit in amyloid precursor protein transgenic mice.

Accumulating evidence suggests that some dietary patterns, specifically high fat diet (HFD), increase the risk of developing sporadic Alzheimer disease (AD). Thus, interventions targeting HFD-induced metabolic dysfunctions may be effective in preventing the development of AD. We previously demonstrated that amyloid precursor protein (APP)-overexpressing transgenic mice fed HFD showed worsening of cognitive function when compared with control APP mice on normal diet. Moreover, we reported that voluntary exercise ameliorates HFD-induced memory impairment and ß-amyloid (Aß) deposition. In the present study, we conducted diet control to ameliorate the metabolic abnormality caused by HFD on APP transgenic mice and compared the effect of diet control on cognitive function with that of voluntary exercise as well as that of combined (diet control plus exercise) treatment. Surprisingly, we found that exercise was more effective than diet control, although both exercise and diet control ameliorated HFD-induced memory deficit and Aß deposition. The production of Aß was not different between the exercise- and the diet control-treated mice. On the other hand, exercise specifically strengthened the activity of neprilysin, the Aß-degrading enzyme, the level of which was significantly correlated with that of deposited Aß in our mice. Notably, the effect of the combination treatment (exercise and diet control) on memory and amyloid pathology was not significantly different from that of exercise alone. These studies provide solid evidence that exercise is a useful intervention to rescue HFD-induced aggravation of cognitive decline in transgenic model mice of AD.

Gain of function by phosphorylation in Presenilin 1-mediated regulation of insulin signaling.

We have recently reported that Presenilin 1 (PS1), a causative gene of familial Alzheimer disease (AD), down-regulates the expression level of insulin receptor (IR) as well as its signaling through a γ-secretase-independent pathway. PS1 is phosphorylated by glycogen synthase kinase 3 ß at the serine 353 and 357 residues. The main purpose of the present study was to clarify the effect of PS1 phosphorylation on IR/insulin signaling. Here, we demonstrate that the pseudo-phosphorylation mutant of PS1 inhibited IR transcription and reduced IR expression compared with wild-type PS1. Importantly, there was a decrease in expression of IR in AD brains, and the phosphorylation ratio of PS1 was negatively correlated with IR level in human brain samples. In the data from mouse models of AD, IR reduction was not observed at the pre-Aß deposition stage but became apparent in that of post-Aß deposition. Together with our previous reports, these results suggest that phosphorylated PS1 can promote the down-regulation of insulin signaling, which may be a positive feed-forward mechanism inhibiting insulin signaling. As insulin resistance is reported to be a risk factor for sporadic AD, this PS1-mediated regulatory mechanism of brain insulin signaling may be causally associated with AD pathology.

Environmental enrichment ameliorated high-fat diet-induced Aß deposition and memory deficit in APP transgenic mice.

The pathogenesis of Alzheimer's disease (AD) is tightly associated with metabolic dysfunctions. In particular, a potential link between type 2 diabetes (T2DM) and AD has been suggested epidemiologically, clinically, and experimentally, and some studies have suggested that exercise or dietary intervention reduces risk of cognitive decline. However, there is little solid molecular evidence for the effective intervention of metabolic dysfunctions for prevention of AD. In the present study, we established the AD model mice with diabetic conditions through high-fat diet (HFD) to examine the effect of environmental enrichment (EE) on HFD-induced AD pathophysiology. Here, we demonstrated that HFD markedly deteriorated memory impairment and increased ß-amyloid (Aß) oligomers as well as Aß deposition in amyloid precursor protein (APP) transgenic mice, which was reversed by exposure to an enriched environment for 10 weeks, despite the continuation of HFD. These studies provide solid evidence that EE is a useful intervention to ameliorate behavioral changes and AD pathology in HFD-induced aggravation of AD symptoms in APP transgenic mice.