Soluble APP-α and APP-ß in cerebrospinal fluid as potential biomarkers for differential diagnosis of mild cognitive impairment.

OBJECTIVES: Concentrations of soluble amyloid precursor proteins-α (sAPPα) and -ß (sAPPß) in cerebrospinal fluid (CSF) may reflect the neuropathology of Alzheimer's disease (AD). We previously reported that the concentrations of both sAPPα and sAPPß were significantly higher in patients with mild cognitive impairment (MCI) due to AD (MCI-AD) than in control subjects without cognitive impairment. The present study analyzed whether these sAPPs are useful in the differential diagnosis of MCI. METHODS: A modified and sensitive method was used to analyze concentrations of sAPPα and sAPPß in CSF of patients with MCI-AD (n = 30) and MCI due to other causes (MCI-others) (n = 24). Phosphorylated tau (p-tau) and amyloid ß-protein 42 (Aß42) were also analyzed using standard methods. RESULTS: CSF concentrations of sAPPα and sAPPß were significantly higher in the MCI-AD than in the MCI-others group (p < 0.001). Furthermore, concentrations of both sAPPα and sAPPß were highly correlated with the concentration of p-tau, consistent with our previous report. CONCLUSIONS: Measurement of both sAPPs in CSF using sensitive methods can be helpful in the precise differential diagnosis of patients with MCI.

Discrete effect of each mild behavioural impairment category on dementia conversion or cognitive decline in patients with mild cognitive impairment.

BACKGROUND: Neuropsychiatric symptoms (NPS) have been recognized as risk factors for conversion to dementia in patients with mild cognitive impairment (MCI). Early detection of NPS may allow for possible interventions in such patients. The present study used mild behavioural impairment to explore the role of NPS in a wide range of patients, from those who are cognitively intact to those with dementia. METHODS: A total of 234 patients with mild cognitive impairment were followed up for up to 3 years in a Japanese cohort study. Longitudinal data from patients who developed dementia during the study and those who did not were statistically analyzed. RESULTS: Cox regression analysis revealed that only abnormal perception and thought was significant in terms of dementia conversion. Moreover, mixed-effects models indicated that baseline mild behavioural impairment symptoms did not affect cognitive trajectories such as changes in Mini-Mental State Examination or Alzheimer's Disease Assessment Scale-cognitive subscale scores. CONCLUSION: We conclude that only abnormal perception and thought content were risk factors for dementia and that NPS may not lead to deterioration of cognitive function in patients with mild cognitive impairment.

Does improvement of cognitive functioning by cognitive remediation therapy effect work outcomes in severe mental illness? A secondary analysis of a randomized controlled trial.

AIM: The aim of this study was to clarify whether improvement of cognitive functioning by cognitive remediation therapy can improve work outcome in schizophrenia and other severe mental illnesses when combined with supported employment. METHODS: The subjects of this study were persons with severe mental illness diagnosed with schizophrenia, major depression, or bipolar disorder (ICD-10) and cognitive dysfunction who participated in both cognitive remediation using the Thinking Skills for Work program and a supported employment program in a multisite, randomized controlled study. Logistic and multiple linear regression analyses were performed to clarify the influence of cognitive functioning on vocational outcomes, adjusting for demographic and clinical variables. RESULTS: Improvement of cognitive functioning with cognitive remediation significantly contributed to the total days employed and total earnings of competitive employment in supported employment service during the study period. Any baseline demographic and clinical variables did not significantly contribute to the work-related outcomes. CONCLUSION: A cognitive remediation program transferring learning skills into the real world is useful to increase the quality of working life in supported employment services for persons with severe mental illness and cognitive dysfunction who want to work competitively.

Clinical impact of (11)C-Pittsburgh compound-B positron emission tomography carried out in addition to magnetic resonance imaging and single-photon emission computed tomography on the diagnosis of Alzheimer's disease in patients with dementia and mild cognitive impairment.

AIMS: The purpose of this study was to evaluate the clinical impact of addition of [(11)C]Pittsburgh compound-B positron emission tomography ((11)C-PiB PET) on routine clinical diagnosis of Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI), and to assess diagnostic agreement between clinical criteria and research criteria of the National Institute on Aging-Alzheimer's Association. METHODS: The diagnosis in 85 patients was made according to clinical criteria. Imaging examinations, including both magnetic resonance imaging and single-photon emission computed tomography/computed tomography to identify neuronal injury (NI), and (11)C-PiB PET to identify amyloid were performed, and all subjects were re-categorized according to the research criteria. RESULTS: Among 40 patients with probable AD dementia (ProAD), 37 were NI-positive, 29 were (11)C-PiB-positive, and 27 who were both NI- and (11C-PiB-positive were categorized as having 'ProAD dementia with a high level of evidence of the AD pathophysiological process'. Among 20 patients with possible AD dementia (PosAD), 17 were NI-positive, and six who were both NI- and (11)C-PiB-positive were categorized as having 'PosAD with evidence of the AD pathophysiological process'. Among 25 patients with MCI, 18 were NI-positive, 13 were (11)C-PiB-positive, and 10 who were both NI- and (11)C-PiB-positive were categorized as having 'MCI due to AD-high likelihood'. CONCLUSIONS: Diagnostic concordance between clinical criteria and research criteria may not be high in this study. (11)C-PiB PET may be of value in making the diagnosis of dementia and MCI in cases with high diagnostic uncertainty.

[The therapeutic structure and clinical staff skills that is needed for establishing the community-based treatment of the people with schizophrenia: the short report of recent reform process of "day care" and outreach team in National Center of Neurology and Psychiatry].

As aging and disease structure has changed mainly in accordance with adult disease, general medical treatment has been expected to take a role as a part of the"Comprehensive Care" that contributes to improve the quality of life. The similar paradigm change is needed for the treatment for the people with severe mental illness. The goal of this change is to realize the dissemination of prevention, early intervention, and comprehensive treatment in the community for the people with severe mental illness. The challenge for this change is reform on traditional structure of hospital based treatment and immaturity of staff skill. This article discuss the recent reforms of "Day care" and outreach team in National Center of Neurology and Psychiatry, focusing on these system-wide change and improvement of clinical skills of the staff. The key points of reforms are summarized as follows: (1) strongly focusing on the consumers' needs in their daily life, (2) establishing case management by the mental health staff, and (3) transforming the hierarchy system from in which psychiatrists are at the top of the multidisciplinary team to in which all staff are as equal members of the team. Some areas for necessary improvement required for the future are indicated in the end of this article.

Assessment of Gray Matter Microstructural Alterations in Alzheimer's Disease by Free Water Imaging.

Background: Cortical neurodegenerative processes may precede the emergence of disease symptoms in patients with Alzheimer's disease (AD) by many years. No study has evaluated the free water of patients with AD using gray matter-based spatial statistics. Objective: The aim of this study was to explore cortical microstructural changes within the gray matter in AD by using free water imaging with gray matter-based spatial statistics. Methods: Seventy-one participants underwent multi-shell diffusion magnetic resonance imaging, 11C-Pittsburgh compound B positron emission tomography, and neuropsychological evaluations. The patients were divided into two groups: healthy controls (n = 40) and the AD spectrum group (n = 31). Differences between the groups were analyzed using voxel-based morphometry, diffusion tensor imaging, and free water imaging with gray matter-based spatial statistics. Results: Voxel-based morphometry analysis revealed gray matter volume loss in the hippocampus of patients with AD spectrum compared to that in controls. Furthermore, patients with AD spectrum exhibited significantly greater free water, mean diffusivity, and radial diffusivity in the limbic areas, precuneus, frontal lobe, temporal lobe, right putamen, and cerebellum than did the healthy controls. Overall, the effect sizes of free water were greater than those of mean diffusivity and radial diffusivity, and the larger effect sizes of free water were thought to be strongly correlated with AD pathology. Conclusions: This study demonstrates the utility of applying voxel-based morphometry, gray matter-based spatial statistics, free water imaging and diffusion tensor imaging to assess AD pathology and detect changes in gray matter.

Combination of Astrogliosis and Phosphorylated Tau for the Preclinical Diagnosis of Alzheimer Disease Using 3-Dimensional Stereotactic Surface Projection Images With 18 F-THK5351.

ABSTRACT: The Alzheimer disease (AD) brain is characterized microscopically by the presence of extracellular amyloid plaques and intraneuronal neurofibrillary tangles consisting of phosphorylated tau aggregations. 18 F-THK5351 is a first-generation PET tau tracer that also binds to monoamine oxidase B, which represents astrogliosis, and is useful to evaluate some non-AD neurodegenerative disorders. We examined the utility of 18 F-THK5351 in preclinical AD using 3-dimensional stereotactic surface projection images optimized for its pathological accumulation by comparison with a normal dataset. By using this 18 F-THK5351 3-dimensional stereotactic surface projection procedure, which can evaluate phosphorylated tau and neuroinflammation, we could diagnose preclinical AD effectively.

Free water derived by multi-shell diffusion MRI reflects tau/neuroinflammatory pathology in Alzheimer's disease.

Introduction: Free-water (FW) imaging, a new analysis method for diffusion magnetic resonance imaging (MRI), can indicate neuroinflammation and degeneration. We evaluated FW in Alzheimer's disease (AD) using tau/inflammatory and amyloid positron emission tomography (PET). Methods: Seventy-one participants underwent multi-shell diffusion MRI, 18F-THK5351 PET, 11C-Pittsburgh compound B PET, and neuropsychological assessments. They were categorized into two groups: healthy controls (HCs) (n = 40) and AD-spectrum group (AD-S) (n = 31) using the Centiloid scale with amyloid PET and cognitive function. We analyzed group comparisons in FW and PET, correlations between FW and PET, and correlation analysis with neuropsychological scores. Results: In AD-S group, there was a significant positive correlation between FW and 18F-THK5351 in the temporal lobes. In addition, there were negative correlations between FW and cognitive function in the temporal lobe and cingulate gyrus, and negative correlations between 18F-THK5351 and cognitive function in the same regions. Discussion: FW imaging could be a biomarker for tau in AD alongside clinical correlations.

Effects of multisession transcranial direct current stimulation as an augmentation to cognitive tasks in patients with neurocognitive disorders in Japan: a study protocol for a randomised controlled trial.

INTRODUCTION: Transcranial direct current stimulation (tDCS) is a potentially novel strategy for cognitive enhancement in patients with disorders. We present a study protocol for a randomised controlled trial designed to evaluate the safety and efficacy of tDCS combined with cognitive tasks on cognition in such patients. METHOD AND ANALYSIS: This is a two-arm, parallel-design, randomised, sham-controlled trial, in which participants and raters will be blinded at a single centre. Stratified randomisation will be conducted, and a randomisation sequence will be generated through the Electronic Data Capture system. Patients who met the Diagnostic and Statistical Manual of Mental Disorders-5 criteria for neurocognitive disorders will be recruited and randomised to receive either active (2 mA for 20 min) or sham (stimulation ramped up and down for 1 min) stimulation in 10 sessions over five consecutive days. A direct current will be transferred by a 35 cm2 saline-soaked sponge electrode. An anode will be placed over the left dorsolateral prefrontal cortex, and a cathode will be placed over the right supraorbital cortex. Calculation tasks will be conducted in both arms as a cognitive task for 20 min during the stimulation. This task consists of basic arithmetic questions, such as single-digit addition, subtraction, multiplication and division. The primary outcome will be the mean change in the Alzheimer Disease Assessment Scale-cognition at Day 5 after baseline. Depressive symptoms, as measured by the geriatric depression scale, and quality of life, as measured by the Medical Outcomes Study 36-item Short-Form Health Survey, will also be assessed. Data will be collected at baseline, within 3 days following the final stimulation and 1 month thereafter. The estimated sample size is 46 per group based on the assumptions that an estimated mean difference is -1.61 and SD is 2.7. Mixed models for repeated measures will be used for the statistical analysis. ETHICS AND DISSEMINATION: The National Center of Neurology and the Psychiatry Clinical Research Review Board (CRB3180006) approved this study. The results of this study will be published in a scientific peer-reviewed journal. TRIAL REGISTRATION DETAILS: Japan Registry of Clinical Trials jRCTs032180016.

Association of deposition of tau and amyloid-ß proteins with structural connectivity changes in cognitively normal older adults and Alzheimer's disease spectrum patients.

INTRODUCTION: Alzheimer's disease (AD) is characterized by accumulation of extracellular amyloid-ß and intracellular tau neurofibrillary tangles. The recent advent of tau positron emission tomography (PET) has enabled in vivo assessment of tau pathology. The aim of this study was to explore whether tau deposition influences the structural connectivity in amyloid-negative and amyloid-positive groups, and further explore the difference between the groups. METHODS: We investigated 18 patients with amnestic mild cognitive impairment/mild AD (AD-spectrum group) and 35 cognitively normal older adults (CN group) using diffusion MRI, amyloid, and tau PET imaging. Diffusion connectometry was performed to identify white matter pathways correlated with each of the six variables of tau deposition in the bilateral hippocampi, temporal lobes, posterior and anterior cingulate cortices, precunei, orbitofrontal lobes, and entire cerebrum. RESULTS: The CN group showed increased connectivity along with an increased tau deposition in the bilateral hippocampi, temporal lobes, and entire cerebrum, whereas the AD-spectrum group showed decreased connectivity in the bilateral hippocampi, temporal lobes, anterior and posterior cingulate cortices, precunei, and entire cerebrum. CONCLUSION: These findings suggest that tau deposition in the CN group seems to induce a compensatory response against early neuronal injury or chronic inflammation associated with normal aging, whereas the coexistence of amyloid and tau in the AD-spectrum group seems to outweigh the compensatory response leading to decreased connectivity, suggesting that amyloid plays a crucial role in alternating structural connectivity.

Dissociation of Tau Deposits and Brain Atrophy in Early Alzheimer's Disease: A Combined Positron Emission Tomography/Magnetic Resonance Imaging Study.

The recent advent of tau-specific positron emission tomography (PET) has enabled in vivo assessment of tau pathology in Alzheimer's disease (AD). However, because PET scanners have limited spatial resolution, the measured signals of small brain structures or atrophied areas are underestimated by partial volume effects (PVEs). The aim of this study was to determine whether partial volume correction (PVC) improves the precision of measures of tau deposits in early AD. We investigated tau deposits in 18 patients with amyloid-positive early AD and in 36 amyloid-negative healthy controls using 18F-THK5351 PET. For PVC, we applied the SPM toolbox PETPVE12. The PET images were then spatially normalized and subjected to voxel-based group analysis using SPM12 for comparison between the early AD patients and healthy controls. We also compared these two groups in terms of brain atrophy using voxel-based morphometry of MRI. We found widespread neocortical tracer retention predominantly in the posterior cingulate and precuneus areas, but also in the inferior temporal lobes, inferior parietal lobes, frontal lobes, and occipital lobes in the AD patients compared with the controls. The pattern of tracer retention was similar between before and after PVC, suggesting that PVC had little effect on the precision of tau load measures. Gray matter atrophy was detected in the medial/lateral temporal lobes and basal frontal lobes in the AD patients. Interestingly, only a few associations were found between atrophy and tau deposits, even after PVC. In conclusion, PVC did not significantly affect 18F-THK5351 PET measures of tau deposits. This discrepancy between tau deposits and atrophy suggests that tau load precedes atrophy.

Regional tau deposition and subregion atrophy of medial temporal structures in early Alzheimer's disease: A combined positron emission tomography/magnetic resonance imaging study.

INTRODUCTION: Molecular imaging and selective hippocampal subfield atrophy are a focus of recent Alzheimer's disease (AD) research. Here, we investigated correlations between molecular imaging and hippocampal subfields in early AD. METHODS: We investigated 18 patients with early AD and 18 healthy control subjects using 11C-Pittsburgh compound-B (PIB) positron emission tomography (PET) and 18F-THK5351 PET and automatic segmentation of hippocampal subfields with high-resolution T2-weighted magnetic resonance imaging. The PET images were normalized and underwent voxelwise regression analysis with each subregion volumes using SPM12. RESULTS: As for 18F-THK5351 PET, the bilateral perirhinal cortex volumes were significantly associated with the ipsilateral or bilateral temporal lobar uptakes, whereas hippocampal subfields showed no correlations. 11C-PIB PET showed relatively broad negative correlation with the right cornu ammonis 3 volumes. DISCUSSION: Regional tau deposition was correlated with extrahippocampal subregional atrophy and not with hippocampal subfields, possibly reflecting different underlying mechanisms of atrophy in early AD. Amyloid might be associated with right cornu ammonis 3 atrophy.

Efficacy of a Peer-Led, Recovery-Oriented Shared Decision-Making System: A Pilot Randomized Controlled Trial.

OBJECTIVE: The effects of a comprehensive shared decision-making system based on the CommonGround approach and incorporating peer support and a computerized decision aid were investigated. METHODS: A pilot randomized controlled trial with six-month follow-up was conducted in Japan. Fifty-six outpatients with mental illness were randomly allocated to a shared decision-making system (intervention) group or treatment as usual (control) group. The implementation process and several outcomes were compared between groups. RESULTS: The core components and processes of shared decision making were observed in the intervention group more frequently than in the control group. The intervention group also reported a significantly more positive participants' view of the relationship with their doctor than the control group. The intervention did not have a significant effect on most clinical and recovery-related outcomes. CONCLUSIONS: The shared decision-making system appeared to partly improve patients' perceptions of communication and relationships with doctors but did not have a significant effect on other patient-level outcomes.

Re-evaluation of soluble APP-α and APP-ß in cerebrospinal fluid as potential biomarkers for early diagnosis of dementia disorders.

BACKGROUND: Because soluble (or secreted) amyloid precursor protein-ß (sAPPß) and -α (sAPPα) possibly reflect pathological features of Alzheimer's disease (AD), they are potential biomarker candidates for dementia disorders, including AD and mild cognitive impairment (MCI) due to AD (MCI-AD). However, controversial results have been reported regarding their alterations in the cerebrospinal fluid (CSF) of AD and MCI-AD patients. In this study, we re-assessed the utility of sAPPα and sAPPß in CSF as diagnostic biomarkers of dementia disorders. METHODS: We used a modified and sensitive detection method to analyze sAPPs levels in CSF in four groups of patients: AD (N = 33), MCI-AD (N = 17), non-AD dementia (N = 27), and disease controls (N = 19). Phosphorylated tau (p-tau), total tau, and Aß42 were also analyzed using standard methods. RESULTS: A strong correlation was observed between sAPPα and sAPPß, consistent with previous reports. Both sAPPα and sAPPß were highly correlated with p-tau and total tau, suggesting that sAPPs possibly reflect neuropathological changes in the brain. Levels of sAPPα were significantly higher in MCI-AD cases compared with non-AD and disease control cases, and those of sAPPß were also significantly higher in MCI-AD and AD cases relative to other cases. A logistic regression analysis indicated that sAPPα and sAPPß have good discriminative power for the diagnosis of MCI-AD. CONCLUSIONS: Our findings collectively suggest that both sAPPs are pathologically relevant and potentially useful biomarkers for early and accurate diagnosis of dementia disorders. We also suggest that careful measurement is important in assessing the diagnostic utility of CSF sAPPs.

Treatment of psychogenic polydipsia with acetazolamide: a report of 5 cases.

OBJECTIVE: Psychogenic polydipsia occurs frequently in patients with chronic psychiatric illness and is often unmanageable. We herein report 5 patients in whom acetazolamide was trialed for this symptom. METHODS: We encountered a case in which polydipsia improved with incidental administration of acetazolamide. We then used this treatment for 4 additional cases of treatment-resistant psychogenic polydipsia, some of which were accompanied by hyponatremia. RESULTS: Acetazolamide improved polydipsia and/or hyponatremia in 4 of the 5 cases. This treatment was well tolerated and allowed 3 of the patients to permanently leave isolation. CONCLUSION: Acetazolamide appears to have a beneficial effect in psychogenic polydipsia.