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.

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.

Season of birth and vulnerability to the pathology of Alzheimer's disease: an in vivo positron emission tomography study.

BACKGROUND: This study used positron emission tomography to examine whether the seasonal birth effect as an exogenic indicator of early life environmental factors influenced vulnerability to Alzheimer's disease (AD) pathology in the elderly. METHODS: We analysed datasets from the Alzheimer's Disease Neuroimaging Initiative, which included the data for 234 cognitively normal (CN) individuals and patients with mild cognitive impairment (MCI) (n = 114) and AD dementia (n = 38). As an index of amyloid ß (Aß)/tau accumulation, the 18 F-AV-45- and 18 F-AV-1451-standardized uptake value ratios (SUVRs) were compared between groups of spring-to-summer births and fall-to-winter births by analysis of covariance. In addition, a multiple linear regression analysis was performed to determine whether the season of birth was a predictor of 18 F-AV-45 and/or 18 F-AV-1451 SUVRs, for which a difference was observed. RESULTS: Seasonal birth difference was a good predictor of 18 F-AV-1451 SUVR. We found that participants with a fall-to-winter birth showed lower 18 F-AV-1451 SUVRs than those with a spring-to-summer birth in both the CN and MCI/AD groups, after correcting for the effect of age, sex, years of education, and Alzheimer's Disease Assessment Scale cognitive subscale score, that could possibly affect tau accumulation. CONCLUSIONS: Participants with a fall-to-winter birth showed less tau accumulation than those with a spring-to-summer birth after accounting for the factors that could affect tau accumulation. Our findings showed a vulnerability to tau pathology in participants with a fall-to-winter birth, which may be caused by perinatal or postnatal brain damage due to the risk factors associated with the cold season.

Significant effects of cholinesterase inhibitors on tau pathology in the Alzheimer's disease continuum: An in vivo positron emission tomography study.

OBJECTIVES: No prior study has assessed the effects of cholinesterase inhibitors (ChEIs) on tau pathology in the brains of patients with Alzheimer's disease (AD). Using positron emission tomography, this study aimed to investigate whether ChEIs reduce tau aggregation in amyloid-positive participants. METHODS: We analyzed datasets from the Alzheimer's Disease Neuroimaging Initiative and included amyloid-positive participants who had undergone baseline and 1- or 2-year follow-up AV-1451 positron emission tomography scans. We included participants treated with and without ChEIs (ChEIs group: n = 15, No-ChEIs group, n = 45). The annual change in tau aggregation was calculated as the difference in AV-1451- standardized uptake value ratio (SUVR) between the two scans divided by the time between scans. Group differences in annual AV-1451-SUVR change were examined. RESULTS: We found a significantly lower annual change in AV-1451-SUVR in the Braak 1/2 regions (entorhinal cortex and hippocampus) of participants taking ChEIs. Increased AV-1451-SUVR between the first and second examinations were observed in 22 of 45 participants not taking ChEIs and 2 of 15 participants taking ChEIs. Fisher's exact test showed a significant difference in the ratio of participants with increased AV-1451-SUVR between the groups. CONCLUSIONS: The findings of this positron emission tomography study suggest that the administration of ChEIs has some neuroprotective effects in patients of the AD continuum, at least in the early stage of the disease progression. This in vivo effect may be mediated via tau, preventing amyloid ß-induced neurotoxicity.

Relationship between neuropsychiatric symptoms and Alzheimer's disease pathology: An in vivo positron emission tomography study.

OBJECTIVES: To investigate the relationship between amyloid-ß- and tau-based Alzheimer's disease (AD) pathologies assessed using positron emission tomography imaging and neuropsychiatric symptoms (NPS) in a sample of AD continuum including clinically normal subjects and patients with mild cognitive impairment or AD. METHODS: We analyzed datasets of the Alzheimer's disease Neuroimaging Initiative and included amyloid-positive subjects who underwent an AV-45 scan within 1 year of an AV-1451 scan (n = 99). Correlation between standardized uptake value ratio (SUVR) of AV-45 and AV-1451 and the Neuropsychiatric Inventory (NPI) score (and its four domain subscores for hyperactivity, psychosis, affective, and apathy) was evaluated. Stepwise logistic regression analysis was used to examine the influence of SUVRs on the presence of NPS. SUVRs were also tested for their ability to discriminate the group with NPS using receiver operating characteristic (ROC) curve analyses. RESULTS: Significant positive relationships were found between the total NPI score and affective symptoms and Braak 1&2 (transentorhinal region) AV-1451 SUVR. Stepwise logistic regression analysis identified tau accumulation in the area of Braak 1&2 as a significant covariate discriminating the presence of affective symptoms. The area under the ROC curve analysis showed that subjects with affective symptoms were discriminated by AV-1451 SUVR with an accuracy of 77.7%. CONCLUSIONS: Tau aggregation in the transentorhinal region, where neurodegeneration affected by tau pathology was seen in the early stage of AD, correlated with more severe NPS, especially affective symptoms. Therefore, tau pathology in the transentorhinal cortex might be associated with affective symptoms in the early stage of AD.

Increased Dendritic Orientation Dispersion in the Left Occipital Gyrus is Associated with Atypical Visual Processing in Adults with Autism Spectrum Disorder.

In autism spectrum disorder (ASD), the complexity-specific hypothesis explains that atypical visual processing is attributable to selective functional changes in visual pathways. We investigated dendritic microstructures and their associations with functional connectivity (FC). Participants included 28 individuals with ASD and 29 typically developed persons. We explored changes in neurite orientation dispersion and density imaging (NODDI) and brain areas whose FC was significantly correlated with NODDI parameters in the explored regions of interests. Individuals with ASD showed significantly higher orientation dispersion index (ODI) values in the left occipital gyrus (OG) corresponding to the secondary visual cortex (V2). FC values between the left OG and the left middle temporal gyrus (MTG) were significantly negatively correlated with mean ODI values. The mean ODI values in the left OG were significantly positively associated with low registration of the visual quadrants of the Adolescent/Adult Sensory Profile (AASP), resulting in a significant positive correlation with passive behavioral responses of the AASP visual quadrants; additionally, the FC values between the left OG and the left MTG were significantly negatively associated with reciprocal social interaction. Our results suggest that abnormal V2 dendritic arborization is associated with atypical visual processing by altered intermediation in the ventral visual pathway.

A retrospective study of factors associated with persistent delirium.

BACKGROUND: It has been reported that delirium causes various problems. Many researchers have reported the risk factors associated with the onset of delirium; however, there are few reports focused on persistent delirium. This study aimed to identify the risk factors associated with persistent delirium. METHODS: A total of 573 patients hospitalised in Nara Prefecture General Medical Centre from October 2014 through September 2017 who were referred to the psychiatry consultation service were included in this study. Persistent delirium was defined as delirium lasting for 14 days or more. A retrospective study was carried out based on the patients' records. The relationship between various background factors and persistent delirium was statistically analysed. RESULTS: Of the 573 hospitalised patients, 295 were diagnosed as having delirium. Forty-six patients with persistent delirium and 181 patients with nonpersistent delirium were included in this study. Multivariable logistic regression analyses revealed that male gender, opioid analgesics use, non-opioid analgesics use, and low serum sodium were significantly and independently associated with persistent delirium. Ramelteon or trazodone was used significantly more in persistent delirium, although each use was not significant. CONCLUSION: This is the first study to reveal that male gender and use of analgesics were associated with persistent delirium in general hospital. However, as this is a case-control study and may contain bias, future cohort studies and intervention studies are needed. It is also necessary to investigate the relevance of the 'degree of pain' behind the use of analgesics.

An evaluation of the amyloid cascade model using in vivo positron emission tomographic imaging.

AIM: The amyloid cascade hypothesis posits that the accumulation of amyloid ß (Aß) is the triggering factor for Alzheimer's disease, which consecutively induces aggregation of tau, synaptic loss, and cell death. Most experimental and clinical evidence supports this model, but the available data are largely qualitative. Here, we tested the amyloid cascade hypothesis by using in vivo evaluation of positron emission tomography and magnetic resonance imaging. METHODS: Path analysis was used to estimate the relationships among Aß accumulation (PiB standardized uptake value ratio (SUVR)), tau aggregation and its related neuroinflammation (THK5351 SUVR), grey matter atrophy in the medial temporal region, and memory function in Aß-positive subjects. We also performed additional regression analyses to evaluate the effect of Aß on the toxicity of tau aggregation/neuroinflammation. RESULTS: Path analysis supported our hypothesized model: Aß accumulation affected tau aggregation/neuroinflammation in the medial temporal region, and these pathological changes caused of the grey matter atrophy and memory dysfunction. In separate regression analyses, THK5351 SUVR had a significant effect on grey matter atrophy only in PiB-positive subjects. The analysis of the interaction effect showed that the effects of THK5351 SUVR on grey matter atrophy were significantly different between PiB-positive and PiB-negative groups. When we included the effect of being an apolipoprotein E ε4 carrier as a covariate, the interaction effect remained significant. CONCLUSION: Our in vivo evaluation of positron emission tomographic and magnetic resonance imaging data supported the amyloid cascade hypothesis. In addition, it indicated that Aß not only accelerates tau aggregation/neuroinflammation but promotes its toxicity. Our findings showed the importance of understanding the role and therapeutic potential of the interaction between amyloid and tau aggregation/neuroinflammation in Alzheimer's disease.

Interaction effect of Alzheimer's disease pathology and education, occupation, and socioeconomic status as a proxy for cognitive reserve on cognitive performance: in vivo positron emission tomography study.

AIM: Educational attainment, occupation, and socioeconomic status have been regarded as major factors influencing cognitive reserve (CR). This study aimed to investigate the interaction effect of amyloid-ß/tau burden and education/occupation/socioeconomic status as a proxy for CR on cognitive performance. METHODS: We analyzed the datasets of the Alzheimer's Disease Neuroimaging Initiative. We included clinically normal subjects and patients with mild cognitive impairment or Alzheimer's disease who had undergone a florbetapir scan within 1 year of a flortaucipir (AV-1451) scan (n = 127). Partial correlation analysis between the standardized uptake value ratio of florbetapir/AV-1451 and the proxy for CR was performed with the 13-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) score as a covariate. Stepwise multiple linear regression analysis was performed to determine the predictors of ADAS-cog performance based on the interaction between the imaging biomarkers and the proxy for CR. RESULTS: We found a significant positive partial correlation between educational level and tau pathology in Braak stage 1/2 areas, and we observed significantly higher tau accumulation among participants with higher education when ADAS-cog score was used as a covariate. The interaction between tau and education was a good predictor of cognitive function, with higher tau accumulation showing a greater association with higher ADAS-cog score among participants with less education than among those with more education. CONCLUSION: Our findings indicate the protective effect of education against cognitive dysfunction in early-stage Alzheimer's disease pathology and suggest that education may exert a beneficial effect by reducing the adverse cognitive consequences of tau aggregation.

Uncinate fasciculus disruption relates to poor recognition of negative facial emotions in Alzheimer's disease: a cross-sectional diffusion tensor imaging study.

BACKGROUND: Recognising facial emotions involves visual and emotional information processing. Patients with dementia, including dementia of Alzheimer's type (DAT), are known to poorly recognise facial emotions, especially negative facial emotions. In this study, we aimed to assess if DAT patients exhibit poor facial emotional recognition, and to identify a neural basis for how poor facial emotional recognition might occur. METHODS: Magnetic resonance imaging and diffusion tensor imaging (DTI) analysis were conducted in 20 DAT patients and 15 cognitive normal (CN) subjects. The uncinate fasciculus (UF), inferior longitudinal fasciculus, and inferior fronto-occipital fasciculus were delineated by deterministic tractography. DTI parameters were calculated for each fibre. Facial emotion recognition was evaluated with the Facial Emotion Selection Test (FEST). The relationships between FEST scores and DTI parameters in each fibre were measured by partial correlation analyses with age, gender, and the Mini-Mental State Examination as covariates. Group-wise comparisons between DAT and CN subjects were performed for each DTI parameter in each fibre. RESULTS: DAT patients showed lower FEST negative emotion scores than CN subjects (P < 0.05). The score of negative emotion subscale was negatively correlated (r = -0.770, P < 0.001) to mean diffusivity of the left UF in DAT patients. There were no relationships between negative emotion subscale and the other fibre tracts. DAT patients showed no differences in the DTI parameters for each fibre compared to CN subjects. CONCLUSIONS: DAT-related prefrontal-limbic network dysfunction is associated with poor recognition of unpleasant emotions; consequently, worse facial recognition of negative emotion is observed in DAT patients.

Amyloid ß deposition in subcortical stroke patients and effects of educational achievement: A pilot study.

OBJECTIVE: A direct causal relationship of cerebrovascular risk factors/stroke to amyloid ß (Aß) deposition has yet to be shown. We conducted [11 C] Pittsburgh compound B (PiB)-positron emission tomography (PET) analysis on subacute ischemic stroke patients and healthy controls. We hypothesized that subacute ischemic stroke patients would show focal Aß accumulation in cortical regions, which would increase and extend over time during the chronic phase after stroke onset. METHODS: Patients were recruited 14 to 28 days after acute subcortical ischemic stroke and examined with [11 C]PiB-PET scans. Regional time-activity data were analyzed with the Logan graphical method. Whole brain voxel-based analysis was conducted to compare stroke patients with healthy controls. We also performed longitudinal comparison of patients with successive [11 C]PiB-PET scans 1 year after stroke. RESULTS: Voxel-based analysis revealed a significant increase of [11 C]PiB-BPND of the precuneus/posterior cingulate cortex (PCu/PCC) in stroke patients at the subacute stage. Based on stepwise multiple regression analysis of [11 C]PiB-BP changes during follow-up as the dependent variable, years of education was the best independent correlate. There was a significant negative relationship between changes in [11 C]PiB-BP and years of education. CONCLUSIONS: Our results suggest that processes before and after the onset of ischemic stroke may trigger Aß deposition in the PCu/PCC, whereby amyloid deposition begins at an early stage of Alzheimer's disease (AD). Our findings support the existence of a cooperative association between vascular risk factors/stroke and AD progression. Further, educational achievement had a protective effect against the increase in Aß accumulation.

Decreased perfusion of the posterior cingulate gyri shown by a cingulate island score is a possible marker of vulnerability to behavioural and psychological symptoms of Alzheimer's disease: a pilot study.

BACKGROUND: The cingulate island score (CIScore), which indicates the Z-score ratio of the posterior cingulate gyri to the medial occipital area, has been shown to be useful for differentiating dementia with Lewy bodies from Alzheimer's disease (AD). Our aim was to investigate associations between the clinical symptoms of AD and the CIScore as an index of the relative decrease in perfusion of the posterior cingulate gyri that occurs in the early stages of AD. METHODS: Seventeen patients with early-stage AD and 13 patients with amnesic mild cognitive impairment were examined. Z-score maps of technetium-99m ethyl cysteinate dimer single-photon emission computed tomography images acquired from the patients were converted, and the CIScore was determined by using the easy Z-score imaging system. The relationships between the CIScore and clinical symptom scores were tested. RESULTS: A significant correlation was identified between the CIScore and the Neuropsychiatric Inventory Questionnaire score. No significant correlations were identified between the CIScore and other measures of cognitive function. Based on a CIScore of 0.39, we correctly differentiated patients with and without behavioural and psychological symptoms of dementia (BPSD), with a sensitivity of 72.2% and specificity of 75.0%. DISCUSSION: Using technetium-99m ethyl cysteinate dimer single-photon emission computed tomography, we observed that decreased posterior cingulate gyri perfusion, relative to the medial occipital area, in prodromal and early AD was closely associated with behavioural and psychological symptoms of dementia. Therefore, our findings suggest that CIScore is not only useful for discriminating dementia with Lewy bodies from AD, but it can also be clinically used as a specific indicator of the vulnerability to behavioural and psychological symptoms of dementia in the early stages of AD.

Detection of brain amyloid-ß deposits due to the repetitive head trauma in a former karate player.

Head trauma is a well-established epidemiological risk factor for Alzheimer's disease, but a study of early detection of its pathology has not yet been performed in human patients in vivo. To address this issue, we performed 11 C-labelled Pittsburgh compound B-positron emission tomography on a right-handed 30-year-old man with cognitive deterioration after repetitive head trauma during karate matches. Structural magnetic resonance imaging was also performed on this patient. The same positron emission tomography analysis was performed on elderly healthy controls (15 men, mean age: 70.7 ± 6.2 years). To analyze grey matter volume, structural magnetic resonance imaging was performed on age-matched healthy controls (15 men, mean age: 28.5 ± 3.6 years). The cognitive deterioration in our patient was fixed and partially improved in the 10 years after the repetitive head trauma. However, Pittsburgh compound B-non-displaceable binding potential was significantly elevated in the patient. Volume reduction was shown in the medial temporal region, cerebellum, and the basal frontal cortex, while amyloid-ß increase was shown in the bilateral prefrontal cortex. This is the first study to show an early degenerative process due to head trauma in the prefrontal cortex, where structural damage is not yet visible. Early recognition of the degenerative pathology due to repetitive head trauma by amyloid and possibly tau imaging would help clinicians determine how to treat those with early symptoms.

Left dorsolateral prefrontal cortex atrophy is associated with frontal lobe function in Alzheimer's disease and contributes to caregiver burden.

OBJECTIVE: Caregivers of patients with dementia experience physical and mental deterioration. We have previously reported a correlation between caregiver burden and the Frontal Assessment Battery (FAB) total scores of patients with Alzheimer's disease (AD), especially regarding the dependency factor from the Zarit Burden Interview. The present study aimed to identify an objective biomarker for predicting caregiver burden. METHODS: The participants were 26 pairs of caregivers and patients with AD and mild-to-moderate dementia. Correlations between regional gray matter volumes in the patients with AD and the FAB total scores were explored by using whole-brain voxel-based morphometric analysis. Path analysis was used to estimate the relationships between regional gray matter volumes, FAB total scores, and caregiver burden based on the Zarit Burden Interview. RESULTS: The voxel-based morphometric revealed a significant positive correlation between the FAB total scores and the volume of the left dorsolateral prefrontal cortex. This positive correlation persisted after controlling for the effect of general cognitive dysfunction, which was assessed by using the Mini-Mental State Examination. Path analysis revealed that decreases in FAB scores, caused by reduced frontal lobe volumes, negatively affected caregiver burden. CONCLUSIONS: The present study revealed that frontal lobe function, based on FAB scores, was affected by the volume of the left dorsolateral prefrontal cortex. Decreased scores were associated with greater caregiver burden, especially for the dependency factor. These findings may facilitate the development of an objective biomarker for predicting caregiver burden.

Computer-assisted cognitive remediation therapy increases hippocampal volume in patients with schizophrenia: a randomized controlled trial.

BACKGROUND: Cognitive remediation therapy (CRT) effectively reduces neurocognitive impairment in patients with schizophrenia, but few studies have used structural neuroimaging methods to assess its neuroanatomical effects. We investigated these effects, as well as the association between changes in cortical volume and neurocognitive performance. METHOD: Between August 2013 and September 2016, we performed a randomized controlled study comprising a CRT group (16 individuals) and a treatment-as-usual (TAU) group (15 individuals) of patients with schizophrenia. CRT participants engaged in twice-weekly computer-assisted CRT sessions and weekly group meetings for 12 weeks. T1-weighted magnetic resonance imaging was performed before and after the intervention period, and whole-brain voxel-based morphometric analysis was used to detect significant cortical gray matter volume changes. We also assessed the correlation between cortical volume changes and CRT-derived neurocognitive improvements. RESULTS: The CRT group exhibited significantly greater improvements than the TAU group in verbal fluency (P = 0.012) and global cognitive scores (P = 0.049). The CRT group also exhibited significantly greater increases in right hippocampal volume than the TAU group (P < 0.001). Changes in verbal fluency scores and right hippocampal volumes were positively correlated (r = 0.53, P = 0.001). CONCLUSION: We found that CRT significantly increased right hippocampal volumes and that these enhancements were positively correlated with changes in verbal fluency scores. Our results indicate that CRT induces cognitive improvement through hippocampal plasticity. TRIAL REGISTRATION: Registration number: UMIN000026146 , 2017/02/15, retrospectively registered.

Mutual effect of cerebral amyloid ß and peripheral lymphocytes in cognitively normal older individuals.

OBJECTIVE: We hypothesized that cerebral amyloid accumulation is reflected in the periphery in the pre-dementia stage and used flow cytometry to investigate the peripheral lymphocytes as an easily accessible biomarker to observe neuro-inflammation. We aimed to determine whether peripheral lymphocytes are related to the cortical amyloid burden or vice versa in cognitively normal older subjects. METHODS: We applied [11 C] Pittsburgh compound B (PiB)-positron emission tomography to 36 cognitively normal older individuals, and Aß deposition was quantified by cortical binding potential (PiB-BPND ). Blood samples were obtained, and lymphocyte subsets were evaluated. We examined differences between low and high PiB-BPND groups in the percentage of B cells, T cells, helper T cells, cytotoxic T cells, regulatory T cells, and natural killer cells. RESULTS: Subjects with high PiB-BPND showed significantly higher percentage of cytotoxic T cells (%CD3+ ). Correlation analysis revealed a significant relationship between the percentage of cytotoxic T cells and global cortical mean PiB-BPND . Hierarchical regression analyses showed that cytotoxic T cells were significantly related to the value of global cortical mean PiB-BPND and vice versa. CONCLUSIONS: Our results indicated that a specific peripheral immune response, reflected in the increased ratio of cytotoxic T cells, could be regarded as a preclinical sign of AD and could be attributed to the Aß neuropathological mechanism. Copyright © 2017 John Wiley & Sons, Ltd.

Frontal lobe function in elderly patients with Alzheimer's disease and caregiver burden.

AIM: Understanding of the relationship between caregiver burden and the degree of behavioural deficits in patients with Alzheimer's disease (AD) is relatively limited. Therefore, it is worthwhile to examine the correlations between the various relevant factors to improve the efficacy of care for patients with AD. The aim of this study was to investigate the specific contributions of frontal lobe dysfunction in AD patients to caregiver burden, while controlling for other predictor variables. METHODS: Participants included 30 pairs of caregivers and patients with AD. The Zarit Burden Interview and Frontal Assessment Battery were used to measure the caregiver burden and patients' frontal lobe function, respectively. To investigate the effects of frontal lobe dysfunction on caregiver burden, hierarchical regression equations with steps incorporating additional predictor variables were fitted. We also performed a correlation analysis between the individual subdomains of the Zarit Burden Interview and the predictor variables. RESULTS: Our study suggests that the degree of frontal lobe dysfunction in AD patients predicts their caregiver burden, when other factors of daily functional limitations and neuropsychiatric symptoms are controlled. Daily functional limitations and neuropsychiatric symptoms affected caregivers' psychosocial burden, whereas frontal lobe dysfunction affected caregivers' burden due to the increase in the dependency of the patients. CONCLUSION: Our findings indicate that to ameliorate the disabilities of patients and reduce caregiver burden, there is a need for interventions that focus on psychosocial burdens, as shown in previous studies, as well as on excessive dependency due to frontal lobe dysfunction.

High amyloid-ß deposition related to depressive symptoms in older individuals with normal cognition: a pilot study.

OBJECTIVE: Previous studies have reported depressive symptoms in the preclinical stages of Alzheimer's disease (AD). The objective of this study was to determine whether depressive symptoms are associated with cortical amyloid burden. In order to do this, we measured cortical amyloid via (11) C-labeled Pittsburgh Compound B ([(11) C]PIB) uptake using positron emission tomography (PET) in cognitively normal subjects. METHODS: We performed [(11) C]PIB-PET in 29 cognitively normal, older participants. Depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS). Aß deposition was quantified by binding potential (BPND ), and the association between cortical mean BPND values and GDS scores was evaluated. Analysis of parametric BPND images was performed to examine the relationship between regional BPND and GDS scores. RESULTS: We found a positive correlation between depressive symptoms and mean cortical PIB-BPND in groups of subjects with middle to high PIB-BPND . There was little change in GDS-depression score between subjects with low and middle PIB-BPND levels, while an increase in GDS was shown in the high PIB-BPND group. The main BPND increase was localized to the precuneus/posterior cingulate cortex (PCu/PCC) in subjects with high PIB-BPND , and we found a significant positive relationship between PIB-BPND in this area and depressive symptoms. CONCLUSIONS: Emotional dysregulation because of Aß neuropathology in the PCu/PCC may relate to depressive symptoms. More specifically, we found that older, cognitively normal patients with depressive episodes were more likely to have underlying AD pathology. Thus, depressive symptoms may increase the predictive ability of the identification of future AD cases. Copyright © 2016 John Wiley & Sons, Ltd.

A structural model of age, grey matter volumes, education, and personality traits.

BACKGROUND: When the relationship between ageing and changes in personality traits is considered, it is important to know how they are influenced by biological and environmental factors. The present study examined the relationships between various factors associated with the effect of ageing on personality traits, including structural changes of the brain and environmental factors such as education. METHODS: We recruited 41 healthy subjects. We administered the NEO Five-Factor Inventory to assess personality factors. Magnetic resonance imaging was performed, and regional grey matter (GM) volumes were obtained. We identified associations in the correlation analysis of age, cerebral GM volume, years of education, and the personality trait of openness. Path analysis was used to estimate the relationships among these factors. RESULTS: The path analysis model of age, GM volume, years of education, and the personality trait of openness revealed that age has an indirect negative association with openness through GM volume and years of education. Ageing was related to a decrease in GM volume, which was in turn related to a decrease in the openness score. Older subjects generally had fewer years of education, which was related to a lower openness score. CONCLUSIONS: Maintaining openness against the effects of ageing is desirable, and our results imply that interventions against age-related cerebral atrophy and the promotion of opportunities for higher education may contribute to the development and stability of a healthy personality during the adult life course.

Low amyloid-ß deposition correlates with high education in cognitively normal older adults: a pilot study.

OBJECTIVE: Several epidemiological studies have found a lower incidence of Alzheimer's disease in highly educated populations, but the protective mechanism of education against the disease is still unclear. Our objective was to investigate the association between education and (11) C-labeled Pittsburgh Compound B (PIB) uptake with positron emission tomography in participants with normal cognitive ability. METHODS: We performed (11) C-labeled PIB positron emission tomography and neuropsychological testing in 30 cognitively normal older participants. Of the participants, 16 had a period of education less than 12 years (low-education group) and 14 had more than 13 years (high-education group). Amyloid-ß deposition was quantified by binding potential (BPND ) in several brain regions and was compared between the groups with different education levels. RESULTS: We found significantly higher cortical PIB-BPND in the cognitively normal participants with low education compared with the ones with high education. None of the brain regions in low-education group showed significantly lower BPND values. This finding was not affected by the inclusion of possible confounding variables such as age, sex, and general intelligence. Our findings indicated a reduced amyloid pathology in highly educated, cognitively normal, participants. CONCLUSIONS: Our findings lead to the proposal that early-life education has a negative association with Alzheimer's disease pathology. This proposal is not in opposition to the brain reserve hypothesis. People with more education might be prone to a greater inhibitory effect against amyloid-ß deposition before the preclinical stage. At the same time, they have a greater reserve capacity, and greater pathological changes are required for dementia to manifest.