Old Age, Female Sex, and Psychotropic Medications Predict Hyposalivation But Not Heart Rate Variability

Objective@#To explore risk factors for dry mouth and examine the clinical utility of the heart rate variability (HRV) test in the prediction of dry mouth. @*Methods@#Every outpatient, who underwent tests for both unstimulated salivary flow and HRV, was retrospectively reviewed. After excluding seven subjects, the demographics and clinical factors in 70 total patients were collected. Based on objective salivary flow rates, patients were classified into normal (≥0.2 mL/min) or hyposalivation groups (<0.2 mL/min), and inter-group comparisons were performed with a two-tailed statistical significance of 0.05. @*Results@#Patients with subjective dry mouth were significantly more likely to show hyposalivation. Advanced age, female sex, and current use of psychotropic medications were identified as risk factors for dry mouth. However, dry mouth was not associated with any HRV parameters. @*Conclusion@#HRV test did not demonstrate a clinical utility in predicting dry mouth. Because subjective dry mouth is significantly associated with objective hyposalivation, a simple probing question would be useful for early recognition of dry mouth. Clinical attention is required for patients meeting criteria of older age, female, and/or using psychotropic prescriptions. Prompt management of hyposalivation may improve quality of life and clinical outcome by enhanced treatment adherence.

Functional Connectivity Change Associated With Apolipoprotein E Allotypes Precedes Structural Connectivity and Neurodegeneration in Cognitive Normal Older Adults Without Cerebral Aβ Deposition

Objective@#Apolipoprotein E (APOE) gene is known to influence cerebral functional connectivity (FC) in Alzheimer’s disease continuum. We investigated association between APOE allotypes and FC, structural connectivity, and cortical thickness in amyloid-PET negative cognitive normal older adults (CN). @*Methods@#A total of 188 CN (37 had ε2/ε2 or ε2/ε3 [ε2 group], 113 had ε3/ε3 [ε3 group], and 38 had ε3/ε4 or ε4/ε4 [ε4 group]) were recruited. Voxel-based morphometry and cortical thickness analysis were used to investigate differences in cortical thickness between three APOE allotypes. To investigate integrity of structural connectivity, we analyzed diffusion weighted imaging using fractional anisotropy and mean diffusivity. In terms of FC, differences of FC in default mode network (DMN) among APOE allotypes were measured using functional magnetic resonance imaging. @*Results@#There were no significant differences in age, sex, education, cerebral beta-amyloid (Aβ) deposition severity, or neuropsychological profiles. No significant differences were found in cortical thickness and structural connectivity among the APOE allotypes. However, FC within the DMN was significantly lower in ε4 and ε2 carriers compared to ε3 homozygotes. @*Conclusion@#This study suggests that both ε4 and ε2 exhibit APOE-associated DMN FC changes before Aβ deposition, structural changes, and neurodegeneration.

Phentermine and Phendimetrazine-Induced Psychotic Disorder and Bipolar Disorder: A Case Series

Objectives@#Recently, weight loss has emerged as a national concern in South Korea, and this has resulted in an increase in the frequency of use of central nervous system (CNS)-stimulating appetite suppressants. This study aimed to collect cases of psychotic disorders and bipolar disorders triggered by phentermine and phendimetrazine and explore the clinical features and courses. @*Methods@#In this retrospective study, we analyzed the electronic medical records of patients and selected eight patients who developed psychotic symptoms and manic symptoms for the first time after taking phentermine and phendimetrazine. All cases were reviewed, and their clinical features and course were summarized. @*Results@#All eight patients developed psychotic symptoms, and one had accompanying manic symptoms. The final diagnosis was appetite-suppressant-induced psychotic disorder in four patients, schizophrenia in three, and appetite-suppressant-induced bipolar disorder in one. In addition, three patients were diagnosed as having substance-use disorder. The key psychotic symptoms of these patients were hallucinations and paranoia. @*Conclusions@#These case findings suggest that phentermine and phendimetrazine can cause psychotic disorder, bipolar disorder, or substance use disorder and that medical professionals and the public should practice caution when prescribing and using these drugs.

Factors Associated With Dementia Knowledge and Dementia Worry in the South Korean Elderly Population

Objective@#South Korea is one of the countries with a very fast aging rate, and the prevalence of dementia is rapidly increasing. However, there are relatively few studies pertaining to sociodemographic and physical health-related factors associated with dementia knowledge and dementia worry. @*Methods@#This was a cross-sectional survey of a community in Seocho-gu, Seoul, Republic of Korea. Overall, 1,869 adults aged 60 years participated. Participants completed an online interview or face-to-face interview. Survey data comprised self-report questions including dementia knowledge, dementia worry, demographic, psychological, exercise, and cognitive activities. We conducted logistic regression analysis. @*Results@#There was a significant positive association between dementia worry and knowledge. Family history of dementia, education, income, sleep problems, depressed mood and loss of volition, chronic diseases, and presence of a past job were associated with dementia knowledge or worry. Reading, art, or social cognitive activities had a significant positive association with dementia knowledge, and writing or musical cognitive activities had a negative association with dementia worry. @*Conclusion@#We found that people with more dementia knowledge and less dementia worry engaged more in cognitive activities that could prevent dementia. Public education should be planned to improve dementia knowledge and reduce dementia worry.

Association of Sub-Threshold Amyloid Retention With Neuropsychological Performance in Cognitively Normal Older Adults Without the APOE ε4 Allele

Objective@#Recent evidence shows that the quantitative value of amyloid-beta (Aβ) deposition below the threshold of Aβ positivi-ty carries biological and clinical significance regarding future cognitive decline. We evaluated whether the quantitative value of sub-threshold Aβ deposition had a significant correlation with neuropsychological test scores in cognitively normal older adults without the APOE ε4 allele. @*Methods@#Sixty cognitively normal APOE ε4 allele non-carriers with negative Aβ retention aged 60 to 85 years were included in this study. We assessed neuropsychological performance with the Korean version of the Consortium to Establish a Registry for Al-zheimer’s Disease (CERAD-K) and obtained standardized [ 18 F] flutemetamol uptake values in the pons as a reference (SUVR PONS), evaluated with PET. Multiple regression analyses were conducted to assess the effect of global and regional Aβ load on cognitive performance, adjusting for age, sex, years of education, and volumes of white matter hyperintensities. @*Results@#We found that Aβ deposition in the precuneus, posterior cingulate cortex, and parietal lobe had a significant association with the total CERAD-K scores. There was also a significant correlation between the SUVR PONS in the precuneus and the CERAD-K total score after Bonferroni correction. @*Conclusion@#Subthreshold Aβ retention in the core brain regions of the default mode network could affect cognitive functions in the cognitively normal APOE ε4 non-carriers, considered to be the lowest risk group for Alzheimer’s disease (AD).

Cerebral Amyloid Positivity Prediction Models Using Clinical Data in Subjects With Mild Cognitive Impairment and Dementia

Objective@#Due to high cost of amyloid imaging, its use of amyloid imaging to confirm amyloid pathology is limited in clinical practice. It is of importance to develop a model to predict cerebral amyloid positivity using clinical data obtained from a memory clinic. @*Methods@#A total of 410 participants who had symptom of subjective cognitive decline and underwent amyloid PET and apolipoprotein ε (APOE) genotyping were retrospectively enrolled from January 2016 to January 2019. Models for cerebral amyloid positivity prediction were developed in all subjects, mild cognitive impairment (MCI) subjects, and Alzheimer’s disease (AD) dementia subjects through multivariate logistic regression analysis. The performance of the models was assessed using receiver operating characteristic (ROC) curve analysis and the area under the curve (AUC) values. @*Results@#Age, sex, years of education, body mass index (BMI), APOE4, and mini mental state examination score (MMSE) were selected for the final model for all subjects. The AUC value of the ROC curve was 0.775. Age, sex, years of education, BMI, and APOE4 were selected for the final model for MCI subjects. The AUC value was 0.735. Age, sex, years of education, BMI, APOE4, MMSE, and history of hypertension were selected for the final model for AD dementia subjects. The AUC value was 0.845. @*Conclusion@#This study found that models using clinical data can predict cerebral amyloid positivity according to cognitive status. These models can be useful as a screening tool predict cerebral amyloid deposition in cognitively impaired patients in a memory clinic.

Development of Random Forest Algorithm Based Prediction Model of Alzheimer’s Disease Using Neurodegeneration Pattern

Objective@#Alzheimer’s disease (AD) is the most common type of dementia and the prevalence rapidly increased as the elderly population increased worldwide. In the contemporary model of AD, it is regarded as a disease continuum involving preclinical stage to severe dementia. For accurate diagnosis and disease monitoring, objective index reflecting structural change of brain is needed to correctly assess a patient’s severity of neurodegeneration independent from the patient’s clinical symptoms. The main aim of this paper is to develop a random forest (RF) algorithm-based prediction model of AD using structural magnetic resonance imaging (MRI). @*Methods@#We evaluated diagnostic accuracy and performance of our RF based prediction model using newly developed brain segmentation method compared with the Freesurfer’s which is a commonly used segmentation software. @*Results@#Our RF model showed high diagnostic accuracy for differentiating healthy controls from AD and mild cognitive impairment (MCI) using structural MRI, patient characteristics, and cognitive function (HC vs. AD 93.5%, AUC 0.99; HC vs. MCI 80.8%, AUC 0.88). Moreover, segmentation processing time of our algorithm (<5 minutes) was much shorter than of Freesurfer’s (6–8 hours). @*Conclusion@#Our RF model might be an effective automatic brain segmentation tool which can be easily applied in real clinical practice.

Cerebral Amyloid Positivity Prediction Models Using Clinical Data in Subjects With Mild Cognitive Impairment and Dementia

Objective@#Due to high cost of amyloid imaging, its use of amyloid imaging to confirm amyloid pathology is limited in clinical practice. It is of importance to develop a model to predict cerebral amyloid positivity using clinical data obtained from a memory clinic. @*Methods@#A total of 410 participants who had symptom of subjective cognitive decline and underwent amyloid PET and apolipoprotein ε (APOE) genotyping were retrospectively enrolled from January 2016 to January 2019. Models for cerebral amyloid positivity prediction were developed in all subjects, mild cognitive impairment (MCI) subjects, and Alzheimer’s disease (AD) dementia subjects through multivariate logistic regression analysis. The performance of the models was assessed using receiver operating characteristic (ROC) curve analysis and the area under the curve (AUC) values. @*Results@#Age, sex, years of education, body mass index (BMI), APOE4, and mini mental state examination score (MMSE) were selected for the final model for all subjects. The AUC value of the ROC curve was 0.775. Age, sex, years of education, BMI, and APOE4 were selected for the final model for MCI subjects. The AUC value was 0.735. Age, sex, years of education, BMI, APOE4, MMSE, and history of hypertension were selected for the final model for AD dementia subjects. The AUC value was 0.845. @*Conclusion@#This study found that models using clinical data can predict cerebral amyloid positivity according to cognitive status. These models can be useful as a screening tool predict cerebral amyloid deposition in cognitively impaired patients in a memory clinic.

Association of Alcohol Intake and Fracture Risk in Elderly Varied by Affected Bones: A Nationwide Longitudinal Study

Objective@#Previous studies investigating association of alcohol intake and fracture risk in elderly yielded conflicting results. We first examined the association between alcohol intake and total fracture risk in elderly subjects and further analyzed whether the association varied by fracture locations. @*Methods@#This is a nationwide population-based cohort study which included all people aged 66 (n=1,431,539) receiving the National Screening Program during 2009–2014. Time-to-event were defined as duration from study recruitment, the day they received health screening, to the occurrence of fracture. @*Results@#Total fracture was significantly lower in mild drinkers [adjusted hazard ratio (aHR)=0.952; 95% confidence interval (95% CI) =0.931–0.973] and higher in heavy drinkers (aHR=1.246; 95% CI=1.201–1.294) than non-drinkers. Risk pattern of alcohol consumption and fracture differed according to affected bones. Similar J-shaped trends were observed for vertebra fractures, but risk of limb fracture showed a linear relationship with alcohol intake. For hip fracture, risk decrement was more pronounced in mild and moderate drinkers, and significant increment was noted only in very severe drinkers [≥60 g/day; (aHR)=1.446; 1.162–1.801]. @*Conclusion@#Light to moderate drinking generally lowered risk of fractures, but association between alcohol and fracture risk varied depending on the affected bone lesions.

Effects of Moderate Intensity Exercise on the Cortical Thickness and Subcortical Volumes of Preclinical Alzheimer’s Disease Patients: A Pilot Study

Objective@#We aimed to explore the impact of moderate intensity exercise on the cortical thickness and subcortical volumes of preclinical Alzheimer’s disease (AD) patients. @*Methods@#Sixty-three preclinical AD patients with magnetic resonance imaging (MRI) and 18-florbetaben positron emission tomography (PET) data were enrolled in the study. Information on demographic characteristics, cognitive battery scores, self-reported exercise habits were attained. Structural magnetic resonance images were analyzed and processed using Freesurfer v6.0. @*Results@#Compared to Exercise group, Non-Exercise group demonstrated reduced cortical thickness in left parstriangularis, rostral middle frontal, entorhinal, superior frontal, lingual, superior parietal, lateral occipital, inferior parietal gyrus, temporal pole, precuneus, insula, fusiform gyrus, right precuneus, superiorparietal, lateral orbitofrontal, rostral middle frontal, medial orbitofrontal, superior frontal, lingual, middle temporal gyrus, insula, supramarginal, parahippocampal, paracentral gyrus. Volumes of right thalamus, caudate, putamen, pallidum, hippocampus, amygdala were also reduced in Non-Exercise group. @*Conclusion@#Moderate intensity exercise affects cortical and subcortical structures in preclinical AD patients. Thus, physical exercise has a potential to be an effective intervention to prevent future cognitive decline in those at high risk of AD.

Differential Impact of Cigarette Smoking on Fracture Risks in Subjective Cognitive Decline and Dementia: A Nationwide Longitudinal Study

Objective@#We aimed to explore the differential impact of cigarette smoking on fracture risks in SCD and dementia. @*Methods@#A nationwide population-based cohort study design was used. Out of all the people aged 66 (n=1,555,103) who went through the National Screening Program from 2009–2014, 968,240 participants with eligible data were included in the study. Time-to-event was calculated as the duration between the NSPTA and fracture incidence. Cox proportional-hazard regression analyses were conducted to evaluate the risk of fractures. @*Results@#Increased risk of all [adjusted hazard ratio (aHR)=1.184; 95% confidence interval (CI)=1.184, 1.093–1.283], hip (aHR=1.518; 95% CI=1.168–4.972), vertebral (aHR=1.235; 95% CI=1.101–1.386) fractures were increased in current smokers with more than 20 or more pack years (≥20 py) of SCD group, after adjusting for all relevant confounding factors. In dementia group, however, current smokers ≥20 py were at reduced risk of hip fractures (aHR=0.249; 95% CI=0.089–0.97). @*Conclusion@#There was a disparate influence of cigarette smoking on the fracture risks in SCD and dementia group. Further studies are warranted to explicate this phenomenon, and personalized preventive measures according to one’s cognitive status are imperative, since risk factors of fractures can exert disparate influence on patients at different stage of cognitive trajectory.

Impact of Repetitive Transcranial Magnetic Stimulation with Computerized Cognitive Enhancement Training on Change in Cognitive Function of Mild Cognitive Impairment Patients : Existing, Sham Treatment Controlled, Pilot Study

An Exploration of the Oryza sativa L. Cyanidin-3-glucoside on the Cognitive Function in Older Adults with Subjective Memory Impairment

OBJECTIVE: Cyanidin-3-glucoside (C3G), is a component of anthocyanin, have been considered to positively influence cognition and be beneficial for the prevention and treatment of dementia. We aimed to assess the safety and efficacy of cyanidin-3-glucoside-rich Oryza sativa L. (black rice) extract on cognitive function. METHODS: A 12-weeks double-blind randomized, placebo controlled trial assessed safety and cognitive outcomes in participants with subjective memory impairment (n=48) following consumption of 6 black rice extract capsules or a placebo. Cognitive function was assessed using the ADAS-cog and the CERAD-K. Subjective memory impairment also assessed. Safety was assessed by hematologic blood test, urine analysis, and participant reports of adverse events. RESULTS: There was significant improvement on subjective memory in intervention group. There was no statistically significant difference in objective cognitive outcomes following 12 weeks of consuming black rice extract. ADAS-cog scores, however, trended toward improvement in the intervention group compared to the placebo group. There was no adverse event. CONCLUSION: Although significant improvement in objective cognitive function was not proved, we found that C3G-rich Oryza sativa L. extract improves subjective memory in this study. Therefore the results may be informative of the possible effectiveness of the C3G-rich Oryza sativa L. on cognitive function.

Diagnostic Validity of an Automated Probabilistic Tractography in Amnestic Mild Cognitive Impairment

OBJECTIVE: Although several prior works showed the white matter (WM) integrity changes in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease, it is still unclear the diagnostic accuracy of the WM integrity measurements using diffusion tensor imaging (DTI) in discriminating aMCI from normal controls. The aim of this study is to explore diagnostic validity of whole brain automated probabilistic tractography in discriminating aMCI from normal controls. METHODS: One hundred-two subjects (50 aMCI and 52 normal controls) were included and underwent DTI scans. Whole brain WM tracts were reconstructed with automated probabilistic tractography. Fractional anisotropy (FA) and mean diffusivity (MD) values of the memory related WM tracts were measured and compared between the aMCI and the normal control groups. In addition, the diagnostic validities of these WM tracts were evaluated. RESULTS: Decreased FA and increased MD values of memory related WM tracts were observed in the aMCI group compared with the control group. Among FA and MD value of each tract, the FA value of left cingulum angular bundle showed the highest area under the curve (AUC) of 0.85 with a sensitivity of 88.2%, a specificity of 76.9% in differentiating MCI patients from control subjects. Furthermore, the combination FA values of WM integrity measures of memory related WM tracts showed AUC value of 0.98, a sensitivity of 96%, a specificity of 94.2%. CONCLUSION: Our results with good diagnostic validity of WM integrity measurements suggest DTI might be promising neuroimaging tool for early detection of aMCI and AD patients.

Relationship between Delusion of Theft and Cognitive Functions in Patients with Mild Alzheimer's Disease

Although delusion of theft (DT) is the most frequent type of delusion in Alzheimer's disease (AD), its relationship to cognitive functions remains unclear. The aim of this study was to demonstrate the relationship between DT and cognitive functions in mild AD. Two hundred eighty-nine mild AD patients were enrolled in this study. These subjects were classified into three groups: patients with no delusions (ND, n=82), patients with paranoid delusions (PD, n=114) and patients with DT (n=93). Cognitive functions and their associations with the degree of delusion were compared among the three groups. The results showed that verbal Fluency scores were significantly lower in the PD group than in the DT and ND groups. Word List Recall scores were significantly lower in the DT group than in the PD and ND groups. Interestingly, delusion severity measured with the Neuropsychiatric Inventory delusion subscale correlated negatively with the Word List Recall scores in the DT group. In this study, we demonstrated that episodic memory functions in mild AD patients were associated with DT, but not with PD. Further studies might be needed to clarify the pathophysiology of delusions associated with AD.

Incidence and Course of Depression in Patients with Alzheimer's Disease

OBJECTIVE: Depressive symptoms are common in Alzheimer's disease (AD) and they might influence the course and prognosis of AD. Depression could appear anytime in the course of the disease, and could either last considerably long or disappear easily. This study is intended to investigate the occurrence of depression in the course of AD and the risk factors of incidence. METHODS: This study targeted 1,272 AD patients without depressive symptoms at the start of this study in Korea. A total of 775 subjects completed the study, and the occurrence of depression was assessed after 12 months. Demographic information of subjects was collected and cognitive functions, overall functions, and depression severity were assessed at the start of this study and after 12 months. RESULTS: Among the 775 subjects, 103 subjects (13.29%) developed depression 12 months later. The MMSE-KC scores showed significant changes in both groups that developed depression and did not. In the univariate analysis, significant differences in the incidence of depression were found in terms of gender, the administration of the antidepressant at the baseline, the SGDS-K score, and the GDS score. The multiple logistic regression analysis showed that the increase in the incidence of depression was associated with a female, in the increase in SGDS-K score and the GDS score. CONCLUSION: The incidence of depression in the subjects who completed the 12-month follow-up observation was 13.29%. Moreover, in the multivariate analysis, a female gender and the severity of dementia, including the overall functions, seemed associated with the occurrence of depression.

Prediction of Treatment Response to Donepezil using Automated Hippocampal Subfields Volumes Segmentation in Patients with Mild Alzheimer's Disease

Previous studies reported some relationships between donepezil treatment and hippocampus in Alzheimer's disease (AD). However, due to methodological limitations, their close relationships remain unclear. The aim of this study is to predict treatment response to donepezil by utilizing the automated segmentation of hippocampal subfields volumes (ASHS) in AD. Sixty four AD patients were prescribed with donepezil and were followed up for 24 weeks. Cognitive function was measured to assess whether there was a response from the donepezil treatment. ASHS was implemented on non-responder (NR) and responder (TR) groups, and receiver operator characteristic (ROC) analysis was conducted to evaluate the sensitivity, specificity, and accuracy of hippocampal subfields in predicting response to donepezil. The left total hippocampus and the CA1 area of the NR were significantly smaller than those of the TR group. The ROC curve analysis showed the left CA1 volumes showed highest area under curve (AUC) of 0.85 with a sensitivity of 88.0%, a specificity of 74.0% in predicting treatment response to donepezil treatment. We expect that hippocampal subfields volume measurements that predict treatment responses to current AD drugs will enable more evidence-based, individualized prescription of medications that will lead to more favorable treatment outcomes.

Whole Brain Voxel-Wise Analysis of Cerebral Retention of Beta-Amyloid in Cognitively Normal Older Adults Using ¹⁸F-Florbetaben

OBJECTIVE: Recently developed 18F-labelled amyloid beta (Aβ) positron emission tomography (PET) tracers have demonstrated potentials to enable more prevalent application of amyloid imaging in the clinical setting. The aim of this study is to demonstrate cerebral retention of Aβ in cognitively normal older adults, by implementing voxel-based analysis on images acquired from 18F-Florbetaben amyloid PET. METHODS: Fifty cognitive normal elderly subjects were recruited and included in the study. Demographic data and cognitive measurements were collected. Magnetic resonance imaging (MRI) and ¹⁸F-Florbetaben PET data were obtained followed by whole brain voxel-based analysis. RESULTS: Compared to the florbetaben (FBB) (−) counterpart, FBB (+) showed significantly higher Aβ deposition in the brain regions comprising anterior cingulate, middle cingulate, posterior cingulate and precuneus (family wise error corrected p < 0.05). There was no significant correlation between amyloid retention and cognitive functions. CONCLUSION: Our results confirms previous results regarding Aβ deposition by using ¹⁸F-Florbetaben, demonstrating potentials in application of 18F-Florbetaben PET imaging in clinical settings.

Erratum to “Prediction of Treatment Response to Donepezil using Automated Hippocampal Subfields Volumes Segmentation in Patients with Mild Alzheimer's Disease”

Unfortunately, the corresponding author's affiliation was incorrect in the original publication of this article..

Feasibility of Psychosocial Distress Screening and Management Program for Hospitalized Cancer Patients

OBJECTIVE: Although the diagnosis and treatment of cancer is associated with psychosocial distress, routine distress screening is difficult in hospitalized oncology settings. We developed a consecutive screening program for psychosocial distress to promote psychiatric treatment of cancer patients and evaluated the feasibility of our program by Distress Thermometer (DT) and Hospital Anxiety and Depression Scale (HADS). METHODS: Among 777 cancer inpatients recruited from the Catholic Comprehensive Institute of Seoul St. Mary's Hospital, 499 agreed to complete primary distress screening through DT. We conducted secondary distress screening through HADS in 229 patients who had high scores of DT. RESULTS: Of the 499 participants, 270 patients with low scores of DT were included in the distress education program. 229 patients with high scores of DT received secondary distress screening through HADS. Among 115 patients with low scores of HADS, 111 patients received distress management. Among 114 patients with high scores in the secondary distress screening, 38 patients received psychiatric consultation service whereas 76 patients refused psychiatric consultation. CONCLUSION: Using consecutive screening for psychosocial distress appeared to be feasible in an inpatient oncology setting. Nevertheless, the low participation rate of psychiatric consultation service in cancer patients with high distress level should be improved.