Relationship between the response to donepezil and plasma amyloid beta oligomers in patients with Alzheimer's disease.

AIM: To date, there is no reported effective biomarker that can predict which Alzheimer's disease (AD) patients will respond to donepezil and which will not. This study aimed to investigate whether baseline values of Aß oligomers (AßOs), measured by the Multimer Detection System-Oligomeric Aß (MDS-OAß), can be used to predict responders after 6 months of donepezil medication. METHODS: The study enrolled 104 patients diagnosed with probable AD. After 6 months of donepezil medication, the response to treatment was evaluated by re-assessing the Korean version of the Mini-Mental State Examination (K-MMSE) and Clinical Dementia Rating scale-Sum of Box (CDR-SB) scales conducted at baseline. The patients were categorized into two groups according to the baseline MDS-OAß values known as the cut-off for AD diagnosis: a group with values below 0.78 and another group with values equal to or above 0.78. RESULTS: After 6 months of medication, the number of responders was 50 (49.5%). Responders exhibited significantly worse baseline CDR, CDR-SB, K-MMSE, and Barthel index compared with non-responders. There was a significantly higher number of responders among patients with MDS-OAß values below the cut-off of 0.78 compared with those with values equal to or above this threshold. Furthermore, there was a significant improvement in the K-MMSE and CDR-SB after 6 months of donepezil medication in patients with MDS-OAß values below 0.78 compared with those with values equal to or above 0.78. CONCLUSIONS: Baseline MDS-OAß values might constitute a novel biochemical marker for the efficacy of 6 months of donepezil treatment in AD. Geriatr Gerontol Int 2024; ••: ••-••.

Clinical Aspects of Neurobehavioral Symptoms of Dementia.

Neurobehavioral symptoms of dementia (NBSD) are very common and are significant symptoms of the illness, contributing most to caregiver burdens and often resulting in premature institutionalization of the person with dementia. The main symptoms of NBSD are anxiety, depression, delusions, and hallucinations. NBSD produce significant problems for both patients and caregivers. The pathophysiology of NBSD is determined by genetic, structural, or environmental factors. Therefore, treatment of NBSD requires continuous and organic cooperation between patients, caregivers, social environments, and doctors. Therefore, it is important for neurologists, who mainly view NBSD for dementia patients, to increase their understanding of these more comprehensive areas as well as the latest insights and treatments to help patients and caregivers.

FDG PET Findings according to Wandering Patterns of Patients with Drug-naïve Alzheimer's Disease.

BACKGROUND AND PURPOSE: To explore anatomic substrate of specific wandering patterns in patients with Alzheimer's disease (AD) by performing positron emission tomography with 18F fluorodeoxyglucose positron emission tomography (FDG PET). METHODS: Drug-naïve AD patients with wandering (n=80) and without wandering (n=262) were recruited. First, the specific pattern of wandering type was operationally classified according to specific wandering score and clinical assessment. Second, brain FDG PET was performed and fluorodeoxyglucose (FDG) uptake differences of specific brain regions according to wandering patterns were compared to those of non-wanderers. RESULTS: In patients with pacing pattern, FDG PET showed significant lower FDG uptake in both middle cingulum and left putamen cluster compared to non-wanderers. The right precuneus and supplementary motor area in patients with random pattern and left calcarine sulcus, right calcarine sulcus, right middle cingulum, and right post central gyrus in patients with lapping pattern had significantly lower FDG uptake compared to non-wanderers. CONCLUSIONS: This study showed that wandering in patients with AD had three distinct patterns. These specific patterns showed significant lower FDG uptake in specific brain areas compared to non-wanderers.

A Multicenter, Randomized, Double-blind, Placebo-controlled Clinical Trial for Efficacy of Acetyl-L-carnitine in Patients with Dementia Associated with Cerebrovascular Disease.

BACKGROUND AND PURPOSE: Acetyl-L-carnitine (ALC) is a widely used drug for various neurodegenerative diseases including dementia. The aim of the present study was to elucidate the efficacy of ALC in dementia patients with cerebrovascular disease (vascular cognitive impairment; VCI). METHODS: Fifty-six patients were randomized to treatment with 500 mg ter in die ALC, or placebo in this 28-week, double-blind, placebo-controlled trial. The primary outcome measure was the Korean version of Montreal Cognitive Assessment (MoCA-K). RESULTS: Following treatment with ALC, the cognitive function measured by the MoCA-K was significantly improved in the ALC-treated groups. However, other secondary outcomes were not statistically significant between ALC- and placebo-treated groups. In MoCA-K analysis, attention and language sub-items significantly favored the ALC-treated group. CONCLUSIONS: Compared with placebo, treatment with ALC 1,500 mg/day produced significant changes in MoCA-K in dementia patients with VCI. ALC was well tolerated in this population. Despite the study limitations, the findings suggested the potential benefits associated with the use of ALC in dementia patients with VCI.

Improvement of Cognitive Function after Computer-Based Cognitive Training in Early Stage of Alzheimer's Dementia.

BACKGROUND AND PURPOSE: Cognitive training is known to be an effective tool in enhancing cognitive functioning. Research has also shown that playing video game improves certain aspects of visual attention and cognitive processing speed. The effect of computer-based cognitive training has not been demonstrated so far. This study therefore evaluated whether computer-based cognitive training improved the cognitive abilities in patients with early stage of Alzheimer's dementia. METHODS: Totally, 20 participants (early stage of Alzheimer's dementia) participated in this study. To test the effectiveness of computer-based cognitive training programs to cognition, all patients were randomly allocated to either an intervention group (n=10) or a control group (n=10). The intervention group regularly received 24 sessions of computer-based cognitive training, over a 12 week period. Neuropsychological examinations were conducted before and after this training period. RESULTS: After 12 weeks, the intervention group showed a significant change in language of Korean version of the Mini-Mental State Examination (K-MMSE), compared with the baseline cognitive examinations. Also, there was greater improvement in language, attention, calculation, verbal memory, and frontal function for the experimental group, as compared with controls. CONCLUSIONS: Computer-based cognitive training might have beneficial effects on the general cognitive functions in early stage of Alzheimer's dementia.

18F-FP-CIT Positron Emission Tomography for Correlating Motor and Cognitive Symptoms of Parkinson's Disease.

BACKGROUND AND PURPOSE: The aim of this paper was to investigate the utility of 18F-N-(3-fluoropropyl)-2ß-carboxymethoxy-3ß-(4-iodophenyl) nortropane (FP-CIT) positron emission tomography (PET) for evaluating the severity of Parkinson's disease (PD) according to various clinical stages, and to identify the relationship between the striatal substructure and the Unified Parkinson's Disease Rating Scale (UPDRS) motor score, cognitive symptoms through 18F-FP-CIT PET. METHODS: We retrospectively identified 542 patients with various clinical stages of PD who underwent an 18F-FP-CIT PET at our clinics. The difference between the 18F-FP-CIT PET according to the Hoehn-Yahr stage, correlation between 18F-FP-CIT PET and the UPDRS III grouped motor items, and the Korean Mini-Mental State Examination (K-MMSE) were investigated. RESULTS: As disease progressed, the right caudate and both the anterior putamen and caudate/putamen ratios exhibited a significantly lower uptake. The uptake of all striatal substructures was significantly correlated with the UPDRS total motor score. The right caudate nucleus was significantly related to both the UPDRS tremor items and the right UPDRS akinesia-rigidity items. The left caudate nucleus was related to both the UPDRS tremor items and UPDRS akinesia-rigidity items. The right anterior putamen was related to the axial items, right tremor and akinesia-rigidity items; while the left anterior putamen was related to the right tremor and right akinesia-rigidity items. Both of the posterior putamens were related to the axil items, left tremor and left akinesia rigidity items. K-MMSE was not significantly related to any striatal substructures. CONCLUSIONS: The UPDRS total motor score was significantly correlated with the uptake of all striatal substructures. However, the 18F-FPCIT uptake in specific striatal substructures was rather complexly correlated with the UPDRS motor grouped items and was not significantly related to K-MMSE. These results suggest the possibility of the complex pathophysiology of motor symptoms of PD and limitation of 18F-FPCIT PET for the evaluation of the severity of PD motor and cognitive symptoms.

Anxiety in Dementia.

Until recently, there is considerable mess regarding the nature of anxiety in dementia. However, anxiety is common in this population affecting from 8% to 71% of prevalence, and resulted in poor outcome and quality of life, even after controlling for depression. Because a presentation of anxiety in the context of dementia can be different from typical early-onset anxiety disorder, it is not easy one to identify and quantify anxiety reliably. Moreover, differentiating anxiety from the depression and/or dementia itself also can be formidable task. Anxiety gradually decreases at the severe stages of dementia and this symptom may be more common in vascular dementia than in Alzheimer's disease. Due to the lack of large randomized clinical trials, optimal treatment and the true degree of efficacy of treatment is not clear yet in this population. However, these treatments can reduce adverse impact of anxiety on patients and caregivers. This article provides a brief review for the diagnosis, evaluation and treatment of anxiety in dementia.

Quantitative EEG findings in different stages of Alzheimer's disease.

Although quantitative EEG (q-EEG) has been used in Alzheimer's disease (AD), q-EEG changes in AD are complex because of the progressive nature of this disease. The topographical spectral power and occipital peak frequency (OPF) were compared among elderly controls, patients with mild cognitive impairment (MCI), and patients with four stages of AD. In AD patients, except those with a Clinical Dementia Rating Scale (CDR) score of 0.5, OPF was lower than that of elderly controls. Compared with elderly controls, the left anterior alpha spectral power was reduced in CDR 0.5; both posterior theta spectral powers were increased and all alpha spectral powers were reduced in CDR 1; all alpha and beta spectral powers were reduced and theta spectral power was increased in CDR 2; and all alpha and beta spectral powers were reduced and all delta and theta spectral powers were increased in CDR 3. Patients with MCI exhibited a reduction in both centrotemporal, posterior delta and left anterior, centrotemporal theta fields. The Mini-Mental State Examination (MMSE) score was related to left OPF, right posterior delta and left anterior theta spectral power, in that order. This study suggests that q-EEG in MCI shows nonoverlapping features between controls and AD patients, and AD patients show dynamic changes as the disease progresses. Finally, the left OPF is the parameter most significantly correlated with MMSE score.

The Effects of Donepezil on 15-Item Geriatric Depression Scale Structure in Patients with Alzheimer Disease.

BACKGROUND/AIMS: In Alzheimer disease (AD), depression is among the most common accompanying neuropsychiatric symptoms and has different clinical manifestations when compared with early-life depression. In patients with drug-naïve AD, we tried to explore the structure of the 15-item Geriatric Depression Scale (GDS15) and the effect of donepezil on these substructures. METHODS: GDS15, cognitive function, and activities of daily living function tests were administered to 412 patients with probable AD who had not been medicated before visiting the hospital. Using principal component analysis, three factors were identified. The patients with AD who received only donepezil were retrospectively analyzed and we compared the change of cognition and GDS15 subgroup after donepezil medication. RESULTS: Our study identified three factors and revealed that the GDS15 may be comprised of a heterogeneous scale. The Barthel index was significantly correlated with factor 1 (positively) and factor 2 (negatively). The Korean version of the MMSE (K-MMSE) was significantly correlated with factor 2 and factor 3. Compared to the baseline state, K-MMSE and GDS15 showed significant improvement after taking donepezil. Among GDS15 subgroups, factor 2 and factor 3 showed significant improvement after donepezil treatment. CONCLUSIONS: These results suggest that the GDS15 may be comprised of a heterogeneous scale and donepezil differentially affects the GDS15 subgroup in AD.

The Neuropsychological Characteristics in Early Stage of Alzheimer's Patients with Depression.

BACKGROUND AND PURPOSE: Although depression is a common psychiatric symptom in Alzheimer's disease (AD), there has not been a lot of research on neuropsychological characteristics of this symptom. To determine the characteristic neuropsychological deficit in patients with depression compared to patients without depression, this study compared each neuropsychological test between AD patients with depression and without depression. METHODS: Psychotropic-naïve (drug-naïve) early stage [Clinical Dementia Rating Scale (CDR)=0.5 or CDR=1] probable AD patients with depression (n=77) and without depression (n=179) were assessed with the Seoul Neuropsychological Screening Battery, which includes measures of memory, intelligence, and executive functioning. RESULTS: AD patients with depression had lower scores on the digit forward, digit backward, calculation, and Color Word Stroop Test tests compared to AD patients without depression. CONCLUSION: Our study showed that AD patients with depression have disproportionate cognitive deficit, suggesting frontal (especially in the left dorsolateral), left hemisphere and left parietal dysfunction. Considering the neuropsychological differences between AD patients with depression and without depression, depression may have specific anatomic substrates.

Is Parkinson's Disease with History of Agent Orange Exposure Different from Idiopathic Parkinson's Disease?

BACKGROUND AND PURPOSE: During Vietnam War, many Korean soldiers were dispatched to fight in the war where they were exposed to Agent Orange. Until now, there exist only limited evidence on existence of association between exposure to Agent Orange and Parkinson's disease (PD). To elucidate the effects of Agent Orange exposure on PD, we compared the clinical characteristics and radiolabeled 18F-FP-CIT PET uptake between patients with Agent Orange exposure and patients with Agent Orange no-exposure. METHODS: We retrospectively evaluated 143 patients exposed to Agent Orange and 500 patients with no exposure to Agent Orange from our movement clinics database. The differences between clinical characteristics and pattern of 18F-FP-CIT PET uptake were investigated. RESULTS: Among Unified Parkinson's Disease Rating Scale III motor subscales, tremor at rest, rigidity, finger taps, and rapid alternating movement was significantly higher in patients exposed to Agent Orange as compared to patients with no exposure to Agent Orange. The facial expression score was significantly lower in patients exposed to Agent Orange as compared to patients with no exposure to Agent Orange. Compared to patients not exposed to Agent Orange, all basal ganglia areas (contra- and ipsilateral caudate nucleus, anterior putamen, and posterior putamen) showed a lower18F-FP-CIT uptake and higher asymmetry index of anterior and posterior putamen was found in patients exposed to Agent Orange. The caudate/putamen ratio was significantly lower in patients exposed to Agent Orange as compared to patients with no exposure to Agent Orange. CONCLUSIONS: This study showed a different clinical profile and FP-CIT PET findings between patients exposed to Agent Orange as compared to patients with no exposure to Agent Orange. This finding suggests the possibility of different pathophysiology of PD in patients exposed to Agent Orange from idiopathic PD.

Depression and Cognition.

Depression is a relatively common agonizing psychiatric disorder that affects the way we feel and think about ourselves and the world around us. Cognitive theories of depression have long posited that various cognitive biases are involved in the development and recurrence of depression. However, the current cognitive theory of depression has been reformulated and expanded from the previous cognitive model of depression based on the results from pharmacological, neuroimaging and neurocognitive studies. This review summarizes the evidence for cognitive dysfunctions in depression and the related pharmacological, neuroanatomical and genetic aspects which aim to integrate our knowledge about the cognitive aspects of depression and its treatment. The newly formulated cognitive theory of depression provides directions for future investigation to identify people at risk, to minimize recurrence, and to maximize long-term beneficial outcomes for those suffering from depression.

Neurosteroids: Cerebrospinal fluid levels for Alzheimer's disease and vascular dementia diagnostics.

A neurodegenerative disease such as Alzheimer's disease (AD) is associated with significantly higher dehydroepiandrosterone (DHEA) levels in cerebrospinal fluid (CSF). Because the human brain is known to transform DHEA into DHEA sulfate (DHEAS), 7 alpha-hydroxy-DHEA, 7 beta-hydroxy-DHEA, and 16 alpha-hydroxy-DHEA, it is possible that DHEA accumulation in the brain results from a decreased production of such metabolites. To test this hypothesis, we have measured and compared CSF levels of DHEA, DHEAS, 7 alpha-hydroxy-DHEA, 7 beta-hydroxy-DHEA, and 16 alpha-hydroxy-DHEA in 14 patients with AD, 12 controls, and eight patients with another common dementia, vascular dementia (VD). Results indicated that DHEAS CSF levels were significantly decreased in AD and VD (P < 0.007), whereas other metabolite levels were not significantly changed. Use of steroid level ratios, such as DHEA/(7 alpha-hydroxy-DHEA + 7 beta-hydroxy-DHEA), 7 beta-hydroxy-DHEA/DHEA, and DHEAS/DHEA ratios, resulted in significant differences between diseased and control patients (P < 0.0003, P < 0.002, and P < 0.002, respectively). In addition, the 7 alpha-hydroxy-DHEA/7 beta-hydroxy-DHEA ratio was significantly different between AD and VD (P < 0.0001) and could be used for differentiating AD from VD. These results indicate that, in AD and VD, increased DHEA levels are not neuroprotective and are neither better sulfated nor better hydroxylated at the 7 alpha, 7 beta, and 16 alpha positions than in controls. The results also suggest that, in AD and VD brains, the sulfotransferase and the cytochromes P450 responsible for the 7 alpha-, 7 beta-, and 16 alpha-hydroxylations of DHEA are either present at lower levels or transformed through natural polymorphism into less-efficient enzymes.

"Closing-in" phenomenon in Alzheimer's disease and subcortical vascular dementia.

BACKGROUND: The 'closing-in' phenomenon is defined as a tendency to close in on a model while copying it. This is one of several constructional apraxia observed in dementia, particularly in Alzheimer's disease (AD). The aim of this study was to investigate the usefulness of it in the differential diagnosis of AD and subcortical vascular dementia (SVD) and to clarify the factors associated with it. METHODS: We operationally defined and classified it into three types, namely overlap, adherent, and near type. We analyzed the incidence of it in patients with AD (n = 98) and SVD (n = 48). RESULTS: AD patients exhibited a significantly higher occurrence of it as compared to SVD patients. Among the different types of it, the overlap and adherent types occurred almost exclusively in AD patients. A discriminant analysis in AD subjects revealed that the scores obtained from the MMSE, CDR, Barthel index, and the Rey-Osterrieth complex figure test were correlated significantly with the occurrence of it. There was no statistical difference between the Q-EEG parameters of patients that exhibited the closing-in phenomenon and those that did not. CONCLUSIONS: This study suggests that the closing-in phenomenon is phase- and AD-specific and might be a useful tool for the differential diagnosis of AD and SVD.

Important link between dementia subtype and apolipoprotein E: a meta-analysis.

To evaluate the differential diagnostic role of apolipoprotein E (apoE) genotype in dementia, we carried out a meta- analysis of 78 case-control series, including our own new data. The dementia subjects were grouped into Alzheimer's disease (AD) and non-AD. AD patients were subgrouped according to their subtypes, and non-AD patients into vascular dementia (VD), mixed dementia (MD), and non-AD non-VD dementia (NAVD). The apoE allele frequencies and apoE genotype-specific odds ratio (OR) of each group were estimated. The (4 allele frequency was higher in all of the dementia subgroups than in the elderly controls, and the associations with (4 allele were lower in the non-AD (OR 1.8) patients than in the AD (OR 4.2) patients. However, the apoE-related risk alsovaried as a function of the subgroup, in both the AD and non-AD groups; for AD, it was dependent on the subtype of AD (OR 2.3 - 11.3), and higher in late- onset and familial cases than in early-onset and sporadic cases, respectively; among non-AD patients, it was higher in MD (OR 2.6) than in VD (OR 1.3), and intermediate in NAVD (OR 1.9), in which a significant difference was also found between Lewy body dementia (LBD) type (OR 5.1) and non-LBD type (OR 1.3). In conclusion, variability in the apoE-related risk was found in both the AD and non-AD cases, depending on the subgroup. Therefore, precise subgrouping of both AD and non-AD patients should be performed, and this information should taken into consideration when interpreting the results of apoE genotyping.

Clinical characteristics according to depression screening tools in patients with Alzheimer's disease: view from self, caregiver-reported and drug-intervention pattern.

AIM: Depression in Alzheimer's disease (AD) has different clinical manifestations from primary depression of non-demented patients. We designed the present study to explore the following: (i) to determine the clinical characteristics of patients with and without depression according to observational and subjective depression screening scale; and (ii) to examine the depression prevalence rate in patients with AD according to these criteria. METHODS: The Geriatric Depression Scale (GDS, observational scale) and Neuropsychiatry Inventory Depression subscale (NPI-D; subjective scale) were administered to 257 patients with drug-naïve probable AD. The study groups were classified into the three subgroups of "no-depression", GDS depression and NPI-DS (NPI-D significant) depression group, and the clinical characteristics of these subgroups were examined. RESULTS: The NPI-DS depression group showed lower scores on the Korean version of the Mini-Mental State Examination compared with the no-depression group, and higher NPI subdomain scores compared with other groups. The GDS depression group showed higher NPI motor subdomain scores compared with the no-depression group. Depression defined by NPI-DS was the least frequent (10.5%), and NPI-DA (NPI-D any) was the most frequent (56.4%). The prevalence of depression defined by GDS and anti-depressant usage was 30.0% and 16.0% each. The level of agreement between the screening tools determined through the kappa index was from low to moderate. CONCLUSIONS: The present study showed that different depression screening tools revealed a different prevalence and poor concordance rate among depression screening tools. Considering lower cognitive functions and higher BPSD symptoms in the NPI-DS depression group, NPI-DS could be associated with disease severity in AD patients. However, the clinical significance of GDS remains uncertain.

Missing data analysis in drug-naïve Alzheimer's disease with behavioral and psychological symptoms.

PURPOSE: To clarify the effects of missing values due to behavioral and psychological symptoms in dementia (BPSD) in Alzheimer's disease (AD) patients on the neuropsychological tests, this study describes the pattern of missing values due to BPSD, and its influence on tests. MATERIALS AND METHODS: Drug-naïve probable AD patients (n=127) with BPSD and without BPSD (n=32) were assessed with Seoul Neuropsychological Screening Battery including measures of memory, intelligence, and executive functioning. Moreover, patients were rated on Korean Neuropsychiatry Inventory (K-NPI). RESULTS: The more severe the K-NPI score, the less neuropsychological tests were assessable, leading to many missing values. Patients with BPSD were more severely demented than those without BPSD. K-NPI scores were significantly correlated with the number of missing values. The effect of BPSD was largest for tests measuring frontal functions. The replacement of the missing values due to BPSD by the lowest observed score also showed the largest effect on tests of frontal function. CONCLUSION: The global cognitive and behavior scales are related with missing values. Among K-NPI sub-domains, delusion, depressing, apathy, and aberrant motor behavior are significantly correlated for missing values. Data imputation of missing values due to BPSD provides a more differentiated picture of cognitive deficits in AD with BPSD.

Delusions of Korean patients with Alzheimer's disease: study of drug-naïve patients.

AIM: Although delusions are one of the most prominent psychiatric symptoms in Alzheimer's disease (AD), research on the subtypes, prevalence and associated factors of delusions, especially in drug (psychotropic)-naïve patients, has been limited. METHODS: Patients (n = 230) with psychotropic-naïve (drug-naïve) probable AD were assessed with the Korean Neuropsychiatric Inventory (K-NPI) delusion subscale at the time of initial presentation. After determining the four delusion subtypes (paranoid, misidentification, mixed and expansive delusion), clinical characteristics and prevalence of each type were compared. RESULTS: Delusions were present in 63 patients (27.4%). Among those patients, paranoid delusions were the most common type of delusion (38, 60.3%), followed by misidentification delusions (12, 19.0%), then mixed delusions (11, 17.5%). Expansive delusions are rare in drug-naïve probable AD patients. Compared with paranoid delusions, misidentification and mixed delusions appeared at a later stage, and were associated with greater cognitive impairment. Mixed delusions were associated with hallucinations. CONCLUSIONS: This study showed that delusions are associated with global cognitive dysfunction. Although paranoid delusions are the most common, misidentification and mixed delusions comprised significant portions of delusions in AD patients, and appeared in the later stages of dementia.