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.

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.

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.

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.

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)-2β-carboxymethoxy-3β-(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.

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.

Neurocognitive Model of Delusion: Two-Factor Theory

The underlying nature of delusions remains unclear despite their importance in psychopathology. Here we present a review of the neurocognitive model of delusions from a cognitive neuroscience viewpoint. There have been numerous reports on cognitive impairments in delusional patients, such as in their reasoning, attention, metacognition, and attribution biases. These findings have been incorporated into several cognitive models that aim to explain the formation, maintenance, and content of delusion. Although delusions are commonly conceptualized as beliefs, not all models make reference to models of normal belief formation. This review focused on two-factor theory models that make a distinction between factors that explain the content of delusions and those that explain their presence. This cognitive theory that includes the 'pragmatic pathology' of delusions can address both the phenomenology and treatment of delusion-related distress.

Late-Onset Psychosis; Is It Real?

The nature of late-onset psychosis in the absence of a dementia or secondary to organic dysfunctions in the fifth decade of life and beyond is contentious and unresolved. Different terminologies, diagnostic criteria and age cut-offs have been applied to late-onset psychosis, which have stymied clinicians and researchers. No official diagnostic designation for patients with late-onset psychosis is included in the current psychiatric diagnostic system (Diagnostic and Statistical Manual of Mental Disorders-V, International Classification of Diseases-10). The validity of this diagnostic exclusion has been questioned. Despite these problems, a relatively consistent clinical picture has reported. However, many questions remain regarding the underlying etiology, pathophysiological mechanisms, treatment and prognosis. Whether late-onset psychosis is distinct from schizophrenia and whether it might be a harbinger of dementia are unclear. Recent studies have suggested an underlying biological pathophysiology of late-onset psychosis.

Wandering in Dementia

Wandering is acknowledged as one of the most complex, challenging, and potentially dangerous dementia-related behaviors, and can result in elopement, injury, and even death. For the healthy people, walking is a common and a pleasurable leisure activity. However, wandering in dementia may be an exhausting behavior for caregivers and raise safety concerns. The term 'wandering' covers different types of behavior, including aimless movement without a discernible purpose. Although with respect to the etiology of wandering, biological, psychosocial and person-environment interaction has been suggested, the etiology of wandering is poorly understood. Although it is possible that management of coexistent psychopathology would help to ameliorate this problematic behavior, evidence on the effectiveness of pharmacological and non-pharmacological interventions is limited.

Understanding of Antipsychotics in Elderly Patients with Dementia

Elderly patients affected with dementia frequently accompany delusions, hallucinations and other psychotic symptoms. As such, these patients are commonly prescribed antipsychotic medications for the treatment of psychosis. However, in recent years, the use of antipsychotics has been widely debated for reasons concerning their efficacy and safety in these patients. Conventional antipsychotics have been widely used for behavioral psychological symptoms in dementia (BPSD) in the past. Atypical antipsychotics showed an efficacy superior to placebo in randomized studies in BPSD treatment, with a better tolerability profile versus conventional drugs. However, in 2002, the Food and Drug Administration alert the possible increase in cerebrovascular adverse events after using antipsychotics and consequent studies reported various adverse (including fatalities) events. Notwithstanding controversial data, antipsychotics are probably the best option for short-term treatment of severe BPSD. However, due to possible serious adverse events, long-term therapy is not recommended and clinician should decrease the dosage and discontinue treatment wherever a sufficient control of behavioral symptoms has been obtained. Before prescribing an antipsychotic drug, the possible risk factor should be structurally reviewed and monitored. The aim of this review is to asses systematically the efficacy and safety concern of antipsychotics in treating elderly patients with BPSD. And we also review how and what we should prescribe and monitor, if once antipsychotic medication is decided.

The Relationship between Geriatric Depression Scale Structure and Cognitive-Behavioral Aspects in Patients with Alzheimer's Disease

BACKGROUND AND PURPOSE: Although the 15-item Geriatric Depression Scale (GDS15) is a widely used depression screening questionnaire, the implications of the GDS15 in patients with Alzheimer's disease (AD) are questionable. We designed this study to explore the GDS15 factor structure and the relationships between these factors and cognitive-behavioral aspects. METHODS: The GDS15, cognitive function tests, and the Korean-Neuropsychiatry Inventory were administered to 310 patients with probable AD, who were not medicated before visiting the hospital. Three factors were identified by principal components analysis. A bivariate correlation analysis was conducted to determine the relationships between factors and neurocognitive and behavior symptoms. RESULTS: Factor 2 was correlated with the Korean Boston Naming Test, calculating ability, the go-no-go test, the Controlled Oral Word Association Test (COWAT), the Color Word Stroop Test (CWST; words and color), aggression, depression, and apathy. Factor 3 was correlated with calculating ability, the Seoul Verbal Learning Test, immediate recall, copy, and delayed recall on the Rey-Osterieth Complex Figure Test, contrasting on the COWAT, and words and delusion on the CWST. We identified three factors and revealed that the GDS15 may be comprised of a heterogeneous scale. CONCLUSIONS: These results suggest that the GDS15 may be comprised of a heterogeneous scale and suggest multi-dimensional properties of the GDS15 in patients with AD.

Depression in Alzheimer's Disease

Depression is one of the most common psychiatric complications of Alzheimer disease (AD), affecting from 30% to 50% of prevalence, with most estimates in the 20-30% range. Because of having a presentation in the context of AD that differs from typical early-onset depression, it is not easy one to detect and quantify reliably, and can be difficulty to differentiate depression from the other neuropsychiatric symptoms of AD. Due to the lack of large randomized trials, optimal treatment and the true degree of efficacy remains undetermined. However, these treatments can reduce adverse impact of depression on patients and caregivers. This article provides a practical discussion of the diagnosis, evaluation, differential diagnosis and treatment of depression in AD for the clinician.

Delusions in Alzheimer's Disease

Alzheimer's disease (AD) is associated with cognitive and functional impairment as well as neuropsychiatric complications, including psychotic symptoms such as delusions and hallucinations. Recent studies strongly suggest that delusions should be separated from hallucinations. While AD with delusions is a phenotypically distinct from AD without delusions, subtypes of delusions may also define further distinct clinical entities. There has been also considerable debate as to whether delusions in patients with AD differ etiologically, phenomenologically, and therapeutically from delusions in other primary psychiatric illnesses. In other words, whether they are caused by changes to key areas of the brain that have been linked to the presence of delusions. This has led to speculation that these symptoms may respond better to certain drugs such as cholinesterase inhibitors. Integrating the epidemiology, clinical phenomenology, neuropathological and genetic literature for delusions in AD allows us to speculate on pathophysiology and is essential to making progress in the area of delusions in AD.

Neuropsychological Characteristics of Wandering in Patients with Drug-naive Alzheimer's Disease

BACKGROUND: Wandering represents one of a major problem occurring in patients with Alzheimer's disease (AD). To find the disproportionate neuropsychological deficit and behavioral psychological symptoms in dementia (BPSD) of AD patients with wandering compared to AD patients without wandering, this study examined the set of neuropsychological tests and caregiver-administered neuropsychiatric inventory (CGA-NPI). METHODS: Psychotropic-naive (drug-naive) probable AD patients with wandering (64) and without wondering (278) were assessed with the Seoul Neuropsychological Screening Battery, which included measures of memory, intelligence, and executive functioning. RESULTS: Patients with wandering had lower scores in the Rey-Osterrieth Complex Figure copy, Fist-edge-palm, Alternating hand movement tests compared to patients without wandering. The degree of wandering in AD patients was significantly related with CGA-NPI subdomains of aggression, disinhibition, depression, and delusions. CONCLUSION: This study showed that 1) AD patients with wandering have disproportionately cognitive deficit suggesting frontal and right parietal dysfunctions, 2) wanderings are related with specific BPSD. Considering these results, AD patients with wandering may have specific neuronal anatomic substrates related with pathology of Alzheimer.

Missing Data Analysis in Drug-Naive 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-naive 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.

Clinical Characteristics of Behavioral and Psychological Symptoms in Patients with Drug-naive Alzheimer's Disease

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are less well-defined aspects of Alzheimer's disease (AD). We designed this study to explore the followings: 1) the clinical profiles of BPSD 2) the clustered-groups domains of the Korean-Neuropsychiatric Inventory (K-NPI) assessment of BPSD 3) the clinical characteristics of the clustered-groups of BPSD in patients with drug-naive probable AD. METHODS: Descriptive and cluster analyses of the 12 K-NPI domains were done in 220 patients with drug-naive probable AD. After clustering these domains, characteristics of these positive symptoms clustered-group of patients were compared with the negative symptoms groups of patients. RESULTS: The mean Korean-Mini Mental Status Examination (K-MMSE), Clinical Dementia Rating (CDR) scale, and K-NPI scores were 15.0, 1.6, and 14.2, respectively. The CDR and K-MMSE scores correlated with total K-NPI scores, and depression was the most common symptom. According to cluster analysis, five major clusters were identified. Using the associated neuropsychological dysfunctions, characteristics of each group were defined. CONCLUSIONS: This study identified the clustered-domains for K-NPI, and suggested the possible anatomical substrates for these groups in drug-naive AD patients. These attempts may clarify the complex and bizarre behavioral and psychological symptoms as more neurologically relevant symptoms.

Whether Alzheimer's Disease is Responsive to a Single Oral Dose of Donepezil and this Response is Predictive Factor in Alzheimer's Disease

OBJECTIVES: Though a proportion of Alzheimer's disease(AD) patients treated with donepezil have shown positive response on cognition, but the responders' characteristics are still uncertain. This study attempts to identify whether a single oral dose of donepezil(5mg) can change cognition and the relationship between single dose responder items and long-term responder are examined. METHODS: Twenty-three AD patients for single donepezil challenge study group and eleven AD patients for controls were participated in the study. Seven days after baseline study for neuropsychological test and EEG, same studies were rechecked after donepezil medication in study group. In donepezil study groups, 12 weeks after donepezil medication, neuropsychological test and EEG were rechecked. RESULTS: After single donepezil challenge, forward digit span, Rey-Osterrieth Complex Figure Test copy, SVLT delayed recall were significantly improved, and beta spectra power in anterior, theta spectra power in posterior field were significantly decreased. According to linear regression analysis, forward digit span after single donepezil challenge was significantly positive correlated with long-term responders. CONCLUSIONS: This study suggests that single donepezil medication can significantly change cognitive functions and EEG in AD patients. Among these responsive items, forward digit span was significantly correlated with long-term responder.