Behavioral Symptoms In Alzheimer's Disease Research Articles

Behavioral and Neurophysiological Implications of Pathological Human Tau Expression in Serotonin Neurons.

Alzheimer's disease (AD) is a progressive degenerative disorder that results in a severe loss of brain cells and irreversible cognitive decline. Memory problems are the most recognized symptoms of AD. However, approximately 90% of patients diagnosed with AD suffer from behavioral symptoms, including mood changes and social impairment years before cognitive dysfunction. Recent evidence indicates that the dorsal raphe nucleus (DRN) is among the initial regions that show tau pathology, which is a hallmark feature of AD. The DRN harbors serotonin (5-HT) neurons, which are critically involved in mood, social, and cognitive regulation. Serotonergic impairment early in the disease process may contribute to behavioral symptoms in AD. However, the mechanisms underlying vulnerability and contribution of the 5-HT system to AD progression remain unknown. Here, we performed behavioral and electrophysiological characterizations in mice expressing a phosphorylation-prone form of human tau (hTauP301L) in 5-HT neurons. We found that pathological tau expression in 5-HT neurons induces anxiety-like behavior and alterations in stress-coping strategies in female and male mice. Female mice also exhibited social disinhibition and mild cognitive impairment in response to 5-HT neuron-specific hTauP301L expression. Behavioral alterations were accompanied by disrupted 5-HT neuron physiology in female and male hTauP301L expressing mice with exacerbated excitability disruption in females only. These data provide mechanistic insights into the brain systems and symptoms impaired early in AD progression, which is critical for disease intervention.

Behavioral or neuropsychiatric symptoms of Alzheimer's disease: from psychopathology to pharmacological management.

Neuropsychiatric or behavioral symptoms of dementia encompass a series of disorders, such as anxiety, depression, apathy, psychosis, and agitation, all commonly present in individuals living with dementia. While they are not required for the diagnosis of Alzheimer's disease (AD), they are ubiquitously present in all stages of the disease, contributing to negative clinical outcomes, including cognitive decline, functional disability, and caregiver burden. Neuropsychiatric symptoms have been conceptualized not only as risk factors but as clinical markers of decline along the AD spectrum. The concept of "mild behavioral impairment", the behavioral correlate of mild cognitive impairment, has been proposed within this framework. The first steps in the management of behavioral symptoms in AD involve defining the target and investigating potential causes and/or aggravating factors. Once these factors are addressed, non-pharmacological approaches are preferred as first-line interventions. Following the optimization of anticholinesterase treatments, specific pharmacological approaches (e.g., antidepressants, antipsychotics) can be considered weighing potential side effects.

Alterations of Audiovisual Integration in Alzheimer's Disease.

Audiovisual integration is a vital information process involved in cognition and is closely correlated with aging and Alzheimer's disease (AD). In this review, we evaluated the altered audiovisual integrative behavioral symptoms in AD. We further analyzed the relationships between AD pathologies and audiovisual integration alterations bidirectionally and suggested the possible mechanisms of audiovisual integration alterations underlying AD, including the imbalance between energy demand and supply, activity-dependent degeneration, disrupted brain networks, and cognitive resource overloading. Then, based on the clinical characteristics including electrophysiological and imaging data related to audiovisual integration, we emphasized the value of audiovisual integration alterations as potential biomarkers for the early diagnosis and progression of AD. We also highlighted that treatments targeted audiovisual integration contributed to widespread pathological improvements in AD animal models and cognitive improvements in AD patients. Moreover, investigation into audiovisual integration alterations in AD also provided new insights and comprehension about sensory information processes.

Exercise Reverses Amyloid β-Peptide-Mediated Cognitive Deficits in Alzheimer's Disease Mice Expressing Mutant Presenilin-2.

The molecular mechanisms by which physical exercise produces beneficial effects on pathologic features and behavioral symptoms of Alzheimer's disease (AD) are not well understood. Herein, we examined whether regular moderate exercise could improve cognitive function and produce transcriptomic responses in the brain. Four groups of mice were studied: nontransgenic control, mice expressing the human presenilin-2 wild type, mice expressing the human presenilin-2 with the N141I mutation (Tg-PS2m), and Tg-PS2m that were subjected to treadmill exercise (TE) at a speed of 10 m·min-1 for 50 min·d-1, 5 d·wk-1, for 6 wk (Tg-PS2m/Ex). Tg-PS2m/Ex mice exhibited increased preference in exploring a novel object than Tg-PS2m in the novel object recognition test, whereas differences observed in the water maze test and passive avoidance test were not significant. Western blot and histological analyses using amyloid oligomer (A11) and β-amyloid (6E10) antibody indicated that amyloid oligomer-reactive bands and plaque deposition in the hippocampus were reduced, although not significantly, after TE. Transcriptomic (RNA-sequencing) analysis and subsequent protein analysis revealed that the cell cycle regulatory gene, Cdc28 protein kinase regulatory subunit 2 (Cks2), was decreased, and the cell cycle- and apoptotic cell death-related factors, including cyclin D1, proliferating cell nuclear antigen, and cleaved caspase-3, were increased in the hippocampus of Tg-PS2m, whereas TE reversed their altered expression. The results support the hypothesis that the pathologic features and behavioral symptoms of AD caused by accumulation of amyloid β-peptide in hippocampus, causing aberrant cell cycle reentry and apoptosis, can be reversed by regular exercise.

Caring for Behavioral Symptoms of Dementia (CBD): A New Investigation into Cannabidiol for the Treatment of Anxiety and Agitation in Alzheimer's Dementia

<h3>Introduction</h3> Alzheimer's disease (AD) is a debilitating neurodegenerative disease accounting for 60-80% of dementia cases worldwide. In the United States alone, 13.8 million Americans are predicted to develop AD by 2050. The neuropsychiatric symptoms (NPS) of dementia affect up to 97% of AD patients over the course of their disease. A common NPS is agitation, characterized by problem behaviors that include combativeness and restlessness. Agitation is commonly associated with greater caregiver burden, shorter time to institutionalization, and anxiety. Anxiety symptoms affect 25-70% of the dementia population, and this wide range speaks to the inability to discern anxiety from agitation. Despite the pervasiveness of anxiety and agitation in the AD population, there are no FDA-approved medications that treat the behavioral symptoms of AD. Current treatments for these symptoms include time-intensive behavioral therapies and prescription of off-label antipsychotic medications that include an FDA warning of increased mortality in this population. Thus, the need for developing safe and efficacious treatments for anxiety and agitation in AD is dire. One potential treatment is cannabidiol (CBD), the major non-intoxicating constituent of cannabis sativa and industrial hemp, a variety of the cannabis plant that contains <0.3% delta9-tetrahydrocannabinol (THC), the main intoxicating constituent in cannabis, by weight. CBD modifies the endocannabinoid system and is thought to modulate effects via the 5-HT serotonergic system, μ-opioid receptors, and TRPV1/TRPV2 receptors. These interactions seem to result in an anxiolytic effect, as studies demonstrate CBD's ability to attenuate acute responses to stress in rats, act as a panicolytic in rats, and attenuate anxiety in humans. The utilization of CBD may extend beyond its role as an anxiolytic, as preclinical studies suggest widespread therapeutic impacts of CBD, including its ability to offer neuroprotective properties and inhibit tau hyperphosphorylation. Despite pre-clinical and animal evidence that CBD could modify neurodegeneration and behavioral symptoms in AD, no human clinical trials have investigated the impact of CBD on anxiety or agitation in AD. The present open-label clinical trial seeks to address this gap in knowledge by assessing the efficacy and tolerability of a high-CBD/low-THC sublingual solution as a treatment for anxiety and agitation in older adults with Alzheimer's disease. <h3>Methods</h3> An 8-week open-label clinical trial of an industrial hemp-derived custom-formulated high-CBD/low-THC sublingual solution developed by Dr. Staci Gruber, PhD, at McLean Hospital. We will recruit 12 research participants with mild to moderate Alzheimer's dementia and behavioral symptoms of anxiety with or without agitation. Our primary efficacy outcome measures are the anxiety domain of the Neuropsychiatric Inventory-Clinician Version (NPI-C) and the Generalized Anxiety Disorder-7 Item Scale (GAD-7). Our secondary safety outcome measures include continuous monitoring for serious adverse events and medication side effects, cognitive decline estimates from the Mini Mental Status Exam (MMSE), and the emergence of possible delirium from the 3D-Confusion Assessment Method (3D-CAM). Agitation and aggression domains on the NPI-C, scores on the Cohen-Mansfield Agitation Inventory (CMAI), and caregiver burden estimates from the Zarit Caregiver Burden Interview will be included as additional exploratory measures. <h3>Results</h3> Dr. Gruber's team is currently conducting a clinical trial for the treatment of anxiety in adults with moderate to severe anxiety using a similar custom-formulated high-CBD/low-THC sublingual solution. Preliminary analyses of Dr. Gruber's ongoing trial reveal that subjects experience significant reduction in anxiety symptoms along with improvements in mood, quality of life, and executive function over 4 weeks of treatment. Given these data and evidence of CBD's anxiolytic effects, we hypothesize that twice daily treatment with a high-CBD/low-THC solution in older adults with AD for 8 weeks will be associated with a statistically significant reduction in anxiety and agitation symptoms compared to baseline, as measured by our efficacy outcome measurements. We predict that the solution will be well-tolerated by the study population, as measured by our safety outcome measurements. <h3>Conclusions</h3> We seek a safe and effective treatment for the neuropsychiatric symptoms of anxiety and agitation in older adults with AD. With no current FDA-approved treatments for these behavioral symptoms, patients with AD risk ineffective therapies or mortality-associated antipsychotic treatments to address their NPS. Treating anxiety and agitation in these patients not only alleviates their symptoms but could also reduce caregiver burden and lengthen the time to institutionalization. CBD is a promising anxiolytic treatment that could advance our available treatment options for anxiety and agitation in AD. <h3>Funding</h3> The Spier Family Foundation

A probabilistic atlas of locus coeruleus pathways to transentorhinal cortex for connectome imaging in Alzheimer's disease

According to the latest Braak staging of Alzheimer's disease (AD), tau pathology occurs earliest in the brain in the locus coeruleus (LC) of the brainstem, then propagates to the transentorhinal cortex (TEC), and later to other neocortical regions. Recent animal and in vivo human brain imaging research also support the trans-axonal propagation of tau pathology. In addition, neurochemical studies link norepinephrine to behavioral symptoms in AD. It is thus critical to examine the integrity of the LC-TEC pathway in studying the early development of the disease, but there has been limited work in this direction. By leveraging the high-resolution and multi-shell diffusion MRI data from the Human Connectome Project (HCP), in this work we develop a novel method for the reconstruction of the LC-TEC pathway in a cohort of 40 HCP subjects carefully selected based on rigorous quality control of the residual distortion artifacts in the brainstem. A probabilistic atlas of the LC-TEC pathway of both hemispheres is then developed in the MNI152 space and distributed publicly on the NITRC website. To apply our atlas on clinical imaging data, we develop an automated approach to calculate the medial core of the LC-TEC pathway for localized analysis of connectivity changes. In a cohort of 138 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we demonstrate the detection of the decreased fiber integrity in the LC-TEC pathways with increasing disease severity.

Alzheimer dementia: Starting, stopping drug therapy.

Alzheimer disease is the most common type of dementia. Two classes of cognition-enhancing drugs are approved to treat the symptoms, and both have provided modest benefit in clinical trials. Psychotropic drugs are sometimes used off-label to treat behavioral symptoms of Alzheimer disease. All these medications should be continuously evaluated for clinical efficacy and, when appropriate, discontinued if the primary benefit--preservation of cognitive and functional status and a reduction in behaviors associated with dementia--is no longer being achieved.

Serotonin 5-HT6 Receptor Antagonists in Alzheimer's Disease: Therapeutic Rationale and Current Development Status.

Alzheimer's disease (AD) is the most common cause of dementia in elderly people. Because of the lack of effective treatments for this illness, research focused on identifying compounds that restore cognition and functional impairments in patients with AD is a very active field. Since its discovery in 1993, the serotonin 5-HT6 receptor has received increasing attention, and a growing number of studies supported 5-HT6 receptor antagonism as a target for improving cognitive dysfunction in AD. This article reviews the rationale behind investigations into the targeting of 5-HT6 receptors as a symptomatic treatment for cognitive and/or behavioral symptoms of AD. In addition to describing the available clinical evidence, this article also describes the purported biochemical and neurochemical mechanisms of action by which 5-HT6 receptor antagonists could influence cognition, and the preclinical data supporting this therapeutic approach to AD. A large number of publications describing the development of ligands for this receptor have come to light and preclinical data indicate the procognitive efficacy of 5-HT6 receptor antagonists. Subsequently, the number of patents protecting 5-HT6 chemical entities has continuously grown. Some of these compounds have successfully undergone phase I clinical studies and have been further evaluated in clinical phase II trials with variable success. Phase II studies have also revealed the potential of combining 5-HT6 receptor antagonism and cholinesterase inhibition. Two of these antagonists, idalopirdine and RVT-101, have been further developed into ongoing phase III clinical trials. Overall, 5-HT6 receptor antagonists can reasonably be regarded as potential drug candidates for the treatment of AD.

Agitation and Irritability in Alzheimer's Disease: Evidenced-Based Treatments and the Black-Box Warning.

More than five million Americans suffer from Alzheimer's disease (AD), and this number is expected to triple by 2050. While impairments in cognition, particularly memory, are typically the defining features of the clinical syndrome, behavioral symptoms are extremely common, affecting up to 90% of patients. Behavioral symptoms in AD can be difficult to manage and may require a combination of non-pharmacological and pharmacological approaches. The latter is complicated by FDA "black-box warnings" for the medication classes most often used to target these symptoms, and currently there are initiatives in place to limit their use. In this review, we describe common behavioral symptoms of AD-with a particular focus on the challenging symptoms of "agitation" and "irritability"-and discuss evidence-based approaches to their management. Ultimately, multidimensional approaches must be tailored to the patient and their environment, though evidence-based practices should define the treatment of agitation and irritability in AD.

A randomized controlled trial of music therapy in managing behavioral symptoms in Alzheimer disease

A randomized controlled trial of music therapy in managing behavioral symptoms in Alzheimer disease

Sleep problems associated with behavioral and psychological symptoms as well as cognitive functions in Alzheimer's disease.

Background and PurposeIt has been shown that sleep problems in Alzheimer's disease (AD) are associated with cognitive impairment and behavioral problems. In fact, most of studies have founded that daytime sleepiness is significantly correlated with cognitive decline in AD. However, a few studies have also shown that nighttime sleep problems are associated with cognitive function and behavioral symptoms in AD. Accordingly, the aim of this study was to evaluate the effects of nighttime sleep on cognition and behavioral and psychological symptoms of dementia (BPSD) in AD.MethodsThe study population comprised 117 subjects: 63 AD patients and 54 age- and sex-matched non-demented elderly subjects. Detailed cognitive functions and behavioral symptoms were measured using the Seoul Neuropsychological Screening Battery (SNSB) and the Korean version of the Neuropsychiatric Inventory (NPI-K). Sleep characteristics were evaluated using the Korean version of the Pittsburgh Sleep Quality Index (PSQI-K). The correlations between PSQI-K and SNSB scores and between PSQI-K and NPI-K scores were analyzed.ResultsIn AD patients, sleep latency was found to be negatively correlated with praxis (p=0.041), Rey-Osterrieth Complex Figure Test (RCFT) immediate recall (p=0.041), and RCFT recognition (p=0.008) after controlling for age and education, while sleep duration and sleep efficiency were positively correlated with praxis (p=0.034 and p=0.025, respectively). Although no significant correlation was found between PSQI-K and NPI-K scores, sleep disturbance and total PSQI-K scores were found to be significantly associated with apathy/indifference in AD.ConclusionsSleep problems such as prolonged sleep duration, sleep latency, and poor sleep efficiency in AD patients were correlated with cognitive dysfunction, and especially frontal executive and visuospatial functions, and BPSD. These findings suggest that treatment of nighttime sleep problems might improve cognition and behavioral symptoms in AD patients.

Targeting neurogenesis ameliorates danger assessment in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) affects 13% of the population over the age of 65. Behavioral and neuropsychiatric symptoms are frequent and affect 80% of patients. Adult hippocampal neurogenesis, which is impaired in AD, is involved in learning and memory. It remains unclear, however, whether increasing adult neurogenesis improves behavioral symptoms in AD. We report that in the 3xTgAD mouse model of AD, chronic Wnt3a overexpression in the ventral hippocampus dentate gyrus (DG) restored adult neurogenesis to physiological levels. The restoration of adult neurogenesis led to full recovery of danger assessment impairment and the effect was blocked by ablation of neurogenesis with X-irradiation. Finally, using a bed nucleus of stria terminalis (BNST) mRNA expression array, we found that the expression of the 5-HT1A receptor in 3xTgAD mice is selectively decreased and normalized by Wnt3a overexpression in the ventral hippocampus DG, and this normalization is neurogenesis dependent. These findings indicate that reestablishing a functional population of hippocampal newborn neurons in adult AD mice rescues behavioral symptoms, suggesting that adult neurogenesis may be a promising therapeutic target for alleviating behavioral deficits in AD patients.

Safety and efficacy of ORM-12741 on cognitive and behavioral symptoms in patients with Alzheimer's disease: A randomized, double-blind, proof-of-concept study

Safety and efficacy of ORM-12741 on cognitive and behavioral symptoms in patients with Alzheimer's disease: A randomized, double-blind, proof-of-concept study

NIA Commentary: Translational Issues in Alzheimer’s Disease Drug Development

Alzheimer's disease (AD) mainly affects elderly individuals, and because of the aging of populations worldwide, this disorder is reaching epidemic proportions, with an enormous human and economic burden. Effective treatments are urgently needed to treat the cognitive and behavioral symptoms of AD and to slow its progression. The National Institute on Aging (NIA) has developed a number of grant and contract mechanisms to support this effort. The NIA has an exploratory R21 grant program (http://grants.nih.gov/grants/guide/pa-files/PAS-10-151.html) for early AD drug discovery, in collaboration with the Alzheimer's Drug Discovery Foundation, and a program for preclinical drug development of small molecules, biologics, or other compounds for the treatment of AD, mild cognitive impairment (MCI), and age-related cognitive decline, using the U01 cooperative agreement mechanism (http://grants.nih.gov/grants/guide/pa-files/PAR-08-266.html). Examples of funded grants include studies of small molecule neurotrophin mimetics, novel anti-inflammatory compounds, and τ-aggregation inhibitors. The NIA provides investigational new drug-enabling toxicology services for novel AD therapeutic drugs through a contract, which is open to individual investigators or small companies. The NIA also participates in many trans-NIH programs including program announcements for drug discovery for nervous system diseases utilizing the R21 and R01 grant mechanisms, Small Business Innovation Research/Small Business Technology Transfer Research grant programs, and translational programs through the NIH Neuroscience Blueprint (http://neuroscienceblueprint.nih.gov/). The overall goal of these translational research initiatives is to provide support to investigators from academia and the biotechnology sector to increase the number of drug candidates that can be clinically tested. Clinical development can be done through partnership with industry or through NIA-supported clinical trial programs. These include a program announcement for pilot clinical trials (http://grants.nih.gov/grants/guide/pa-files/PAR-11-100.html), large R01 grant applications, and the Alzheimer's Disease Cooperative Study, an NIA-supported clinical trials consortium. Examples of pilot trials include intranasal insulin in people with AD/MCI, and carvedilol in AD, which is an anti-hypertensive drug that was re-purposed for AD, with support from the U01 program. Through these programs, the NIA hopes to facilitate the discovery, development, and testing of new therapeutic agents for AD, MCI, and age-related cognitive impairment. There are very few drugs that have been approved by the Food and Drug Administration for the treatment of AD. There have been many recent clinical trials of potential new therapeutic agents, but none has been shown to be effective in providing symptomatic benefit or slowing disease progression. This indicates the critical nature of the NIA/NIH programs in trying to facilitate getting new therapies out to the patients and families who desperately need them.

Disturbed neurotransmitter transporter expression in Alzheimer's disease brain.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and behavioral and psychological symptoms of dementia. An imbalance of different neurotransmitters--glutamate, acetylcholine, dopamine, and serotonin--has been proposed as the neurobiological basis of behavioral symptoms in AD. The molecular changes associated with neurotransmission imbalance in AD are not clear. We hypothesized that altered reuptake of neurotransmitters by vesicular glutamate transporters (VGLUTs), excitatory amino acid transporters (EAATs), the vesicular acetylcholine transporter (VAChT), the serotonin reuptake transporter (SERT), or the dopamine reuptake transporter (DAT) are involved in the neurotransmission imbalance in AD. We tested this hypothesis by examining protein and mRNA levels of these transporters in postmortem prefrontal cortex from 10 AD patients and 10 matched non-AD controls. Compared with controls, protein and mRNA levels of VGLUTs, EAAT1-3, VAChT, and SERT were reduced significantly in AD. Expression of DAT and catechol O-methyltransferase was unchanged. Reduced VGLUTs and EAATs may contribute to an alteration in glutamatergic recycling, and reduced SERT could exacerbate depressive symptoms in AD. The reduced VAChT expression could contribute to the recognized cholinergic deficit in AD. Altered neurotransmitter transporters could contribute to the pathophysiology of AD and are potential targets for therapy.

Depression in Alzheimer's Disease. Pathophysiology, Diagnosis, and Treatment

Depression is a comorbid condition in Alzheimer's disease (AD) with negative consequences in patients and caregivers. Pathophysiology and optimal treatment are matters to be elucidated. A search of articles dealing with depression in AD was conducted in MEDLINE with special attention to epidemiology, pathophysiology, and treatment. Depression may predate dementia and tends to occur in up to 50% of AD patients with a decrease of noradrenalin and serotonin in the brain being the most plausible cause. Only 7 small double-blind randomized placebo-controlled clinical trials with antidepressants in AD patients with depression were found: 4 with sertraline, 1 with fluoxetine, 1 with imipramine, and another one with clomipramine. The total number of treated patients was 318. The weighted odds ratio (OR) was calculated with the method of Mantel-Haenszel. Both tricyclic antidepressants and selective serotonin reuptake inhibitors are better than placebo in treating depression in AD (weighted OR: 1.82, 95% CI: 1.13-2.96), with sertraline being one of the most used drugs. The differences were significant in 2 trials and not significant in four. The magnitude of effect is globally modest. Moreover, it is noteworthy mentioning the high rates of response to placebo in most studies. Depression is one of the most frequent behavioral symptoms in AD. Although antidepressants may work in AD, given the small number of patients treated, the effect is unclear. Further large randomized controlled clinical trials are warranted in order to know the best drug to begin with and the actual degree of efficacy.

Differential involvement of hippocampal serotonin1A receptors and re-uptake sites in non-cognitive behaviors of Alzheimer’s disease

Previous studies have shown extensive serotonergic deficits in the hippocampus of Alzheimer's disease (AD) patients. However, it is unclear whether such deficits play a role in non-cognitive, neuropsychiatric behaviors that occur frequently in AD and cause significant caregiver distress. In this study, we aimed to correlate serotonergic markers in the AD hippocampus with neuropsychiatric behaviors. Using postmortem hippocampal homogenates from aged controls as well as a cohort of longitudinally assessed AD patients, measurements of 5-HT(1A) receptors, 5-HT(2A) receptors, and serotonin re-uptake (5-HTT) sites were performed by binding with (3)H-labeled 8-OH-DPAT, ketanserin, and citalopram, respectively. Alterations of 5-HT(1A) receptors and 5-HTT were found to be differentially involved in neuropsychiatric behaviors, with loss of 5-HT(1A) receptors specifically correlated with depressive symptoms, while 5-HTT sites were preserved or up-regulated in patients with aggressive behaviors. Our data suggest that neuropsychiatric behaviors in AD share certain neurochemical features with psychiatric disorders like major depression and that serotonergic drugs used in psychiatric disorders may also be efficacious against behavioral symptoms in AD.

Non-pharmacological and pharmacological treatment of the cognitive and behavioral symptoms of Alzheimer disease

This paper discusses the various pharmacological and behavioral treatments for the cognitive, emotional, and behavioral symptoms of Alzheimer disease (AD). The medications that are currently FDA-approved for the treatment of the cognitive/functional deficits of AD will first be discussed. Next, neuropsychiatric behavioral disturbances, including hallucinations and delusions, agitation and aggression, activity disturbances, depression, and anxiety will be described along with treatment interventions. Sleep disturbance and its treatment in AD and the issue of fitness to drive a motor vehicle are also reviewed. Principles of behavioral management, tips for communication, and recommendations for caregivers are discussed. Lastly, risk and protective factors and their relevance to delaying the expression of dementia are also examined.

Two dimensions of anosognosia in patients with Alzheimer's disease: Reliability and validity of the Japanese version of the Anosognosia Questionnaire for Dementia (AQ‐D)

Although a number of studies have examined anosognosia of cognitive deficits in patients with Alzheimer's disease (AD), not much is known about the anosognosia of behavioral symptoms in AD. The aims of the present study were to establish a Japanese version of the Anosognosia Questionnaire-Dementia (AQ-D) and to examine its factor structure, reliability and validity, and to identify the effects of various variables on the AQ-D. Factor structure, internal consistency, test-retest reliability and concurrent validity of the Japanese version of the AQ-D were analyzed. Multiple regression was then done using the results of the AQ-D as dependent variables and entering all relevant predictor variables. Both the internal consistency and the test-retest reliability of the AQ-D were excellent. Factor analysis indicated four factors: anosognosia of basic and instrumental activities of daily living; that of episodic memory and orientation; that of disinhibited behaviors; and that of apathy and depression. The first two factors were regarded as anosognosia of cognitive deficits and were associated with Mini-Mental State Examination scores, while the latter two factors were regarded as anosognosia of behavioral symptoms and were associated with the Neuropsychiatric Inventory (NPI) score. A dissociation between the two domains of anosognosia was confirmed, namely of cognitive deficits and of behavioral symptoms using the Japanese version of the AQ-D. The knowledge that various factors may have different effects on different domains of anosognosia in patients with AD may serve as useful information for clinicians assessing anosognosia in AD.

Galantamine Treatment of Problematic Behavior in Alzheimer Disease: Post-Hoc Analysis of Pooled Data From Three Large Trials

The authors explored the effect of galantamine on behavioral symptoms in Alzheimer disease (AD). Data were pooled from 2,033 subjects with mild-to-moderate AD who had participated in one of three randomized, double-blind, placebo-controlled trials of 3-, 5-, and 6-month durations. Subjects included in this post hoc analysis had received treatment with either placebo (N=686) or galantamine (N=1347) in total daily doses of 16 mg, 24 mg, or 32 mg. Behavioral symptoms were measured on the 10-item Neuropsychiatric Inventory (NPI). Four symptom clusters were defined a priori: 1) delusions, hallucinations; 2) agitation, depression, anxiety, apathy, irritability; 3) disinhibition, elation, aberrant motor behavior; 4) hallucinations, anxiety, apathy, aberrant motor behavior. At endpoint, mean changes from baseline in NPI scores were significantly different between galantamine-treated subjects and placebo-treated subjects, favoring galantamine for several measures: total NPI, individual domains of agitation/aggression, anxiety, disinhibition, and aberrant motor behavior, and Clusters 1, 3, and 4. The magnitude of the effect sizes was small. In this pooled sample of more than 2,000 subjects with mild-to-moderate AD, those who received galantamine therapy experienced modestly better, but statistically significant, outcomes in their behavioral symptoms than placebo-treated subjects. The cluster of hallucinations, anxiety, apathy and aberrant motor behaviors may represent a specific group of cholinergic-responsive behavioral symptoms.