Validation of the APP23 transgenic mouse model of Alzheimer's disease through evaluation of risperidone treatment on aggressive behaviour.

Valid animal models are indispensable in the drug discovery pipeline for dementia. Transgenic APP23 mice model Alzheimer's disease patients' memory deficits and additionally present with various behavioural disturbances, such as aggressive behaviour. The present study investigated and confirmed significant sensitivity of the model to the aggression-lowering ability of the antipsychotic agent risperidone (CAS 106266-06-2). The sensitivity for such anti-aggressive action contributes to the therapeutic predictive validity of the APP23 model of Alzheimer's disease, which can be used as a pre-clinical screening tool for the identification of novel anti-aggressive agents.

Altered ingestive behavior, weight changes, and intact olfactory sense in an APP overexpression model.

Transgenic APP23 mice were generated to model Alzheimer's disease. The APP23 model develops pathological features, learning deficits, and memory deficits analogous to dementing patients. In this report, transgenic mice exhibited several behavioral disturbances indicating the presence of neuropsychiatric symptoms of dementia. Aiming to verify whether the model also develops other behavioral problems, the authors investigated ingestive behavior in APP23 males of 3, 6 and 12 months. In addition, body weights of a naive male group were longitudinally monitored starting at weaning. Olfactory acuity was evaluated in mice of different age groups. Although olfactory functioning of APP23 mice appeared intact, they drank more and took more food pellets compared with wild-type littermates during a 1-week registration period. From the age of 4.5 weeks onward, APP23 males weighed significantly less than their control littermates, whereas this difference became more prominent with increasing age. Our results suggest the presence of a hypermetabolic state in this model. This is the first report, evidencing the presence of changes in eating and drinking behavior in a single transgenic Alzheimer mouse model.

Evaluation of the APP23-model for Alzheimer's disease in the odour paired-associate test for hippocampus-dependent memory.

The APP23 model is a transgenic mouse model for Alzheimer's disease. Cognitive performance in the APP23-model was assessed by Morris Water Maze (MWM) and passive avoidance learning, but the latter failed to show any difference between the genotypes. In search of a non-spatial alternative for assessment of hippocampus-dependent memory, we evaluated an odour paired-associate test, which is based on learning an association between two sets of odours. The protocol includes a shaping phase, in which the animals learn to dig up a reward, a preliminary training phase and a training phase, where the actual association is learned. Subsequently, mice are tested for transitive inference and subjected to a symmetry test. Impairment was seen in the APP23 mice, in comparison with wild type mice, in training; however, both groups failed the transitivity and symmetry test. Possible explanations for this discrepancy with earlier published results are the advanced age of the mice or the C57Bl/6J background, in which the model was established.

The dopaminergic neurotransmitter system is associated with aggression and agitation in frontotemporal dementia.

To identify neurochemical correlates of behavioral and psychological signs and symptoms of dementia (BPSD), we set up a prospective study. Patients with probable Alzheimer's disease (AD) (n=181), mixed dementia (MXD) (n=28), frontotemporal dementia (FTD) (n=25) and dementia with Lewy bodies (DLB) (n=24) were included. At inclusion, all patients underwent lumbar puncture, neuropsychological examination and behavioral assessment (battery of behavioral assessment scales). Cerebrospinal fluid (CSF) levels of norepinephrine and of (nor)epinephrine (MHPG), serotonin (5HIAA) and dopamine (DOPAC, HVA) metabolites were determined by HPLC and electrochemical detection. Spearman Rank-Order followed by Bonferroni correction was used for calculating correlations. In FTD patients, CSF norepinephrine levels were positively correlated with dementia severity (r=0.539; p=0.021). CSF DOPAC levels were correlated with BPSD in general (r=0.537; p=0.007), associated caregiver burden (r=0.567; p=0.004) and agitated and aggressive behavior (r=0.568; p=0.004). In a subgroup of FTD patients who did not receive psychotropic pharmacological treatment, a strong correlation between CSF HVA/5HIAA ratios (reflecting serotonergic modulation of dopaminergic neurotransmission) and aggressive behavior (r=0.758; p=0.009) was found. In MXD patients, (verbally) agitated behavior was positively associated with the turnover of norepinephrine (r=0.633; p=0.002). No significant correlations were found in AD and DLB groups. In FTD, increased activity of dopaminergic neurotransmission and altered serotonergic modulation of dopaminergic neurotransmission is associated with agitated and aggressive behavior respectively. This study demonstrated that neurochemical mechanisms underlying the pathophysiology of BPSD are both BPSD-specific and disease-specific which might have implications for future development of new and more selective pharmacological treatments of BPSD.

Mood and male sexual behaviour in the APP23 model of Alzheimer's disease.

Alzheimer's disease is characterised by both cognitive deterioration and the development of a wide range of neuropsychiatric disturbances, among which affective disturbances, stereotyped behaviour, dietary hyperactivity and changes in sexual behaviour. The transgenic APP23 mouse models Alzheimer's disease and has shown to be a unique tool in the study of this condition. APP23 mice develop, next to the age-dependent cognitive decline, also a range of behavioural problems, such as circadian activity disturbances and increased aggression, in analogy with the dementing patients. The present study aimed to investigate whether this model also develops mood disturbances and changes in sexual behaviour. Using two behavioural despair paradigms and the sucrose preference test, we did not find evidence for the development of depression-related behaviours. A sophisticated protocol was neither able to unravel changes in male sexual behaviour between APP23 and WT mice. The present study nevertheless provides evidence that the APP23 mice are more anxious and fearful in comparison with control littermates, which opens perspectives to future treatment studies.

APP23 mice display working memory impairment in the plus-shaped water maze.

Alzheimer's disease (AD) patients typically present short-term memory deficits, before long-term memory capacity declines with disease progression. Several studies have described learning and memory deficits in the APP23 mouse model. Our group reported a decline of learning and memory capacities from the age of 3 months onwards using a hidden-platform Morris water maze (MWM). The aim of the present study was to evaluate working and reference memory in APP23 mice in the same plus-shaped water maze. The transgenic mice had slower learning curves; however, consolidation of the learned information appeared intact in this learning paradigm. This report demonstrates impairment of working memory in this transgenic Alzheimer model.

Behavioural and neuropsychological correlates of frontal lobe features in dementia.

BACKGROUND: In order to characterize frontal lobe features and their behavioural and cognitive correlates across diagnostic categories, we performed a cross-sectional analysis of behavioural and neuropsychological data from a large, prospective Belgian study on behavioural and psychological signs and symptoms of dementia (BPSD). METHOD: Patients with probable Alzheimer's disease (AD) (n=170), frontotemporal dementia (FTD) (n=28), mixed dementia (MXD) (n=29) and dementia with Lewy bodies (DLB) (n=21) were included and underwent neuropsychological and behavioural assessment by means of a battery of tests and scales. Frontal lobe symptoms were quantified by means of the Middelheim Frontality Score (MFS). RESULTS: In AD (and to a lesser extent in MXD), MFS total scores were negatively correlated with scores on MMSE (Spearman: r=-0.36, p<0.001) and a Verbal Fluency Task (r=-0.38, p<0.001) and were associated with increased severity and frequency of psychosis (r=0.24, p<0.01), activity disturbances (r=0.44, p<0.001) and aggressiveness (r=0.43, p<0.001). In DLB, MFS total scores were negatively correlated with MMSE scores (r=-0.50, p=0.020). No associations were found in FTD patients. CONCLUSIONS: A cross-sectional analysis of frontal lobe features, behavioural characteristics and neuropsychological data demonstrated that, in AD (and to a lesser extent in MXD) patients, frontal lobe symptoms were associated with more pronounced cognitive deficits (of frontal origin), with increased severity and frequency of agitated and aggressive behaviour, and with increased severity of psychosis and depressive symptoms. Given the small sample sizes of the DLB and FTD patient groups, negative findings in these patient groups should be interpreted cautiously.

Actigraphic measurement of agitated behaviour in dementia.

OBJECTIVES: This study examines the correlation between actigraphic measures and a validated assessment scale of agitated behaviour in dementia, the Cohen-Mansfield Agitation Inventory (CMAI). METHODS: A total of 110 patients were included. Patients either suffered from Alzheimer dementia (AD), mixed dementia (MXD), frontotemporal dementia (FTD) or diffuse Lewy body disease (DLB). All patients underwent actigraphic recordings for 48 h. CMAI was scored by professional caretakers, who were responsible for the patient during his or her actigraphic recording. RESULTS: Patients with high total CMAI scores (>or= 50) clearly had higher levels of activity during the day as measured by means of actigraphy than patients with low total CMAI scores (ANOVA, F=126.75, p<0.0001). Patients with low MMSE scores (<20) also had higher activity levels during the day than patients with higher MMSE scores (ANOVA, F= 85.74, p<0.0001). Correlations between ctigraphic data and CMAI total scores were moderate but highly significant. CONCLUSION: We conclude that actigraphy is a useful tool to examine agitated behaviour in dementia.

Neuropsychological and behavioural correlates of CSF biomarkers in dementia.

To improve clinical, neuropsychological and behavioural characterisation of the cerebrospinal fluid (CSF) biomarkers beta-amyloid((1-42)) protein (Abeta42), protein tau (tau) and tau phosphorylated at threonine 181 (P-tau181) across diagnostic dementia categories, a prospective study was set up. Patients with probable Alzheimer's disease (AD) (n=201), AD with cerebrovascular disease (CVD) (AD+CVD) (n=33), frontotemporal dementia (FTD) (n=27), dementia with Lewy bodies (DLB) (n=22) and healthy controls (n=148) were included. All patients underwent neuropsychological examination and behavioural assessment by means of a battery of behavioural assessment scales. CSF was obtained by lumbar puncture and levels of Abeta42, tau and P-tau181 were determined with commercially available ELISA kits. Negative correlations between CSF Abeta42 levels and aggressiveness (Spearman: r=-0.223; p=0.002) and positive correlations with age at inclusion (r=0.195; p=0.006), age at onset (r=0.205; p=0.003) and MMSE scores (r=0.198; p=0.005) were found in AD. In AD+CVD, CSF Abeta42 levels were correlated with MMSE (r=0.482; p=0.006), Hierarchic Dementia Scale (r=0.503; p=0.017) and Boston Naming Test (r=0.516; p=0.012) scores. In controls, age was positively correlated with CSF tau (r=0.465; p<0.001) and P-tau181 levels (r=0.312; p<0.001). CSF tau and P-tau181 levels correlated significantly in all groups, whereas CSF Abeta42 correlated with tau and P-tau181 levels in healthy controls only. Negative correlations between CSF Abeta42 levels and aggressiveness were found in AD patients. CSF Abeta42 seems to be a stage marker for AD (+/-CVD) given the positive correlations with neuropsychological test results suggesting that CSF Abeta42 might be of help for monitoring disease progression. Different correlations between age and CSF biomarker levels were obtained in healthy controls compared to AD patients, indicating that AD-induced pathophysiological processes change age-dependent regulation of CSF biomarker levels.

Dose dependent effect of APOE epsilon4 on behavioral symptoms in frontal lobe dementia.

To determine whether apolipoprotein alleles (APOE) influence behavioral and psychological signs and symptoms of dementia (BPSD), we initiated a prospective, longitudinal study. Patients with Alzheimer's disease (AD) (N=186), frontotemporal dementia (FTD) (N=29), mixed dementia (MXD) (N=28), dementia with Lewy bodies (DLB) (N=11) and Parkinson's disease dementia (PDD) (N=7) were included. Blood was collected for DNA extraction and APOE genotyping. Behavioral assessments were performed at baseline and semi-annually thereafter, using behavioral assessment scales (Middelheim frontality score, behavioral pathology in Alzheimer's disease rating scale (Behave-AD)). In FTD patients, we identified dose dependent effects of APOE epsilon4 on the Behave-AD total and cluster aggressiveness scores. APOE epsilon2 was associated with a higher score on the Behave-AD cluster delusions in PDD/DLB patients. No APOE effects on frequency or severity of BPSD in AD and MXD patients were found. In conclusion, APOE has disease-specific effects on BPSD in FTD and PDD/DLB patients, given the reported associations of APOE epsilon4 with aggression (FTD) and of APOE epsilon2 with delusions (PDD/DLB).

Aggressive male APP23 mice modeling behavioral alterations in dementia.

In addition to cognitive deterioration, Alzheimer's disease patients exhibit behavioral and psychological signs and symptoms of dementia. Behavioral alterations are a major source of caregiver stress and an important contributor in the decision to institutionalize patients. The amyloid precursor protein (APP) 23 transgenic mouse model develops amyloid plaques from the age of 6 months onward and exhibits tau pathology, which is absent in most other amyloid-based models. Besides mimicking the demented patients' memory deficits, these transgenic mice present with various behavioral disturbances, thereby approximating the clinical situation remarkably well. Using an isolation-induced/resident-intruder paradigm of aggression, the authors revealed increased aggressiveness in male APP23 mice at the ages of 6 and 12 months. The presence of aggressive disturbances in this valuable mouse model opens perspectives to evaluate aggression-modulating therapies.

Neuropsychiatric symptoms of dementia: cross-sectional analysis from a prospective, longitudinal Belgian study.

OBJECTIVE: Given the rather limited knowledge on profiles of neuropsychiatric symptoms (behavioural and psychological signs and symptoms of dementia, BPSD) in several degenerative dementias, we designed a prospective study of which we here present the baseline data. METHODS: Diagnosed according to strictly applied clinical diagnostic criteria, patients with probable Alzheimer's disease (AD) (n = 205), frontotemporal dementia (FTD) (n = 29), mixed dementia (MXD) (n = 39) and dementia with Lewy bodies (DLB) (n = 23) were included. All patients underwent a neuropsychological examination and behavioural assessment by means of a battery of scales (Middelheim Frontality Score (MFS), Behave-AD, Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia). RESULTS: In AD and MXD, activity disturbances and aggressiveness occurred in more than 80% of the patients. With a prevalence of 70%, apathy was very common whereas delusions and hallucinations were rare in FTD patients. Frequently used behavioural assessment scales like the Behave-AD systematically underestimated BPSD in FTD whereas the MFS displayed high sensitivity for frontal lobe symptoms. Hallucinations discriminated DLB patients from other dementias. A high prevalence of disinhibition (65%) in DLB pointed to frontal lobe involvement. CONCLUSIONS: Behavioural assessment may help differentiating between different forms of dementia, further stressing the need for the development of new and more sensitive behavioural assessment scales. By means of the MFS, frontal lobe involvement was frequently observed in DLB. As 70% of FTD patients displayed apathy, prevalence was about two times higher compared to the other disease groups, meanwhile indicating that apathy is frequently observed in dementia, irrespective of its etiology.

APP23 mice as a model of Alzheimer's disease: an example of a transgenic approach to modeling a CNS disorder.

Animal models are considered essential in research ensuing elucidation of human disease processes and subsequently, testing of potential therapeutic strategies. This is especially true for neurodegenerative disorders, in which the first steps in pathogenesis are often not accessible in human patients. Alzheimer's disease is vastly becoming a major medical and socioeconomic problem in our aging society. Valid animal models for this uniquely human condition should exhibit histopathological, biochemical, cognitive, and behavioral alterations observed in Alzheimer's disease patients. Major progress has been made since the understanding of the genetic basis of Alzheimer's disease and the development and improvement of transgenic mouse models. All present Alzheimer's disease models developed are partial but nevertheless essential in further unraveling the nature and spatial and temporal development of the complex molecular pathology underlying this condition. One of the more recent transgenic attempts to model Alzheimer's disease is the APP23 transgenic mouse. This article describes the development and assessment of this human amyloid precursor protein overexpression model. We summarize histopathological and biochemical, cognitive and behavioral observations made in heterozygous APP23 mice, thereby emphasizing the model's contribution to clarification of neurodegenerative disease mechanisms. In addition, the first therapeutic interventions in the APP23 model are included.

Altered circadian locomotor activity in APP23 mice: a model for BPSD disturbances.

Over the past decade, clinical Alzheimer's disease research has been challenged with an increased interest in noncognitive symptomatology, commonly referred to as behavioural and psychological signs and symptoms of dementia (BPSD). In accordance, major attention is being paid to behavioural alterations in the phenotyping of transgenic mouse models. Besides an age-dependent decline of cognitive functions, the APP23 model was previously shown to exhibit cage activity disturbances, reminiscent of diurnal rhythm disturbances in Alzheimer patients. To further scrutinize these observations, circadian patterns of horizontal locomotor activity were assessed in 3-, 6- and 12-month-old APP23 mice and wild-type littermates in a test paradigm continuously recording cage activity over a period ranging from 1 to 3 days. At the age of 3 months, APP23 profiles resembled the wild-type pattern to a large extent, although minor differences were already noticeable. Six-month-old APP23 mice displayed an altered activity profile with a first indication of increased activity during the second half of the active phase, reminiscent of sundowning behaviour in Alzheimer patients. This bimodal overnight activity pattern became even more evident at the age of 12 months. The APP23 model was therefore shown to display an age-dependent development of cage activity disturbances and sundowning-like behaviour. A comparison is made with actigraphic recordings of human Alzheimer patients exhibiting sundowning behaviour. This first report of diurnal rhythm disturbances and sundowning-like phenomena in a transgenic mouse model greatly adds to the validity of the APP23 model.

Correlations between cognitive, behavioural and psychological findings and levels of vitamin B12 and folate in patients with dementia.

BACKGROUND: Associations between low levels of folate and vitamin B12 and cognitive impairment in patients with dementia have been reported. Some studies revealed correlations between low levels of vitamin B12 and behavioural and psychological signs and symptoms of dementia (BPSD) in Alzheimer's disease (AD) patients. Given the lack of studies in frontotemporal dementia (FTD) and on folate and given the methodological shortcomings of former publications, we set up a prospective study. METHODS: At inclusion, AD (n=152) and FTD (n=28) patients underwent a neuropsychological examination. Behaviour was assessed using a battery of behavioural assessment scales. Determination of serum vitamin B12 and red cell folate levels were performed within a time frame of two weeks of inclusion. RESULTS: In both patient groups, significantly negative correlations between levels of serum vitamin B12 and red cell folate and the degree of cognitive deterioration were found. No correlations with BPSD were found in the AD patient group. In FTD patients, levels of vitamin B12 were negatively correlated with both hallucinations (p=0.022) and diurnal rhythm disturbances (p=0.036). CONCLUSIONS: The observed negative correlations between levels of vitamin B12 and folate and cognitive impairment in both AD and FTD patients, raise the possibility of a non-specific etiological role. Although levels of vitamin B12 and folate did not correlate with BPSD in AD patients, negative correlations between serum vitamin B12 levels and BPSD in FTD patients were revealed. Decreased serum vitamin B12 levels may predispose FTD patients to develop hallucinations and diurnal rhythm disturbances.