Neuropsychiatric symptoms in 921 elderly subjects with dementia: a comparison between vascular and neurodegenerative types

Objective: i) to describe the neuropsychiatric profile of elderly subjects with dementia by comparing vascular (VaD) and degenerative dementias, i.e. dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD); ii) to assess whether the severity and type of dementia are associated with clinically relevant neuropsychiatric symptoms (CR‐NPS). Method: One hundred and thirty‐one out‐patients with VaD, 100 with DLB and 690 with AD were studied. NPS were evaluated by the neuropsychiatric inventory (NPI). Results: Vascular dementia had lower total and domain‐specific NPI scores and a lower frequency of CR‐NPS than AD and DLB, for which frequency of CR‐NPS increased significantly with disease severity, particularly in AD. Logistic regression analysis showed that a higher CDR score and a diagnosis of degenerative dementia were independently associated with CR‐NPS. Conclusion: Vascular dementia is associated less with CR‐NPS than AD and DLB. Frequency of CR‐NPS increases with disease severity in AD and, to a lesser extent, in DLB.     

Neuropsychiatric symptoms and functional status in Alzheimer's disease and vascular dementia patients

Neuropsychiatric symptoms (NPS) are increasingly recognized as common in patients with dementia, both of degenerative (Alzheimer's disease, AD) or vascular origin (vascular dementia, VaD). In this study, 302 demented patients, 166 with AD and 136 with VaD, were evaluated for NPS according to the Neuropsychiatric Inventory (NPI) score at the Alzheimer's Evaluation Unit of Casa Sollievo della Sofferenza Hospital-IRCCS, San Giovanni Rotondo, Italy. A comprehensive geriatric assessment was also performed in all demented patients. The means of NPI scores did not differ in two groups. The overall prevalence of NPS was similar in both groups of patients (69.7% vs. 69.4%). Patients with AD had higher frequency in agitation/aggression and irritability/lability than VaD patients. Logistic analysis demonstrated a significant association between severity of the cognitive impairment and depression and eating disorders in both AD and VaD patients. The association with agitation/aggression, irritability/lability, and aberrant motor activity was found in AD only, and with apathy in VaD patients only. In both AD and VaD patients, there was a significant association between the impairment in activities of daily living (ADL) and the majority of NPI domains. A significant association was also found between the impairment of the instrumental activities of daily living (IADL) and agitation/aggression, anxiety, aberrant motor activity in AD and depression, apathy, irritability/lability, sleep disturbance and eating disorders in both AD and VaD patients. In particular, a causal mediation analysis was performed to better understand whether the relationship of NPS to functional impairment was direct or mediated by severity of cognitive dysfunction, i.e., Clinical dementia rating scale (CDR) score. Only agitation/aggression was mediated by the CDR score in affecting ADL status in VaD patients (OR: 1.12, 95% CI: 1.01-1.27). The NPI-Distress scores showed a significantly higher levels of distress in caregivers of AD than VaD. There were significant differences between AD and VaD patients with NPS, and these symptoms varied according to dementia subtype and severity and induced marked disability in ADL and IADL, increasing, prevalently, the distress of the caregivers of AD patients.     

The prevention of the dementia epidemic

Alzheimer's disease (AD) is considered to be the most common dementing disorder. The understanding of this disorder has greatly advanced over the past few years, and new therapeutic options have been developed. Another disorder, vascular dementia (VaD), is a syndrome with multiple etiologies operating through a variety of different mechanisms. The combination of AD and VaD is extremely common, making mixed dementia the most common type of dementia. Risk factors for VaD, which are the common vascular risk factors, are presently known to apply also to AD. Cholinergic deficits occur in both conditions. The identification of several genetic factors that can contribute to vascular damage, as well as possible auto-immune damage to vascular components, are important. It is remarkable that amyloid precursor protein (APP) mutations can cause the typical pathological changes of AD as well as amyloid deposition around blood vessels. These may lead to deficient blood perfusion to the brain, changes of the blood-brain barrier, as well as cerebral hemorrhages. Interestingly, attention to risk factors, such as hypertension, coronary artery disease, hyperlipidemia and smoking could reduce or delay the incidence of dementia, both vascular and AD.     

Dementia Neuropsychiatric Symptom Frequency,Severity, and Correlates in Community-Dwelling Thai Older Adults

BackgroundThailand is experiencing a rapid increase in the number of older people with dementia (PWD). We examined the frequency, severity, and correlates of dementia neuropsychiatric symptoms (NPS) among community-dwelling Thai older adults.MethodsThis study was based on analysis of baseline data from a larger clinical trial comparing two different implementation approaches of an evidence-based exercise intervention for people with dementia. To be eligible, participants needed to be age 60 and above, have probable dementia, have one or more NPS, be ambulatory, and have an adult (age 18+) family caregiver. In the 353 eligible participants, we examined the correlation between NPS severity and caregiver distress (assessed by the Neuropsychiatric Inventory Questionnaire or NPI-Q) and used ordinary least squares (OLS) regression to examine associations between PWD and caregiver characteristics and NPS severity.ResultsNPS frequency varied from 18% for appetite and/or eating changes to 42% for delusions. NPS severity was significantly (p <0.05) associated with caregiver stress for all individual NPS. Among PWD characteristics, higher ADL score (less functional impairment) was inversely associated with NPS total severity (b = -0.16, p <0.05). More physical role limitation was significantly associated with higher NPS total severity (b = 0.77, p <0.001). Among caregivers’ characteristics, higher burden was significantly associated with higher NPS total severity (b = 0.19, p <0.001).ConclusionOur study found NPS to be common among community-dwelling PWD in Thailand and have adverse impacts on both PWD and family caregivers. These findings highlight the clinical importance of NPS symptoms among Thai older adults.     

The canine model of human cognitive aging and dementia: pharmacological validity of the model for assessment of human cognitive-enhancing drugs

For the past 15 years we have investigated the aged beagle dog as a model for human aging and dementia. We have shown that dogs develop cognitive deficits and neuropathology seen in human aging and dementia. These similarities increase the likelihood that the model will be able to accurately predict the efficacy of Alzheimer's disease (AD) treatments as well as detect therapeutics with limited or no efficacy. Better predictive validity of cognitive-enhancing therapeutics (CETs) could lead to enormous cost savings by reducing the number of failed human clinical trials and also may reduce the likelihood of negative outcomes such as those recently observed in the AN-1792 clinical trials. The current review assesses the pharmacological validity of the canine model of human aging and dementia. We tested the efficacy of (1) CP-118,954 and phenserine, two acetylcholinesterase inhibitors, (2) an ampakine, (3) selegiline hydrochloride, two drugs that have failed human AD trials, and (4) adrafinil, a putative CET. Our research demonstrates that dogs not only develop isomorphic changes in human cognition and brain pathology, but also accurately predict the efficacy of known AD treatments and the absence or limited efficacy of treatments that failed clinical trials. These findings collectively support the utilization of the dog model as a preclinical screen for identifying novel CETs for both age-associated memory disorder and dementia.     

Vascular factors and risk for neuropsychiatric symptoms in Alzheimer's disease: the Cache County Study

OBJECTIVE: To examine, in an exploratory analysis, the association between vascular conditions and the occurrence of neuropsychiatric symptoms (NPS) in a population-based sample of incident Alzheimer's disease (AD). METHODS: The sample consisted of 254 participants, identified through two waves of assessment. NPS were assessed using the Neuropsychiatric Inventory. Prior to the onset of AD, data regarding a history of stroke, hypertension, hyperlipidemia, heart attack or coronary artery bypass graft (CABG), and diabetes were recorded. Logistic regression procedures were used to examine the relationship of each vascular condition to individual neuropsychiatric symptoms. Covariates considered were age, gender, education, APOE genotype, dementia severity, and overall health status. RESULTS: One or more NPS were observed in 51% of participants. Depression was most common (25.8%), followed by apathy (18.6%), and irritability (17.7%). Least common were elation (0.8%), hallucinations (5.6%), and disinhibition (6.0%). Stroke prior to the onset of AD was associated with increased risk of delusions (OR = 4.76, p = 0.02), depression (OR = 3.87, p = 0.03), and apathy (OR = 4.48, p = 0.02). Hypertension was associated with increased risk of delusions (OR = 2.34, p = 0.02), anxiety (OR = 4.10, p = 0.002), and agitation/aggression (OR = 2.82, p = 0.01). No associations were observed between NPS and diabetes, hyperlipidemia, heart attack or CABG, or overall health. CONCLUSIONS: Results suggest that a history of stroke and hypertension increase the risk of specific NPS in patients with AD. These conditions may disrupt neural circuitry in brain areas involved in NPS. Findings may provide an avenue for reduction in occurrence of NPS through the treatment or prevention of vascular risk conditions.     

Changes in dietary or eating behavior in frontotemporal dementia versus Alzheimer's disease

BACKGROUND: Changes in dietary or eating behavior are common in dementia and may help distinguish between different dementing illnesses. Objective: To evaluate and characterize differences in dietary and eating behavior among patients with early frontotemporal dementia (FTD) versus Alzheimer's disease (AD). METHODS: This study administered the Food-Related Problems Questionnaire (FRPQ) to caregivers of 16 patients with FTD and 16 comparable patients with AD. The FRPQ was evaluated at initial presentation when patients presented for a diagnostic evaluation. RESULTS: Compared with the AD patients, the FTD patients had significantly more changes on the FRPQ. Subscale analysis indicated that the FTD patients showed impairment of observed satiety, improper taking of food, and inappropriate responses when food was not available. CONCLUSIONS: The use of food-related questionnaires, such as the FRPQ, can help distinguish FTD patients, early in their course, from those with AD and can further characterize the altered dietary and eating behavior.     

Neuropsychiatric symptoms in older people with and without cognitive impairment

Neuropsychiatric symptoms (NPS) are non-cognitive disturbances such as depression. Rates of NPS have been shown to increase as cognitive ability declines and may be useful in predicting transition from mild cognitive impairment (MCI) to dementia. This community-based study reports the association between NPS and cognitive decline over two years. Participants included 873 community dwelling adults aged 70-90 years enrolled in the Sydney Memory and Ageing Study. NPS were assessed by the Neuropsychiatric Inventory (NPI). Cognitive impairment was defined by diagnosis (MCI or incident dementia) or neuropsychological test performance across five cognitive domains. Cognitive decline was defined by progression to dementia or worse neuropsychological performance. Total NPS at baseline did not differ between those without cognitive impairment (26.2%) and those with MCI (28.8%), but agitation and apathy were associated with MCI. Only baseline depression was associated with dementia at follow-up. Total NPS at baseline was cross-sectionally associated with cognitive impairment in executive function, attention, and global cognition, but did not predict cognitive decline. Depression, anxiety, agitation, anxiety, and apathy were all associated with impairment in at least one cognitive domain, but only anxiety and agitation were significantly associated with cognitive decline. Sensitivity analyses applied more stringent criteria for NPS and cognitive impairment in MCI but did not alter interpretation of results from the main analysis. Overall rates of NPS at baseline were not associated with MCI, dementia, or cognitive decline over two years. Additional follow-up is needed to further examine this association over a longer time course.     

The ABC of Alzheimer's disease: cognitive changes and their management in Alzheimer's disease and related dementias

Cognitive decline, commonly first recognized as memory impairment, is a typical feature of Alzheimer's disease (AD). Neuropathological changes in the cerebral cortex and limbic system lead to deficits in learning, memory, language, and visuospatial skills. The precise nature of cognitive dysfunction reflects the distribution of pathological changes in AD. These will vary along the disease severity continuum and may also depend on where the disease sits in the spectrum of dementia. For example, AD-related disorders such as Lewy body dementia (LBD) and Parkinson's disease dementia (PDD) also show symptoms of cognitive decline and share several pathological features, including degeneration of cortical cholinergic and striatal dopaminergic neurons. In vascular dementia (VaD), there is often an unequal distribution of cognitive deficit, with severe impairment in some functions and relative sparing of others. Cholinesterase (ChE) inhibitors, which help restore acetylcholine levels in the brain, are licensed for the symptomatic treatment of AD and have shown additional benefit in related dementias. Physiological correlates of cholinergic function/dysfunction in the brain include regional cerebral blood flow, glucose metabolism, and cerebrospinal fluid levels of ChE enzymes. These variables represent valuable markers of the clinical efficacy of ChE inhibitors. However, direct assessment of cognitive improvement, stabilization or decline is usually considered the key efficacy parameter in clinical studies of ChE inhibitors in AD and related dementias. Large-scale, placebo-controlled clinical studies of ChE inhibitors have demonstrated efficacy in treating the cognitive impairments associated with AD. Randomized comparative studies of ChE inhibitors are now under way to directly compare symptomatic efficacy and effects on disease progression. Clinical trial data of the cognitive effects of ChE inhibitors in AD, LBD, PDD, and VaD are discussed in detail in this article. The benefits of long-term treatment on symptomatic improvement in cognition and further potential disease-modifying effects are highlighted.     

Molecular imaging of neuropsychiatric symptoms in Alzheimer's and Parkinson's disease

Neuropsychiatric symptoms (NPS) are very common in neurodegenerative diseases and are a major contributor to disability and caregiver burden. There is accumulating evidence that NPS may be a prodrome and/or a “risk factor” of neurodegenerative diseases. The medications used to treat these symptoms in younger patients are not very effective in patients with neurodegenerative disease and may have serious side effects. An understanding of the neurobiology of NPS is critical for the development of more effective intervention strategies. Targeting these symptoms may also have implications for prevention of cognitive or motor decline. Molecular brain imaging represents a bridge between basic and clinical observations and provides many opportunities for translation from animal models and human post-mortem studies to in vivo human studies. Molecular brain imaging studies in Alzheimer's disease (AD) and Parkinson's disease (PD) are reviewed with a primary focus on positron emission tomography studies of NPS. Future directions for the field of molecular imaging in AD and PD to understand the neurobiology of NPS will be discussed.     

Cholinergic deficits contribute to behavioral disturbance in patients with dementia

BACKGROUND: Noncognitive behavioral changes such as depression, aggressive behavior, psychosis, and overactivity occur frequently in patients with dementia, in addition to cognitive impairment, and often determine the need for institutionalization. The biochemical basis of such changes is poorly understood. Clinical trial data indicate that cholinomimetics improve noncognitive behaviors. This study investigated the relationship between markers of the cholinergic and dopaminergic neurotransmitter systems and noncognitive behavioral symptoms assessed during the course of dementing illness. METHOD: Brains from 46 patients with dementia (36 with AD and 10 with mixed or other dementias using Consortium to Establish a Registry for AD criteria) were examined together with 32 normal controls. The patients with dementia had been evaluated every 4 months, often over several years, for cognitive performance (Mini-Mental State Examination) and behavior (Present Behavioral Examination). Concentrations of dopamine (DA) and major metabolites, choline acetyltransferase activity (ChAT), and density (Bmax) of DA D1 receptors in frontal and temporal cortex were studied by radioligand binding protocols. None of the patients was receiving cholinomimetic drugs. RESULTS: ChAT activity, but no other neurochemical markers, was reduced in AD compared with controls. Loss of ChAT activity correlated with cognitive impairment. Lowered ChAT activity also correlated with increasing overactivity in patients with dementia in both frontal and temporal cortex whereas ChAT:DA and ChAT:D1 ratios in temporal cortex correlated negatively with aggressive behavior. CONCLUSIONS: Disturbance of the cholinergic system may underlie both cognitive and some noncognitive behavioral changes in dementia, providing a basis for rational therapy.-1467     

The new DSM-5 diagnosis of mild neurocognitive disorder and its relation to research in mild cognitive impairment

The Diagnostic Statistical Manual-5 (DSM-5) has included a category named the neurocognitive disorder which was formally known in DSM-IV as ‘dementia, delirium, amnestic, and other cognitive disorders’. The DSM-5 distinguishes between ‘mild’ and ‘major’ neurocognitive disorders. Major neurocognitive disorder replaces the DSM-IV's term ‘dementia or other debilitating conditions’. A pivotal addition is ‘mild neurocognitive disorder (mNCD)’ defined by a noticeable decrement in cognitive functioning that goes beyond normal changes seen in aging. It is a disorder that may progress to dementia – importantly, it may not.

Presently, our understanding of mNCD is derived from research on mild cognitive impairment (MCI). Whereas there is currently no clear treatment for mNCD, many experimental therapies now and into the future will focus upon secondary prevention, namely decreasing the risk of progression to major NCD. In this article, we will focus on mNCD by reviewing the relevant literature on MCI. We will review the research on the incidence and prevalence of MCI, conversion rates from MCI to dementia, risk factors for conversion of MCI to dementia, comorbidity of MCI with other neuropsychiatric disorders (NPS), and the development of treatment strategies for neuropsychiatric disorders in MCI.

The presence of NPS is common among individuals with MCI and is an important risk for progression to dementia. However, there has been little research on effective treatments for NPS in MCI. Clinicians and investigators must determine if the treatment of the NPS in mNCD will improve quality of life and help reduce the progression of the cognitive impairment.     

When and How to Treat Agitation in Alzheimer's Disease Dementia With Citalopram and Escitalopram

Agitation is a common neuropsychiatric symptom (NPS) in the early and middle stages of Alzheimer's disease (AD) dementia, which is difficult to treat and causes much distress. The U.S. Food and Drug Administration (U.S. FDA) issued black box warnings against the use of antipsychotics in dementia in 2005 and 2008 due to the increased risk of morbidity and mortality, resulting in the reduction in antipsychotic use for treating dementia-related NPS and spurring the quest for safer and more effective pharmacological options. The data favoring the use of citalopram for treating agitation in AD dementia is particularly compelling, and this may be a class effect for all selective serotonin reuptake inhibitors. However, concerns about the cardiac side-effects of citalopram have limited its widespread use for this indication. In this article, available efficacy and safety data for the use of citalopram and escitalopram in treating agitation in AD dementia is reviewed, using a composite case to illustrate key points. Practical recommendations are made to facilitate the use of these medications in routine clinical practice, risk mitigation strategies are discussed and salient issues for future clinical research are emphasized.     

Neuropsychiatric Symptoms as Risk Factors for Cognitive Decline in Clinically Normal Older Adults: The Cache County Study

IntroductionThere has been considerable progress in identifying early cognitive and biomarker predictors of Alzheimer's disease (AD). Neuropsychiatric symptoms (NPS) are common in AD and appear to predict progression after the onset of mild cognitive impairment or dementia.ObjectivesThe objective of the study is to examine the relationship between NPS in clinically normal older adults and subsequent cognitive decline in a population-based sample.MethodsThe Cache County Study on Memory in Aging consists of a population-based sample of 5,092 older adults. We identified 470 clinically normal adults who were followed for an average period of 5.73 years. NPS were evaluated at the baseline clinical assessment using the Neuropsychiatric Inventory (NPI). NPI domain scores were quantified as the product of frequency X severity in individual NPI domains, and then summed for the NPI-Total. Neuropsychological measures were collected at baseline and at each subsequent follow-up wave. Linear mixed-effects models assessed the association of NPI-Total, NPI-Depression, and NPI-Anxiety scores (obtained at baseline) on longitudinal change in neuropsychological performance, controlling for age, sex, and education.ResultsBaseline NPI-Total score was associated with a more rapid rate of decline in word list memory, praxis recall, and animal fluency. Baseline NPI-Depression was not associated with later decline on any of the cognitive tests, while baseline NPI-Anxiety was associated with decline in Symbol Digit Modality.ConclusionIn conclusion, among clinically normal older adults derived from this population-based study, total burden of NPS was associated with longitudinal cognitive decline. These results add to the evidence that NPS are risk factors for or clinical indicators of preclinical dementia syndrome. Our study was an exploratory study and we did not control for multiple comparisons.     

Neuropsychiatric symptoms associated multimodal brain networks in Alzheimer's disease

Concomitant neuropsychiatric symptoms (NPS) are associated with accelerated Alzheimer's disease (AD) progression. Identifying multimodal brain imaging patterns associated with NPS may help understand pathophysiology correlates AD. Based on the AD continuum, a supervised learning strategy was used to guide four-way multimodal neuroimaging fusion (Amyloid, Tau, gray matter volume, brain function) by using NPS total score as the reference. Loadings of the identified multimodal patterns were compared across the AD continuum. Then, regression analyses were performed to investigate its predictability of longitudinal cognition performance. Furthermore, the fusion analysis was repeated in the four NPS subsyndromes. Here, an NPS-associated pathological–structural–functional covaried pattern was observed in the frontal-subcortical limbic circuit, occipital, and sensor-motor region. Loading of this multimodal pattern showed a progressive increase with the development of AD. The pattern significantly correlates with multiple cognitive domains and could also predict longitudinal cognitive decline. Notably, repeated fusion analysis using subsyndromes as references identified similar patterns with some unique variations associated with different syndromes. Conclusively, NPS was associated with a multimodal imaging pattern involving complex neuropathologies, which could effectively predict longitudinal cognitive decline. These results highlight the possible neural substrate of NPS in AD, which may provide guidance for clinical management.     

A review of transcranial magnetic stimulation in the in vivo functional evaluation of central cholinergic circuits in dementia

Central cholinergic circuits of human brain can be tested non-invasively by coupling electrical peripheral stimulation with transcranial magnetic stimulation (TMS) of the motor cortex. The short-latency afferent inhibition (SAI) is reduced in cholinergic forms of dementia, such as Alzheimer disease (AD) and dementia with Lewy bodies, while it is normal in non-cholinergic forms of dementia, such as frontotemporal dementia. This finding suggests that this method can be used as a non-invasive additional tool for discriminating between cholinergic and non-cholinergic forms of dementia. Interestingly, SAI was also found to be significantly smaller in early AD patients. Identification of SAI abnormalities that occur early in the course of AD will allow earlier diagnosis and treatment with cholinergic drugs. In patients with vascular dementia, SAI responses varied widely; the number of patients with abnormal SAI conceivably reflects the percentage of subjects with a significant cholinergic dysfunction. It has recently been demonstrated that brain microbleeds have an impact on SAI that is independent of the extent of associated white matter changes and ischemic stroke. Since SAI can be increased by acetylcholinesterase inhibitors, TMS may help in identifying the patients who would be suitable for long-term treatment with cholinergic agents.     

Lipid metabolism in cognitive decline and dementia

This review will focus on the current knowledge on circulating serum and plasma risk factors of cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin (vascular dementia, VaD) linked to cholesterol homeostasis and lipoprotein disturbances, i.e. total cholesterol (TC), 24S-hydroxy-cholesterol, lipoprotein(a) (Lp(a)), or apolipoprotein E (APOE). These measures linked to lipoprotein metabolism appear to be altered in AD, VaD, or predementia syndrome relative to controls, but with contrasting results. At present, several studies have demonstrated the dependence of APOE serum levels upon the APOE genotype, nonetheless serum APOE levels seems not to be a credible risk factor or a biochemical marker for AD instead of APOE genotyping. In fact, there was no consistent association of serum or plasma apoE protein levels with the disease when controlled for APOE genotype. In addition, there are some evidence that higher Lp(a) levels could be linked with AD, although there are studies suggesting an increased presence of low molecular weight apo(a) in AD, VaD, and frontotemporal dementia, that are associated with elevated Lp(a) levels. In fact, the apo(a) gene is highly polymorphic in length due to variation in the numbers of a sequence encoding the apo(a) kringle 4 domain, and plasma levels of Lp(a) are inversely correlated with apo(a) size. Furthermore, although serum/plasma levels of TC and 24S-hydroxycholesterol are not credible diagnostic markers for AD and cognitive decline, the current evidence suggests that they may be modifiable risk/protective factors. The prevailing wisdom is that high TC is a risk factor for dementia. However, the relationship between TC and dementia may vary considerably depending on when cholesterol is measured over the life course or, alternatively, in relation to the underlying course of the disease. Several observational studies have suggested that statins, which are effective in lowering cholesterol, may reduce the risk of dementia, but the results of these reports are inconclusive. Thus, more studies with long-term follow-up and serial assessments of TC are needed to further clarify the causal relationship between cholesterol and dementia.     

Apathy and executive dysfunction in mild cognitive impairment and Alzheimer disease.

OBJECTIVE: The authors assessed and contrasted frontally mediated behavior changes in patients diagnosed with Mild Cognitive Impairment (MCI) and Alzheimer disease (AD). Apathy, executive dysfunction, and disinhibition are common in AD, but these behaviors have not been studied in MCI. METHODS: Participants were patients diagnosed with AD (n=25) or MCI (n=20). Current behavior and behavior before the onset of cognitive impairment was rated by knowledgeable informants on the Frontal Systems Behavior Scale (FrSBe). RESULTS: Apathy and executive dysfunction exhibited the greatest increase in both MCI and AD, and both increased significantly over baseline scores. No significant differences in behavior change were found between the two groups. Behavior change was moderately correlated with a measure of dementia severity, indicating that greater disease severity was associated with more abnormal behavior. CONCLUSION: Changes in frontally-mediated behaviors are common in very early and mild stages of cognitive impairment, even before functional decline in daily living is evident. These behaviors deserve more study in MCI because they may have implications for prognosis, treatment adherence, family distress, and patient quality of life.     

Cerebral pattern of pro- and anti-inflammatory cytokines in dementias

The knowledge regarding putative inflammatory component(s) participating in Alzheimer's disease (AD) and vascular dementia (VAD) is scarce. Recently, we have demonstrated the presence of certain inflammatory cytokines in the cerebrospinal fluid (CSF) of demented patients. Although the initial event(s) triggering the neurodegenerative processes in AD versus VAD may be different and lead to different neuropathological changes, it may initiate a similar cascade of cytokine production in response to neuronal injury. The cytokines released in the central nervous system (CNS) may, in turn, act in a similar manner in both diseases, amplifying some pathological changes such as amyloidogenesis and white matter lesions or on the contrary acting as neuroprotective molecules. This review will focus on the intracerebral production of the pro- and anti-inflammatory cytokines interleukin IL-1beta, IL-1 receptor antagonist (IL-1ra), IL-6 and TNF-alpha in dementia, and their relation to gene polymorphism, to cerebral neuronal damage, apoptosis, and to clinical variables of dementia. Our results, which show for the first time strikingly increased CSF levels of TNF-alpha but not of TNF-beta, IL-1beta or IL-6 in AD and VAD, may form a conceptual framework for further studies of neuroprotective mechanisms in dementias.     

Independence of changes in behavior from cognition and function in community-dwelling persons with Alzheimer's disease: a factor analytic approach

The authors' main objective was to investigate the relationship between changes in psychopathological, cognitive and activity of daily living (ADL) instrument scores over 12 months in community-dwelling persons with Alzheimer's disease (AD). A secondary objective was to evaluate the validity of dividing the Clinical Dementia Rating (CDR), a global dementia staging instrument into cognitive and functional subscores. Changes in measures of psychopathology, cognition and function between the baseline and 12-month visits were entered into these post hoc analyses of data from a one-year clinical trial to evaluate behavioral, cognitive and functional assessment instruments for use in clinical trials with AD patients. Exploratory factor analysis was used to determine whether there was independence between changes in any of these three domains of interest for this disease population; participants were a cohort of 187 well-characterized, community-dwelling persons with AD. One-year change in the behavioral symptoms of this cohort of persons with AD was statistically independent from changes in scores on cognitive and functional measures. Some evidence of independence of 12 month changes in cognitive and functional measures was found. Cognitive and functional subscores for the CDR were supported. These findings suggest that changes in behavior and cognition in dementia may have distinct pathophysiologies.