Both the neuropsychiatric syndrome of apathy and major depressive disorder comprise a heterogenous cluster of symptoms which span multiple behavioural domains. Despite this heterogeneity, there is a tendency in the preclinical literature to conclude a MDD or apathy-like phenotype from a single dimensional behavioural task used in isolation, which may lead to inaccurate phenotypic interpretation. This is significant, as apathy and major depressive disorder are clinically distinct with different underlying mechanisms and treatment approaches. At the clinical level, apathy and major depressive disorder can be dissociated in the negative valence (loss) domain of the Research Domain Criteria. Symptoms of MDD in the negative valence (loss) domain can include an exaggerated response to emotionally salient stimuli and low mood, while in contrast apathy is characterised by an emotionally blunted state. In this article, we highlight how using a single dimensional approach can limit psychiatric model interpretation. We discuss how integrating behavioural findings from both the positive and negative (loss) valence domains of the Research Domain Criteria can benefit interpretation of findings. We focus particularly on behaviours relating to the negative valence (loss) domain, which may be used to distinguish between apathy and major depressive disorder at the preclinical level. Finally, we consider how future approaches using home cage monitoring may offer a new opportunity to detect distinct behavioural profiles and benefit the overall translatability of findings.

Dysregulated cortisol in older individuals is associated with neurodegeneration and executive dysfunction, among other negative health outcomes. Executive functioning deficits are believed to underlie declines in functioning among older adults. Despite these associations, there is limited research examining the relationship between cortisol and impaired functional status.

The present study examined the relationship between cortisol and functional status in a community sample of 51 older adults with depression. Pearson correlations and ordinal regressions were used to determine whether greater cortisol dysregulation was associated with ADL and IADL impairment.

Results indicated that individuals who had higher levels of cortisol also tended to demonstrate greater functional deficits. These findings remained true when functional status was measured by either a clinician-rated tool or a self-report measure.

The results of this study provide preliminary support for the hypothesis that elevated cortisol, in the context of depression, is associated with functional status deficits in older adults.

Findings from this study begin to fill the gap in research examining the relationship between cortisol and functional impairment in older adults and suggest that unique information can be gathered with the use of different functional status measures.

Preclinical-clinical translation of cognitive functions has been difficult in Alzheimer's disease (AD) research but is crucial to the (predictive) validity of AD animal models. Reversal learning, a representation of flexibility and adaptability to a changing environment, might represent such a translatable feature of human cognition. We, therefore, examined visual discrimination (VD) and reversal learning in the APPPS1-21 mouse model of amyloid-based AD pathology. We used touchscreen operant cages in novel and translationally valid, as well as objective testing methodology that minimizes within- or between-trial handling. Mice were trained to associate a visual cue with a food reward (VD learning), and subsequently learned to adjust their response when this rule changed (reversal learning). We assessed performance at two different ages, namely at 6 months of age, considered an early disease stage, and at 9 months, a stage of established pathology. Both at 6 and 9 months, transgenic animals needed more sessions to reach criterion performance, compared to wild-type controls. Overall, transgenic animals do not show a general cognitive, motivational or motor deficit, but experience specific difficulties to adapt to reward contingency changes, already at an early pathology stage.

The Frontal Systems Behavior Scale (FrSBe) (Grace & Malloy, 2001) assesses behavioral dysfunction associated with frontal-subcortical damage; it is often used to measure these indicators of executive dysfunction in older adults with possible dementia. Although prior research supports the FrSBe's clinical utility and factorial validity, little attempt has been made to examine which items are most useful for geriatric cases. The goal of the present study is to identify these items.

Data from 304 older patients referred for neuropsychological assessment were used to examine the FrSBe's three subscales: Apathy (A; 14 items), Executive Dysfunction (E; 17 items), and Disinhibition (D; 15 items). Item properties were investigated using the Graded Response Model, a two-parameter polytomous item response theory model.

Difficulty parameters, discrimination parameters, and information curves identified 18 items that effectively discriminate (a ≥ 1.70) between levels of behavioral dysfunction and measure a range of dysfunction (b_A: -1.23 - 2.22; b_D: -.29 - 2.14; b_E: -1.81 - 1.77).

Most FrSBe items were effective at discriminating various levels of behavioral dysfunction, though weaker items were identified.

The findings suggest the FrSBe is a useful clinical tool when working with a geriatric population, though some items provide more information than others.

To compare patients with autopsy-confirmed Alzheimer disease (AD) and dementia with Lewy bodies (DLB) on the frequency of behaviors related to frontal system dysfunction and the association of these behaviors with dementia severity.

We performed a cross-sectional survey of a longitudinal cohort at a university research center for AD on a volunteer sample of 19 DLB and 38 AD participants with autopsy-confirmed diagnoses, similar in age (DLB: 77.3, AD: 77.5), education (DLB: 15.2, AD: 14.7), and Mini-Mental State Examination (MMSE) score (DLB: 20.6, AD: 20.5), with impairment ranging from mild deficits to moderate dementia. The Frontal Systems Behavior Scale (FrSBe)-Family Rating Form assessing patient apathy, disinhibition, and executive dysfunction by a knowledgeable informant was used.

A two-way analysis of variance with the FrSBe total as the dependent variable revealed a significant MMSE by diagnosis interaction (F(1,53) = 9.34, p = 0.004). Mean FrSBe total for AD patients showed significant impairment across the range of dementia severity, whereas it was relatively preserved for DLB patients in the early stage of disease. The interaction term showed the same pattern for the executive dysfunction (F(1,53) = 7.62, p = 0.008), disinhibition (F(1,53) = 4.90, p = 0.031), and apathy (F(1,53) = 9.77, p = 0.003) subscales.

Although frontal behavioral symptoms in AD patients were present regardless of stage of dementia, DLB patients showed significant frontal dysfunction only in later stages. Results suggest that frontal subcortical circuits associated with behaviors assessed by the FrSBe are affected early in AD but not until later stages in DLB. Assessing specific behaviors related to frontal systems, coupled with stage of cognitive decline, may aid in clinical differentiation of AD and DLB.

Apathy is one of the most challenging and prevalent behavioral symptoms of dementia. It is associated with increased disability and caregiver frustration as well as reduced quality of life, rehabilitation outcomes and survival after nursing home admission. A literature search to set criteria yielded 56 nonpharmacological intervention studies with outcomes relevant to apathy in dementia. Studies were rated according to quality and categorized into 7 groups: exercise, music, multisensory, animals, special care programming, therapeutic activities and miscellaneous. Despite a lack of methodological rigor, it is apparent that nonpharmacological interventions have the potential to reduce apathy. This review indicates that therapeutic activities, particularly those provided individually, have the best available evidence for effectiveness in dementia. Recommendations are provided for quality research.

 Previous research has described the executive dysfunction that occurs in patients with amnestic-mild cognitive impairments (A-MCI) and early-stage Alzheimer's disease (EAD), which are comparatively similar stages of dementia. The aim of the present cross-sectional study is to evaluate executive dysfunction using the Frontal Assessment Battery (FAB) screening test in two groups and to investigate the interaction with other cognitive impairments.

Among 170 consecutive patients with Alzheimer's disease or A-MCI, we recruited 48 subjects who were under 75 years of age and had been diagnosed as having either A-MCI or EAD. We then compared the total and the subtest scores of the mini-mental state examination (MMSE) and the FAB between the two groups. Moreover, we investigated the statistical interactive associations of the FAB subtest scores with the influential MMSE subtest scores or the diagnosis (A-MCI or EAD).

No significant differences in the age, sex ratio, duration of illness, and education years were observed between the two groups. However, significant differences in the FAB total and subtest scores (conflicting instructions and go/no-go) were found between the two groups. Furthermore, significant differences in the MMSE total and subtest scores (orientation, memory delayed recall, and attention and calculation) were also noted between the two groups. In a generalized linear model analysis, only two FAB subtest scores (conflicting instructions and go/no-go) were significantly influenced by the diagnosis (A-MCI or EAD) in a manner that was independent of the interaction with the orientation or memory delayed recall.

The present findings suggest that the FAB total score and subtest scores reflecting interference performances (conflicting instructions and go/no-go) significantly declined in patients with EAD, independent of the disorientation and memory disorder. Such characteristics of neuropsychological screening test scores may be useful to clinicians for differentiating EAD and A-MCI at bedside.

Apathy is highly prevalent among neuropsychiatric populations and is associated with greater morbidity and worse functional outcomes. Despite this, it remains understudied and poorly understood, primarily due to lack of consensus definition and clear diagnostic criteria for apathy. Without a gold standard for defining and measuring apathy, the availability of empirically sound measures is imperative. This paper provides a psychometric review of the most commonly used apathy measures and provides recommendations for use and further research.

Pertinent literature databases were searched to identify all available assessment tools for apathy in adults aged 18 and older. Evidence of the reliability and validity of the scales were examined. Alternate variations of scales (e.g., non-English versions) were also evaluated if the validating articles were written in English.

Fifteen apathy scales or subscales were examined. The most psychometrically robust measures for assessing apathy across any disease population appear to be the Apathy Evaluation Scale and the apathy subscale of the Neuropsychiatric Inventory based on the criteria set in this review. For assessment in specific populations, the Dementia Apathy Interview and Rating for patients with Alzheimer's dementia, the Positive and Negative Symptom Scale for schizophrenia populations, and the Frontal System Behavior Scale for patients with frontotemporal deficits are reliable and valid measures.

Clinicians and researchers have numerous apathy scales for use in broad and disease-specific neuropsychiatric populations. Our understanding of apathy would be advanced by research that helps build a consensus as to the definition and diagnosis of apathy and further refine the psychometric properties of all apathy assessment tools.

Clinical and epidemiologic research has focused on the identification of risk factors that may be modified in predementia syndromes, at a preclinical and early clinical stage of dementing disorders, with specific attention to the role of depression. Our goal was to provide an overview of these studies and more specifically to describe the prevalence and incidence of depression in individuals with mild cognitive impairment (MCI), the possible impact of depressive symptoms on incident MCI, or its progression to dementia and the possible mechanisms behind the observed associations. Prevalence and incidence of depressive symptoms or syndromes in MCI vary as a result of different diagnostic criteria and different sampling and assessment procedures. The prevalence of depression in individuals with MCI was higher in hospital-based studies (median: 44.3%, range: 9%-83%) than in population-based studies (median: 15.7%, range: 3%-63%), reflecting different referral patterns and selection criteria. Incidence of depressive symptoms varied from 11.7 to 26.6/100 person-years in hospital-based and population-based studies. For depressed normal subjects and depressed patients with MCI, the findings on increased risk of incident MCI or its progression to dementia were conflicting. These contrasting findings suggested that the length of the follow-up period, the study design, the sample population, and methodological differences may be central for detecting an association between baseline depression and subsequent development of MCI or its progression to dementia. Assuming that MCI may be the earliest identifiable clinical stage of dementia, depressive symptoms may be an early manifestation rather than a risk factor for dementia and Alzheimer disease, arguing that the underlying neuropathological condition that causes MCI or dementia also causes depressive symptoms. In this scenario, at least in certain subsets of elderly patients, late-life depression, MCI, and dementia could represent a possible clinical continuum.

As people live longer, there is increasing potential for mental disorders to interfere with testamentary distribution and render older people more vulnerable to "undue influence" when they are making a will. Accordingly, clinicians dealing with the mental disorders of older people will be called upon increasingly to advise the courts about a person's vulnerability to undue influence.

A Subcommittee of the IPA Task Force on Testamentary Capacity and Undue Influence undertook to establish consensus on the definition of undue influence and the provision of guidelines for expert assessment of risk factors for undue influence.

International jurisdictions differ in their approach to the notion of undue influence. Despite differences in legal systems, from a clinical perspective, the subcommittee identified some common "red flags" which might alert the expert to risk of undue influence. These include: (i) social or environmental risk factors such as dependency, isolation, family conflict and recent bereavement; (ii) psychological and physical risk factors such as physical disability, deathbed wills, sexual bargaining, personality disorders, substance abuse and mental disorders including dementia, delirium, mood and paranoid disorders; and (iii) legal risk factors such as unnatural provisions in a will, or provisions not in keeping with previous wishes of the person making the will, and the instigation or procurement of a will by a beneficiary.

This review provides some guidance for experts who are requested by the courts to provide an opinion on the risk of undue influence. Whilst international jurisdictions require different thresholds of proof for a finding of undue influence, there is good international consensus on the clinical indicators for the concept.

Increasing evidence suggests that functional impairment can be detected in older persons with mild cognitive impairment (MCI). This study explores the functional profiles and the clinical correlates of a population-based sample of Chinese older persons with MCI in Hong Kong.

A random sample of 765 Chinese elderly subjects without dementia was recruited, of which 389 were elderly normal controls (Clinical Dementia Rating = 0), and 376 had questionable dementia (CDR = 0.5). The latter were categorized into an MCI group (n = 291) and a very mild dementia (VMD) group (n = 85). Their functional performances were measured and compared with the normal controls (NC). Multiple regression analyses investigated the associations between functional scores (Disability Assessment in Dementia) and clinical correlates (cognitive test scores, neuropsychiatric symptoms and motor signs) in the NC subjects and cognitively impaired subjects.

Subjects with MCI had intermediate functional performance between the NC and those with VMD. Regression analyses revealed that lower scores of cognitive tests (delayed recall and categorical verbal fluency tests), apathy, aberrant motor symptoms and parkinsonism features were associated with lower functional scores in clinically non-demented subjects. Functional scores had no correlation with age, education and medical illness burden.

Neuropsychiatric symptoms and parkinsonism features were associated with functional impairment in the clinically non-demented elderly in the community. Assessment of these should be incorporated in the evaluation of older persons for early cognitive impairment.

Patients with mild cognitive impairment (MCI) experience cognitive declines and often report significant emotional/behavioral changes. Despite this, few studies have examined the impact of MCI on caregiver burden. The purpose of this study was to confirm the presence of caregiver burden in MCI and examine the relationship between burden and patients' neuropsychological, behavioral and emotional functioning.

The current study included 51 individuals who had been diagnosed as having MCI using Petersen's criteria. The patients underwent a thorough neuropsychological evaluation and completed the Beck Depression Inventory and Cognitive Difficulties Scale. The caregivers completed the Zarit Burden Interview and the Revised Memory and Behavior Checklist.

More than 30% of the caregivers reported clinically significant burden. Increased caregiver burden was associated with a longer course of cognitive symptoms, patient reports of worse depression and greater cognitive difficulties, and informant reports of patients having more behavior, mood and memory problems. Caregiver burden was not significantly associated with patients' neuropsychological test performance.

The results highlight the importance of addressing patients' behavioral and emotional difficulties, as well as caregiver burden, as part of the clinical exam in MCI.

Mild cognitive impairment (MCI) is an etiologically heterogeneous condition that is characterized by cognitive changes without impairment of activities of daily living and insufficient to represent dementia. MCI is an important risk state for dementia. Neuropsychiatric symptoms may be present in MCI.

We executed a PubMed search for articles on the neuropsychiatric manifestations in MCI and reviewed their findings.

Behavioral abnormalities are reported in 35-75% of MCI patients with the most common being depression, apathy, anxiety and irritability. The observed variability in symptom prevalence can be explained by the different sampling methods, MCI diagnostic criteria and behavioral instruments used. There is a compelling body of evidence that MCI patients with behavioral features are more prone to develop Alzheimer's disease (AD) than patients without these features.

Neuropsychiatric symptoms are common features of MCI. The behavioral changes observed in MCI are similar to those of AD and may help identify the subgroup of MCI patients with prodromal AD. Large prospective longitudinal studies would greatly contribute to our understanding of the epidemiology, diagnostic and prognostic value of the neuropsychiatric features in MCI.

The present study investigated arithmetic processing in patients with mild dementia of Alzheimer's type (DAT) and patients with mild cognitive impairment (MCI) without dementia. Arithmetic processing (e.g., 2+3=?, 3 x 4=?) was evaluated in (1) 'blocked' condition (without extra load on attentional and executive functions), in (2) 'mixed' condition (shifting between different operations was required), and in (3) 'Stroop-like' condition (executive control and inhibition of automatic retrieval processes were needed). Both DAT and MCI patients showed intact arithmetic knowledge retrieval from long-term memory in the blocked condition. However, DAT patients were compromised whenever load was put on executive functions, whereas MCI patients succeeded to shift between operations (mixed condition) but had difficulties to inhibit overlearned associations (Stroop-like condition). In line with previous studies, these findings point to the contribution of attentional and executive functions in arithmetic. The present investigation is also of clinical relevance: it suggests that it may be important to assess arithmetic processing not only in blocked presentation but also in mixed presentation. The mixed condition has a high ecological value because it mimics daily-life arithmetic activities (e.g., checking the grocery bill). As indicated by the present results, DAT and MCI patients who are in the normal range at routine neuropsychological (blocked) arithmetic assessments may experience difficulties by extra requirement of non-numerical resources. That means, they possibly process arithmetic not efficiently in daily-life situations.

Awareness of cognitive dysfunction shown by individuals with Mild Cognitive Impairment (MCI), a condition conferring risk for Alzheimer's disease (AD), is variable. Anosognosia, or unawareness of loss of function, is beginning to be recognized as an important clinical symptom of MCI. However, little is known about the brain substrates underlying this symptom. We hypothesized that MCI participants' activation of cortical midline structures (CMS) during self-appraisal would covary with level of insight into cognitive difficulties (indexed by a discrepancy score between patient and informant ratings of cognitive decline in each MCI participant). To address this hypothesis, we first compared 16 MCI participants and 16 age-matched controls, examining brain regions showing conjoint or differential BOLD response during self-appraisal. Second, we used regression to investigate the relationship between awareness of deficit in MCI and BOLD activity during self-appraisal, controlling for extent of memory impairment. Between-group comparisons indicated that MCI participants show subtly attenuated CMS activity during self-appraisal. Regression analysis revealed a highly significant relationship between BOLD response during self-appraisal and self-awareness of deficit in MCI. This finding highlights the level of anosognosia in MCI as an important predictor of response to self-appraisal in cortical midline structures, brain regions vulnerable to changes in early AD.

The objectives of this study are to describe the distribution of apathy in community-based older adults and to investigate its relationships with cognition and day-to-day functioning.

Data from the Cache County Study on Memory, Health and Aging were used to estimate the frequency of apathy in groups of elders defined by demographic, cognitive, and functional status and to examine the associations of apathy with impairments of cognition and day-to-day functioning.

Apathy was measured with the Neuropsychiatric Inventory. Clinical apathy (Neuropsychiatric Inventory score > or = 4) was found in 1.4% of individuals classified as cognitively normal, 3.1% of those with a mild cognitive syndrome, and 17.3% of those with dementia. Apathy status was associated with cognitive and functional impairments and higher levels of stress experienced by caregivers. Among participants with normal cognition, apathy was associated with worse performance on the Mini-Mental State Examination, the Boston Naming and Animal Fluency tests, and the Trail Making Test-Part B. The association of apathy with cognitive impairment was independent of its association with Neuropsychiatric Inventory depression.

In a cohort of community-based older adults, the frequency and severity of apathy is positively correlated with the severity of cognitive impairment. In addition, apathy is associated with cognitive and functional impairments in elders adjudged to have normal cognition. The results suggest that apathy is an early sign of cognitive decline and that delineating phenotypes in which apathy and a mild cognitive syndrome co-occur may facilitate earlier identification of individuals at risk for dementia.

Apathy is usually defined as a lack of motivation leading to reduced interest and participation in various activities. From a pathophysiological viewpoint, the most common cause of apathy is dysfunction of the frontal lobes, following either direct lesion of the frontal cortex or damage to regions tightly connected to the latter (such as the basal ganglia). The frontal-subcortical circuits often seem to be involved. Apathy is a common behavioral consequence of neurodegenerative disorders (Alzheimer's disease, parkinsonian syndromes, fronto-temporal dementia). The methods for detecting apathy and assessing its severity are various, the main difficulty being to disentangle apathy and depression. The treatment of apathy per se remains anecdotal and, to date, little research into the efficacy of medication therapy has been performed.

To investigate the neuropsychological characteristics of patients diagnosed with mild cognitive impairment (MCI) with and without apathy.

A cohort of 245 MCI patients (mean age = 72 +/- 5.5 years; mean MMSE = 27.5 +/- 1.3) was divided into two subgroups according to their Apathy Inventory score and underwent an extensive neuropsychological battery.

There were 94 (38.4%) patients with and 151 (61.6%) patients without apathy. At baseline the apathetic subgroup had a significantly lower total score on the free and cued selective reminding test (FCSR). Furthermore, the apathetic subgroup showed a significant deterioration in FCSR total recall score between baseline and the 1-year assessment. In conclusion, the presence of apathy in MCI patients is not associated with frontal task performance but with a higher degree of memory impairment.

Although substantial numbers of stroke patients suffer from apathy, its causes are still poorly understood. Previous studies suggest that dysfunction of the frontal lobes is implicated in the pathophysiology of motivation. Our aim was to investigate the association between proton magnetic resonance spectroscopy (H1-MRS) measurements in unaffected frontal lobes and apathy in a group of first-time stroke patients.

31 patients with a first-time ischemic stroke located outside the frontal lobes and 20 healthy subjects were included in the study. The authors performed single voxel H1-MRS in order to measure the N-acetylaspartate/creatine (NAA)/Cr, glutamate+glutamine (Glx)/Cr, choline (Cho)/Cr and myo-inositol (mI)/Cr ratios in the frontal lobes. Patients were assessed between days 7 and 12 post stroke. Diagnosis of apathy was made on the basis of clinical observation, interview and Apathy Scale.

13 out of 31 patients (42%) demonstrated apathy. Patients with apathy had lower NAA/Cr ratios in the right frontal lobe than non-apathetic subjects. The patient group was divided into two subgroups: Those with left hemisphere strokes, and those with right hemisphere strokes. Of these subjects, significantly lowered NAA/Cr ratios were found in the right hemispheres of apathetic patients in the subgroup with left-sided brain lesions.

These findings point to the association between apathy and frontal lobe integrity, suggest different reactions of the hemispheres and indicate that changes in the NAA/Cr ratio are related to the apathy.

Mild cognitive impairment in the elderly may represent a transitional phase between normal aging and early Alzheimer's disease (AD). It recently has been recognized as a distinct clinical entity with potentially different cognitive subtypes and etiologies. Like AD, studies have shown that psychiatric symptoms are more common than in the cognitively normal geriatric population. Understanding these symptoms has been recognized as important not only because they may impair patient function and caregiver burden, but also these symptoms may be relevant to understanding the development of AD in general. This article presents current information on psychiatric symptoms in mild cognitive impairment, their suggested role in the pathophysiology of AD and future research considerations on the subject.

In this study, individuals with mild cognitive impairment (MCI) were tested to see if executive dysfunction impacts their implementation of expectancy biases in a priming task. Young adults, healthy older adults, and individuals with MCI made speed-related decisions to sequentially presented word pairs. The proportion of category related (e.g., apple-fruit) versus coordinate related (apple-pear) pairs was varied to create different expectancy biases. When the proportion of category pairs was high (80%), the control groups showed an expectancy bias: Significant inhibition was observed for coordinate pairs compared with category pairs. The MCI group also demonstrated an expectancy bias but with much larger costs for unexpected targets. The findings suggest that individuals with MCI are inordinately sensitive to expectancy violations, and these findings are discussed in terms of possible executive dysfunction.

Apathy, a syndrome of decreased initiation and motivation, affects over 70% of individuals with Alzheimer's disease (AD) and is the most common neuropsychiatric symptom reported in AD patients. The syndrome of apathy is associated with functional impairment among patients and elevated stress among their caregivers. Apathy is one of the primary neuropsychiatric manifestations of frontal system dysfunction, and AD-related apathy is thought to reflect the interaction between cholinergic deficiency and neuropathological changes in frontal brain regions. This article reviews the assessment and treatment of apathy in AD, with emphasis on the utility of acetylcholinesterase inhibitors for reducing apathy in AD. The potential benefits of other pharmacologic agents and combined pharmacologic-behavioral interventions are also discussed, and recommendations for future research are provided.