Mental Status Examination in Primary Care.

The mental status examination relies on the physician's clinical judgment for observation and interpretation. When concerns about a patient's cognitive functioning arise in a clinical encounter, further evaluation is indicated. This can include evaluation of a targeted cognitive domain or the use of a brief cognitive screening tool that evaluates multiple domains. To avoid affecting the examination results, it is best practice to ensure that the patient has a comfortable, nonjudgmental environment without any family member input or other distractions. An abnormal response in a domain may suggest a possible diagnosis, but neither the mental status examination nor any cognitive screening tool alone is diagnostic for any condition. Validated cognitive screening tools, such as the Mini-Mental State Examination or the St. Louis University Mental Status Examination, can be used; the tools vary in sensitivity and specificity for detecting mild cognitive impairment and dementia. There is emerging evidence for the validity of cognitive screening performed during telemedicine visits, but it should not replace in-person evaluation of patients who have comorbidities that would preclude reliable testing via telephone or video. The workup after abnormal results of a mental status examination or cognitive screening tool is based on clinical judgment and primarily focuses on ruling out reversible causes of impairment and considering the need for further neuropsychiatric evaluation.

The Performance of Saccade Tasks Correlates with Cognitive Test Scores in Elderly Population: Evidence for the Usefulness of Oculomotor Tests in Cognitive Assessment.

BACKGROUND: Among the elderly, dementia is a common and disabling disorder with primary manifestations of cognitive impairments. Diagnosis and intervention in its early stages is the key to effective treatment. Nowadays, the test of cognitive function relies mainly on neuropsychological tests, such as the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). However, they have noticeable shortcomings, e.g., the biases of subjective judgments from physicians and the cost of the labor of these well-trained physicians. Thus, advanced and objective methods are urgently needed to evaluate cognitive functions. METHODS: We developed a cognitive assessment system through measuring the saccadic eye movements in three tasks. The cognitive functions were evaluated by both our system and the neuropsychological tests in 310 subjects, and the evaluating results were directly compared. RESULTS: In general, most saccadic parameters correlate well with the MMSE and MoCA scores. Moreover, some subjects with high MMSE and MoCA scores have high error rates in performing these three saccadic tasks due to various errors. The primary error types vary among tasks, indicating that different tasks assess certain specific brain functions preferentially. Thus, to improve the accuracy of evaluation through saccadic tasks, we built a weighted model to combine the saccadic parameters of the three saccadic tasks, and our model showed a good diagnosis performance in detecting patients with cognitive impairment. CONCLUSION: The comprehensive analysis of saccadic parameters in multiple tasks could be a reliable, objective, and sensitive method to evaluate cognitive function and thus to help diagnose cognitive impairments.

Reliability and Factor Structure of the Saint Louis University Mental Status (SLUMS) Examination.

OBJECTIVES: Compared to its alternatives (e.g., Mini-Mental State Examination [MMSE] and Montreal Cognitive Assessment [MoCA]), little is known about the psychometric properties and factor structure of the Saint Louis University Mental Status (SLUMS) Examination. The purpose of the current study is to describe the internal consistency, factor structure, and temporal stability of the SLUMS, a widely used cognitive screening measure. METHODS: We examined the SLUMS of 108 mostly White male Veterans seen for home-based primary care services, 101 of whom had complete data and 28 who completed retesting approximately one year later. RESULTS: At time one, Veterans averaged 76.44 (SD = 9.88) years of age and 13.07 (SD = 2.26) years of formal education. Results indicated that the SLUMS had acceptable internal consistency (α = .709) and temporal stability (ρ =.723), with strongest evidence for a one-factor structure. CONCLUSIONS: The SLUMS appears to have adequate reliability and clear one-factor structure in this sample. Additional research with diverse samples is needed to characterize the psychometrics of the SLUMS more comprehensively. CLINICAL IMPLICATIONS: The SLUMS appears to be an efficient method for approximating global cognitive functioning among medically complex older adults.

Systematic Review of the Psychometric Properties of the Saint Louis University Mental Status (SLUMS) Examination.

OBJECTIVES: This systemic review qualitatively synthesizes existing psychometric support for the Saint Louis University Mental Status (SLUMS) Examination, a cognitive screening measure which presents as a free alternative to other widely used dementia screening measures including the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). METHODS: A total of 90 peer-reviewed articles on the SLUMS were identified from PsycINFO and PubMed databases. RESULTS: Sixty-eight records were identified and reviewed by the lead author for eligibility. Studies that included at least one psychometric property of the SLUMS (n = 20) were included in this review. CONCLUSIONS: Support for the SLUMS remains preliminary; however, it appears to have adequate validity, and adequate sensitivity and specificity in detecting cognitive impairment. Numerous shortcomings were identified, including lack of sufficient normative data, information on test-reliability, explored factor structure, and limited application of criterion measures (e.g., imaging studies, biomarkers). Research is needed to establish diverse normative samples and describe the reliability and validity of the SLUMS to strengthen the empirical support for its use. CLINICAL IMPLICATIONS: Until its psychometric properties are better established the SLUMS should be used cautiously when screening for cognitive impairment.

A comparison of the Mini-Mental State Examination (MMSE) with the Montreal Cognitive Assessment (MoCA) for mild cognitive impairment screening in Chinese middle-aged and older population: a cross-sectional study.

BACKGROUND: The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are the most commonly used scales to detect mild cognitive impairment (MCI) in population-based epidemiologic studies. However, their comparison on which is best suited to assess cognition is scarce in samples from multiple regions of China. METHODS: We conducted a cross-sectional analysis of 4923 adults aged ≥55 years from the Community-based Cohort Study on Nervous System Diseases. Objective cognition was assessed by Chinese versions of MMSE and MoCA, and total score and subscores of cognitive domains were calculated for each. Education-specific cutoffs of total score were used to diagnose MCI. Demographic and health-related characteristics were collected by questionnaires. Correlation and agreement for MCI between MMSE and MoCA were analyzed; group differences in cognition were evaluated; and multiple logistic regression model was used to clarify risk factors for MCI. RESULTS: The overall MCI prevalence was 28.6% for MMSE and 36.2% for MoCA. MMSE had good correlation with MoCA (Spearman correlation coefficient = 0.8374, p < 0.0001) and moderate agreement for detecting MCI with Kappa value of 0.5973 (p < 0.0001). Ceiling effect for MCI was less frequent using MoCA versus MMSE according to the distribution of total score. Percentage of relative standard deviation, the measure of inter-individual variance, for MoCA (26.9%) was greater than for MMSE (19.0%) overall (p < 0.0001). Increasing age (MMSE: OR = 2.073 for ≥75 years; MoCA: OR = 1.869 for≥75 years), female (OR = 1.280 for MMSE; OR = 1.163 for MoCA), living in county town (OR = 1.386 and 1.862 for MMSE and MoCA, respectively) or village (OR = 2.579 and 2.721 for MMSE and MoCA, respectively), smoking (OR = 1.373 and 1.288 for MMSE and MoCA, respectively), hypertension (MMSE: OR = 1.278; MoCA: OR = 1.208) and depression (MMSE: OR = 1.465; MoCA: OR = 1.350) were independently associated with greater likelihood of MCI compared to corresponding reference group in both scales (all p < 0.05). CONCLUSIONS: MoCA is a better measure of cognitive function due to lack of ceiling effect and with good detection of cognitive heterogeneity. MCI prevalence is higher using MoCA compared to MMSE. Both tools identify concordantly modifiable factors for MCI, which provide important evidence for establishing intervention measures.

Sensitivity and Specificity of the Saint Louis University Mental Status Examination to Detect Mild Cognitive Impairment and Dementia in Chinese Population.

INTRODUCTION: The Saint Louis University Mental Status (SLUMS) examination is a common screening instrument to detect mild cognitive impairment (MCI) in Western countries. However, further work is needed to identify optimal SLUMS cutoff scores for screening MCI and dementia in Chinese populations. OBJECTIVE: The aim of this study was to evaluate the utility and diagnostic accuracy of the SLUMS examination in the diagnosis of dementia and MCI in Chinese population. METHODS: A cross-sectional multicenter design was conducted. Patients were recruited from the outpatient department of our neurology and psychiatric clinics. The establishment of the gold standard for the SLUMS-Chinese version (SLUMS-C) to detect MCI and dementia was based on the clinical criteria of the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) and related neuropsychological testing conducted by 3 certified dementia specialists. The consistency of the diagnosis process and administering SLUMS-C were established prior to the beginning of the study. Data were analyzed, and sensitivity, specificity, and areas under the curve (AUCs) were calculated. RESULTS: A total of 367 subjects were recruited. The SLUMS-C did not show satisfactory AUCs for the preliminary detection of normal cognitive status and MCI by different educational levels (all AUC 0.32-0.54). However, the SLUMS-C showed acceptable AUCs for the preliminary detection of dementia by different educational levels (all AUC 0.78-0.81). An educational level of senior high school showed the best cutoff, sensitivity, and specificity. The SLUMS-C scores to detect dementia for individuals with at least high school education and less than high school education were <24 and 22, respectively. CONCLUSIONS: Our results indicate that the SLUMS-C could be a beneficial and convenient screening instrument to detect dementia in Chinese population. After community screening, a comprehensive clinical evaluation including cognitive assessment, functional status, corroborative history, and imaging confirmation is needed.

Recent-Onset Altered Mental Status: Evaluation and Management.

Potential precipitating factors for the recent onset of altered mental status (AMS) include primary central nervous system insults, systemic infections, metabolic disturbances, toxin exposure, medications, chronic systemic diseases, and psychiatric conditions. Delirium is also an important manifestation of AMS, especially in older people who are hospitalized. Clinicians should identify and treat reversible causes of the AMS, some of which require urgent intervention to minimize morbidity and mortality. A history and physical examination guide diagnostic testing. Laboratory testing, chest radiography, and electrocardiography help diagnose infections, metabolic disturbances, toxins, and systemic conditions. Neuroimaging with computed tomography or magnetic resonance imaging should be performed when the initial evaluation does not identify a cause or raises concern for intracranial pathology. Lumbar puncture and electroencephalography are also important diagnostic tests in the evaluation of AMS. Patients at increased risk of AMS benefit from preventive measures. The underlying etiology determines the definitive treatment. When intervention is needed to control patient behaviors that threaten themselves or others, nonpharmacologic interventions are preferred to medications. Physical restraints should rarely be used and only for the shortest time possible. Medications should be used only when nonpharmacologic treatments are ineffective.

A modern network approach to revisiting the Positive and Negative Affective Schedule (PANAS) construct validity.

INTRODUCTION: The factor structure of the Positive and Negative Affective Schedule (PANAS) is still a topic of debate. There are several reasons why using Exploratory Graph Analysis (EGA) for scale validation is advantageous and can help understand and resolve conflicting results in the factor analytic literature. OBJECTIVE: The main objective of the present study was to advance the knowledge regarding the factor structure underlying the PANAS scores by utilizing the different functionalities of the EGA method. EGA was used to (1) estimate the dimensionality of the PANAS scores, (2) establish the stability of the dimensionality estimate and of the item assignments into the dimensions, and (3) assess the impact of potential redundancies across item pairs on the dimensionality and structure of the PANAS scores. METHOD: This assessment was carried out across two studies that included two large samples of participants. RESULTS AND CONCLUSION: In sum, the results are consistent with a two-factor oblique structure.

The mental health status of asylum seekers in middle- to high-income countries: a synthesis of current global evidence.

INTRODUCTION: The last 5 years have witnessed a significant increase in the number of people fleeing their countries of origin and seeking refuge in host countries. By the end of 2018, there were 3.5 million asylum seekers awaiting outcomes on their applications, the majority of whom were hosted by middle- to high-income countries. This review aimed to identify and synthesize current knowledge regarding the mental health status of asylum seekers in middle- to high-income countries. SOURCES OF DATA: A search was conducted across various databases for research literature published within the last 5 years (2014-2019). The final review and synthesis included 25 articles. AREAS OF AGREEMENT: Findings highlighted significant differences in the mental health status of asylum seekers compared to those with refugee status and permanent residence. AREAS OF CONTROVERSY: Guidelines from the World Health Organization and the United Nations High Commissioner for Refugees emphasize the need to understand and address mental health issues. Instead, there have been policy changes in many host countries regarding asylum applications, and the associated effects of these changes have been shown to negatively impact mental health. GROWING POINTS: The synthesized findings from the present review provide information regarding the current mental health status of asylum seekers hosted by middle- to high-income countries. Areas of intervention and resource allocation were also identified. AREAS TIMELY FOR DEVELOPING RESEARCH: Future research should consider the impact of large-scale, low-cost interventions to support the mental health of those seeking asylum.

Recognition, prevention, and treatment of delirium in emergency department: An evidence-based narrative review.

BACKGROUND: Delirium is an acute disorder of attention and cognition that is common, serious, costly, under-recognized, and potentially fatal. Delirium is particularly problematic in the emergency department (ED) care of medically complex older adults, who are being seen in greater numbers. OBJECTIVE: This evidence-based narrative review focuses on the key components of delirium screening, prevention, and treatment. DISCUSSION: The recognition of delirium requires a systematic approach rather than a clinical gestalt alone. Several delirium assessment tools with high sensitivity and specificity, such as delirium triage screen and brief Confusion Assessment Method, can be used in the ED. The prevention of delirium requires environmental modification and unique geriatric care strategies tailored to the ED. The key approaches to treatment include the removal of the precipitating etiology, re-orientation, hydration, and early mobilization. Treatment of delirium requires a multifaceted and comprehensive care plan, as there is limited evidence for significant benefit with pharmacological agents. CONCLUSION: Older ED patients are at high risk for current or subsequent development of delirium, and a focused screening, prevention, and intervention for those who are at risk for delirium and its associated complications are the important next steps.

Effects of a combined transcranial magnetic stimulation (TMS) and cognitive training intervention in patients with Alzheimer's disease.

INTRODUCTION: This clinical trial evaluates the efficacy and safety of a 6-week course of daily neuroAD™ therapy. METHODS: 131 subjects between 60 and 90 years old, unmedicated for Alzheimer's disease (AD), or on stable doses of an acetylcholinesterase inhibitor and/or memantine, with Mini-Mental State Examination scores between 18 and 26, clinical dementia rating scale scores of 1 or 2, enrolled for a prospective, randomized, double-blind, sham-controlled, multicenter clinical trial. Structural brain MRIs were obtained for transcranial magnetic stimulation targeting. Baseline Alzheimer's disease assessment scale-cognitive (ADAS-Cog) and Clinical Global Impression of Change were assessed. 129 participants were randomized to active treatment plus standard of care (SOC) or sham treatments plus SOC. RESULTS: Subjects with baseline ADAS-Cog ≤ 30 (~85% of study population) showed a statistically significant benefit favoring active over sham. Responder analysis showed 31.7% participants in the active group with ≤ -4 point improvement on ADAS-Cog versus 15.4% in the sham group. DISCUSSION: neuroAD™ Therapy System provides a low-risk therapeutic benefit for patients with milder AD (baseline ADAS-Cog ≤30) beyond pharmacologic SOC.

A new scoring system for increasing the sensitivity of the MMSE.

BACKGROUND: The mini mental state examination (MMSE) has been criticized for its lack of sensitivity, especially in mild cases of dementia. There have been several attempts to increase the sensitivity by adding or deleting items, which never became accepted in clinical practice. OBJECTIVE: In the current study a new scoring system for improving the sensitivity of the MMSE is proposed, which preserves the original items and the total score of 30 points. Instead of changing the number of items or the total score of 30 points, the weighting of the different items in the total score of 30 points was changed. MATERIAL AND METHODS: Neuropsychological test data of 765 patients were retrospectively included in the study to determine the difficulty of each MMSE item. Multiple scoring systems for the MMSE were developed by inclusion of the item difficulty and clinical relevance. The sensitivity of the new scoring system was compared to the original scoring system by using the DemTect as an established measure. RESULTS: The results showed that an increase of 24.3% in sensitivity was statistically significant. Within the mild cognitive impairment subgroup, the sensitivity of the new scoring system was twice as high in comparison to the original MMSE and within the dementia group the sensitivity was increased by 8.2%. CONCLUSION: A new scoring system with a higher sensitivity than the original MMSE was developed, which can easily be administered in clinical practice because it preserves all items and the total score of 30 points.

Nonconvulsive Seizure Detection by Reduced-Lead Electroencephalography in Children with Altered Mental Status in the Emergency Department.

OBJECTIVES: To evaluate the proportion of children presenting to the emergency department (ED) with altered mental status who demonstrate nonconvulsive seizures on reduced-lead electroencephalography (EEG), and to further investigate the characteristics, treatment, and outcomes in these patients compared with patients without nonconvulsive seizures. STUDY DESIGN: In this retrospective cohort study, we reviewed the database and medical records of pediatric patients (aged <18 years) in a single ED between May 1, 2016, and April 30, 2018. We first determined the proportion of nonconvulsive seizures among patients with altered mental status (Glasgow Coma Scale <15). We then compared the clinical presentation, demographic data, clinical diagnosis, EEG results, treatment, and outcomes of patients with altered mental status with nonconvulsive seizures and those without nonconvulsive seizures. RESULTS: In total, 16.9% of the patients with altered mental status (41 of 242; 95% CI, 12.2%-21.6%) evaluated by EEG had detectable nonconvulsive seizure, equivalent to 4.4% (41 of 932) of all patients with altered mental status presenting at our hospital. More than 80% of patients monitored for nonconvulsive seizures had a previous history of seizures, often febrile. Patients with nonconvulsive seizures were older (median, 68.5 vs 36.1 months) and had a higher Pediatric Cerebral Performance Category score at presentation (median, 2.0 vs 1.0). In addition, the proportion of patients admitted to the intensive care unit was significantly higher in the patients with nonconvulsive seizures (30.3% vs 15.0%). However, total duration of hospitalization, neurologic sequelae, and 30-day mortality rate did not differ between the 2 groups. CONCLUSIONS: A relatively high percentage of pediatric patients with altered mental status in the ED experience nonconvulsive seizures. The use of reduced-lead EEG monitoring in the ED might facilitate the recognition and treatment of nonconvulsive seizures, especially among patients with a history of seizures.

Memory complaints, dementia, and neuropathology in older blacks and whites.

OBJECTIVE: To determine relationships of memory complaints to cognitive function and decline, incident dementia, and neurodegenerative and other neuropathologies, as well as the population-attributable risk for dementia in older black and white persons. METHODS: A total of 4,015 community-based persons (28% black; 74% women; mean baseline age = 78 years) were enrolled in 1 of 4 longitudinal cohort studies, and another 2,937 in a population-based cohort. Memory scores, assessed using 2 questions (5-point Likert scales) were categorized as complaints present or absent. Global cognition and 5 cognitive domains were derived from annual neuropsychological tests. Dementia was assessed from these tests and additional data. Neuropathologic data were available for 1,350 deceased subjects with brain autopsies. Regression and mixed effects models were used to examine relationships of memory complaints to cognition and neuropathology. RESULTS: Baseline memory complaints (n = 1,310; 33% of 4,015) were associated with lower cognition and faster decline in all domains (global score estimate = -0.032, standard error = 0.004, p < 0.0001), during a mean follow-up of 6 (standard deviation = 2) years. Persons with memory complaints had higher dementia risk (hazard ratio = 1.64, 95% confidence interval [CI] = 1.42-1.89) and odds of pathologic Alzheimer disease (odds ratio [OR] = 1.96, 95% CI = 1.51-2.54), neocortical Lewy bodies (OR = 2.47, 95% CI = 1.54-3.96), and other neurodegenerative pathologies. Results for dementia risk were similar among blacks and whites. Among 2,937 older persons in a population-based cohort with similar data, the population-attributable risk for incident dementia due to memory complaints was 14.0% (95% CI = 2.6-23.0), and did not vary between the black and white groups. INTERPRETATION: Memory complaints are common in older black and white persons, and relate to cognitive decline, dementia risk, and neurodegenerative pathologies. Ann Neurol 2018;83:718-729.

Altruistic decisions following penetrating traumatic brain injury.

The cerebral correlates of altruistic decisions have increasingly attracted the interest of neuroscientists. To date, investigations on the neural underpinnings of altruistic decisions have primarily been conducted in healthy adults undergoing functional neuroimaging as they engaged in decisions to punish third parties. The chief purpose of the present study was to investigate altruistic decisions following focal brain damage with a novel altruistic decision task. In contrast to studies that have focused either on altruistic punishment or donation, the Altruistic Decision Task allows players to anonymously punish or donate to 30 charitable organizations involved with salient societal issues such as abortion, nuclear energy and civil rights. Ninety-four Vietnam War veterans with variable patterns of penetrating traumatic brain injury and 28 healthy veterans who also served in combat participated in the study as normal controls. Participants were asked to invest $1 to punish or reward real societal organizations, or keep the money for themselves. Associations between lesion distribution and performance on the task were analysed with multivariate support vector regression, which enables the assessment of the joint contribution of multiple regions in the determination of a given behaviour of interest. Our main findings were: (i) bilateral dorsomedial prefrontal lesions increased altruistic punishment, whereas lesions of the right perisylvian region and left temporo-insular cortex decreased punishment; (ii) altruistic donations were increased by bilateral lesions of the dorsomedial parietal cortex, whereas lesions of the right posterior superior temporal sulcus and middle temporal gyri decreased donations; (iii) altruistic punishment and donation were only weakly correlated, emphasizing their dissociable neuroanatomical associations; and (iv) altruistic decisions were not related to post-traumatic personality changes. These findings indicate that altruistic punishment and donation are determined by largely non-overlapping cerebral regions, which have previously been implicated in social cognition and moral experience such as evaluations of intentionality and intuitions of justice and morality.10.1093/brain/awy064_video1awy064media15758316955001.

Fibre-specific white matter reductions in Alzheimer's disease and mild cognitive impairment.

Alzheimer's disease is increasingly considered a large-scale network disconnection syndrome, associated with progressive aggregation of pathological proteins, cortical atrophy, and functional disconnections between brain regions. These pathological changes are posited to arise in a stereotypical spatiotemporal manner, targeting intrinsic networks in the brain, most notably the default mode network. While this network-specific disruption has been thoroughly studied with functional neuroimaging, changes to specific white matter fibre pathways within the brain's structural networks have not been closely investigated, largely due to the challenges of modelling complex white matter structure. Here, we applied a novel technique known as 'fixel-based analysis' to comprehensively investigate fibre tract-specific differences at a within-voxel level (called 'fixels') to assess potential axonal loss in subjects with Alzheimer's disease and mild cognitive impairment. We hypothesized that patients with Alzheimer's disease would exhibit extensive degeneration across key fibre pathways connecting default network nodes, while patients with mild cognitive impairment would exhibit selective degeneration within fibre pathways connecting regions previously identified as functionally implicated early in Alzheimer's disease. Diffusion MRI data from Alzheimer's disease (n = 49), mild cognitive impairment (n = 33), and healthy elderly control subjects (n = 95) were obtained from the Australian Imaging, Biomarkers and Lifestyle study of ageing. We assessed microstructural differences in fibre density, and macrostructural differences in fibre bundle morphology using fixel-based analysis. Whole-brain analysis was performed to compare groups across all white matter fixels. Subsequently, we performed a tract of interest analysis comparing fibre density and cross-section across 11 selected white matter tracts, to investigate potentially subtle degeneration within fibre pathways in mild cognitive impairment, initially by clinical diagnosis alone, and then by including amyloid status (i.e. a positive or negative amyloid PET scan). Our whole-brain analysis revealed significant white matter loss manifesting both microstructurally and macrostructurally in Alzheimer's disease patients, evident in specific fibre pathways associated with default mode network nodes. Reductions in fibre density and cross-section in mild cognitive impairment patients were only exhibited within the posterior cingulum when statistical analyses were limited to tracts of interest. Interestingly, these degenerative changes did not appear to be associated with high amyloid accumulation, given that amyloid-negative, but not positive, mild cognitive impairment subjects exhibited subtle focal left posterior cingulum deficits. The findings of this study demonstrated a stereotypical distribution of white matter degeneration in patients with Alzheimer's disease, which was in line with canonical findings from other imaging modalities, and with a network-based conceptualization of the disease.awx355media15726254535001.

Effect of cholinergic treatment depends on cholinergic integrity in early Alzheimer's disease.

In early Alzheimer's disease, which initially presents with progressive loss of short-term memory, neurodegeneration especially affects cholinergic neurons of the basal forebrain. Pharmacotherapy of Alzheimer's disease therefore often targets the cholinergic system. In contrast, cholinergic pharmacotherapy of mild cognitive impairment is debated since its efficacy to date remains controversial. We here investigated the relationship between cholinergic treatment effects and the integrity of the cholinergic system in mild cognitive impairment due to Alzheimer's disease. Fourteen patients with high likelihood of mild cognitive impairment due to Alzheimer's disease and 16 age-matched cognitively normal adults performed an episodic memory task during functional magnetic resonance imaging under three conditions: (i) without pharmacotherapy; (ii) with placebo; and (iii) with a single dose of rivastigmine (3 mg). Cortical acetylcholinesterase activity was measured using PET with the tracer 11C-N-methyl-4-piperidyl acetate (MP4A). Cortical acetylcholinesterase activity was significantly decreased in patients relative to controls, especially in the lateral temporal lobes. Without pharmacotherapy, mild cognitive impairment was associated with less memory-related neural activation in the fusiform gyrus and impaired deactivation in the posterior cingulate cortex, relative to controls. These differences were attenuated under cholinergic stimulation with rivastigmine: patients showed increased neural activation in the right fusiform gyrus but enhanced deactivation of the posterior cingulate cortex under rivastigmine, compared to placebo. Conversely, controls showed reduced activation of the fusiform gyrus and reduced deactivation of the posterior cingulate under rivastigmine, compared to placebo. In both groups, the change in neural activation in response to rivastigmine was negatively associated with local acetylcholinesterase activity. At the behavioural level, an analysis of covariance revealed a significant group × treatment interaction in episodic memory performance when accounting for hippocampal grey matter atrophy and function. Our results indicate that rivastigmine differentially affects memory-related neural activity in patients with mild cognitive impairment and cognitively normal, age-matched adults, depending on acetylcholinesterase activity as a marker for the integrity of the cortical cholinergic system. Furthermore, hippocampal integrity showed an independent association with the response of memory performance to acetylcholinesterase inhibition.

Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer's disease.

Although brain neuroinflammation may play an instrumental role in the pathophysiology of Alzheimer's disease, its actual impact on disease progression remains controversial, being reported as either detrimental or protective. This work aimed at investigating the temporal relationship between microglial activation and clinical progression of Alzheimer's disease. First, in a large cohort of patients with Alzheimer's disease we analysed the predictive value of microglial activation assessed by 18F-DPA-714 PET imaging on functional, cognitive and MRI biomarkers outcomes after a 2-year follow-up. Second, we analysed the longitudinal progression of 18F-DPA-714 binding in patients with Alzheimer's disease by comparison with controls, and assessed its influence on clinical progression. At baseline, all participants underwent a clinical assessment, brain MRI, 11C-PiB, 18F-DPA-714 PET imaging and TSPO genotyping. Participants were followed-up annually for 2 years. At the end of the study, subjects were asked to repeat a second 18F-DPA-714-PET imaging. Initial 18F-DPA-714 binding was higher in prodromal (n = 33) and in demented patients with Alzheimer's disease (n = 19) compared to controls (n = 17). After classifying patients into slow and fast decliners according to functional (Clinical Dementia Rating change) or cognitive (Mini-Mental State Examination score decline) outcomes, we found a higher initial 18F-DPA-714 binding in slow than fast decliners. Negative correlations were observed between initial 18F-DPA-714 binding and the Clinical Dementia Rating Sum of Boxes score increase, the MMSE score loss and the progression of hippocampal atrophy. This suggests that higher initial 18F-DPA-714 binding is associated with better clinical prognosis. Twenty-four patients with Alzheimer's disease and 15 control subjects performed a second DPA-PET. We observed an increase of 18F-DPA-714 in patients with Alzheimer's disease as compared with controls (mean 13.2% per year versus 4.2%) both at the prodromal (15.8%) and at the demented stages (8.3%). The positive correlations between change in 18F-DPA-714 binding over time and the three clinical outcome measures (Clinical Dementia Rating, Mini-Mental State Examination, hippocampal atrophy) suggested a detrimental effect on clinical Alzheimer's disease progression of increased neuroinflammation after the initial PET examination, without correlation with PiB-PET uptake at baseline. High initial 18F-DPA-714 binding was correlated with a low subsequent increase of microglial activation and favourable clinical evolution, whereas the opposite profile was observed when initial 18F-DPA-714 binding was low, independently of disease severity at baseline. Taken together, our results support a pathophysiological model involving two distinct profiles of microglial activation signatures with different dynamics, which differentially impact on disease progression and may vary depending on patients rather than disease stages.

Neuroinflammation and Tau Interact with Amyloid in Predicting Sleep Problems in Aging Independently of Atrophy.

Sleep problems relate to brain changes in aging and disease, but the mechanisms are unknown. Studies suggest a relationship between ß-amyloid (Aß) accumulation and sleep, which is likely augmented by interactions with multiple variables. Here, we tested how different cerebrospinal fluid (CSF) biomarkers for brain pathophysiology, brain atrophy, memory function, and depressive symptoms predicted self-reported sleep patterns in 91 cognitively healthy older adults over a 3-year period. The results showed that CSF levels of total- and phosphorylated (P) tau, and YKL-40-a marker of neuroinflammation/astroglial activation-predicted poor sleep in Aß positive older adults. Interestingly, although brain atrophy was strongly predictive of poor sleep, the relationships between CSF biomarkers and sleep were completely independent of atrophy. A joint analysis showed that unique variance in sleep was explained by P-tau and the P-tau × Aß interaction, memory function, depressive symptoms, and brain atrophy. The results demonstrate that sleep relates to a range of different pathophysiological processes, underscoring the importance of understanding its impact on neurocognitive changes in aging and people with increased risk of Alzheimer's disease.

Prescription of Benzodiazepines and Related Drugs in Patients with Mild Cognitive Deficits and Alzheimer's Disease.

INTRODUCTION: Benzodiazepines and related drugs (BZDR) should be avoided in patients with cognitive impairment. We evaluated the relationship between a BZDR treatment and the health status of patients with Alzheimer's disease (AD). METHODS: Cross-sectional study in 395 AD patients using bivariate and multiple logistic analyses to assess correlations between the prescription of BZDR and patients' characteristics (cognitive and functional capacity, health-related quality of life (HrQoL), neuropsychiatric symptoms). RESULTS: BZDR were used in 12.4% (n=49) of all participants. In bivariate analyses, the prescription was associated with a lower HrQoL, a higher need of care, and the presence of anxiety. Multivariate models revealed a higher risk of BZDR treatment in patients with depression (OR 3.85, 95% CI: 1.45 - 10.27). Community-dwelling participants and those treated by neurologists/psychiatrists had a lower risk of receiving BZDR (OR 0.33, 95% CI: 0.12 - 0.89 and OR 0.16, 95% CI: 0.07 - 0.36). DISCUSSION: The inappropriate use of BZDR conflicts with national and international guidelines. We suggest evaluating indications and treatment duration and improving the knowledge of alternative therapies in healthcare institutions.