Improvement in cognitive impairment following a 12-week aerobic exercise intervention in individuals with non-cirrhotic chronic hepatitis C.

Cognitive impairment occurs in 30%-50% of patients with non-cirrhotic chronic hepatitis C virus (HCV) infection. Exercise is beneficial in preventing and treating cognitive impairment and cardiometabolic abnormalities in many chronic inflammatory diseases, but there are few studies investigating the impact of exercise in HCV infection. The study aimed to assess the effect of a 12-week aerobic exercise intervention on cognition and extrahepatic manifestations in individuals with HCV. In this nonrandomized controlled pilot study, individuals with HCV participated in a 12-week aerobic exercise intervention. Outcome measures included cognition (Montreal Cognitive Assessment [MOCA], Trail Making Test A & B [TMT-A; TMT-B], Digit Symbol Test [DST]), cardiorespiratory fitness (estimated V˙O2max ), physical activity (accelerometry), anthropometry, quality of life (depression; fatigue; sleep quality) and biochemical markers. Outcomes were assessed at baseline (T0), intervention completion (T1) and 12 weeks after intervention completion (T2). Thirty-one patients completed the study (exercise group n = 13, control group n = 18). In the exercise group, cognition improved at T1 in the TMT-A (31% mean improvement, p = 0.019), TMT-B (15% mean improvement, p = 0.012) time and MOCA (14% mean improvement, p ≤ 0.001). These improvements were not maintained at T2. Depression (p = 0.038), sleep quality (p = 0.002), fatigue (p = 0.037) and estimated V˙O2max (7.8 mL kg-1  min-1 [22%] mean increase, p = 0.004) also improved at T1. In conclusion, this study demonstrates the benefits of a 12-week aerobic exercise intervention in improving cognition, quality of life and cardiorespiratory fitness in individuals with HCV. Larger studies are needed to confirm these findings and strategies for continued exercise engagement in individuals with HCV are warranted for sustained benefits.

Clinical utility of mild cognitive impairment subtypes and number of impaired cognitive domains at predicting progression to dementia: A 20-year retrospective study.

OBJECTIVE: To determine the utility of mild cognitive impairment (MCI) subtypes and number of impaired cognitive domains on initial assessment at predicting progression to dementia in a sample of memory clinic patients over a 20-year period. METHODS: A retrospective analysis was conducted of those presenting to a memory clinic with MCI from 1 January 1999 to 31 December 2018 inclusive. Those with MCI were broken down into one of the four subtypes using recommended cut-off scores on the Cambridge Cognitive Assessment (CAMCOG). Binomial logistic regression analysis was used to determine the utility of MCI subtypes and number of impaired cognitive domains as predictors for dementia. RESULTS: Overall 1188 individuals with MCI diagnosis were identified, with 378 (32%) progressing to dementia, with median [range] time to diagnosis of 2 years [1-8.4]. Six hundred and forty-nine (55%) were identified as amnestic MCI and 539 (45%) as non-amnestic MCI. Amnestic MCI was a significant predictor of progression compared to non-amnestic MCI (OR = 1.85, df = 1, P < .001). Number of cognitive domains impaired was also a significant predictor of progression to dementia (OR = 1.07, df = 1, P = .01) but the single-/multi-domain distinction was not (OR = 1.29, df = 1, P = .36). CONCLUSION: This study shows that approximately 32% of those diagnosed with MCI in a memory clinic progressed to dementia, with a median time to progression of 2 years. Those with amnestic MCI are almost twice as likely to progress to dementia than non-amnestic MCI and that therefore this is a useful distinction. However, the utility of the single- and multi-domain MCI distinction is called into question by our findings.

Is the Quick Mild Cognitive Impairment Screen (QMCI) more accurate at detecting mild cognitive impairment than existing short cognitive screening tests? A systematic review of the current literature.

OBJECTIVES: Differentiating normal cognition, mild cognitive impairment (MCI), and dementia is important, as these conditions differ in terms of their prognosis and treatment. Existing short cognitive screening tests vary widely in their accuracy, sensitivity, and specificity at detecting MCI and dementia. The Quick Mild Cognitive Impairment Screen (QMCI) was developed in 2012 as a fast and accurate "MCI specific" screening test. The aim of the current study was to conduct a literature review to compare the accuracy, sensitivity, and specificity of the QMCI at differentiating normal cognition, MCI, and dementia to existing short cognitive screening tests at their optimal cut-off scores. METHODS: A search of the electronic journal databases EBSCO, Psych info, and Science Direct was undertaken using the keywords "Quick Mild Cognitive Impairment Screen," "QMCI," "accuracy," "sensitivity," and "specificity." Results of individual studies were examined, and 2 × 2 tables were drawn up to obtain the overall accuracy, sensitivity, and specificity of each test across the studies included. RESULTS: Results from individual studies show that the QMCI has higher accuracy at detecting MCI and dementia than these cognitive screens. Pooled analysis shows that it also has greater sensitivity and specificity at optimal cut-off points for each test. CONCLUSIONS: Based in the current review, the QMCI represents a more accurate, sensitive, and specific screening test for MCI and dementia than the SMMSE or the MoCA. This has important implications in screening for cognitive impairment.

Comprehensive Neuropsychological Assessment of Cognitive Functioning of Adults With Lower Limb Amputation in Rehabilitation.

OBJECTIVE: To establish a comprehensive profile of cognitive functioning in people engaged in lower limb amputation (LLA) rehabilitation. DESIGN: Cross-sectional study as part of a longitudinal prospective cohort. SETTING: A national tertiary rehabilitation hospital. PARTICIPANTS: Adult volunteer participants (N=87) referred for comprehensive rehabilitation for major LLA were sampled from 207 consecutive admissions. Participants with both vascular (n=69) and nonvascular (n=18) LLA etiologies were included. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Demographic and health information and a battery of standardized neuropsychological assessments. RESULTS: Compared to normative data, impairment was evident in overall cognitive functioning (P≤.003). Impairment was also evident in particular areas, including reasoning, psychomotor function, information processing, attention, memory, language/naming, visuospatial functions, and executive functions (all P≤.003 Holm-corrected). There were also higher frequencies of impaired functions across most aspects of functioning in this group compared with expected frequencies in normative data (P≤.003 Holm-corrected). There were no significant differences in cognitive functioning between participants of vascular and nonvascular LLA etiology. CONCLUSIONS: Findings support the need for cognitive screening at rehabilitation admission regardless of etiology. Administration of comprehensive neuropsychological assessment with a battery sensitive to vascular cognitive impairment is recommended in some cases to generate an accurate and precise understanding of relative strengths and weaknesses in cognitive functioning. Cognitive functioning is a potential intervention point for improvement of rehabilitation outcomes for those with LLA, and further research is warranted in this area.

Neuropolypathology as a result of severe traumatic brain injury?

A history of brain trauma has long been acknowledged as increasing an individual's risk of developing dementia in later life. The underlying mechanisms that belie this pre-disposition are, however, very poorly understood. Here, we report a clinical-neuropathological correlation of a man who presented at the age of 66 with a progressive complex atypical dementia with early and prominent neurobehavioral symptoms. His neurological condition continued to decline up to his death at the age of 74. During the compilation of his clinical history, it was established that the subject had experienced a single severe traumatic brain injury (TBI) aged 12 years in 1954 resulting in loss of consciousness, hospitalization, and coma for a number of days after which he was deemed to have recovered. Following post-mortem neuropathological analysis, numerous distinct neuropathologies were observed in various brain regions and these included i) widespread Braak stage VI neurofibrillary tangle formation, ii) widespread α-synuclein positive Lewy bodies and Lewy neurites and iii) diffuse amyloid plaques and severe cerebral amyloid angiopathy (CAA). Added to this, a comprehensive analysis of blood-brain barrier (BBB) integrity, known to be disrupted during and after TBI, showed iv) distinct BBB breakdown with extravasated IgG and activated microglia present. This report represents an interesting documented case of neuropolypathology that may be associated with prior history of severe TBI. We propose one testable theory that a history of brain trauma may be a potential trigger for late onset dementia due to damage and unresolved functioning of the cerebral microvasculature.
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Rehabilitation of emergent awareness of errors post traumatic brain injury: A pilot intervention.

Impaired awareness of errors is common following traumatic brain injury (TBI) and can be a barrier to successful rehabilitation. The objective of this study was to develop and evaluate a computer-based intervention programme aimed at improving error awareness in individuals with TBI. A further aim was to explore its effects on metacognitive awareness and variability of performance. Participants were 11 individuals with TBI and impaired error awareness who performed a sustained attention task twice-weekly for four weeks. The intervention consisted of audio-visual feedback-on-errors during the sustained attention task. Six participants received audio-visual feedback-on-error, five did not receive feedback. Emergent and metacognitive awareness were measured pre- and post-intervention. Between-groups comparisons of emergent awareness from pre- to post-intervention showed that audio-visual feedback-on-error improved emergent awareness compared to no feedback-on-error. Some changes in metacognitive awareness of executive behaviours as a result of feedback were observed. Audio-visual feedback-on-error improved emergent awareness in individuals with TBI following a four-week/eight-session intervention. This improvement was not observed in the no-feedback group. This pilot intervention is not a stand-alone treatment but it has potential to be usefully incorporated into cognitive or clinical rehabilitation programmes to improve emergent awareness.

Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial.

BACKGROUND: This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. METHODS AND FINDINGS: NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease-specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, -0.07-1.64) at 13 weeks, 6.41 (5.33-7.49) at 52 weeks, and 9.63 (8.33-10.93) at 78 weeks and on nilvadipine was 0.88 (0.02-1.74) at 13 weeks, 5.75 (4.66-6.85) at 52 weeks, and 9.41 (8.09-10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. CONCLUSIONS: The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. TRIAL REGISTRATION: Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.

Preservation of the Semantic Verbal Fluency Advantage in a Large Population-Based Sample: Normative Data from the TILDA Study.

OBJECTIVES: It is widely believed that phonemic fluency is more difficult than naming exemplars from a semantic category. Normative data in this regard are scarce, and there is considerable disagreement in the literature regarding the pattern in normal ageing and neurodegenerative conditions. Our objective was to provide normative data for semantic phonemic discrepancy scores from a large sample of older adults. METHODS: A total of 5780 community-dwelling older adults were included in this prospective, longitudinal study. Discrepancy scores were calculated by subtracting phonemic fluency score from semantic fluency score for each participant. Quantile regression was used to estimate normative values stratified for age. RESULTS: Subjects did better on testing of semantic fluency. The average discrepancy score was 9.18±6.89 words, (range, -20 to 37; n=5780). At the fiftieth percentile, those in their fifth decade produced 10 more "animals" than "letter F" words. Subjects scored one word less per decade, with an average of seven more "animal" words produced by those in their eighth decade. CONCLUSIONS: Our study is the first to provide normative data and confirms that, for animal versus letter F fluency, the semantic advantage persists into later life in a population-based sample of community-dwelling older adults. Given that a majority of clinical samples have confirmed a reverse of this pattern in Alzheimer's dementia (i.e., loss of semantic advantage in Alzheimer's disease, yielding a phonemic advantage), our findings support the clinical utility of brief fluency tests and encourage further research into their use in diagnosis and prediction of progression to dementia.

Strengths and Limitations of the MoCA for Assessing Cognitive Functioning: Findings From a Large Representative Sample of Irish Older Adults.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) is a very widely used test for mild cognitive impairment. Differing recommendations have been made regarding its utility in providing a profile of performance across several cognitive domains. OBJECTIVES: To examine the factor structure of the MoCA in a nationally representative population study of older Irish adults and evaluate its utility in providing domain-specific information. METHODS: A cross-sectional analysis of wave 1 data from the Irish Longitudinal Study on Ageing was undertaken. Data from a subset of 2342 participants assessed using the MoCA were analyzed using both confirmatory factor analytic (CFA) and exploratory factor analytic (EFA) methods. RESULTS: Mean age was 72.64 (range 65 to 98), 53% female. The CFA provided evidence of adequate overall model fit for a previously proposed 6-factor model. In contrast, EFA yielded a 3-factor solution and test items cross-loaded onto a number of factors with no clear pattern of underlying cognitive domains. Using EFA to explore the 6-factor model yielded good fit, but again test items cross-loaded onto a number of factors with no clear pattern evident. CONCLUSION: Lack of concordance between the CFA and EFA findings demonstrates that the correspondence between individual tests and their assumed cognitive domains is not robust, reflecting at least in part a current lack of consensus on how core cognitive constructs are defined and on what subcomponents can be subsumed under different cognitive domains. The MoCA should not be viewed as a substitute for more in-depth neuropsychological assessment when domain-specific information is required.

The Frontal Assessment Battery: Normative Performance in a Large Sample of Older Community-Dwelling Hospital Outpatient or General Practitioner Attenders.

BACKGROUND: The Frontal Assessment Battery (FAB) is a short battery designed to assess frontal executive functioning, but data for interpretation of performance are limited. OBJECTIVES: The Trinity, Ulster, Department of Agriculture (TUDA) study provided the opportunity to derive performance data from a large sample of community-dwelling hospital outpatient or general practitioner (GP) attenders. METHODS: Normative analysis based on 2508 TUDA participants meeting these criteria: Mini-Mental State Examination (MMSE) >26/30, not depressed (Center for Epidemiologic Studies Depression <16) or anxious (Hospital Anxiety and Depression Scale <8), no history of stroke, or transient ischemic attack. Correlation and regression analyses were used to evaluate the effects of age, education, gender, and general cognition (MMSE). Norms for FAB were created stratified by age and education, using overlapping midpoint ranges of 10 years with a 3-year interval from age 60 to 97. RESULTS: Age and education accounted for 9.6% of variance in FAB score ( r2 = .096) with no significant effect of gender. The FAB and MMSE were modestly correlated ( r = .29, P < .01) with MMSE increasing the model's total explained variance in FAB score from 9.6% to 14%. CONCLUSION: This is the largest study to date to create normative data for the FAB. Age and education had the most significant impact on FAB performance, which was largely independent of global cognition (MMSE). These data may be of benefit in interpreting FAB performance in individuals with similar demographic/health status characteristics in hospital outpatient or GP settings.

Frailty: a costly phenomenon in caring for elders with cognitive impairment.

OBJECTIVES: Dementia draws on a variety of public and private resources. There is increasing pressure to define the cost components in this area to improve resource allocation and accountability. The aim of this study was to characterize frailty in a group of cognitively impaired community-dwelling elders and evaluate its relationship with cost and resource utilization. METHODS: We assessed a cross-sectional, convenient sample of 115 cognitively impaired patients of age >55 years who attended the National Memory Clinic in St James' University Hospital, a Trinity College-affiliated hospital in Dublin, Ireland. Participants had a clinical diagnosis of possible Alzheimer's disease or mild cognitive impairment. Frailty was measured using the biological syndrome model. Formal health and social care costs and daily informal caregiving costs were collected and the total costs of care estimated by applying the appropriate unit cost estimate for each resource activity. Stepwise regression models were constructed to establish the factors associated with increased care costs. RESULTS: Patient dependence, frailty and number of co-morbid illnesses explained 43.3% of the variance in observed daily informal care costs in dementia and cognitively impaired patients. Dependence was the sole factor retained in an optimal model explaining 19% of the variance in formal health and social care costs. CONCLUSION: Frailty retained a strong association with daily informal care costs even in the context of other known risk factors for increasing care costs. Interventions that reduce frailty as well as patient dependence on others may be associated with cost savings.

Cognitive function is associated with impaired heart rate variability in ageing adults: the Irish longitudinal study on ageing wave one results.

OBJECTIVE: To examine the independent association between heart rate variability (HRV) and cognitive performance, in a nationally representative population study of older adults. METHODS: Cross-sectional analysis of wave 1 data from the Irish longitudinal study on ageing (TILDA) was performed. A subset of 4,763 participants who underwent ECG recording during resting and paced breathing periods were used for the analysis. HRV indices were divided into quintiles for comparison of values and cognitive performance was defined using the Montreal cognitive assessment (MOCA) score. Multivariate linear regression was used to model the association between cognition and different quintiles of each HRV index, after adjustment for covariates. RESULTS: The mean age was 61.7 ± 8.3 years and 2,618 (55 %) were female. Lower quintiles of SDNN (P = 0.01-paced), LF (P = 0.001-paced), and LF:HF ratio (P = 0.049-paced) were significantly associated with lower MOCA scores (during both recording periods), independent of confounders. Sub-domains of MOCA responsible for the relationship were predominantly memory recall and language. INTERPRETATION: Reduced HRV is significantly associated with lower cognitive performance at a population level in people aged 50 and older. This further strengthens the relationship between autonomic dysfunction and cognitive disorders.

Encouraging lifestyle behaviour change in mild cognitive impairment patients: development of appropriate educational material.

OBJECTIVES: A healthy lifestyle may help maintain cognitive function and reduce the risk of developing dementia. This study employed a focus group approach in order to gain insight into opinions of mild cognitive impairment (MCI) patients, caregivers (CG) and health professionals (HP) regarding lifestyle and its relationship with cognition. The qualitative data were used to design, develop and pilot test educational material (EM) to help encourage lifestyle behaviour change. METHOD: Data gathering phase: structured interviews were conducted with HP (n = 10), and focus groups with MCI patients (n = 24) and CG (n = 12). EM was developed and pilot tested with a new group of MCI patients (n = 21) and CG (n = 6). RESULTS: HP alluded to the lack of clinical trial evidence for a lifestyle and MCI risk link. Although they felt that lifestyle modifications should be recommended to MCI patients, they appeared hesitant in communicating this information and discussions were often patient-driven. MCI patients lacked awareness of the lifestyle cognition link. Participants preferred EM to be concise, eye-catching and in written format, with personal delivery of information favoured. Most pilot testers approved of the EM but were heterogeneous in terms of lifestyle, willingness to change and support needed to change. CONCLUSION: MCI patients need to be made more aware of the importance of lifestyle for cognition. EM such as those developed here, which are specifically tailored for this population would be valuable for HP who, currently, appear reticent in initiating lifestyle-related discussions. Following further evaluation, the EM could be used in health promotion activities targeting MCI patients.

Subjective well-being amongst community-dwelling elders: what determines satisfaction with life? Findings from the Dublin Healthy Aging Study.

BACKGROUND: Life satisfaction is a subjective expression of well-being and successful aging. Subjective well-being is a major determinant of health outcomes in older people. The aim of this study was to determine which factors predicted well-being in older people living in the community as measured by their satisfaction with life. METHODS: The relationship between life satisfaction, as measured by the Life Satisfaction Index (LSI-A) and physical, cognitive and demographic variables was examined in 466 older people living in the community using a stepwise regression model. RESULTS: Depression, loneliness, neuroticism, extraversion, recent participation in physical activity, age and self-reported exhaustion, were the independent predictors of life satisfaction in our elderly cohort. CONCLUSION: Subjective well-being, as measured by the Life Satisfaction Scale, is predicted by depression, loneliness, personality traits, recent participation in physical activity and self-reported exhaustion. The mental and emotional status of older individuals, as well as their engagement in physical activity, are as important as physical functionality when it comes to life satisfaction as a measure of well-being and successful aging. These areas represent key targets for intervention.

Omega-3 fatty acid, carotenoid and vitamin E supplementation improves working memory in older adults: A randomised clinical trial.

BACKGROUND & AIMS: Accumulating evidence suggests that omega-3 fatty acids (ω-3FAs), carotenoids and vitamin E can improve cognitive performance. However, their collective impact on cognition has not yet been investigated in healthy individuals. This study investigated the combined effect of ω-3FA, carotenoid and vitamin E supplementation on the cognitive performance of older adults. METHODS: Cognitively healthy individuals aged ≥65 years consumed daily 1 g fish oil (of which 430 mg docosahexaenoic acid, 90 mg eicosapentaenoic acid), 22 mg carotenoids (10 mg lutein, 10 mg meso-zeaxanthin, 2 mg zeaxanthin) and 15 mg vitamin E or placebo for 24 months in a double-blind, placebo-controlled, randomised clinical trial. RESULTS: Following 24-month supplementation, individuals in the active group (n = 30; aged 69.03 ± 4.41 years; 56.7% female) recorded significantly fewer errors in working memory tasks than individuals receiving placebo (n = 30; aged 69.77 ± 3.74 years; 70% female) (point estimate effect sizes ranged 0.090-0.105). Interestingly, as the cognitive load of the working memory tasks increased, the active group outperformed the placebo group. Statistically significant improvements in tissue carotenoid concentrations, serum xanthophyll carotenoid concentrations and plasma ω-3FA concentrations were also observed in the active group versus placebo (point estimate effect sizes ranged 0.078-0.589). Moreover, the magnitude of change of carotenoid concentrations in tissue, and ω-3FA and carotenoid concentrations in blood were related to the magnitude of change in working memory performance. CONCLUSION: These results support a biologically plausible rationale whereby these nutrients work synergistically, and in a dose-dependent manner, to improve working memory in cognitively healthy older adults. Increasing nutritional intake of carotenoids and ω-3FAs may prove beneficial in reducing cognitive decline and dementia risk in later life. STUDY ID NUMBER: ISRCTN10431469; https://doi.org/10.1186/ISRCTN10431469.

Structural Correlates of Overt Sentence Reading in Mild Cognitive Impairment and Mild-to-Moderate Alzheimer's Disease.

BACKGROUND: Overt sentence reading in mild cognitive impairment (MCI) and mild-tomoderate Alzheimer's disease (AD) has been associated with slowness of speech, characterized by a higher number of pauses, shorter speech units and slower speech rate and attributed to reduced working memory/ attention and language capacity. OBJECTIVE: This preliminary case-control study investigates whether the temporal organization of speech is associated with the volume of brain regions involved in overt sentence reading and explores the discriminative ability of temporal speech parameters and standard volumetric MRI measures for the classification of MCI and AD. METHODS: Individuals with MCI, mild-to-moderate AD, and healthy controls (HC) had a structural MRI scan and read aloud sentences varying in cognitive-linguistic demand (length). The association between speech features and regional brain volumes was examined by linear mixed-effect modeling. Genetic programming was used to explore the discriminative ability of temporal and MRI features. RESULTS: Longer sentences, slower speech rate, and a higher number of pauses and shorter interpausal units were associated with reduced volumes of the reading network. Speech-based classifiers performed similarly to the MRI-based classifiers for MCI-HC (67% vs. 68%) and slightly better for AD-HC (80% vs. 64%) and AD-MCI (82% vs. 59%). Adding the speech features to the MRI features slightly improved the performance of MRI-based classification for AD-HC and MCI-HC but not HC-MCI. CONCLUSION: The temporal organization of speech in overt sentence reading reflects underlying volume reductions. It may represent a sensitive marker for early assessment of structural changes and cognitive- linguistic deficits associated with healthy aging, MCI, and AD.

Everyday episodic memory in amnestic mild cognitive impairment: a preliminary investigation.

BACKGROUND: Decline in episodic memory is one of the hallmark features of Alzheimer's disease (AD) and is also a defining feature of amnestic Mild Cognitive Impairment (MCI), which is posited as a potential prodrome of AD. While deficits in episodic memory are well documented in MCI, the nature of this impairment remains relatively under-researched, particularly for those domains with direct relevance and meaning for the patient's daily life. In order to fully explore the impact of disruption to the episodic memory system on everyday memory in MCI, we examined participants' episodic memory capacity using a battery of experimental tasks with real-world relevance. We investigated episodic acquisition and delayed recall (story-memory), associative memory (face-name pairings), spatial memory (route learning and recall), and memory for everyday mundane events in 16 amnestic MCI and 18 control participants. Furthermore, we followed MCI participants longitudinally to gain preliminary evidence regarding the possible predictive efficacy of these real-world episodic memory tasks for subsequent conversion to AD. RESULTS: The most discriminating tests at baseline were measures of acquisition, delayed recall, and associative memory, followed by everyday memory, and spatial memory tasks, with MCI patients scoring significantly lower than controls. At follow-up (mean time elapsed: 22.4 months), 6 MCI cases had progressed to clinically probable AD. Exploratory logistic regression analyses revealed that delayed associative memory performance at baseline was a potential predictor of subsequent conversion to AD. CONCLUSIONS: As a preliminary study, our findings suggest that simple associative memory paradigms with real-world relevance represent an important line of enquiry in future longitudinal studies charting MCI progression over time.

Anxiety and behavioural disturbance as markers of prodromal Alzheimer's disease in patients with mild cognitive impairment.

BACKGROUND: Depression and anxiety have been reported to be independently predictive of conversion to Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI). Anxiety symptoms have been less well studied and findings in this regard have been inconsistent. The objectives of this study are to determine which symptoms among a range of neuropsychiatric symptoms known to commonly occur in patients with MCI are predictive of later conversion to AD. We also wish to determine whether these symptoms track existing measures of declining cognitive and functional status or may be considered distinct and sensitive biomarkers of evolving Alzheimer's pathology. METHODS: One hundred and sixty-one patients with MCI were identified from consecutive referrals to a memory clinic. Univariate, multivariate and cox regression analyses were conducted. RESULTS: Seventy-six per cent of all patients had at least one neuropsychiatric symptom at baseline of which anxiety (52%), affective disturbance (37%) and aggression (32%) were the most common. Increasing symptom frequency was observed with increasing clinical severity. Anticipatory anxiety and activity disturbances were significantly associated with earlier conversion to AD although this association did not remain significant following adjustment for cognitive status at baseline. CONCLUSION: Neuropsychiatric symptoms and anxiety symptoms in particular are common in patients with MCI. In this sample anxiety for upcoming events and purposeless activity frequently co-occurred and were significant clinical predictors of earlier conversion to AD. However, these findings were not independent of cognitive status at baseline and therefore may be markers of severity rather than independent predictors of disease progression.

Self-efficacy for managing dementia may protect against burden and depression in Alzheimer's caregivers.

BACKGROUND: Self-efficacy is the belief that one can perform a specific task or behaviour and is a modifiable attribute which has been shown to influence health behaviours. Few studies have examined the relationship between self-efficacy for dementia-related tasks and symptoms of burden and depression in caregivers. METHODS: Eighty four patient/caregiver dyads with Alzheimer's disease were recruited through a memory clinic. Patient function, cognition and neuropsychiatric symptoms were assessed together with caregiver burden, personality, depressive symptoms, coping strategies and self-efficacy for completing tasks related to dementia care. RESULTS: 33% (28) of caregivers reported significant depressive symptoms (CES-D ≥ 10). In multivariate analyses, caregiver burden was predicted by self-efficacy for symptom management, neuroticism, patient function and neuropsychiatric symptoms while caregiver depression was predicted by self-efficacy for symptom management, caregiver educational level, neuroticism, emotion-focused coping, dysfunctional coping and patient function. In patients with moderate to severe impairment (MMSE ≤ 20), self-efficacy for symptom management behaved as a mediator between patient neuropsychiatric symptoms and symptoms of burden and depression in caregivers. CONCLUSIONS: Further longitudinal investigation is warranted to determine if self-efficacy might be usefully considered a target in future interventional studies to alleviate symptoms of burden and depression in Alzheimer's caregivers.

Cognitive and Structural Correlates of Conversational Speech Timing in Mild Cognitive Impairment and Mild-to-Moderate Alzheimer's Disease: Relevance for Early Detection Approaches.

Background: Increasing efforts have focused on the establishment of novel biomarkers for the early detection of Alzheimer's disease (AD) and prediction of Mild Cognitive Impairment (MCI)-to-AD conversion. Behavioral changes over the course of healthy ageing, at disease onset and during disease progression, have been recently put forward as promising markers for the detection of MCI and AD. The present study examines whether the temporal characteristics of speech in a collaborative referencing task are associated with cognitive function and the volumes of brain regions involved in speech production and known to be reduced in MCI and AD pathology. We then explore the discriminative ability of the temporal speech measures for the classification of MCI and AD. Method: Individuals with MCI, mild-to-moderate AD and healthy controls (HCs) underwent a structural MRI scan and a battery of neuropsychological tests. They also engaged in a collaborative referencing task with a caregiver. The associations between the conversational speech timing features, cognitive function (domain-specific) and regional brain volumes were examined by means of linear mixed-effect modeling. Genetic programming was used to explore the discriminative ability of the conversational speech features. Results: MCI and mild-to-moderate AD are characterized by a general slowness of speech, attributed to slower speech rate and slower turn-taking in conversational settings. The speech characteristics appear to be reflective of episodic, lexico-semantic, executive functioning and visuospatial deficits and underlying volume reductions in frontal, temporal and cerebellar areas. Conclusion: The implementation of conversational speech timing-based technologies in clinical and community settings may provide additional markers for the early detection of cognitive deficits and structural changes associated with MCI and AD.