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.

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.

A clinical, molecular genetics and pathological study of a FTDP-17 family with a heterozygous splicing variant c.823-10G>T at the intron 9/exon 10 of the MAPT gene.

We report the first clinical-radiological-genetic-molecular-pathological study of a kindred with c.823-10G>T MAPT intronic variant (rs63749974) associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We describe the clinical spectrum within this family and emphasize the association between MAPT gene variants and motor neuron disease. This report of a second family with FTDP-17 associated with c.823-10G>T MAPT variant strongly supports pathogenicity of the variant and confirms it is a 4-repeat (4R) tauopathy. This intronic point mutation, probably strengthens the polypyrimidine tract and alters the splicing of exon 10 (10 nucleotides into intron 9) close to the 3' splice site.

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.

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.

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.

Targeted Nutritional Intervention for Patients with Mild Cognitive Impairment: The Cognitive impAiRmEnt Study (CARES) Trial 1.

Omega-3 fatty acids (ω-3FAs), carotenoids, and vitamin E are important constituents of a healthy diet. While they are present in brain tissue, studies have shown that these key nutrients are depleted in individuals with mild cognitive impairment (MCI) in comparison to cognitively healthy individuals. Therefore, it is likely that these individuals will benefit from targeted nutritional intervention, given that poor nutrition is one of the many modifiable risk factors for MCI. Evidence to date suggests that these nutritional compounds can work independently to optimize the neurocognitive environment, primarily due to their antioxidant and anti-inflammatory properties. To date, however, no interventional studies have examined the potential synergistic effects of a combination of ω-3FAs, carotenoids and vitamin E on the cognitive function of patients with MCI. Individuals with clinically confirmed MCI consumed an ω-3FA plus carotenoid plus vitamin E formulation or placebo for 12 months. Cognitive performance was determined from tasks that assessed global cognition and episodic memory. Ω-3FAs, carotenoids, and vitamin E were measured in blood. Carotenoid concentrations were also measured in tissue (skin and retina). Individuals consuming the active intervention (n = 6; median [IQR] age 73.5 [69.5-80.5] years; 50% female) exhibited statistically significant improvements (p < 0.05, for all) in tissue carotenoid concentrations, and carotenoid and ω-3FA concentrations in blood. Trends in improvements in episodic memory and global cognition were also observed in this group. In contrast, the placebo group (n = 7; median [IQR] 72 (69.5-75.5) years; 89% female) remained unchanged or worsened for all measurements (p > 0.05). Despite a small sample size, this exploratory study is the first of its kind to identify trends in improved cognitive performance in individuals with MCI following supplementation with ω-3FAs, carotenoids, and vitamin E.

HALO: Study protocol for a single-case experimental design study evaluating the moderating impact of a befriending intervention on the association between loneliness and health in older adults.

Background: Loneliness in later life is often addressed with befriending interventions, yet evidence for their effectiveness is limited. Meanwhile it is known that loneliness has a deleterious impact on health. The aim of the study is to evaluate whether a befriending service for older adults mitigates the impact of loneliness on health outcomes, and to identify mechanisms through which befriending interventions might impact upon health. Methods: A mixed methods design is used. The quantitative component utilises an AB single-case experimental design, to gather intensive longitudinal data. These data will be analysed using a generalised additive modelling approach. The qualitative component of the study uses semi-structured dyadic interviews, structured and analysed according to the principles of constructivist grounded theory. Findings will then be triangulated according to an existing mixed methods integration protocol. Discussion: This mixed methods design has the potential to inform national and international policy in relation to befriending interventions for older adults. In addition, there is the potential for study results to inform our theoretical understanding of the nature of the relationship between loneliness and health. Trial registration: ClinicalTrials.gov identifier NCT04301167 (10 th March 2020). Protocol version 1.1, 26 th June 2020.

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.

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.

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.
.

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.

Prosopagnosia as a Type of Conversion Disorder.

BACKGROUND: Conversion disorder is a common and debilitating condition that remains poorly understood. We present a previously undescribed form of conversion disorder to highlight the complexity of the condition and consider the interplay of factors that produce conversion symptoms. CASE: A 50-year-old male presented with acquired prosopagnosia and language impairment. Neuropsychological testing indicated right temporal lobe dysfunction. Extensive work-up outruled an organic aetiology. Reactivation of childhood trauma coincided with the onset of his symptoms. Childhood trauma is known to have adverse effects on the developing brain which may affect an individual's emotional behaviour and coping style. Functional neuroimaging techniques suggest that conversion symptoms may be linked to the disruption of higher order neural circuitry involved in the integration of emotional processing and cortical functioning. CONCLUSIONS: We propose that our patient's adverse childhood experiences led to the development of a particular personality and coping style that "primed" him for a later abnormal emotional and behavioural response when confronted with reminders of his traumatic background. Further interdisciplinary studies are required to further elucidate the neurobiological basis for this condition.

Changes in Speech Chunking in Reading Aloud is a Marker of Mild Cognitive Impairment and Mild-to-Moderate Alzheimer's Disease.

BACKGROUND: Speech and Language Impairments, generally attributed to lexico-semantic deficits, have been documented in Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD). This study investigates the temporal organisation of speech (reflective of speech production planning) in reading aloud in relation to cognitive impairment, particularly working memory and attention deficits in MCI and AD. The discriminative ability of temporal features extracted from a newly designed read speech task is also evaluated for the detection of MCI and AD. METHOD: Sixteen patients with MCI, eighteen patients with mild-to-moderate AD and thirty-six healthy controls (HC) underwent a battery of neuropsychological tests and read a set of sentences varying in cognitive load, probed by manipulating sentence length and syntactic complexity. RESULTS: Our results show that Mild-to-Moderate AD is associated with a general slowness of speech, attributed to a higher number of speech chunks, silent pauses and dysfluences, and slower speech and articulation rates. Speech chunking in the context of high cognitive-linguistic demand appears to be an informative marker of MCI, specifically related to early deficits in working memory and attention. In addition, Linear Discriminant Analysis shows the ROC AUCs (Areas Under the Receiver Operating Characteristic Curves) of identifying MCI vs. HC, MCI vs. AD and AD vs. HC using these speech characteristics are 0.75, 0.90 and 0.94 respectively. CONCLUSION: The implementation of connected speech-based technologies in clinical and community settings may provide additional information for the early detection of MCI and AD.

Semantic and Phonemic Verbal Fluency Discrepancy in Mild Cognitive Impairment: Potential Predictor of Progression to Alzheimer's Disease.

OBJECTIVES: To assess the utility of verbal fluency discrepancy scores in predicting progression to Alzheimer's disease (AD) in a cohort of individuals with mild cognitive impairment (MCI). DESIGN: Case control. SETTING: Cases identified from new referrals to a memory clinic and controls identified from The Irish Longitudinal Study on Ageing. PARTICIPANTS: Of 308 individuals with MCI at baseline identified from consecutive referrals to a memory clinic and compared at with age-, sex-, and education-matched controls (n=302), 161 completed 2 years of follow-up or progressed to AD during the study period. MEASUREMENTS: Verbal fluency discrepancy (semantic-phonemic fluency) scores at baseline were calculated for each participant. Each case was followed with repeated neuropsychological measurements, and multidisciplinary consensus diagnosis was recorded. RESULTS: Mean discrepancy score for those who progressed to AD (2.7) was significantly lower than for those who retained a MCI diagnosis (4.8) and normal controls (7.7) (p<.001). Logistic regression revealed that, for each unit decrease in discrepancy score at baseline, the odds of progressing to AD were 9% greater. (Exp(B) = 1.09, p=.02) CONCLUSION: Individuals with MCI have less of a semantic advantage than those without MCI. Those with MCI presenting with a phonemic advantage at initial assessment warrant close follow-up and a high index of suspicion for progression to AD.

Supplemental Retinal Carotenoids Enhance Memory in Healthy Individuals with Low Levels of Macular Pigment in A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: There is a biologically plausible rationale whereby the dietary carotenoids lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ), which are collectively referred to as macular pigment (MP) in the central retina (macula), support the maintenance of cognition via their antioxidant and anti-inflammatory properties. OBJECTIVE: To investigate the impact of supplemental L, Z, and MZ on memory, executive function, and verbal fluency among healthy individuals with low MP levels. METHODS: In this double-blind, placebo-controlled, randomized clinical trial, subjects (n = 91; mean±SD age = 45.42±12.40; % male = 51.6) consumed a daily formulation of 10 mg L, 10 mg MZ, and 2 mg Z (n = 45) or placebo (n = 46) for 12 months. Cognitive domains assessed included verbal and visual learning, immediate and delayed memory, executive function, and verbal fluency. MP and serum carotenoid concentrations of L, Z, and MZ were also measured. RESULTS: Following 12-month supplementation, individuals in the active group exhibited statistically significant improvements in memory when compared to the placebo group (paired associated learning [PAL] memory score [rANOVA, p = 0.009]; PAL errors [rANOVA, p = 0.017]). Furthermore, the observed reduction in the number of errors made in the PAL task among those in the intervention group was positively and significantly related to observed increases in MP volume (p = 0.005) and observed increases in serum concentrations of L (p = 0.009). CONCLUSION: This randomized, double-blind, placebo-controlled clinical trial demonstrates a memory-enhancing effect of daily supplementation with L, Z, and MZ in healthy subjects with low MP at baseline. The implications of these findings for intellectual performance throughout life, and for risk of cognitive decline in later life, warrant further study.

A High Prevalence Rate of a Positive Screen for Cognitive Impairment in Patients With Human Immunodeficiency Virus Attending an Irish Clinic.

BACKGROUND: Human immunodeficiency virus (HIV)-associated neurocognitive disorders occurs in 20%-50% of HIV-positive patients. We undertook this study to assess the prevalence of a positive screen for cognitive impairment in the clinic population at our institution and to demonstrate the feasibility of implementing a screening program in routine clinical encounters. METHODS: This was a cross-sectional study, and patients were recruited prospectively between December 2010 and February 2013. Inclusion criteria were as follows: patients were HIV positive, over the age of 18, capable of giving informed consent, and had sufficient ability to communicate in English. Patients were screened for cognitive impairment using the Brief Neurocognitive Screen. RESULTS: A total of 604 patients were recruited, and 51.5% had a positive screen for cognitive impairment. The majority of the study cohort were male (78.8%), mean age was 40.9 (standard deviation, 10.2) years, 70.9% were Irish, the most common mode of transmission was men who have sex with men (49.3%), 83% were on antiretroviral therapy, and 88.7% were virally suppressed. Logistic regression showed that the main factors predictive of a positive screen for cognitive impairment were the endorsement of cognitive symptoms (P = .024), being born in Africa (P < .000001), the use of benzodiazepines (P = .00341), being unemployed (P = .008), and consumption of more than 40 units of alcohol weekly (P = .035). There was a positive screen for depression in 9.1% and a positive screen for anxiety in 24.5%. CONCLUSIONS: The study highlights the necessity for a structured, prospective, large-scale screening program for cognitive impairment across countries with limited resources and demonstrates the feasibility of easily implementing this with minimal training.

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.

European multicentre double-blind placebo-controlled trial of Nilvadipine in mild-to-moderate Alzheimer's disease-the substudy protocols: NILVAD frailty; NILVAD blood and genetic biomarkers; NILVAD cerebrospinal fluid biomarkers; NILVAD cerebral blood flow.

INTRODUCTION: In conjunction with the NILVAD trial, a European Multicentre Double-Blind Placebo Controlled trial of Nilvadipine in Mild-to-Moderate Alzheimer's disease (AD), there are four NILVAD substudies in which eligible NILVAD patients are also invited to participate. The main NILVAD protocol was previously published in BMJ Open (2014). The objectives of the NILVAD substudies are to determine whether frailty, cerebrospinal fluid (CSF), blood biomarker profile and Apolipoprotein E (APOE) status predict response to Nilvadipine, and to investigate the effect of Nilvadipine on cerebral blood flow and blood biomarkers. METHODS AND ANALYSIS: All participants who fulfil criteria for the main NILVAD study are eligible for participation in the NILVAD substudies. Participation is subject to informed consent and whether the substudy is available at a particular NILVAD study site. Each substudy entails extra measurements during the course of the main NILVAD study. For example, in the blood and genetic biomarkers substudy, extra blood (30 mL) will be collected at week 0, week 13, week 52 and week 78, while in the cerebral blood flow substudy, participants will receive an MRI and transcranial Doppler measurements at week 0, week 26 and week 78. In the CSF substudy, 10 mL CSF is collected at week 0 and week 78. ETHICS AND DISSEMINATION: All NILVAD substudies and all subsequent amendments have received ethical approval within each participating country, according to national regulations. Each participant provides written consent to participate. All participants remain anonymised throughout and the results of each substudy will be published in an international peer reviewed journal. TRIAL REGISTRATION NUMBER: EUDRACT 2012-002764-27; Pre-results.