Delivery of Neuropsychological Interventions for Adult and Older Adult Clinical Populations: An Australian Expert Working Group Clinical Guidance Paper.

Delivery of neuropsychological interventions addressing the cognitive, psychological, and behavioural consequences of brain conditions is increasingly recognised as an important, if not essential, skill set for clinical neuropsychologists. It has the potential to add substantial value and impact to our role across clinical settings. However, there are numerous approaches to neuropsychological intervention, requiring different sets of skills, and with varying levels of supporting evidence across different diagnostic groups. This clinical guidance paper provides an overview of considerations and recommendations to help guide selection, delivery, and implementation of neuropsychological interventions for adults and older adults. We aimed to provide a useful source of information and guidance for clinicians, health service managers, policy-makers, educators, and researchers regarding the value and impact of such interventions. Considerations and recommendations were developed by an expert working group of neuropsychologists in Australia, based on relevant evidence and consensus opinion in consultation with members of a national clinical neuropsychology body. While the considerations and recommendations sit within the Australian context, many have international relevance. We include (i) principles important for neuropsychological intervention delivery (e.g. being based on biopsychosocial case formulation and person-centred goals); (ii) a description of clinical competencies important for effective intervention delivery; (iii) a summary of relevant evidence in three key cohorts: acquired brain injury, psychiatric disorders, and older adults, focusing on interventions with sound evidence for improving activity and participation outcomes; (iv) an overview of considerations for sustainable implementation of neuropsychological interventions as 'core business'; and finally, (v) a call to action.

Access to psychosocial support for people with brain tumor and family members: Healthcare professional perspectives.

OBJECTIVES: Ongoing access to psychosocial support is important to maintain the well-being of people with brain tumor (PwBT) and their families; yet, there is limited knowledge of psychosocial care access. This qualitative study aimed to develop an understanding of psychosocial support pathways specific to PwBT from the perspectives of Australian healthcare professionals. METHODS: Semi-structured interviews were conducted with 21 healthcare professionals working in hospital and community services supporting PwBT and their family members. Transcribed interviews were coded and analyzed thematically. RESULTS: The three major themes identified were: (1) Challenges in fitting people into the care system within existing pathways; (2) Benefits of longer-term care coordination and interdisciplinary connections; and (3) Brain tumor affects the whole family. Despite established psychosocial care pathways, service access varied and lacked continuity for individuals with lower-grade glioma and benign tumors across the illness trajectory. CONCLUSIONS: Healthcare professionals recognize the need for improved access to care coordination and multidisciplinary psychosocial care tailored to the varying needs of PwBT and their families.

Examination of the Feasibility, Acceptability, and Efficacy of the Online Personalised Training in Memory Strategies for Everyday Program for Older Adults: Single-Arm Pre-Post Trial.

BACKGROUND: Memory strategy training for older adults helps maintain and improve cognitive health but is traditionally offered face-to-face, which is resource intensive, limits accessibility, and is challenging during a pandemic. Web-based interventions, such as the Online Personalised Training in Memory Strategies for Everyday (OPTIMiSE) program, may overcome such barriers. OBJECTIVE: We report on OPTIMiSE's feasibility, acceptability, and efficacy. METHODS: Australians aged ≥60 years reporting subjective cognitive decline participated in this single-arm pre-post web-based intervention. OPTIMiSE is a 6-module web-based program offered over 8-weeks with a 3-month booster. It has a problem-solving approach to memory issues, focusing on psychoeducation about memory and aging, knowledge and practice of compensatory memory strategies, and personalized content related to individual priorities. We examined the feasibility (recruitment, attrition, and data collection), acceptability (recommendation to others, suggestions for improvement, and withdrawal reasons), and efficacy (change in goal satisfaction, strategy knowledge and use, self-reported memory, memory satisfaction and knowledge, and mood; thematic content analysis of the most significant change; and the application of knowledge and strategies in daily life) of OPTIMiSE. RESULTS: OPTIMiSE was feasible, demonstrated by strong interest (633 individuals screened), a satisfactory level of attrition (158/312, 50.6%), and minimal missing data from those completing the intervention. It was acceptable, with 97.4% (150/154) of participants agreeing they would recommend OPTIMiSE, the main suggestion for improvement being more time to complete modules, and withdrawal reasons similar to those in in-person interventions. OPTIMiSE was also efficacious, with linear mixed-effects analyses revealing improvements, of moderate to large effect sizes, across all primary outcomes (all P<.001): memory goal satisfaction (Cohen d after course=1.24; Cohen d at 3-month booster=1.64), strategy knowledge (Cohen d after course=0.67; Cohen d at 3-month booster=0.72) and use (Cohen d after course=0.79; Cohen d at 3-month booster=0.90), self-reported memory (Cohen d after course=0.80; Cohen d at 3-month booster=0.83), memory satisfaction (Cohen d after course=1.25; Cohen d at 3-month booster=1.29) and knowledge (Cohen d after course=0.96; Cohen d at 3-month booster=0.26), and mood (Cohen d after course=-0.35; nonsignificant Cohen d at booster). Furthermore, the most significant changes reported by participants (strategy use, improvements in daily life, reduced concern about memory, confidence and self-efficacy, and sharing and shame busting with others) reflected the course objectives and were consistent with themes arising from previous in-person interventions. At the 3-month booster, many participants reported continued implementation of knowledge and strategies in their daily lives. CONCLUSIONS: This feasible, acceptable, and efficacious web-based program has the potential to enable access to evidence-based memory interventions for older adults worldwide. Notably, the changes in knowledge, beliefs, and strategy use continued beyond the initial program. This is particularly important for supporting the growing number of older adults living with cognitive concerns. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12620000979954; https://tinyurl.com/34cdantv. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.3233/ADR-200251.

Observed Strategies on Naturalistic Associative Memory Tasks in Healthy Older Adults and Amnestic Mild Cognitive Impairment.

BACKGROUND: Understanding the strategies people with amnestic mild cognitive impairment (aMCI) spontaneously use can inform targeted memory training. METHOD: Strategy use was observed for 99 people with aMCI and 100 healthy older adults (HOA) on two memory tasks. RESULTS: No differences were found between aMCI and HOA in the amount or types of strategies used, but strategy use varied with task. Association was more effective for one task, whereas on the other task, use of written notes or multiple strategies were detrimental to performance and related to poorer performance than active (spaced) retrieval, for aMCI. CONCLUSION: Our findings suggest the importance of identifying ineffective habits, in addition to instruction in more beneficial approaches.

Subjective Cognitive Decline: Level of Risk for Future Dementia and Mild Cognitive Impairment, a Meta-Analysis of Longitudinal Studies.

Subjective Cognitive Decline (SCD) in older adults has been identified as a risk factor for dementia, although the literature is inconsistent, and it is unclear which factors moderate progression from SCD to dementia. Through separate meta-analyses, we aimed to determine if SCD increased the risk of developing dementia or mild cognitive impairment (MCI). Furthermore, we examined several possible moderators. Longitudinal studies of participants with SCD at baseline, with data regarding incident dementia or MCI, were extracted from MEDLINE and PsycINFO. Articles were excluded if SCD occurred solely in the context of dementia, MCI, or as part of a specific disease. Pooled estimates were calculated using a random-effects model, with moderator analyses examining whether risk varied according to SCD definition, demographics, genetics, recruitment source, and follow-up duration. Risk of study bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool. 46 studies with more than 74,000 unique participants were included. SCD was associated with increased risk of developing dementia (HR = 1.90, 95% CI 1.52-2.36; OR = 2.48, 95% CI 1.97-3.14) and MCI (HR = 1.73, 95% CI 1.18-2.52; OR = 1.83, 95% CI 1.56-2.16). None of the potential moderating factors examined influenced the HR or OR of developing dementia. In contrast, including worry in the definition of SCD, younger age, and recruitment source impacted the OR of developing MCI, with clinic samples demonstrating highest risk. SCD thus represents an at-risk phase, ideal for early intervention, with further research required to identify effective interventions for risk reduction, and cognitive-behavioural interventions for cognitive management. PROSPERO, protocol number: CRD42016037993.

Scoping the psychological support practices of Australian health professionals working with people with primary brain tumor and their families.

OBJECTIVES: This study aimed to scope the psychological support practices of Australian health professionals providing supportive care to adults with primary brain tumor. METHOD: Health professionals from multidisciplinary organizations and cancer support services completed an online survey focused on psychological support for people with brain tumor (PwBT) and family members, and perceived barriers or gaps in support provision. RESULTS: 107 professionals, mainly from psychology (45%), nursing (20%), and social work (10%) backgrounds, completed the survey. Scope of practice differed according to discipline, with psychologists and nurses most likely to screen for psychological distress (71%-76%), and psychologists more typically providing at least one psychological support session (78%). Psychologists were more likely to screen for cognitive impairment (31%), whereas nurses and social workers more commonly provided family-based support (62%-73%). Psychological support was more frequently provided in the long-term management phase (78%) than early post-diagnosis/treatment (45%). System-level barriers to accessing psychological support were most frequently identified, which included limited resources and funding, insufficient staff time, lengthy waitlists and costs, poor service coordination, and lack of staff with brain tumor-specific training. CONCLUSIONS: The provision of psychological support for PwBT varies according to discipline, setting and management phase. Further research on different models of psychosocial care is needed to inform strategies to address organizational and policy factors impacting professionals' scope of practice.

Physical activity and cognition in young-onset Parkinson's disease.

BACKGROUND: A relationship has been observed between physical activity and cognition in older-onset Parkinson's disease, as well as improvements in cognition after a physical activity intervention. To date, this has not been investigated in young-onset Parkinson's disease (YOPD). OBJECTIVES: To examine the baseline relationship between physical activity and cognition in YOPD; and to examine whether a physical activity intervention can improve cognition in YOPD. METHODS: Two interrelated online studies were conducted. In the first study, 132 participants with YOPD completed self-reported measures of physical activity, and objective and subjective measures of cognition. A subset of 38 participants was then randomly allocated to either a six-week physical activity intervention or control condition. Following the intervention, participants repeated the objective and subjective cognitive measures. RESULTS: No relationship was found between self-reported physical activity and objective cognition; however, there was a relationship between physical activity and subjective cognition. Similarly, following the intervention subjective improvements were found for concentration, attention, and processing speed, but not for memory. Furthermore, medium effect sizes were evident for objective measures of processing speed and small-medium effect sizes for planning and cognitive flexibility, although statistical significance was not reached. CONCLUSIONS: In this first study investigating physical activity and cognition in YOPD, the results suggest that increased physical activity relates to improved processing speed and attention. Replication is recommended with a larger sample size. A longer, more intense physical activity manipulation and utilizing the study's strengths of online recruitment and intervention delivery are also recommended.

Long-term effects of a memory group intervention reported by older adults.

The aim of this study was to examine older adults' experiences of change following a group memory intervention, the La Trobe and Caulfield Hospital (LaTCH) Memory Group programme. Semi-structured qualitative interviews were conducted with 30 individuals. Participants were healthy older adults and older adults with amnestic mild cognitive impairment (MCI) who had participated in the memory group five years previously. Transcripts were analysed for emergent themes in a workshop, using the Most Significant Change technique. The focus group derived four major themes relating to participants' experiences of change. Particularly noteworthy were themes describing a process of acceptance and normalising of memory difficulties in older age, as well as enhancement of coping and self-efficacy. The results highlight the importance of group support for older adults with and without objective memory impairment. Memory groups may use the group format to full advantage by (a) enhancing participants' experiences of universality to alleviate distress and promote coping, and (b) developing group norms to promote positive ageing, encompassing enhanced acceptance and self-efficacy.

Brachial and Cerebrovascular Functions Are Enhanced in Postmenopausal Women after Ingestion of Chocolate with a High Concentration of Cocoa.

Background: Cocoa contains polyphenols that are thought to be beneficial for vascular health.Objective: We assessed the impact of chocolate containing distinct concentrations of cocoa on cerebrovascular function and cognition.Methods: Using a counterbalanced within-subject design, we compared the acute impact of consumption of energy-matched chocolate containing 80%, 35%, and 0% single-origin cacao on vascular endothelial function, cognition, and cerebrovascular function in 12 healthy postmenopausal women (mean ± SD age: 57.3 ± 5.3 y). Participants attended a familiarization session, followed by 3 experimental trials, each separated by 1 wk. Outcome measures included cerebral blood flow velocity (CBFv) responses, recorded before and during completion of a computerized cognitive assessment battery (CogState); brachial artery flow-mediated dilation (FMD); and hemodynamic responses (heart rate and blood pressure).Results: When CBFv data before and after chocolate intake were compared between conditions through the use of 2-factor ANOVA, an interaction effect (P = 0.003) and main effects for chocolate (P = 0.043) and time (P = 0.001) were evident. Post hoc analysis revealed that both milk chocolate (MC; 35% cocoa; P = 0.02) and dark chocolate (DC; 80% cocoa; P = 0.003) induced significantly lower cerebral blood flow responses during the cognitive tasks, after normalizing for changes in arterial pressure. DC consumption also increased brachial FMD compared with the baseline value before chocolate consumption (P = 0.002), whereas MC and white chocolate (0% cocoa) caused no change (P-interaction between conditions = 0.034).Conclusions: Consumption of chocolate containing high concentrations of cocoa enhanced vascular endothelial function, which was reflected by improvements in FMD. Cognitive function outcomes did not differ between conditions; however, cerebral blood flow responses during these cognitive tasks were lower in those consuming MC and DC. These findings suggest that chocolate containing high concentrations of cocoa may modify the relation between cerebral metabolism and blood flow responses in postmenopausal women. This trial was registered at www.ANZCTR.orgau as ACTRN12616000990426.

Naturalistic prospective memory in older adults: Predictors of performance on a habitual task.

Age-related difficulties in episodic prospective memory (PM) are common. However, little is known about habitual PM, which involves remembering to carry out intended actions that are regular and repeated. This is important for many health-related tasks and for maintaining independence in daily living activities. This study investigates, in older people, the predictors of habitual PM performance in a naturalistic setting. A group of 191 community-based, older adults (aged 65-89 years) wore an actigraph over two weeks. The habitual PM task involved pressing a button twice daily (Bed-time, Rise-time) on the actigraph. Accuracy of response was calculated for Bed-time and Rise-time, determined by light, movement, and diary data. The contribution of retrospective memory and executive function to PM performance was assessed. PM was more accurate at Bed-time compared to Rise-time (p < .01), and better in the first compared to the second week (p < .01). Retrospective memory contributed small but significant unique variance (ß = .24) to PM accuracy. For older adults living in the community, both contextual factors (e.g., time of day) and retrospective memory are important for individuals' ability to remember to perform daily tasks. This is relevant when planning interventions for maintaining independent living in ageing.

Objective but not subjective sleep predicts memory in community-dwelling older adults.

Research on the relationship between habitual sleep patterns and memory performance in older adults is limited. No previous study has used objective and subjective memory measures in a large, older-aged sample to examine the association between sleep and various domains of memory. The aim of this study was to examine the association between objective and subjective measures of sleep with memory performance in older adults, controlling for the effects of potential confounds. One-hundred and seventy-three community-dwelling older adults aged 65-89 years in Victoria, Australia completed the study. Objective sleep quality and length were ascertained using the Actiwatch 2 Mini-Mitter, while subjective sleep was measured using the Pittsburgh Sleep Quality Index. Memory was indexed by tests of retrospective memory (Hopkins Verbal Learning Test - Revised), working memory (n-back, 2-back accuracy) and prospective memory (a habitual button pressing task). Compared with normative data, overall performance on retrospective memory function was within the average range. Hierarchical regression was used to determine whether objective or subjective measures of sleep predicted memory performances after controlling for demographics, health and mood. After controlling for confounds, actigraphic sleep indices (greater wake after sleep onset, longer sleep-onset latency and longer total sleep time) predicted poorer retrospective (∆R(2)  = 0.05, P = 0.016) and working memory (∆R(2)  = 0.05, P = 0.047). In contrast, subjective sleep indices did not significantly predict memory performances. In community-based older adults, objectively-measured, habitual sleep indices predict poorer memory performances. It will be important to follow the sample longitudinally to determine trajectories of change over time.

Predicting Alzheimer disease with ß-amyloid imaging: results from the Australian imaging, biomarkers, and lifestyle study of ageing.

OBJECTIVE: Biomarkers for Alzheimer disease (AD) can detect the disease pathology in asymptomatic subjects and individuals with mild cognitive impairment (MCI), but their cognitive prognosis remains uncertain. We aimed to determine the prognostic value of ß-amyloid imaging, alone and in combination with memory performance, hippocampal atrophy, and apolipoprotein E ε4 status in nondemented, older individuals. METHODS: A total of 183 healthy individuals (age = 72.0 ± 7.26 years) and 87 participants with MCI (age = 73.7 ± 8.27) in the Australian Imaging, Biomarkers, and Lifestyle study of ageing were studied. Clinical reclassification was performed after 3 years, blind to biomarker findings. ß-Amyloid imaging was considered positive if the (11) C-Pittsburgh compound B cortical to reference ratio was ≥1.5. RESULTS: Thirteen percent of healthy persons progressed (15 to MCI, 8 to dementia), and 59% of the MCI cohort progressed to probable AD. Multivariate analysis showed ß-amyloid imaging as the single variable most strongly associated with progression. Of combinations, subtle memory impairment (Z score = -0.5 to -1.5) with a positive amyloid scan was most strongly associated with progression in healthy individuals (odds ratio [OR] = 16, 95% confidence interval [CI] = 3.7-68; positive predictive value [PPV] = 50%, 95% CI = 19-81; negative predictive value [NPV] = 94%, 95% CI = 88-98). Almost all amnestic MCI subjects (Z score ≤ -1.5) with a positive amyloid scan developed AD (OR = ∞; PPV = 86%, 95% CI = 72-95; NPV = 100%, 95% CI = 80-100). Hippocampal atrophy and ε4 status did not add further predictive value. INTERPRETATION: Subtle memory impairment with a positive ß-amyloid scan identifies healthy individuals at high risk for MCI or AD. Clearly amnestic patients with a positive amyloid scan have prodromal AD and a poor prognosis for dementia within 3 years.

Rates of diagnostic transition and cognitive change at 18-month follow-up among 1,112 participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL).

BACKGROUND: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing is a prospective study of 1,112 individuals (211 with Alzheimer's disease (AD), 133 with mild cognitive impairment (MCI), and 768 healthy controls (HCs)). Here we report diagnostic and cognitive findings at the first (18-month) follow-up of the cohort. The first aim was to compute rates of transition from HC to MCI, and MCI to AD. The second aim was to characterize the cognitive profiles of individuals who transitioned to a more severe disease stage compared with those who did not. METHODS: Eighteen months after baseline, participants underwent comprehensive cognitive testing and diagnostic review, provided an 80 ml blood sample, and completed health and lifestyle questionnaires. A subgroup also underwent amyloid PET and MRI neuroimaging. RESULTS: The diagnostic status of 89.9% of the cohorts was determined (972 were reassessed, 28 had died, and 112 did not return for reassessment). The 18-month cohort comprised 692 HCs, 82 MCI cases, 197 AD patients, and one Parkinson's disease dementia case. The transition rate from HC to MCI was 2.5%, and cognitive decline in HCs who transitioned to MCI was greatest in memory and naming domains compared to HCs who remained stable. The transition rate from MCI to AD was 30.5%. CONCLUSION: There was a high retention rate after 18 months. Rates of transition from healthy aging to MCI, and MCI to AD, were consistent with established estimates. Follow-up of this cohort over longer periods will elucidate robust predictors of future cognitive decline.

What does cognitive screening reveal about early cognitive performance following endovascular clot retrieval and intravenous thrombolysis in acute ischaemic stroke?

Background Little is known regarding cognitive outcomes following treatment with endovascular clot retrieval (ECR) and intravenous tissue plasminogen activator (t-PA). We aimed to determine if there were any differences on a measure of cognitive screening between patients treated with ECR, t-PA, and those who were managed conservatively. Methods The medical records of ischaemic stroke patients admitted to Monash Medical Centre between January 2019 and December 2019 were retrospectively reviewed. Information extracted from medical records included age, sex, National Institutes of Health Stroke Scale at presentation, location of occlusion, treatment type, medical history, and cognitive screening performance measured by the Montreal Cognitive Assessment (MoCA). Results Eighty-two patients met the inclusion criteria (mean age = 66.5 ± 13.9; 49 male, 33 female). Patients treated with ECR performed significantly better on the MoCA (n = 36, 24.1 ± 4.3) compared to those who were managed conservatively (n = 26, 20.7 ± 5.5). Performance for patients treated with t-PA (n = 20, 23.9 ± 3.5) fell between the ECR and conservative management groups, but they did not significantly differ from either. Conclusion Our retrospective chart review found that ischaemic stroke patients treated with ECR appear to perform better on cognitive screening compared to patients who are managed conservatively. We also found that patients treated with ECR and t-PA appear to have similar cognitive screening performances in the acute stages following ischaemic stroke, although this finding is likely to have been impacted by group differences in stroke characteristics and may reflect the possibility that the ECR group performed better than expected based on their stroke severity.

Unmet needs in people with high-grade glioma: defining criteria for stepped care intervention.

BACKGROUND: We aimed to define levels of unmet supportive care needs in people with primary brain tumor and to reach expert consensus on feasibility of addressing patients' needs in clinical practice. METHODS: We conducted secondary analysis of a prospective cohort study of people diagnosed with high-grade glioma (n = 116) who completed the Supportive Care Needs Survey-Short Form during adjuvant chemoradiation therapy. Participants were allocated to 1 of 3 categories: no need ("no need" for help on all items), low need ("low need" for help on at least 1 item, but no "moderate" or "high" need), or moderate/high need (at least 1 "moderate" or "high" need indicated). Clinical capacity to respond to the proportion of patients needing to be prioritized was assessed. RESULTS: Overall, 13% (n = 5) were categorized as no need, 23% (n = 27) low need, and 64% (n = 74) moderate/high need. At least 1 moderate/high need was reported in the physical and daily living domain (42%) and the psychological (34%) domain. In recognition of health system capacity, the moderate/high need category was modified to distinguish between moderate need ("moderate" need indicated for at least 1 item but "high" need was not selected for any item) and high need (at least 1 "high" need indicated). Results revealed 24% (n = 28) moderate need and 40% (n = 46) high need. Those categorized as high need indicated needing assistance navigating the health system and information. CONCLUSIONS: Using four step allocations resulted in 40% of patients indicating high need. Categories may facilitate appropriate triaging and guide stepped models of healthcare delivery.

Exploring the clinical utility of a brief screening measure of unmet supportive care needs in people with high-grade glioma.

Background: People living with high-grade glioma (HGG) have diverse and complex needs. Screening aims to detect patients with some level of unmet need requiring triaging and further assessment. However, most existing measures of unmet need are not suitable for screening in this population due to their length. We aimed to explore the clinical utility of a brief screening tool (SCNS-ST9) in people with HGG in detecting unmet needs. Methods: Secondary analysis of data collected in a prospective cohort study of 116 people with HGG who completed the Supportive Care Needs Survey (SCNS-SF34) and a brain cancer-specific needs survey (BrTSCNS) during chemoradiation (T1) and 6 months later (T2). The SCNS-ST9 contains a subset of 9 items from the SCNS-SF34. Data analysis determined the number of individuals with unmet needs on the SCNS-SF34 and the BrTSCNS, not identified as having some level of need by the SCNS-ST9. Results: Overall, 3 individuals (T1: 2.6% [3/116]; T2: 4.8% [3/63]) at each time point reported other unmet needs on the SCNS-SF34 that were missed by the SCNS-ST9. Domain-specific screening items missed a higher proportion of individuals (3.2%-26%), particularly in the psychological and health systems domains. Only 1 individual with brain cancer-specific needs was missed by SCNS-ST9 overall. Conclusion: Findings demonstrate the sensitivity and clinical utility of a brief screening tool (SCNS-ST9) of unmet needs in people with HGG. Routine use of this screening tool, supported by clinical pathways, may improve access to support services, potentially reducing the burden of disease for these patients.

Longitudinal assessment of Aß and cognition in aging and Alzheimer disease.

OBJECTIVE: Assess Aß deposition longitudinally and explore its relationship with cognition and disease progression. METHODS: Clinical follow-up was obtained 20 ± 3 months after [¹¹C]Pittsburgh compound B (PiB)-positron emission tomography in 206 subjects: 35 with dementia of the Alzheimer type (DAT), 65 with mild cognitive impairment (MCI), and 106 age-matched healthy controls (HCs). A second PiB scan was obtained at follow-up in 185 subjects and a third scan after 3 years in 57. RESULTS: At baseline, 97% of DAT, 69% of MCI, and 31% of HC subjects showed high PiB retention. At 20-month follow-up, small but significant increases in PiB standardized uptake value ratios were observed in the DAT and MCI groups, and in HCs with high PiB retention at baseline (5.7%, 2.1%, and 1.5%, respectively). Increases were associated with the number of apolipoprotein E ε4 alleles. There was a weak correlation between PiB increases and decline in cognition when all groups were combined. Progression to DAT occurred in 67% of MCI with high PiB versus 5% of those with low PiB, but 20% of the low PiB MCI subjects progressed to other dementias. Of the high PiB HCs, 16% developed MCI or DAT by 20 months and 25% by 3 years. One low PiB HC developed MCI. INTERPRETATION: Aß deposition increases slowly from cognitive normality to moderate severity DAT. Extensive Aß deposition precedes cognitive impairment, and is associated with ApoE genotype and a higher risk of cognitive decline in HCs and progression from MCI to DAT over 1 to 2 years. However, cognitive decline is only weakly related to change in Aß burden, suggesting that downstream factors have a more direct effect on symptom progression.

Clinical measures of prospective memory in amnestic mild cognitive impairment.

Recent research has established that individuals with amnestic mild cognitive impairment (aMCI) have impaired prospective memory (PM); however, findings regarding differential deficits on time-based versus event-based PM have been less clear. Furthermore, the diagnostic utility of PM measures has received scant attention. Healthy older adults (n = 84) and individuals with aMCI (n = 84) were compared on the Cambridge Prospective Memory Test (CAMPROMPT) and two single-trial event-based PM tasks. The aMCI participants showed global impairment on all PM measures. Measures of retrospective memory and complex attention predicted both time and event PM performance for the aMCI group. Each of the PM measures was useful for discriminating aMCI from healthy older adults and the time- and event-based scales of the CAMPROMPT were equivalent in their discriminative ability. Surprisingly, the brief PM tasks were as good as more comprehensive measures of PM (CAMPROMPT) at predicting aMCI. Results indicate that single-trial PM measures, easily integrated into clinical practice, may be useful screening tools for identifying aMCI. As PM requires retrospective memory skills along with complex attention and executive skills, the interaction between these skills may explain the global PM deficits in aMCI and the good discriminative ability of PM for diagnosing aMCI.

Independent contribution of temporal beta-amyloid deposition to memory decline in the pre-dementia phase of Alzheimer's disease.

The relationship between ß-amyloid deposition and memory deficits in early Alzheimer's disease is unresolved, as past studies show conflicting findings. The present study aims to determine the relative contribution of regional ß-amyloid deposition, hippocampal atrophy and white matter integrity to episodic memory deficits in non-demented older individuals harbouring one of the characteristic hallmarks of Alzheimer's disease, i.e. with ß-amyloid pathology. Understanding these relationships is critical for effective therapeutic development. Brain magnetic resonance imaging and [(11)C]Pittsburgh Compound B-positron emission tomography scans were obtained in 136 non-demented individuals aged over 60 years, including 93 healthy elderly and 43 patients with mild cognitive impairment. Voxel-based correlations were computed between a memory composite score and grey matter volume, white matter volume and ß-amyloid deposition imaging datasets. Hierarchical linear regression analyses were then performed using values extracted in regions of most significant correlations to determine the relative contribution of each modality to memory deficits. All analyses were conducted pooling all groups together as well as within separate subgroups of cognitively normal elderly, patients with mild cognitive impairment and individuals with high versus low neocortical ß-amyloid. Brain areas of highest correlation with episodic memory deficits were the hippocampi for grey matter volume, the perforant path for white matter volume and the temporal neocortex for ß-amyloid deposition. When considering these three variables together, only hippocampal volume and temporal ß-amyloid deposition provided independent contributions to memory deficits. In contrast to global ß-amyloid deposition, temporal ß-amyloid deposition was still related to memory independently from hippocampal atrophy within subgroups of cognitively normal elderly, patients with mild cognitive impairment or cases with high neocortical ß-amyloid. In the pre-dementia stage of Alzheimer's disease, subtle episodic memory impairment is related to ß-amyloid deposition, especially in the temporal neocortex, and independently from hippocampal atrophy, suggesting that both factors should be independently targeted in therapeutic trials aimed at reducing cognitive decline.

Subtypes of progressive aphasia: application of the International Consensus Criteria and validation using ß-amyloid imaging.

Primary progressive aphasia comprises a heterogeneous group of neurodegenerative conditions with diverse clinical profiles and underlying pathological substrates. A major development has been the publication of the recent International Consensus Criteria for the three major variants namely: semantic, non-fluent/agrammatic and logopenic. The logopenic variant is assumed to represent an atypical presentation of Alzheimer pathology although evidence for this is, at present, limited. The semantic and non-fluent/agrammatic variants are largely associated with frontotemporal lobar degeneration with TDP-43 and tau pathology, respectively. The applicability of the International Consensus Criteria to an unselected clinical sample is unknown and no agreed clinical evaluation scale on which to derive the diagnosis exists. We assessed 47 consecutive cases of primary progressive aphasic seen over a 3-year period in a specialist centre, using a newly developed progressive aphasia language scale. A subgroup of 30 cases underwent (11)C-labelled Pittsburgh Compound B positron emission tomography imaging, a putative biomarker of Alzheimer's disease that detects ß-amyloid accumulation, and they were compared with an age-matched group (n = 10) with typical, predominately amnestic Alzheimer's disease. The application of an algorithm based on four key speech and language variables (motor speech disorders, agrammatism, single-word comprehension and sentence repetition) classified 45 of 47 (96%) of patients and showed high concordance with the gold standard expert clinical diagnosis based on the International Consensus Criteria. The level of neocortical ß-amyloid burden varied considerably across aphasic variants. Of 13 logopenic patients, 12 (92%) had positive ß-amyloid uptake. In contrast, one of nine (11%) semantic variant and two of eight (25%) non-fluent/agrammatic cases were positive. The distribution of ß-amyloid across cortical regions of interest was identical in cases with the logopenic variant to that of patients with typical Alzheimer's disease although the total load was lower in the aphasic cases. Impairments of sentence repetition and sentence comprehension were positively correlated with neocortical burden of ß-amyloid, whereas impaired single-word comprehension showed a negative correlation. The International Consensus Criteria can be applied to the majority of cases with primary progressive aphasic using a simple speech and language assessment scale based upon four key variables. ß-amyloid imaging confirms the higher rate of Alzheimer pathology in the logopenic variant and, in turn, the low rates in the other two variants. The study offers insight into the biological basis of clinical manifestations of Alzheimer's disease, which appear topographically independent of ß-amyloid load.