Hear Me Out: A Meta-Analysis of Third-Party Disability Due to Presbycusis.

OBJECTIVES: Hearing-related third-party disability is the transferrable impact of presbycusis on an affected individual's surrounding social network. Previous research suggests that interventions to overcome hearing-related communication challenges benefit both the individual with presbycusis and their communication partner. However, there have been no comparisons of the effects of different interventions on third-party disability. We conducted meta-analyses of hearing aid or communication-based longitudinal interventions to determine if: both kinds of interventions significantly benefit communication partners across three categories of third-party disability (communication, emotional health and lifestyle outcomes), hearing aid and communication interventions differ in the size of treatment effects, and demographic variables moderate intervention efficacy. DESIGN: Four databases were systematically searched for studies published after 1990 that included preintervention and postintervention data for communication partners of individuals receiving a hearing aid or communication-based intervention. Studies were included if participants had presbycusis, were aged 45 or over, with no known physical or mental disorders, and had a willing study partner over 18 years old. Databases were last comprehensively and hand-searched in January 2023. One researcher applied the inclusion and exclusion criteria to select studies and complete data extraction. Depending on study design, risk of bias was assessed using the "Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group" or the "Risk of Bias 2." Random effects models were run for effect sizes for both intervention types (together and separately) for each third-party disability category. Meta-regressions were run to inspect the effect of demographic variables on intervention efficacy. RESULTS: Six studies satisfied inclusion criteria and showed that for both hearing and communication interventions, communication partners experienced significant improvements in all three outcomes. Communication interventions showed greater benefits for lifestyle outcomes, but hearing aid and communication interventions did not differ for communication and emotional health outcomes. Meta-regressions revealed previously undetected relationships between demographic variables and intervention efficacy. CONCLUSIONS: The results of this meta-analysis and meta-regressions may have clinical and real-world implications in terms of highlighting the widespread benefits of these interventions, and the need to build in greater consideration of an individual's wider network when designing and implementing interventions. Noted limitations included certain combinations of intervention type and third-party disability category that were underrepresented (in absolute and/or relative terms), a lack of combined intervention (hearing aids and communication training) studies, and variation in the types of questionnaires used between studies. The current study discusses possible ways to unite the current literature for more consistent research practices.

Development of a new computer simulated environment to screen cognition: assessing the feasibility and acceptability of Leaf Café in younger and older adults.

BACKGROUND: Existing traditional cognitive screening tools for dementia have various limitations, including overreliance on tests assessing verbal memory and, to a lesser extent, on some aspects of executive functioning. Comprehensive neuropsychological assessment is sensitive to impairment but time-intensive and expensive. Virtual reality may provide a dynamic and unique understanding of cognitive performance and increase the ecological validity of cognitive assessment. The use of virtual reality in screening for cognitive function in older persons is promising, but evidence for its use remains sparse. OBJECTIVE: Our primary aim was to examine the feasibility and acceptability of a newly developed, virtual reality assessment module, 'Leaf Café', a computer-based program that assesses cognition in an engaging, efficient, and ecologically relevant way. The secondary aim was to assess the ability of the module to discriminate between performances of younger and older adults. METHODS: A cross-sectional study was carried out in Sydney, Australia, targeting adults aged 18 years and above. Participants completed a traditional cognitive screening tool (Telephone Interview for Cognitive Status-Modified, TICS-M) and Leaf Café, a low-immersive virtual reality module designed to evaluate learning and memory, perceptual-motor function, and executive functioning. The total performance score for each participant, ranging from 0 to 180, was correlated with their cognitive performance assessed by TICS-M, using Pearson's correlation coefficient. Following module completion, participants were presented with an open and closed-question survey to capture their perceptions, attitudes, and feedback on the module, encompassing practicality, acceptability, and enjoyment. Both descriptive and content analyses were employed to interpret the obtained data. RESULTS: A sample of 131 participants (mean age 54.9 years, SD = 20.8, range 20-85) took part. The majority were female (71.8%) and born in an English-speaking country (75.8%). The mean amount of time spent in the module was 32.8 min (SD = 13.3) with a mean module score of 107.6 (SD = 38.7). Most participants completed the highest level (5; 80.5%). There was a significant correlation between Leaf Café total scores with TICS-M cognitive scores overall, and for both younger (aged 18-64 years) and older adult (aged 65 + years) groups. No significant difference was found on performance between age groups on TICS-M performance, however, younger adults had significantly better performance on the Leaf Café module than older adults (M = 124.1 vs 95.9; p < .001). Participants had similar response proportions regarding user experience with most agreeing that the module was easy to use (84%) and to navigate (85%). Compared with younger adults, older adults had lower rates of agreement on the module's design (36.8% vs 64.3%; p = .020) and support experienced (20.5% vs 53.6%; p = .007). Participants highlighted the significance of practicality and the cognitive challenges presented by the module, in terms of memory strain and user interface concerns. Feedback encompassed different opinions on the usefulness of music, with suggestions for improvements centred around clearer instructions, varied game dynamics, and considerations for diverse user needs. CONCLUSIONS: Leaf Café is a feasible and acceptable tool to be used for screening for cognitive impairment in older adults and has real-world assessment value. Further verification on the game's utility in detecting cognitive impairment is required.

The Impact of Right Temporal Lobe Epilepsy On Nonverbal Memory: Meta-regression of Stimulus- and Task-related Moderators.

Nonverbal memory tests have great potential value for detecting the impact of lateralized pathology and predicting the risk of memory loss following right temporal lobe resection (TLR) for temporal lobe epilepsy (TLE) patients, but this potential has not been realized. Previous reviews suggest that stimulus type moderates the capacity of nonverbal memory tests to detect right-lateralized pathology (i.e., faces > designs), but the roles of other task-related factors have not been systematically explored. We address these limitations using mixed model meta-regression (k = 158) of right-lateralization effects (right worse than left TLE) testing the moderating effects of: 1) stimulus type (designs, faces, spatial), 2) learning format (single trial, repeated trials), 3) testing delay (immediate or long delay), and 4) testing format (recall, recognition) for three patient scenarios: 1) presurgical, 2) postsurgical, and 3) postsurgical change. For presurgical patients the size of the right-lateralization effect was significantly moderated by stimulus type (faces > designs), testing format (recall > recognition) and its interaction with the learning format (repeated trials more affected by format effect than single trials) of the nonverbal memory tests. For postsurgical patients and presurgical-postsurgical change, test format moderated the size of the right-lateralization effect (recognition > recall) and this explained and overshadowed effects of stimulus type (i.e., faces > designs). This comprehensive review reveals the value of recognition testing in gauging the risk of nonverbal memory decline.

Androgen receptor CAG repeat length as a moderator of the relationship between free testosterone levels and cognition.

Age-related decrease in testosterone levels is a potential risk factor for cognitive decline in older men. However, observational studies and clinical trials have reported inconsistent results on the effects of testosterone on individual cognitive domains. Null findings may be attributed to factors that studies have yet to consider. In particular, individual variations in polyglutamine (CAG) length in the androgen receptor (AR) gene could alter androgenic activity in brain regions associated with cognitive processes including memory and executive functions. However, the role of AR CAG repeat length as a moderator of the relationship between testosterone levels and cognition has not been investigated. Therefore, we aimed to examine the relationship between baseline calculated free testosterone (cFT) levels, change in cFT levels over 18 months and CAG repeat length on cognitive performance in memory, executive function, language, attention and processing speed domains. These relationships were examined in 304 cognitively normal older male participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. In the attention and processing speed domain, a short CAG repeat length appears to exacerbate the effects of low baseline cFT levels that are also lower than expected at follow-up. These results highlight that individual variations in AR CAG repeat length should be considered in future studies and clinical trials that examine the complex relationship between testosterone and cognition.

Aggregation of Abnormal Memory Scores and Risk of Incident Alzheimer's Disease Dementia: A Measure of Objective Memory Impairment in Amnestic Mild Cognitive Impairment.

OBJECTIVES: The criteria for objective memory impairment in mild cognitive impairment (MCI) are vaguely defined. Aggregating the number of abnormal memory scores (NAMS) is one way to operationalise memory impairment, which we hypothesised would predict progression to Alzheimer's disease (AD) dementia. METHODS: As part of the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing, 896 older adults who did not have dementia were administered a psychometric battery including three neuropsychological tests of memory, yielding 10 indices of memory. We calculated the number of memory scores corresponding to z ≤ -1.5 (i.e., NAMS) for each participant. Incident diagnosis of AD dementia was established by consensus of an expert panel after 3 years. RESULTS: Of the 722 (80.6%) participants who were followed up, 54 (7.5%) developed AD dementia. There was a strong correlation between NAMS and probability of developing AD dementia (r = .91, p = .0003). Each abnormal memory score conferred an additional 9.8% risk of progressing to AD dementia. The area under the receiver operating characteristic curve for NAMS was 0.87 [95% confidence interval (CI) .81-.93, p < .01]. The odds ratio for NAMS was 1.67 (95% CI 1.40-2.01, p < .01) after correcting for age, sex, education, estimated intelligence quotient, subjective memory complaint, Mini-Mental State Exam (MMSE) score and apolipoprotein E ϵ4 status. CONCLUSIONS: Aggregation of abnormal memory scores may be a useful way of operationalising objective memory impairment, predicting incident AD dementia and providing prognostic stratification for individuals with MCI.

The effect of semantic memory degeneration on creative thinking: A voxel-based morphometry analysis.

Increasing attention is being directed towards explicating the neurocognitive mechanisms of divergent thinking. While neuroimaging studies have tended to dominate the contemporary creativity literature, lesion studies provide important converging evidence by revealing the regions that are not only implicated in, but essential for, task performance. Here we explored the capacity for divergent thinking in semantic dementia (SD), a neurodegenerative disorder characterised by the progressive degeneration of the conceptual knowledge base. The performance of 10 SD patients on a divergent thinking task was contrasted with that of 15 patients with the behavioural variant of frontotemporal dementia (bvFTD) and 20 healthy control participants. In addition, all participants underwent neuropsychological testing and structural MRI. Relative to controls, both patient groups generated significantly fewer responses on the divergent thinking task, with disproportionate impairment in the SD group. Further, the responses generated by patient groups were less original and reflected less flexible thinking when compared with controls. For SD patients, fluency of responses correlated with performance on a measure of semantic association, and originality of responses correlated with semantic naming and comprehension ability. In bvFTD, originality of ideas correlated with letter fluency and response inhibition. Voxel-based morphometry analyses revealed two grey matter clusters consistently associated with diminished Fluency of ideas, namely a left medial temporal lobe cluster centred on the left anterior hippocampus, and a left middle frontal gyrus cluster. Our study highlights the importance of distinct temporal and prefrontal contributions to divergent thinking via a lesion approach, and underscores the pivotal role of semantic processes in creative cognition.

Long-married couples recall their wedding day: the influence of collaboration and gender on autobiographical memory recall.

The current study examined the influence of collaboration, expertise, and communication on autobiographical memory, by considering gender differences in recall and how they may influence the products and processes of remembering when male-female couples recall events together. Thirty-nine long-married, male-female couples recalled their memories of their wedding day. In Session 1, they recalled it individually for an experimenter. One week later, in Session 2, they recalled the same event jointly as a collaborative pair. Women reported more details, especially episodic details, than men across both sessions. Notably, collaborative recall included many new details that neither spouse had recalled individually. Exploratory analyses suggest that women were less influenced by collaboration than were men: women's communication behaviours influenced men's recall, but the reverse was not found for men's communication. Additionally, when couples' individual recall was more similar in content, men were more likely to decrease their contribution to the collaborative session. We consider these findings in light of transactive memory theory, in which joint meta-memory and the distribution of expertise influence the processes and products of recall in the interdependent system of a couple who extensively share their autobiographical memories.

A Systematic Review of Cognition in Chiari I Malformation.

Displacement of the cerebellar tonsils in Chiari type I malformation (CMI) can affect functions controlled by the cerebellum and brainstem. While playing an integral role in the control of movement, the cerebellum also has widespread cortical connections, influencing a range of cognitive process. A systematic literature review was conducted to examine the relationship between cognition and CMI, assessing evidence for general or domain-specific cognitive change. The search protocol examined the AMED, CINAHL, Cochrane Library, EMBASE, MEDLINE, PsycINFO, and Scopus databases. Articles meeting the following criteria were included in this review (i) examined children or adults with a clinically defined diagnosis of CMI, (ii) assessed cognitive function with a prospective examination, (iii) included at least one standardized instrument designed to measure general or specific domains of cognitive function, and (iv) were published in English in a peer-reviewed journal. Twelve articles were identified, including 783 cases aged 3 months to 64 years. General cognition, processing speed, and learning and memory appeared less affected, while language deficits appeared to diminish with age. Executive dysfunction was the most commonly reported cognitive impairment, while attention and working memory, and visuospatial and perceptual skills also appeared vulnerable. Numerous methodological limitations were identified that should be considered in interpreting the impact of CMI and planning future investigations. Overall, there is currently insufficient evidence to describe a valid and reliable profile of cognitive impairment in CMI. Further research is required to confirm these preliminary psychometric results and integrate them with pathophysiological models.

Addenbrooke's Cognitive Examination III: Psychometric Characteristics and Relations to Functional Ability in Dementia.

OBJECTIVES: The Addenbrooke's Cognitive Examination (ACE) is a common cognitive screening test for dementia. Here, we examined the relationship between the most recent version (ACE-III) and its predecessor (ACE-R), determined ACE-III cutoff scores for the detection of dementia, and explored its relationship with functional ability. METHODS: Study 1 included 199 dementia patients and 52 healthy controls who completed the ACE-III and ACE-R. ACE-III total and domain scores were regressed on their corresponding ACE-R values to obtain conversion formulae. Study 2 included 331 mixed dementia patients and 87 controls to establish the optimal ACE-III cutoff scores for the detection of dementia using receiver operator curve analysis. Study 3 included 194 dementia patients and their carers to investigate the relationship between ACE-III total score and functional ability. RESULTS: Study 1: ACE-III and ACE-R scores differed by ≤1 point overall, the magnitude varying according to dementia type. Study 2: a new lower bound cutoff ACE-III score of 84/100 to detect dementia was identified (compared with 82 for the ACE-R). The upper bound cutoff score of 88/100 was retained. Study 3: ACE-III scores were significantly related to functional ability on the Clinical Dementia Rating Scale across all dementia syndromes, except for semantic dementia. CONCLUSIONS: This study represents one of the largest and most clinically diverse investigations of the ACE-III. Our results demonstrate that the ACE-III is an acceptable alternative to the ACE-R. In addition, ACE-III performance has broader clinical implications in that it relates to carer reports of functional impairment in most common dementias. (JINS, 2018, 24, 854-863).

Baseline Amnestic Severity Predicts Progression From Amnestic Mild Cognitive Impairment to Alzheimer Disease Dementia at 3 Years.

BACKGROUND: Given the long preclinical disease course of Alzheimer disease (AD) pathology, novel treatments may be more efficacious if administered before the emergence of dementia. Thus, accurate prediction of who will develop AD dementia is of key importance in selecting individuals for trials of treatment and may become crucial for future selection of patients for therapy. METHODS: As part of the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing, 901 individuals who did not have dementia were recruited. We assigned individuals according to Petersen criteria and Winblad criteria for Mild Cognitive Impairment (MCI) at baseline. We then stratified individuals with amnestic MCI into 2 groups according to the severity of their memory impairment on baseline neuropsychological assessment. Incident diagnosis of AD dementia was established by consensus of an expert panel at 36 months. RESULTS: At 36 months, 725 (80.5%) participants were followed up, 54 (7.4%) of whom developed AD dementia. Subjects with amnestic MCI according to Petersen criteria were more likely to develop AD dementia [positive predictive value; PPV, 24.1%; 95% confidence interval (CI), 18.4-30.6] than healthy controls (PPV, 1.0%; 95% CI, 0.3-2.3). Winblad criteria were also effective, with multiple domain amnestic MCI being most accurate at predicting AD dementia (PPV, 47.3%; 95% CI, 33.7-61.2). Finally, more severe amnestic impairment below the median was useful for predicting the development of AD dementia in single domain amnestic MCI (PPV, 28.1%; 95% CI, 17.0-41.5) and in multiple domain amnestic MCI (PPV, 65.7%; 95% CI, 47.8-80.9). CONCLUSIONS: Memory impairment per se, impairment in multiple cognitive domains and severity of memory impairment were all associated with greater risk of developing AD dementia in this sample. Characterizing the severity of memory impairment may provide prognostic stratification within Petersen or Winblad taxonomies of amnestic MCI.

Adaptive Motor Imagery: A Multimodal Study of Immobilization-Induced Brain Plasticity.

The consequences of losing the ability to move a limb are traumatic. One approach that examines the impact of pathological limb nonuse on the brain involves temporary immobilization of a healthy limb. Here, we investigated immobilization-induced plasticity in the motor imagery (MI) circuitry during hand immobilization. We assessed these changes with a multimodal paradigm, using functional magnetic resonance imaging (fMRI) to measure neural activation, magnetoencephalography (MEG) to track neuronal oscillatory dynamics, and transcranial magnetic stimulation (TMS) to assess corticospinal excitability. fMRI results show a significant decrease in neural activation for MI of the constrained hand, localized to sensorimotor areas contralateral to the immobilized hand. MEG results show a significant decrease in beta desynchronization and faster resynchronization in sensorimotor areas contralateral to the immobilized hand. TMS results show a significant increase in resting motor threshold in motor cortex contralateral to the constrained hand, suggesting a decrease in corticospinal excitability in the projections to the constrained hand. These results demonstrate a direct and rapid effect of immobilization on MI processes of the constrained hand, suggesting that limb nonuse may not only affect motor execution, as evidenced by previous studies, but also MI. These findings have important implications for the effectiveness of therapeutic approaches that use MI as a rehabilitation tool to ameliorate the negative effects of limb nonuse.

Subjective memory decline predicts greater rates of clinical progression in preclinical Alzheimer's disease.

INTRODUCTION: The objective of this study was to determine the utility of subjective memory decline (SMD) to predict episodic memory change and rates of clinical progression in cognitively normal older adults with evidence of high ß-amyloid burden (CN Aß+). METHODS: Fifty-eight CN Aß+ participants from the Australian Imaging, Biomarkers, and Lifestyle study responded to an SMD questionnaire and underwent comprehensive neuropsychological assessments. Participant data for three follow-up assessments were analyzed. RESULTS: In CN Aß+, subjects with high SMD did not exhibit significantly greater episodic memory decline than those with low SMD. High SMD was related to greater rates of progression to mild cognitive impairment or Alzheimer's disease (AD) dementia (hazard ratio = 5.1; 95% confidence interval, 1.4-20.0, P = .02) compared with low SMD. High SMD was associated with greater depressive symptomatology and smaller left hippocampal volume. DISCUSSION: High SMD is a harbinger of greater rates of clinical progression in preclinical AD. Although SMD reflects broader diagnostic implications for CN Aß+, more sensitive measures may be required to detect early subtle cognitive change.

Long-term plasticity in adult somatosensory cortex: functional reorganization after surgical removal of an arteriovenous malformation.

The temporal scale of neuroplasticity following acute alterations in brain structure due to neurosurgical intervention is still under debate. We conducted a longitudinal study with the objective of investigating the postoperative changes in a patient who underwent cerebrovascular surgery and who subsequently lost proprioception in the fingers of her right hand. The results show increased activation in contralesional somatosensory areas, additional recruitment of premotor and posterior parietal areas, and changes in functional connectivity with left postcentral gyrus. These findings demonstrate long-term modifications of cortical organization and as such have important implications for treatment strategies for patients with brain injury.

Disruption of learning and long-term retention of prose passages in patients with focal epilepsy.

Recent investigations of accelerated long-term forgetting, a condition in which newly acquired memory is normal initially but decays rapidly over days or weeks, indicate that multiple factors might influence whether this phenomenon is seen in patients with epilepsy. Test-based differences such as learning condition or type of memory measure (e.g., recall vs recognition) as well as epilepsy variables (e.g., side, site, or frequency of epileptiform activity) may be important. The present study sought to characterize factors affecting learning and memory for prose passages in patients with focal epilepsy. We enrolled 21 patients with temporal lobe epilepsy, with and without hippocampal lesions, 11 patients with extratemporal epilepsy (ETE), and 29 healthy controls. Two matched passages were used to compare effects of initial learning condition (one exposure versus learning-to-criterion) on subsequent patterns of retention. Recall and recognition were tested at different delays (i.e., immediately, 30min, 24h, and 4days). Regression analyses and one-way ANOVAs indicated that having a left-hemisphere epileptic focus had a negative impact on learning, whilst presence of a hippocampal lesion (irrespective of side) was associated with deterioration in recall for intervals up to 24h postencoding. Learning condition affected patterns of memory decay in that the ETE group showed significant decline in recall between 24h and 4days only when stories were learned to criterion. In contrast with recall, no changes over time were evident in recognition memory, as patients with hippocampal lesions were impaired from 30min onward. Epilepsy variables other than side and site of epilepsy/lesion did not influence performance. In conclusion, the left hemisphere is involved in learning of prose material, and the hippocampus is involved in the consolidation of this material mainly for the first 24h. After this, cortical regions outside the hippocampus become important for recall.

Self and informant memory concerns align in healthy memory complainers and in early stages of mild cognitive impairment but separate with increasing cognitive impairment.

BACKGROUND: Information provided by an informant about a patient with cognitive change is an essential component of clinical history taking. How an informant's report relates to the patient's phenomenological experience of memory loss is yet to be understood. The aim was to examine patterns of relationships between self and informant reports from a phenomenological perspective. METHODS: Forty-three healthy non-memory complainers (HC-NMC), 37 healthy subjective memory complainers (HC-SMC) and 43 individuals with mild cognitive impairment (MCI) were administered a semi-structured interview, which measured their concerns of frequency of memory lapses and impact on mood. Informants responded to questionnaires. RESULTS: Self-reported concerns of increasing frequency and impacted mood related to informant concerns in HC-SMCs. MCI with lower informant concern showed a similar pattern to HC-SMCs on complaints of increasing frequency. In those with higher informant concern, self-reports markedly separated from informant concern. The MCI group with greater informant concern performed comparatively poor on verbal and non-verbal memory measures. CONCLUSIONS: Our results suggest that the association between self-reported and informant memory concerns is moderated by MCI severity. Self and informant reports of increasing memory lapse frequency aligned in HC-SMC and MCIs with low informant concern, suggesting a similar dyadic experience of memory change. In MCIs with greater informant concern, the pattern changed exposing a changing insight with advancing memory impairment. These individuals are potentially reflecting a 'forgetting that they forget' phenomenon in elements of their concern.

Genetic algorithm with logistic regression for prediction of progression to Alzheimer's disease.

BACKGROUND: Assessment of risk and early diagnosis of Alzheimer's disease (AD) is a key to its prevention or slowing the progression of the disease. Previous research on risk factors for AD typically utilizes statistical comparison tests or stepwise selection with regression models. Outcomes of these methods tend to emphasize single risk factors rather than a combination of risk factors. However, a combination of factors, rather than any one alone, is likely to affect disease development. Genetic algorithms (GA) can be useful and efficient for searching a combination of variables for the best achievement (eg. accuracy of diagnosis), especially when the search space is large, complex or poorly understood, as in the case in prediction of AD development. RESULTS: Multiple sets of neuropsychological tests were identified by GA to best predict conversions between clinical categories, with a cross validated AUC (area under the ROC curve) of 0.90 for prediction of HC conversion to MCI/AD and 0.86 for MCI conversion to AD within 36 months. CONCLUSIONS: This study showed the potential of GA application in the neural science area. It demonstrated that the combination of a small set of variables is superior in performance than the use of all the single significant variables in the model for prediction of progression of disease. Variables more frequently selected by GA might be more important as part of the algorithm for prediction of disease development.

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.

Lack of reliable evidence for a distinctive ε4-related cognitive phenotype that is independent from clinical diagnostic status: findings from the Australian Imaging, Biomarkers and Lifestyle Study.

Individuals who carry the apolipoprotein E ε4 polymorphism have an increased risk of late-onset Alzheimer's disease. However, because possession of the ε4 allele confers an increased risk for the diagnosis of dementia, it has proven problematic in older individuals to dissociate the influence of ε4 on cognitive capacity per se as distinct from its influence on clinical diagnostic status. We report a statistical approach that attempts to partial out the influence of diagnostic group membership (Alzheimer's disease, mild cognitive impairment, healthy control) from the influence of apolipoprotein ε4 genetic status on cognitive functioning. The cognitive phenotype hypothesis predicts that ε4-positive individuals will show cognitive deficits (relative to matched ε4-negative individuals) independent of the development of Alzheimer's disease. By contrast, the prodromal/preclinical Alzheimer's disease hypothesis proposes that the effect of apolipoprotein E status on cognitive performance is a function of the increased risk of dementia in individuals with the ε4 allele. We evaluated these hypotheses in the Australian Imaging, Biomarkers and Lifestyle cohort (n = 1112). We first determined whether previously reported findings concerning ε4 status and age-related neuropsychological performance could be explained by the inadvertent recruitment of people with mild cognitive impairment into the healthy control group. We then tested each diagnostic group in isolation to identify any neuropsychological patterns that may be attributed to the ε4 allele. Finally, as interactions between the ε4 allele and age have previously been reported in cognitive functioning within healthy elderly populations, we attempted to determine whether the inclusion of mild cognitively impaired individuals in the sample may drive this relationship. An extensive battery of standardized, well-validated neuropsychological tasks was administered to a final sample of 764 healthy control subjects, 131 individuals with mild cognitive impairment and 168 individuals with Alzheimer's disease. The effect of the ε4 allele on cognitive performance was assessed using a statistical mediation analysis and supplemented with Bayesian methods to address a number of the limitations associated with Fisherian/Neyman-Pearsonian significance testing. Our findings support the prodromal/preclinical Alzheimer's disease hypothesis and do not support the concept of a distinctive ε4-related cognitive phenotype.

Autobiographical narratives relate to Alzheimer's disease biomarkers in older adults.

BACKGROUND: Autobiographical memory (ABM), personal semantic memory (PSM), and autonoetic consciousness are affected in individuals with mild cognitive impairment (MCI) but their relationship with Alzheimer's disease (AD) biomarkers are unclear. METHODS: Forty-five participants (healthy controls (HC) = 31, MCI = 14) completed the Episodic ABM Interview and a battery of memory tests. Thirty-one (HC = 22, MCI = 9) underwent ß-amyloid positron emission tomography (PET) and magnetic resonance (MR) imaging. Fourteen participants (HC = 9, MCI = 5) underwent one imaging modality. RESULTS: Unlike PSM, ABM differentiated between diagnostic categories but did not relate to AD biomarkers. Personal semantic memory was related to neocortical ß-amyloid burden after adjusting for age and apolipoprotein E (APOE) ɛ4. Autonoetic consciousness was not associated with AD biomarkers, and was not impaired in MCI. CONCLUSIONS: Autobiographical memory was impaired in MCI participants but was not related to neocortical amyloid burden, suggesting that personal memory systems are impacted by differing disease mechanisms, rather than being uniformly underpinned by ß-amyloid. Episodic and semantic ABM impairment represent an important AD prodrome.