Selam Negash

Effects of ApoE genotype and mild cognitive impairment on implicit learning

The goals were to investigate implicit learning in mild cognitive impairment (MCI), and to determine the relations of implicit learning systems to apolipoprotein E (ApoE) genotype in healthy controls. Elderly controls grouped by ApoE status (ApoE-e4 allele carriers versus ApoE-e4 allele non-carriers) and MCI patients participated in the study. Individuals in all three groups completed both contextual cueing and serial reaction time (SRT) tasks. In the former, people learn to use repeated spatial configurations to facilitate search for a target, whereas in the latter, they learn to use subtle sequence regularities to respond more quickly and accurately to a series of events. Results revealed that healthy elderly individuals carrying the ApoE-e4 allele showed contextual cueing deficits compared to those who did not carry the ApoE-e4 allele. Further, elderly controls carrying the ApoE-e4 allele revealed similar amounts of contextual cueing as the MCI group, while the non-carriers performed better. Sequence learning, by contrast, was uninfluenced by either MCI or by ApoE genotype in healthy controls. This study provides further support for the medial temporal lobe dysfunction and relative integrity of fronto-striatal systems in MCI, and indicates the influence of ApoE genotype on implicit learning even in healthy older individuals without cognitive impairment.

The influence of apolipoprotein E genotype on visuospatial attention dissipates after age 80.

Although it is established that apolipoprotein E (APOE) e4 allele increases the risk of Alzheimers disease (AD), epidemiological studies indicate that genetic risk decreases late in life. This raises the question of whether the effects of APOE on cognition that are seen in midlife arise from a cognitive phenotype of APOE or from the presence of early AD in some APOE-e4 carriers. The authors addressed this question by comparing the cognitive consequences of variation in the APOE gene between individuals over the age of 80 (old-old) and middle-aged and young-old individuals. A spatially cued discrimination paradigm--previously shown to be sensitive to AD and to APOE genotype--required a speeded categorization of a target letter following cues that were valid, invalid, or neutral in predicting target location. Results revealed greater costs of invalid cues in the APOE-e4 carriers of middle-aged and young-old, but not old-old, groups. The dissipation of the APOE effect in old-old individuals at lower risk of AD suggests that visuospatial attention impairments seen as early as midlife in APOE-e4 carriers may be a preclinical marker of AD.

Implicit Learning of Sequential Regularities and Spatial Contexts in Corticobasal Syndrome

The present study investigated two forms of implicit learning in patients with corticobasal syndrome (CBS): contextual cueing and sequence learning. The former primarily implicates the medial temporal lobe system, and the latter, fronto-striatal-cerebellar circuits. Results revealed relatively preserved contextual cueing in patients with CBS. By contrast, sequence learning showed impairments, which seemed to reflect inability to execute correct responses in the presence of intact learning of the sequence. These findings provide the first characterization of implicit learning systems in CBS, and show that the two systems are differentially affected in patients with CBS.

Chapter 26 Neuropsychological characterization of mild cognitive impairment

Publisher Summary Mild cognitive impairment (MCI) is proposed as a condition of intermediate symptomology between the cognitive changes of aging and fully developed symptoms of dementia such as those seen in Alzheimers disease (AD). The rationale for the study of MCI is derived from the assumption that the sooner one intervenes in a degenerative process, the more likely the damage done to the central nervous system can be prevented. Hence, the construct is developed to represent a transitional stage between the cognitive changes of aging and very early dementia. Once the diagnosis of MCI is established, the next task is to identify the clinical subtype. Here, the clinician should first determine whether memory is impaired, since memory impairment strongly predisposes the individual towards AD. This can be determined by office memory tests, usually involving an instrument with a delayed recall component or by more detailed neuropsychological testing. The clinical characterization of the patients symptoms is determined and thereafter the next step involves determining the etiology of the symptoms. As the focus of dementia research moves toward prevention, numerous clinical trials on MCI are being undertaken. Currently, there are no FDA approved treatments for MCI.

THE REPEATABLE BATTERY FOR THE ASSESSMENT OF NEUROPSYCHOLOGICAL STATUS (RBANS) AS A USEFUL OUTCOME MEASURE IN PRODROMAL AD TRIALS

Until now, no curative treatment is accessible. During the last years, our group designed all D-enantiomeric peptides, with the effort to capture toxic amyloid-beta (Ab) species. Here, we investigated the therapeutic in vivo efficacy of a newly developed D-enantiomeric peptide in old APP/PS1 animals at an age, when they have developed already a full blown amyloid pathology and in pyroglutamate-Ab expressing TBA2.1 mice, which are characterized by a motoric phenotype.Methods:Aged male APP/PS1 mice were orally treated with placebo or 200mg/kg peptide for 3 months. Homozygous TBA2.1 mice and non-transgenic littermates were treated with placebo, 20 mg/kg or 100 mg/kg peptide orally for 3 months. After treatment, mice were tested in different general, cognitive (APP/PS1) and motoric (TBA2.1) behavioural tests (Morris Water Maze, Open field test, SHIRPA test battery). Brains were analysed for changes in amyloid pathology, inflammation and neurodegeneration (histological and biochemical). Results:Analysis of general behavioural tests resulted in no difference in behaviour of treated mice in comparison to non-transgenic littermates. After peptide treatment, APP/PS1 mice showed a significant improved cognitive performance in the Morris Water Maze compared to placebo controls (p 1⁄4 0,05). Treated TBA2.1 mice revealed a significant lower SHIRPA-Score than non-treated littermates, indicating an improvedmotoric phenotype. APP/PS1mice exhibited a significant decrease in plaque burden in the cortex. Treated non-transgenic littermates showed no abnormalities due to treatment with the peptide. Conclusions:We were able to show that the D-enantiomeric peptide has a truly curative effect on cognitive performance, motoric phenotype and plaque load in both mouse models without side effects on behaviour. These results qualify the peptide as promising candidate for the treatment of AD.

VIRGIL ELECTRONIC CLINICAL OUTCOME ASSESSMENTS (ECOA) PLATFORM: IMPROVING SIGNAL DETECTION IN ALZHEIMER'S DISEASE CLINICAL TRIALS

age, education level, and gender. There was a significant e4 x age interaction (p1⁄40.03). We found no associations between e4+ and processing speed or attention, or between family history of e4+ and cognitive test scores. There were significant associations between self-reported memory problems and both e4+ (p<0.001) and family history of e4+ (p<0.001). We identified 2032 “likely prodromal” and 6227 “likely preclinical” participants for AD trials. Of those likely eligible participants who reported their e4 genotype (n1⁄41650), 16% of prodromal and 4% of preclinical were e4+. Conclusions: In a large, novel, internet-based cohort, self-reported e4 is associated with online memory test scores in younger participants, and cognitively-normal participants. In the general cohort, age eclipses the effects of e4 genotype on memory scores. Self-reportedmemory problems are strongly associated with e4 evenwhen controlling for other variables. BHR participants identified as likely prodromal have four times greater prevalence of e4+ than older adults with normal cognitive test scores. Self-report of e4 in BHR can be used to prescreen for AD trials requiring e4, facilitate AD trials, and accelerate development of new AD treatments.

P2-193: Progression of cognitive impairments in mild cognitive impairment: What is the next domain to be impaired after memory?

general cognitive functions, normal activities of daily living, and absence of pathology associated with dementia or memory disorders. Converging evidence suggests that episodic memory deficits are most pronounced in amnestic MCI, yet it is unclear what aspects of episodic memory are affected and how the pattern of impairment may differ from mild AD. Objective: This study compared aspects of episodic memory including learning rate, immediate, delayed, and cued recall, and retention rate in a sample of amnestic MCI, mild AD, and healthy older individuals. Methods: Episodic memory profiles from neuropsychological evaluations were examined for 22 AD (mean MMSE 23.77, SD 2.87), 23 amnestic MCI (mean MMSE 27.52, SD 2.25), and 21 healthy adults (mean MMSE 28.57, SD 1.25). The groups were equated for age, education, and vocabulary level. The memory battery included a visual memory test (Visual Reproduction subtest from the Wechsler Memory Scale-III) and verbal memory tests assessing prose (Logical Memory Scale from the WMS-III), and word list (California Verbal Learning Test-II) learning and recall. Results: In general, episodic memory for prose, word lists, and visual reproduction was impaired for MCI compared to healthy adults, but was higher than for AD individuals. Although the learning rate for MCI and healthy adults was comparable, MCI individuals retained less, recalled less verbal and visual information, gained less from semantic cueing, and had a higher number of intrusions during recall than did healthy adults. In comparison to AD individuals, MCI adults displayed a higher learning rate, greater retention for visual information, more benefit from semantic cueing, and higher recall for verbal and visual material. MCI and AD individuals did not differ significantly either in retention rate for verbal material or susceptibility to interference during verbal recall. Conclusions: The memory profile for amnestic MCI individuals suggests general impairment compared to healthy adults across most aspects of episodic memory including immediate, delayed and cued recall and susceptibility to interference, with deficits in retention rate for verbal memory comparable to mild AD.