Kevin R. Peters

A canadian cohort study of cognitive impairment and related dementias (ACCORD): Study methods and baseline results

The overall objective of the Canadian Collaborative Cohort of Related Dementias (ACCORD) study is to describe the diagnostic distribution, natural history and treatment outcomes of individuals referred from the community to dementia clinics in Canada. Between 1997 and 1999, an inception cohort of 1,136 subjects entered into this longitudinal study. At the baseline assessment, 10.9% of the subjects were classified as ‘not cognitively impaired’ (NCI), 30.1% as ‘cognitively impaired not demented’ (CIND), and 59% as demented. A subclassification of CIND included amnestic 25.1%, vascular cognitive impairment 18.1%, psychiatric 17.2%, neurologic 7.3%, medical/toxic metabolic 3.5%, mixed 7.6% and not specified 19.0%. The percentage of the cohort referred with dementia increased progressively each decade, while the proportions of CIND and NCI decreased. Within the dementia group, Alzheimer’s disease accounted for 47.2% of the subjects, mixed dementias 33.7%, vascular dementia 8.7%, frontotemporal degenerations 5.4%, dementia with Lewy bodies 2.5%, and unclassifiable 1.8%. The ACCORD cohort will allow a detailed study of the longitudinal course of CIND, and the longer-term outcomes of both treated and untreated dementia subjects.

Changes in Sleep Architecture following Motor Learning Depend on Initial Skill Level

Previous research has linked both rapid eyemovement (REM) sleep and Stage 2 sleep to procedural memory consolidation. The present study sought to clarify the relationship between sleep stages and procedural memory consolidation by examining the effect of initial skill level in this relationship in young adults. In-home sleep recordings were performed on participants before and after learning the pursuit rotor task. We divided the participants into low- and high-skill groups based on their initial performance of the pursuit rotor task. In high-skill participants, there was a significant increase in Stage 2 spindle density after learning, and there was a significant correlation between the spindle density that occurred after learning and pursuit rotor performance at retest 1 week later. In contrast, there was a significant correlation between changes in REM density and performance on the pursuit rotor task during retest 1 week later in low-skill participants, although the actual increase in REM density failed to reach significance in this group. The results of the present study suggest the presence of a double dissociation in the sleep-related processes that are involved in procedural memory consolidation in low- and high-skill individuals. These results indicate that the changes in sleep microarchitecture that take place after learning depend on the initial skill level of the individual and therefore provide validation for the model proposed by Smith et al. [Smith, C. T., Aubrey, J. B., & Peters, K. R. Different roles for REM and Stage 2 sleep in motor learning. Psychologica Belgica, 44, 79102, 2004]. Accordingly, skill level is an important variable that needs to be considered in future research on sleep and memory consolidation.

Changes in the density of stage 2 sleep spindles following motor learning in young and older adults

The purpose of this study was to compare the changes that occur in sleep architecture following the acquisition of a simple motor learning task in young and older adults. Subjects included 14 young (range = 17–24 years) and 14 older (range = 62–79 years) adults, all of whom were in good health. Using in‐home recording systems, sleep architecture (sleep stages and the density of Stage 2 sleep spindles) was examined before and after learning the pursuit rotor. To control for possible age differences in baseline motor performance and spindle density, both absolute and relative (percent change) measures were examined. Both groups improved significantly on the pursuit rotor task at Retest (1 week later); however, the magnitude of absolute improvement was larger in the young group than in the older group. There was no group difference when a relative measure of improvement (percent increase across sessions) was used. The density of Stage 2 sleep spindles increased significantly following task Acquisition in the young group but not in the older group. These age differences failed to reach significance when change was measured as a percentage of baseline level of spindle density. The increase in spindle density was correlated with performance level during acquisition in the young group but not the older group. The results of the present study are largely consistent with previous studies on sleep and memory in young adults and suggest that more detailed examination of this relationship in older adults is warranted.

Disability in multiple sclerosis is related to normal appearing brain tissue MTR histogram abnormalities

Background: Magnetization transfer ratio (MTR) histogram analysis provides a global measure of disease burden in multiple sclerosis (MS). MTR abnormalities in normal appearing brain tissue (NABT) provide quantitative information on the extent of tissue damage undetected by conventional T2-weighted (T2W) magnetic resonance imaging (MRI). A ims: 1) To compare the MTR histograms from NABT across a broad spectrum of relapse onset MS patients, including relapsing-remitting (RR) MS (including newly diagnosed and benign subgroups) and secondary progressive (SP) MS. 2) To determine the relationship between clinical disability and NA BT MTR histograms. Methods: 2D spin echo magnetization transfer imaging was performed on 70 RRMS and 25 SPMS patients and compared with 63 controls. MTR histograms were acquired for NA BT after extracting lesions and cerebrospinal fluid (C SF). T2W images were used to measure the brain parenchymal fraction (BPF) and T2 lesion load. Results: MS patients had a disease duration ranging from 0.5 to 37 years and an Expanded Disability Status Scale (EDSS) score ranging from 0 to 8.5. There was a significant decrease in NA BT mean MTR (± standard deviation) compared with controls (33.07 pu± 1.06 versus 34.26 pu± 0.47; P < 0.001) with an effect size of 2.56. The reductio n in NA BT mean MTR varied among patient groups from 4.9% for SPMS, 3% for all RRMS, 2.7% for early RRMS and 2.5% for benign MS, compared with controls. NA BT mean MTR correlated significantly with T2 lesion load (r = -0.82) and BPF (r =0.58). EDSS score correlated with NA BT mean MTR (r = -0.43), BPF (r = -0.33) and with T2 lesion load (r =0.59). Multivariate analysis using NA BT MTR peak height, T2 lesion load and BPF combined only accounted for 38% of the variance in the EDSS (r =0.62; P <0.001). Disease duration accounted for an additional 14% of variance in the EDSS (r =0.72; P <0.001). Conclusions: There is evidence of diffuse abnormalities in NA BT in addition to global brain atrophy in relapse onset MS patients, including those with recently diagnosed RRMS and benign MS. The abnormalities are greatest in patients with the more disabling SPMS. A trophy, NA BT and lesion abnormalities are all partly correlated; the processes marked by these MR measures all contribute to disability in MS, providing complementary information relevant to the complex pathological processes that occur in MS.

Validating an automated sleep spindle detection algorithm using an individualized approach.

The goal of the current investigation was to develop a systematic method to validate the accuracy of an automated method of sleep spindle detection that takes into consideration individual differences in spindle amplitude. The benchmarking approach used here could be employed more generally to validate automated spindle scoring from other detection algorithms. In a sample of Stage 2 sleep from 10 healthy young subjects, spindles were identified both manually and automatically. The minimum amplitude threshold used by the prana® (PhiTools, Strasbourg, France) software spindle detection algorithm to identify a spindle was subject‐specific and determined based upon each subject’s mean peak spindle amplitude. Overall sensitivity and specificity values were 98.96 and 88.49%, respectively, when compared to manual scoring. Selecting individual amplitude thresholds for spindle detection based on systematic benchmarking data may validate automated spindle detection methods and improve reproducibility of experimental results. Given that interindividual differences are accounted for, we feel that automatic spindle detection provides an accurate and efficient alternative approach for detecting sleep spindles.

Characterizing neuropsychiatric symptoms in subjects referred to dementia clinics

Objective: To characterize the neuropsychiatric symptoms (NPS) of subjects classified as not cognitively impaired (NCI), cognitively impaired–not demented (CIND), and dementia. Methods: A Canadian Cohort Study of Cognitive Impairment and Related Dementias (ACCORD) is a longitudinal investigation of individuals referred to eight Canadian dementia centers for evaluation of cognitive impairment and neurobehavioral symptoms. Of the inception cohort of 804 subjects for whom the informant-based Neuropsychiatric Inventory (NPI) was completed at study entry, 35 were classified as NCI, 193 as CIND, and 576 as dementia. The three diagnostic groups were compared on each of the 12 NPI items. Within each diagnostic group, comparisons were also made between symptomatic (NPS+; total score > 1) and asymptomatic (NPS−; total score = 0) subjects on measures of general cognitive status and functional disability. A subset of the NCI and CIND individuals were also compared on a comprehensive neuropsychological test battery. Results: There was at least one NPI item reported in 60% of subjects with NCI, 74% with CIND, and 89% with dementia. The item scores for delusions, hallucinations, agitation, apathy, disinhibition, aberrant motor behavior, and problems with appetite were greater in dementia subjects than in NCI or CIND. There were no significant differences between subjects with NCI and CIND on any NPI item. For each diagnostic group, NPS+ subjects were more impaired on functional but not neuropsychological measures. Conclusions: Across all levels of cognition, neuropsychiatric symptoms (NPS) are an important feature in individuals referred to dementia clinics. The current data suggest that NPS may precede cognitive deficits in individuals classified as not cognitively impaired and cognitively impaired–not demented.

A conceptual framework and ethics analysis for prevention trials of Alzheimer Disease.

As our understanding of the neurobiology of Alzheimer Disease deepens, it has become evident that early intervention is critical to achieving successful therapeutic impact. The availability of diagnostic criteria for preclinical Alzheimer Disease adds momentum to research directed at this goal and even to prevention. The landscape of therapeutic research is thus poised to undergo a dramatic shift in the next 5-10 years, with clinical trials involving subjects at risk for Alzheimer Disease who have few or no symptoms. These trials will also likely rely heavily on genetics, biomarkers, and or risk factor stratification to identify individuals at risk for Alzheimer Disease. Here, we propose a conceptual framework to guide this next generation of pharmacological and non-pharmacological clinical pursuit, and discuss some of the foreseeable ethical considerations that may accompany them.

Cognitive Impairment No Dementia – Neuropsychological and Neuroimaging Characterization of an Amnestic Subgroup

Background/Aims: Cognitive impairment no dementia (CIND) describes individuals whose cognitive functioning falls below normal but who do not meet dementia criteria. An important goal within CIND is to identify subgroups that will predictably progress to Alzheimer disease. CIND with amnestic deficits has been associated with high risk of Alzheimer disease but has until now been investigated on a retrospective basis. In this study a prospectively defined amnestic CIND group was characterized on a detailed neuropsychological test battery and on structural magnetic resonance imaging (MRI) measures. Methods: Amnestic CIND was defined as meeting at least 1 but not all DSM-IV-TR criteria for dementia, scoring ≧1 SD below norms on Rey Auditory Verbal Learning Test delayed recall, having a Clinical Dementia Rating score of 0.5 and a Mini-Mental State Exam score ≧24. This cross-sectional study compared subjects meeting these criteria (n = 25) to age- and education-matched controls (n = 26). The neuropsychological battery included memory and nonmemory measures that were analyzed as continuous variables and dichotomized into impaired (≧1 SD below controls) versus nonimpaired. MRI scans were evaluated with a global-brain volumetric measure [brain fractional ratio (BFR)] and with visually based medial temporal lobe atrophy (MTA) ratings. Results: Amnestic CIND had neuropsychological impairment in the episodic memory domain and also in nonmemory domains. There were 80% of CIND subjects with multidomain impairment. The most clear-cut nonmemory impairment was in the verbal ability domain, with 64% of subjects affected and a moderate effect size (d = 0.7). On MRI, BFR was lower (74.5 ± 4.6 vs. 75.5 ± 4.4) and MTA higher (72 vs. 38% with MTA ≧1) in CIND than in control subjects. BFR correlated with MTA (r = –0.45) and with a composite memory score (r = 0.296). Conclusion: A prospective amnestic CIND grouping appears to identify individuals with a multidomain pattern of neuropsychological impairment and with both medial temporal lobe and global brain atrophy.

Age Differences in the Variability and Distribution of Sleep Spindle and Rapid Eye Movement Densities

The present study had two main objectives. The first objective was to compare the sleep architecture of young and older adults, with an emphasis on sleep spindle density and REM density. The second objective was to examine two aspects of age differences that have not been considered in previous studies: age differences in the variability of sleep measures as well as the magnitude of age differences in phasic events across the distribution of values (i.e., at each decile rather than a single measure of location such as the mean or median. A total of 24 young (mean age = 20.75±1.78 years) and 24 older (mean age = 71.17±6.15 years) adults underwent in-home polysomnography. Whole-night spindle density was significantly higher in young adults than older adults. The two age groups did not differ significantly in whole-night REM density, although significant increases in REM density across the night were observed in both age groups. These results suggest that spindle density is more affected by age than REM density. Although age differences were observed in the degree of absolute variability (older adults had significantly larger variances than young adults for sleep efficiency and time spent awake after sleep onset), a similar pattern was also observed within the two age groups: the four sleep measures with the lowest degrees of relative variability were the same and included time spent in REM and Stage 2 sleep, total sleep time, and sleep efficiency. The distributional analysis of age differences in sleep spindle density revealed that the largest age differences were initially observed in the middle of the distributions, but as the night progressed, they were seen at the upper end of the distributions. The results reported here have potential implications for the causes and functional implications of age-related changes in sleep architecture.

Neuropsychological Subgroups of Cognitively-Impaired-Not-Demented (CIND) Individuals: Delineation, Reliability, and Predictive Validity

The objectives of the present investigation were to determine whether subgroups of Cognitively-Impaired-Not-Demented (CIND) individuals with distinct neuropsychological profiles exist in two independent samples, and whether subgroup membership is related to diagnostic outcome over periods of 2 to 5 years. A series of cluster analyses was performed on ipsative factor z-scores derived from principal component analyses. Five subgroups were identified in the Base Sample (n = 461): Verbal Dysfunction,Verbal/Visuospatial Dysfunction,Memory/Verbal Dysfunction,Memory Dysfunction, and Visuospatial Dysfunction. This five-cluster solution was replicated in an independent sample of CIND individuals (n = 166). The highest rates of conversion to dementia were observed in the Memory Dysfunction and Memory/Verbal Dysfunction subgroups. The Verbal Dysfunction subgroup was most likely to show improvement in cognitive status. The cognitive heterogeneity of the CIND condition must be taken into account in future research focusing on the early identification of dementia. The research described herein was conducted as part of a doctoral dissertation by the first author (K.R.P.). While conducting this research, the first author (K.R.P.) received support from a Doctoral Training Award jointly funded by the Alzheimer Society of Canada and the Canadian Institutes of Health Research and by a Postgraduate Scholarship funded by the Natural Sciences and Engineering Research Council of Canada. The CSHA was supported through the National Health Research and Development program grant # 6606-3954-MC[S]. The ACCORD study was supported through the MRC PMAC program grant # PA14197 awarded to H.F. We would like to express our sincerest gratitude to the participants and their families for their commitment to both the CSHA and ACCORD studies. We would also like to acknowledge the hard work performed by each centre that participated in each of these two studies.