Summary Alzheimer's disease (AD) is classically defined as a dual clinicopathological entity. The recent advances in use of reliable biomarkers of AD that provide in-vivo evidence of the disease has ...stimulated the development of new research criteria that reconceptualise the diagnosis around both a specific pattern of cognitive changes and structural/biological evidence of Alzheimer's pathology. This new diagnostic framework has stimulated debate about the definition of AD and related conditions. The potential for drugs to intercede in the pathogenic cascade of the disease adds some urgency to this debate. This paper by the International Working Group for New Research Criteria for the Diagnosis of AD aims to advance the scientific discussion by providing broader diagnostic coverage of the AD clinical spectrum and by proposing a common lexicon as a point of reference for the clinical and research communities. The cornerstone of this lexicon is to consider AD solely as a clinical and symptomatic entity that encompasses both predementia and dementia phases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary The NINCDS–ADRDA and the DSM-IV-TR criteria for Alzheimer's disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of ...scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET, and cerebrospinal fluid analyses. This progress provides the impetus for our proposal of revised diagnostic criteria for AD. Our framework was developed to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. These new criteria are centred on a clinical core of early and significant episodic memory impairment. They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid β or tau proteins. The timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis, particularly at the production and clearance of amyloid β as well as at the hyperphosphorylation state of tau. Validation studies in existing and prospective cohorts are needed to advance these criteria and optimise their sensitivity, specificity, and accuracy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
When analyzing large multicenter databases, the effects of multiple confounding covariates increase the variability in the data and may reduce the ability to detect changes due to the actual effect ...of interest, for example, changes due to disease. Efficient ways to evaluate the effect of covariates toward the data harmonization are therefore important. In this article, we showcase techniques to assess the “goodness of harmonization” of covariates. We analyze 7,656 MR images in the multisite, multiscanner Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We present a comparison of three methods for estimating total intracranial volume to assess their robustness and correct the brain structure volumes using the residual method and the proportional (normalization by division) method. We then evaluated the distribution of brain structure volumes over the entire ADNI database before and after accounting for multiple covariates such as total intracranial volume, scanner field strength, sex, and age using two techniques: (a) Zscapes, a panoramic visualization technique to analyze the entire database and (b) empirical cumulative distributions functions. The results from this study highlight the importance of assessing the goodness of data harmonization as a necessary preprocessing step when pooling large data set with multiple covariates, prior to further statistical data analysis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Summary Background The primary outcome results for the SPS3 trial suggested that a lower systolic target blood pressure (<130 mm Hg) might be beneficial for reducing the risk of recurrent stroke ...compared with a higher target (130–149 mm Hg), but that the addition of clopidogrel to aspirin was not beneficial compared with aspirin plus placebo. In this prespecified secondary outcome analysis of the SPS3 trial, we aimed to assess whether blood pressure reduction and dual antiplatelet treatment affect changes in cognitive function over time in patients with cerebral small vessel disease. Methods In the SPS3 trial, patients with recent (within 6 months) symptomatic lacunar infarcts from 81 centres in North America, Latin America, and Spain were randomly assigned, in a two-by-two factorial design, to target levels of systolic blood pressure (1:1; 130–149 mm Hg vs <130 mm Hg; open-label) and to a once-daily antiplatelet treatment (1:1; aspirin 325 mg plus clopidogrel 75 mg vs aspirin 325 mg plus placebo; double-blind). For this analysis, the main cognitive outcome was change in Cognitive Abilities Screening Instrument (CASI) during follow-up. Patients were tested annually for up to 5 years, during which time the mean difference in systolic blood pressure was 11 mm Hg (SD 16) between the two targets (138 mm Hg vs 127 mm Hg at 1 year). We used linear mixed models to compare changes in CASI Z scores over time. The SPS3 trial is registered with ClinicalTrials.gov , number NCT00059306. Findings The study took place between March 23, 2003, and April 30, 2012. 2916 of 3020 SPS3 participants (mean age 63 years SD 11) with CASI scores at study entry were included in the analysis, with a median follow-up of 3·0 years (IQR 1·0–4·9). Mean changes in CASI Z scores from study entry to assessment at years 1 (n=2472), 2 (n=1968), 3 (n=1521), 4 (n=1135), and 5 (n=803) were 0·12 (SD 0·83), 0·15 (0·84), 0·16 (0·95), 0·19 (0·99), and 0·14 (1·09), respectively. Changes in CASI Z scores over time did not differ between assigned antiplatelet groups (p=0·858) or between assigned blood pressure target groups (p=0·520). There was no interaction between assigned antiplatelet groups and assigned blood pressure target groups and change over time (p=0·196). Interpretation Cognitive function is not affected by short-term dual antiplatelet treatment or blood pressure reduction in fairly young patients with recent lacunar stroke. Future studies of cognitive function after stroke should be of longer duration or focus on patients with higher rates of cognitive decline. Funding US National Institute of Neurological Disorders and Stroke.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective:
Lacunar strokes are a leading cause of cognitive impairment and vascular dementia. However, adequate characterization of cognitive impairment is lacking. The aim of this study was to ...estimate the prevalence and characterize the neuropsychological impairment in lacunar stroke patients.
Methods:
All English‐speaking participants in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial (National Clinical Trial 00059306) underwent neuropsychological testing at baseline. Raw scores were converted to z scores using published norms. Those with impairment (z ≤ −1.5) in memory and/or nonmemory domains were classified as having mild cognitive impairment (MCI).
Results:
Among the 1,636 participants, average z scores on all tests were <0, with the largest deficits seen on tests of episodic memory (range of means, −0.65 to −0.92), verbal fluency (mean, −0.89), and motor dexterity (mean, −2.5). Forty‐seven percent were classified as having MCI (36% amnestic, 37% amnestic multidomain, 28% nonamnestic). Of those with modified Rankin score 0–1 and Barthel score = 100, 41% had MCI. Younger age (odds ratio OR per 10‐year increase, 0.87), male sex (OR, 1.3), less education (OR, 0.13–0.66 for higher education levels compared to 0–4 years education), poststroke disability (OR, 1.4), and impaired activities of daily living (OR, 1.8) were independently associated with MCI.
Interpretation:
In this large, well‐characterized cohort of lacunar stroke patients, MCI was present in nearly half, including many with minimal or no physical disabilities. Cognitive dysfunction in lacunar stroke patients may commonly be overlooked in clinical practice but may be as important as motor and sensory sequelae. ANN NEUROL 2012;72:351–362
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To quantitatively characterize domain-specific cognition in individuals with symptomatic lacunar stroke in a systematic review.
Systematic searches of MEDLINE and EMBASE were conducted. Inclusion ...criteria were all articles published prior to December 2011 evaluating domain-specific cognitive status in individuals with a symptomatic lacunar infarct. Data extraction identified cognitive domains with reported impairment and effect size calculations and heterogeneity analyses were completed to assess the magnitude of this impairment for all studies with control group data.
Results of the search yielded 12 cross-sectional and 5 longitudinal studies that met inclusion criteria. Effect size calculations revealed small to medium effect sizes (ES) estimations for impairment after stroke in the domains of executive function (ES -0.44, 95% confidence interval CI -0.83, -0.50), memory (ES -0.55, 95% CI -0.96, -0.13), language (ES -0.63, 95% CI -0.92, -0.33), attention (ES -0.37, 95% CI -0.67, -0.07), and visuospatial abilities (ES -0.61, 95% CI -1.03, 0.19), and large effect sizes for global cognition (ES -0.90, 95% CI -1.48, -0.31) and information processing speed (ES -0.93, 95% CI -1.63, -0.23). Heterogeneity analyses revealed that a subset of these domains were heterogeneous and identified moderating factors accounting for this heterogeneity.
Results of this systematic review are consistent with previous characterizations of cognitive impairment associated with lacunar strokes. However, impaired cognition in this stroke subtype appears less selective than previously thought, involving all major cognitive domains.
Background: Research on person-centered cognitive testing is beginning to emerge. The current study is the first to focus on eliciting concrete preferences around the test experience. Methods: Adults ...≥50 years old completed the Attitudes Around Cognitive Testing (AACT) questionnaire on mturk.com. AACT elicits preferences for cognitive tests, the importance attributed to having choices, and willingness to engage in testing. Results: Data are reported for 289 respondents. The proportion of participants expressing preferences varied by domain (modality 49.5%, location 47.2%, company 80.1%, result delivery 78.3–89.7%). Importance ratings for all domains had a median of 4 and a range of 1–5 using a Likert scale of agreement. Most participants (85.5%) were willing to engage in testing. Conclusion: Older adults have preferences for cognitive tests, especially with delivery of results.
The assessment of quality of life is critical in ascertaining the benefit of interventions aimed to reduce morbidity among individuals with cognitive impairment. However, the assessment of quality of ...life is challenging in this population due to the uncertain validity of patient responses as cognitive function declines. Hence, we examined the level of agreement between patient and proxy assessments of health related quality of life (HRQoL) and wellbeing based on the domains that comprise each of these constructs.
Analysis of baseline data from 71 community-dwelling older adults with mild Vascular Cognitive Impairment (VCI) who participated in a six-month proof-of-concept single-blinded randomized trial. Level of agreement between patient and caregiver ratings of HRQoL (EQ-5D-3L) and wellbeing (ICECAP-O) were compared using raw agreement (%), intraclass correlation coefficient (ICC) and weighted Cohen's kappa statistic.
Self-care (assessed via the EQ-5D-3L) demonstrated almost perfect raw agreement between the patient and caregiver ratings. Three domains (mobility, pain and anxiety) of the EQ-5D-3L demonstrated fair agreement between the patient and caregiver ratings. Two (attachment and control) of the five ICECAP-O domains demonstrated slight agreement. The ICC indicated good agreement for the EQ-5D-3L and poor agreement for the ICECAP-O.
There is better patient-proxy agreement for the EQ-5D-3L compared with the ICECAP-O among individuals with mild VCI. These findings imply that the ICECAP-O may have limited clinical, research and policy related utility among individuals with mild VCI.
ClinicalTrials.gov NCT01027858.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Diagnosis and treatment of dementia: 2. Diagnosis Feldman, Howard H., MD; Jacova, Claudia, PhD; Robillard, Alain, MD ...
Canadian Medical Association journal,
03/2008, Volume:
178, Issue:
7
Journal Article
Peer reviewed
Open access
Dementia can now be accurately diagnosed through clinical evaluation, cognitive screening, basic laboratory evaluation and structural imaging. A large number of ancillary techniques are also ...available to aid in diagnosis, but their role in the armamentarium of family physicians remains controversial. In this article, we provide physicians with practical guidance on the diagnosis of dementia based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, held in March 2006.
We developed evidence-based guidelines using systematic literature searches, with specific criteria for study selection and quality assessment, and a clear and transparent decision-making process. We selected studies published from January 1996 to December 2005 that pertained to key diagnostic issues in dementia. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care.
Of the 1591 articles we identified on all aspects of dementia diagnosis, 1095 met our inclusion criteria; 620 were deemed to be of good or fair quality. From a synthesis of the evidence in these studies, we made 32 recommendations related to the diagnosis of dementia. There are clinical criteria for diagnosing most forms of dementia. A standard diagnostic evaluation can be performed by family physicians over multiple visits. It involves a clinical history (from patient and caregiver), a physical examination and brief cognitive testing. A list of core laboratory tests is recommended. Structural imaging with computed tomography or magnetic resonance imaging is recommended in selected cases to rule out treatable causes of dementia or to rule in cerebrovascular disease. There is insufficient evidence to recommend routine functional imaging, measurement of biomarkers or neuropsychologic testing.
The diagnosis of dementia remains clinically integrative based on history, physical examination and brief cognitive testing. A number of core laboratory tests are also recommended. Structural neuroimaging is advised in selected cases. Other diagnostic approaches, including functional neuroimaging, neuropsychological testing and measurement of biomarkers, have shown promise but are not yet recommended for routine use by family physicians.
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