Mini-Mental State Examination (MMSE) for the detection of dementia in clinically unevaluated people aged 65 and over in community and primary care populations.

BACKGROUND: The Mini Mental State Examination (MMSE) is a cognitive test that is commonly used as part of the evaluation for possible dementia. OBJECTIVES: To determine the diagnostic accuracy of the Mini-Mental State Examination (MMSE) at various cut points for dementia in people aged 65 years and over in community and primary care settings who had not undergone prior testing for dementia. SEARCH METHODS: We searched the specialised register of the Cochrane Dementia and Cognitive Improvement Group, MEDLINE (OvidSP), EMBASE (OvidSP), PsycINFO (OvidSP), LILACS (BIREME), ALOIS, BIOSIS previews (Thomson Reuters Web of Science), and Web of Science Core Collection, including the Science Citation Index and the Conference Proceedings Citation Index (Thomson Reuters Web of Science). We also searched specialised sources of diagnostic test accuracy studies and reviews: MEDION (Universities of Maastricht and Leuven, www.mediondatabase.nl), DARE (Database of Abstracts of Reviews of Effects, via the Cochrane Library), HTA Database (Health Technology Assessment Database, via the Cochrane Library), and ARIF (University of Birmingham, UK, www.arif.bham.ac.uk). We attempted to locate possibly relevant but unpublished data by contacting researchers in this field. We first performed the searches in November 2012 and then fully updated them in May 2014. We did not apply any language or date restrictions to the electronic searches, and we did not use any methodological filters as a method to restrict the search overall. SELECTION CRITERIA: We included studies that compared the 11-item (maximum score 30) MMSE test (at any cut point) in people who had not undergone prior testing versus a commonly accepted clinical reference standard for all-cause dementia and subtypes (Alzheimer disease dementia, Lewy body dementia, vascular dementia, frontotemporal dementia). Clinical diagnosis included all-cause (unspecified) dementia, as defined by any version of the Diagnostic and Statistical Manual of Mental Disorders (DSM); International Classification of Diseases (ICD) and the Clinical Dementia Rating. DATA COLLECTION AND ANALYSIS: At least three authors screened all citations.Two authors handled data extraction and quality assessment. We performed meta-analysis using the hierarchical summary receiver-operator curves (HSROC) method and the bivariate method. MAIN RESULTS: We retrieved 24,310 citations after removal of duplicates. We reviewed the full text of 317 full-text articles and finally included 70 records, referring to 48 studies, in our synthesis. We were able to perform meta-analysis on 28 studies in the community setting (44 articles) and on 6 studies in primary care (8 articles), but we could not extract usable 2 x 2 data for the remaining 14 community studies, which we did not include in the meta-analysis. All of the studies in the community were in asymptomatic people, whereas two of the six studies in primary care were conducted in people who had symptoms of possible dementia. We judged two studies to be at high risk of bias in the patient selection domain, three studies to be at high risk of bias in the index test domain and nine studies to be at high risk of bias regarding flow and timing. We assessed most studies as being applicable to the review question though we had concerns about selection of participants in six studies and target condition in one study.The accuracy of the MMSE for diagnosing dementia was reported at 18 cut points in the community (MMSE score 10, 14-30 inclusive) and 10 cut points in primary care (MMSE score 17-26 inclusive). The total number of participants in studies included in the meta-analyses ranged from 37 to 2727, median 314 (interquartile range (IQR) 160 to 647). In the community, the pooled accuracy at a cut point of 24 (15 studies) was sensitivity 0.85 (95% confidence interval (CI) 0.74 to 0.92), specificity 0.90 (95% CI 0.82 to 0.95); at a cut point of 25 (10 studies), sensitivity 0.87 (95% CI 0.78 to 0.93), specificity 0.82 (95% CI 0.65 to 0.92); and in seven studies that adjusted accuracy estimates for level of education, sensitivity 0.97 (95% CI 0.83 to 1.00), specificity 0.70 (95% CI 0.50 to 0.85). There was insufficient data to evaluate the accuracy of the MMSE for diagnosing dementia subtypes.We could not estimate summary diagnostic accuracy in primary care due to insufficient data. AUTHORS' CONCLUSIONS: The MMSE contributes to a diagnosis of dementia in low prevalence settings, but should not be used in isolation to confirm or exclude disease. We recommend that future work evaluates the diagnostic accuracy of tests in the context of the diagnostic pathway experienced by the patient and that investigators report how undergoing the MMSE changes patient-relevant outcomes.

Quantitative T1 and T2 MRI signal characteristics in the human brain: different patterns of MR contrasts in normal ageing.

OBJECTIVE: The objective of this study was to examine age-dependent changes in both T1-weighted and T2-weighted image contrasts and spin-echo T2 relaxation time in the human brain during healthy ageing. METHODS: A total of 37 participants between the ages of 49 and 87 years old were scanned with a 3 Tesla system, using T1-weighted, T2 weighted and quantitative spin-echo T2 imaging. Contrast between image intensities and T2 values was calculated for various regions, including between individual hippocampal subfields. RESULTS: The T1 contrast-to-noise (CNR) and gray:white signal intensity ratio (GWR) did not change in the hippocampus, but it declined in the cingulate cortex with age. In contrast, T2 CNR and GWR declined in both brain regions. T2 relaxation time was almost constant in gray matter and most (but not all) hippocampal subfields, but increased substantially in white matter, pointing to an age effect on water relaxation in white matter. CONCLUSIONS: Changes in T1 and T2 MR characteristics influence the appearance of brain images in later life and should be considered in image analyses of aged subjects. It is speculated that alterations at the cell biology level, with concomitant alterations to the local magnetic environment, reduce dephasing and subsequently prolong spin-echo T2 through reduced diffusion effects in later life.

Dopamine and Consolidation of Episodic Memory: Timing is Everything.

Memory consolidation underpins adaptive behavior and dopaminergic networks may be critical for prolonged, selective information storage. To understand the time course of the dopaminergic contribution to memory consolidation in humans, here we investigate the effect of dopaminergic medication on recall and recognition in the short and longer term in Parkinson disease (PD). Fifteen people with PD were each tested on or off dopaminergic medication during learning/early consolidation (Day 1) and/or late consolidation (Day 2). Fifteen age-matched healthy participants were tested only once. On Day 1 participants learned new information, and early episodic memory was tested after 30 min. Then on Day 2, recall and recognition were retested after a 24-hr delay. Participants on medication on Day 1 recalled less information at 30 min and 24 hr. In contrast, patients on medication on Day 2 (8-24 hr after learning) recalled more information at 24 hr than those off medication. Although recognition sensitivity was unaffected by medication, response bias was dependent on dopaminergic state: Medication during learning induced a more liberal bias 24 hr later, whereas patients off medication during learning were more conservative responders 24 hr later. We use computational modeling to propose possible mechanisms for this change in response bias. In summary, dopaminergic medication in PD patients during learning impairs early consolidation of episodic memory and makes delayed responses more liberal, but enhances late memory consolidation presumably through a dopamine-dependent consolidation pathway that may be active during sleep.

T2 heterogeneity: a novel marker of microstructural integrity associated with cognitive decline in people with mild cognitive impairment.

BACKGROUND: Early Alzheimer's disease (AD) diagnosis is vital for development of disease-modifying therapies. Prior to significant brain tissue atrophy, several microstructural changes take place as a result of Alzheimer's pathology. These include deposition of amyloid, tau and iron, as well as altered water homeostasis in tissue and some cell death. T2 relaxation time, a quantitative MRI measure, is sensitive to these changes and may be a useful non-invasive, early marker of tissue integrity which could predict conversion to dementia. We propose that different microstructural changes affect T2 in opposing ways, such that average 'midpoint' measures of T2 are less sensitive than measuring distribution width (heterogeneity). T2 heterogeneity in the brain may present a sensitive early marker of AD pathology. METHODS: In this cohort study, we tested 97 healthy older controls, 49 people with mild cognitive impairment (MCI) and 10 with a clinical diagnosis of AD. All participants underwent structural MRI including a multi-echo sequence for quantitative T2 assessment. Cognitive change over 1 year was assessed in 20 participants with MCI. T2 distributions were modelled in the hippocampus and thalamus using log-logistic distribution giving measures of log-median value (midpoint; T2µ) and distribution width (heterogeneity; T2σ). RESULTS: We show an increase in T2 heterogeneity (T2σ; p < .0001) in MCI compared to healthy controls, which was not seen with midpoint (T2µ; p = .149) in the hippocampus and thalamus. Hippocampal T2 heterogeneity predicted cognitive decline over 1 year in MCI participants (p = .018), but midpoint (p = .132) and volume (p = .315) did not. Age affects T2, but the effects described here are significant even after correcting for age. CONCLUSIONS: We show that T2 heterogeneity can identify subtle changes in microstructural integrity of brain tissue in MCI and predict cognitive decline over a year. We describe a new model that considers the competing effects of factors that both increase and decrease T2. These two opposing forces suggest that previous conclusions based on T2 midpoint may have obscured the true potential of T2 as a marker of subtle neuropathology. We propose that T2 heterogeneity reflects microstructural integrity with potential to be a widely used early biomarker of conditions such as AD.

Novel Blood Biomarkers that Correlate with Cognitive Performance and Hippocampal Volumetry: Potential for Early Diagnosis of Alzheimer's Disease.

BACKGROUND: Differential diagnosis of people presenting with mild cognitive impairment (MCI) that will progress to Alzheimer's disease (AD) remains clinically challenging. Current criteria used to define AD include a series of neuropsychological assessments together with relevant imaging analysis such as magnetic resonance imaging (MRI). The clinical sensitivity and specificity of these assessments would be improved by the concomitant use of novel serum biomarkers. The branched chain aminotransferase proteins (BCAT) are potential candidates as they are significantly elevated in AD brain, correlate with Braak Stage, and may have a role in AD pathology. OBJECTIVE: In this hypothesis-driven project, we aimed to establish if serum BCAT and its metabolites are significantly altered in AD participants and assess their role as markers of disease pathology. METHODS: Serum amino acids were measured using a triple quadrupole mass spectrometer for tandem mass spectroscopy together with BCAT levels using western blot analysis, coupled with neuropsychological assessments and MRI. RESULTS: We present data supporting a substantive mutually correlated system between BCAT and glutamate, neuropsychological tests, and MRI for the diagnosis of AD. These three domains, individually, and in combination, show good utility in discriminating between groups. Our model indicates that BCAT and glutamate accurately distinguish between control and AD participants and in combination with the neuropsychological assessment, MoCA, improved the overall sensitivity to 1.00 and specificity to 0.978. CONCLUSION: These findings indicate that BCAT and glutamate have potential to improve the clinical utility and predictive power of existing methods of AD assessment and hold promise as early indicators of disease pathology.

Effects of dopamine on reinforcement learning and consolidation in Parkinson's disease.

Emerging evidence suggests that dopamine may modulate learning and memory with important implications for understanding the neurobiology of memory and future therapeutic targeting. An influential hypothesis posits that dopamine biases reinforcement learning. More recent data also suggest an influence during both consolidation and retrieval. Eighteen Parkinson's disease patients learned through feedback ON or OFF medication, with memory tested 24 hr later ON or OFF medication (4 conditions, within-subjects design with matched healthy control group). Patients OFF medication during learning decreased in memory accuracy over the following 24 hr. In contrast to previous studies, however, dopaminergic medication during learning and testing did not affect expression of positive or negative reinforcement. Two further experiments were run without the 24 hr delay, but they too failed to reproduce effects of dopaminergic medication on reinforcement learning. While supportive of a dopaminergic role in consolidation, this study failed to replicate previous findings on reinforcement learning.

The impact of ageing reveals distinct roles for human dentate gyrus and CA3 in pattern separation and object recognition memory.

Both recognition of familiar objects and pattern separation, a process that orthogonalises overlapping events, are critical for effective memory. Evidence is emerging that human pattern separation requires dentate gyrus. Dentate gyrus is intimately connected to CA3 where, in animals, an autoassociative network enables recall of complete memories to underpin object/event recognition. Despite huge motivation to treat age-related human memory disorders, interaction between human CA3 and dentate subfields is difficult to investigate due to small size and proximity. We tested the hypothesis that human dentate gyrus is critical for pattern separation, whereas, CA3 underpins identical object recognition. Using 3 T MR hippocampal subfield volumetry combined with a behavioural pattern separation task, we demonstrate that dentate gyrus volume predicts accuracy and response time during behavioural pattern separation whereas CA3 predicts performance in object recognition memory. Critically, human dentate gyrus volume decreases with age whereas CA3 volume is age-independent. Further, decreased dentate gyrus volume, and no other subfield volume, mediates adverse effects of aging on memory. Thus, we demonstrate distinct roles for CA3 and dentate gyrus in human memory and uncover the variegated effects of human ageing across hippocampal regions. Accurate pinpointing of focal memory-related deficits will allow future targeted treatment for memory loss.

Quantitative T2 mapping of white matter: applications for ageing and cognitive decline.

In MRI, the coherence lifetime T2 is sensitive to the magnetic environment imposed by tissue microstructure and biochemistry in vivo. Here we explore the possibility that the use of T2 relaxometry may provide information complementary to that provided by diffusion tensor imaging (DTI) in ageing of healthy controls (HC), Alzheimer's disease (AD) and mild cognitive impairment (MCI). T2 and diffusion MRI metrics were quantified in HC and patients with MCI and mild AD using multi-echo MRI and DTI. We used tract-based spatial statistics (TBSS) to evaluate quantitative MRI parameters in white matter (WM). A prolonged T2 in WM was associated with AD, and able to distinguish AD from MCI, and AD from HC. Shorter WM T2 was associated with better cognition and younger age in general. In no case was a reduction in T2 associated with poorer cognition. We also applied principal component analysis, showing that WM volume changes independently of T2, MRI diffusion indices and cognitive performance indices. Our data add to the evidence that age-related and AD-related decline in cognition is in part attributable to WM tissue state, and much less to WM quantity. These observations suggest that WM is involved in AD pathology, and that T2 relaxometry is a potential imaging modality for detecting and characterising WM in cognitive decline and dementia.