Laura S. Hemmy

Ecology of the Aging Human Brain

BACKGROUND Alzheimer disease, cerebral vascular brain injury, and isocortical Lewy body disease (LBD) are the major contributors to dementia in community- and population-based studies. OBJECTIVE To estimate the prevalence of clinically silent forms of these diseases in cognitively normal (CN) adults. DESIGN Autopsy study. SETTING Community- and population based. PARTICIPANTS A total of 1672 brain autopsies from the Adult Changes in Thought study, Honolulu-Asia Aging Study, Nun Study, and Oregon Brain Aging Study, of which 424 met the criteria for CN. MAIN OUTCOME MEASURES Of these, 336 cases had a comprehensive neuropathologic examination of neuritic plaque density, Braak stage for neurofibrillary tangles, LB distribution, and number of cerebral microinfarcts. RESULTS Forty-seven percent of CN cases had moderate or frequent neuritic plaque density; of these, 6% also had Braak stage V or VI for neurofibrillary tangles. Fifteen percent of CN cases had medullary LBD; 8% also had nigral and 4% isocortical LBD. The presence of any cerebral microinfarcts was identified in 33% and of high-level cerebral microinfarcts in 10% of CN individuals. Overall, the burden of lesions in each individual and their comorbidity varied widely within each study but were similar across studies. CONCLUSIONS These data show an individually varying complex convergence of subclinical diseases in the brain of older CN adults. Appreciating this ecology should help guide future biomarker and neuroimaging studies and clinical trials that focus on community- and population-based cohorts.

Synchronous neural interactions assessed by magnetoencephalography: a functional biomarker for brain disorders

We report on a test to assess the dynamic brain function at high temporal resolution using magnetoencephalography (MEG). The essence of the test is the measurement of the dynamic synchronous neural interactions, an essential aspect of the brain function. MEG signals were recorded from 248 axial gradiometers while 142 human subjects fixated a spot of light for 45-60 s. After fitting an autoregressive integrative moving average (ARIMA) model and taking the stationary residuals, all pairwise, zero-lag, partial cross-correlations (PCC(ij)(0)) and their z-transforms (z(ij)(0)) between i and j sensors were calculated, providing estimates of the strength and sign (positive, negative) of direct synchronous coupling at 1 ms temporal resolution. We found that subsets of z(ij)(0) successfully classified individual subjects to their respective groups (multiple sclerosis, Alzheimers disease, schizophrenia, Sjögrens syndrome, chronic alcoholism, facial pain, healthy controls) and gave excellent external cross-validation results.

Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies

Objective: To examine frequencies and relationships of 5 common neuropathologic abnormalities identified at autopsy with late-life cognitive impairment and dementia in 2 different autopsy panels. Methods: The Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS) are population-based investigations of brain aging that included repeated cognitive assessments and comprehensive brain autopsies. The neuropathologic abnormalities assessed were Alzheimer disease (AD) neuropathologic changes, neocortical Lewy bodies (LBs), hippocampal sclerosis, microinfarcts, and low brain weight. Associations with screening tests for cognitive impairment were examined. Results: Neuropathologic abnormalities occurred at levels ranging from 9.7% to 43%, and were independently associated with cognitive impairment in both studies. Neocortical LBs and AD changes were more frequent among the predominantly Caucasian NS women, while microinfarcts were more common in the Japanese American HAAS men. Comorbidity was usual and very strongly associated with cognitive impairment. Apparent cognitive resilience (no cognitive impairment despite Braak stage V) was strongly associated with minimal or no comorbid abnormalities, with fewer neocortical AD lesions, and weakly with longer interval between final testing and autopsy. Conclusions: Total burden of comorbid neuropathologic abnormalities, rather than any single lesion type, was the most relevant determinant of cognitive impairment in both cohorts, often despite clinical diagnosis of only AD. These findings emphasize challenges to dementia pathogenesis and intervention research and to accurate diagnoses during life.

Tractography reveals diffuse white matter abnormalities in Myotonic Dystrophy Type 1

Cerebral involvement in Myotonic Dystrophy Type 1 (DM1) is well-established but not well characterized. This study applied new Diffusion Tensor Imaging (DTI) tractography to characterize white matter disturbance in adults with DM1. Forty-five participants with DM1 and 44 control participants had MRIs on a Siemens 3T TIM Trio scanner. Data were processed with TRActs Constrained by UnderLying Anatomy (TRACULA) and 7 tracts were evaluated. Bilateral disturbances in white matter integrity were seen in all tracts in participants with DM1 compared to controls. There were no right-left hemisphere differences. The resulting DTI metrics were correlated with cognitive functioning, particularly working memory and processing speed. Motor speed was not significantly correlated with white matter microstructural integrity and, thus, was not the core explanation for the working memory and processing speed findings. White matter integrity was correlated with important clinical variables including the muscular impairment rating scale (MIRS). CTG repeat length was moderately associated with white matter status in corticospinal tract and cingulum. Sleepiness (Epworth Sleepiness Scale) was moderately associated with white matter status in the superior longitudinal fasciculus and cingulum. Overall, the results add to an emerging literature showing widespread white matter disturbances in both early-onset and adult-onset DM1. Results suggest that further investigation of white matter pathology is warranted in DM1 and that non-invasive measures such as DTI have a potentially important clinical value in characterizing the status of individuals with DM1.

Intermediate- and Long-Term Cognitive Outcomes After Cardiovascular Procedures in Older Adults: A Systematic Review

Approximately 200000 coronary artery bypass graft (CABG) surgeries, 50000 carotid revascularizations, 50000 cardiac valve replacements or repairs, and 10000 catheter ablations for atrial fibrillation are performed annually in U.S. adults aged 65 years or older (16). The older U.S. population also has a high rate of cognitive impairment and dementia, with a combined incidence of 77.5 cases per 1000 person-years in adults aged 72 years or older with normal cognition at baseline (7). However, great uncertainty surrounds the relationship between these cardiovascular interventions and subsequent cognitive outcomes in older patients. Most attention has addressed the possible relationship between CABG and cognitive impairment. Early studies reported a high prevalence of cognitive impairment after CABG, possibly attributable to surgical factors, such as anesthesia and cardiopulmonary bypass (8, 9). Later studies suggested that much cognitive impairment after CABG predated the procedure (10) and was related to patient factors, such as age, education, and vascular disease (8, 1114). Studies of carotid revascularization have reported mixed cognitive outcomes, with some suggesting early improvement (15). Studies of cardiac valve procedures and catheter ablation for atrial fibrillation commonly report imaging-detected cerebral emboli, but cognitive outcomes have been less clear (16, 17). However, understanding the longer-term cognitive outcomes attributable to these cardiovascular procedures in older adults has been limited because many studies had no control group, had short follow-up, had a predominance of middle-aged patients, or used surrogate outcomes for cognitive function. Meanwhile, older adults, who have the highest risk for intermediate- and long-term cognitive impairment, increasingly are having these procedures. Therefore, improved understanding of any relationship between these cardiovascular procedures and cognitive outcomes in older patients could enhance physicianpatient clinical decision making. This systematic review evaluates the evidence from randomized, controlled trials (RCTs) and prospective cohort studies on the association of coronary and carotid revascularization, cardiac valve replacement and repair, and ablation for atrial fibrillation on intermediate- and long-term cognitive outcomes in adults aged 65 years or older. We further sought to evaluate whether these associations were modified by procedural and patient characteristics and by procedure-related stroke or transient ischemic attack (TIA). Methods We followed a protocol developed with input from the Agency for Healthcare Research Quality (AHRQ) and the Coverage and Analysis Group at the Centers for Medicare & Medicaid Services (CMS) (Supplement). The full technical report, which incorporated AHRQ, CMS, peer, and public review, is available on the CMS Web site (www.cms.gov/Medicare/Coverage/DeterminationProcess/Downloads/id97ta.pdf). Supplement. Evidence-based Practice Center Systematic Review Protocol Data Sources We searched the MEDLINE, Cochrane Library, Scopus, and ClinicalTrials.gov databases using a combination of search terms for cognitive function, cardiovascular procedures of interest, and study design (Supplement). We also reviewed reference lists of eligible studies, relevant review articles, and articles suggested by experts. We included only studies published from 1990 to January 2015 to reasonably reflect current clinical practice. Study Selection We included English-language RCTs, controlled clinical trials, and prospective cohort studies. Eligible studies predominately consisted of adults aged 65 years or older. They also reported clinically diagnosed cognitive impairment (such as dementia or mild cognitive impairment) or results of neuropsychological tests (such as Trail Making Test B) or global cognitive screening tests (such as the Mini-Mental State Examination) at least 3 months after coronary or carotid artery revascularization, cardiac valve replacement or repair, or ablation for atrial fibrillation. Clinically diagnosed cognitive impairment must have been based on an assessment of symptoms, function, and formal neuropsychological testing. Treatment group cognitive outcomes must have been compared with those in a control group. The Supplement shows the detailed eligibility criteria. Two reviewers independently examined titles, abstracts, and full articles for eligibility and resolved discrepancies by discussion and consensus. Data Extraction and Quality Assessment For each article, 1 reviewer extracted details on study design, patient characteristics, cardiovascular procedure characteristics, and cognitive outcomes, and a second reviewer checked accuracy. Using Cochrane Collaboration (for trials) and AHRQ (for prospective cohort studies) criteria (18, 19), 2 reviewers rated individual-study risk of bias as low, moderate, high, or unknown (Appendix Tables 1 and 2). For trials, ratings were based on adequacy of randomization and allocation concealment, masking, accounting for attrition bias, use of intention-to-treat analyses, and selectiveness of outcome reporting. For prospective cohort studies, ratings were based on similarity of prognostic factors between comparison groups, accounting for attrition bias, masking, and selectiveness of outcome reporting. Following AHRQ Effective Health Care Program methods (20), 2 reviewers graded the strength of evidence (SOE) for the association of each treatment comparison with subsequent cognitive outcomes as high, moderate, low, or insufficient based on risk of bias, consistency, precision, and directness (Appendix Table 3). We resolved discrepancies in risk-of-bias ratings and SOE grades by discussion and consensus. Appendix Table 1. Risk of Bias in RCTs Appendix Table 2. Risk of Bias in Prospective Cohort Studies Appendix Table 3. Strength of Evidence Appendix Table 3.Continued Data Synthesis and Analysis We used Review Manager, version 5.2 (Cochrane Collaboration), to estimate relative risks and 95% CIs for the incidence of dichotomous outcomes and standardized mean differences and 95% CIs for continuous outcomes. We did not pool results between studies because no 2 studies had clinically similar patient populations, cardiovascular procedure and control groups, and definitions of cognitive outcomes. Role of the Funding Source This review was nominated to AHRQ by the CMS and was funded by AHRQ. Staff at AHRQ and CMS helped to develop and refine the scope of the study and reviewed the draft AHRQ report. Results Twenty-five reports of 21 unique studies (17 RCTs and 4 prospective cohort studies) met eligibility criteria (Figure) (2145). Sixteen of these reports studied CABG; 2 studied cardiac valve replacement, including 1 study of CABG combined with cardiac valve replacement; and 3 studied carotid revascularization. Figure. Summary of evidence search and selection. * Some references were identified in several databases. Sixty-five additional references were identified by hand searching; 61 of them were excluded at the title and abstract review stage, and 4 were excluded after full-text review. Ninety studies were identified from ClinicalTrials.gov. Among studies not already included in the review, 2 seemed possibly eligible: 1 (NCT02108093) that was still enrolling patients and the other (NCT01743456) that is listed as completed but for which no results appear reported. Included 21 unique studies. We rated risk of bias as high in 3 studies, moderate in 11, and unclear in 7. Eighty percent of study patients were men, and mean age was 68 years (mean age was between 65 and 69 years in all but 4 studies). In the 6 studies that reported education, patients completed a mean of 11 years (range, 7 to 14). Few patients had a history of stroke (study range, 0% to 8%; 10 studies) except in the 3 carotid revascularization studies (range, 50% to 100%). All studies reported baseline results for individual neuropsychological tests (such as attention, memory, and executive functioning). Five studies excluded patients with baseline dementia (39, 40), abnormal baseline cognitive screening (25, 26, 30, 39, 40), or a learning disorder (36, 40). Among included patients, mean baseline scores in individual studies were similar to estimated age-based norms for IQ and global cognitive screening tests, but more than half of studies reported mean baseline scores in the impaired range for at least 1 neuropsychological test, most frequently with impairment in timed tests. All studies reported follow-up results for individual neuropsychological tests. Twelve studies reported incident cognitive impairment as defined by a composite of neuropsychological test results (definitions differed in every study [Appendix Table 4]), but none reported incidence of mild cognitive impairment or dementia. Only 2 studies reported cognitive outcomes more than 1 year after the procedure. Appendix Table 4. Individual Study Definitions of Incident Cognitive Impairment Based on Combining Results of Individual Neuropsychological Tests Coronary Artery Revascularization CABG Versus Medical Management One prospective cohort study (n=326) compared on- or off-pump CABG versus medical management in older adults with catheter-proven coronary artery disease (Table 1) (2729). It found that both the CABG and medical groups had small to moderate improvements in memory versus baseline at 1 year and no changes versus baseline at 6 years for all neuropsychological tests measured. Further, there were no between-group differences at any follow-up or in change from baseline to any follow-up. Risk of bias for this study was high due to important baseline differences between treatment groups and substantial loss to follow-up. The higher dropout rates in the CABG group could have biased the results if they were related to cognitive decline. We rated SOE as insufficient because of these limitations and the absence of corroborating studies. Table 1. Cor

A Computational Linguistic Measure of Clustering Behavior on Semantic Verbal Fluency Task Predicts Risk of Future Dementia in the Nun Study

Generative semantic verbal fluency (SVF) tests show early and disproportionate decline relative to other abilities in individuals developing Alzheimers disease. Optimal performance on SVF tests depends on the efficiency of using clustered organization of semantically related items and the ability to switch between clusters. Traditional approaches to clustering and switching have relied on manual determination of clusters. We evaluated a novel automated computational linguistic approach for quantifying clustering behavior. Our approach is based on Latent Semantic Analysis (LSA) for computing strength of semantic relatedness between pairs of words produced in response to SVF test. The mean size of semantic clusters (MCS) and semantic chains (MChS) are calculated based on pairwise relatedness values between words. We evaluated the predictive validity of these measures on a set of 239 participants in the Nun Study, a longitudinal study of aging. All were cognitively intact at baseline assessment, measured with the Consortium to Establish a Registry for Alzheimers Disease (CERAD) battery, and were followed in 18-month waves for up to 20 years. The onset of either dementia or memory impairment were used as outcomes in Cox proportional hazards models adjusted for age and education and censored at follow-up waves 5 (6.3 years) and 13 (16.96 years). Higher MCS was associated with 38% reduction in dementia risk at wave 5 and 26% reduction at wave 13, but not with the onset of memory impairment. Higher [+1 standard deviation (SD)] MChS was associated with 39% dementia risk reduction at wave 5 but not wave 13, and association with memory impairment was not significant. Higher traditional SVF scores were associated with 22-29% memory impairment and 35-40% dementia risk reduction. SVF scores were not correlated with either MCS or MChS. Our study suggests that an automated approach to measuring clustering behavior can be used to estimate dementia risk in cognitively normal individuals.

Automated semantic indices related to cognitive function and rate of cognitive decline

The objective of our study is to introduce a fully automated, computational linguistic technique to quantify semantic relations between words generated on a standard semantic verbal fluency test and to determine its cognitive and clinical correlates. Cognitive differences between patients with Alzheimers disease and mild cognitive impairment are evident in their performance on the semantic verbal fluency test. In addition to the semantic verbal fluency test score, several other performance characteristics sensitive to disease status and predictive of future cognitive decline have been defined in terms of words generated from semantically related categories (clustering) and shifting between categories (switching). However, the traditional assessment of clustering and switching has been performed manually in a qualitative fashion resulting in subjective scoring with limited reproducibility and scalability. Our approach uses word definitions and hierarchical relations between the words in WordNet(®), a large electronic lexical database, to quantify the degree of semantic similarity and relatedness between words. We investigated the novel semantic fluency indices of mean cumulative similarity and relatedness between all pairs of words regardless of their order, and mean sequential similarity and relatedness between pairs of adjacent words in a sample of patients with clinically diagnosed probable (n=55) or possible (n=27) Alzheimers disease or mild cognitive impairment (n=31). The semantic fluency indices differed significantly between the diagnostic groups, and were strongly associated with neuropsychological tests of executive function, as well as the rate of global cognitive decline. Our results suggest that word meanings and relations between words shared across individuals and computationally modeled via WordNet and large text corpora provide the necessary context to account for the variability in language-based behavior and relate it to cognitive dysfunction observed in mild cognitive impairment and Alzheimers disease.

Physical Activity Interventions in Preventing Cognitive Decline and Alzheimer-Type Dementia: A Systematic Review

Forty-seven million people worldwide live with dementia (1), and this number is expected to triple by 2050 (2). Despite evidence that the overall incidence of dementia has declined in the United States (3, 4), the number of U.S. adults older than 70 years with dementia or mild cognitive impairment (MCI) increases as our population ages (5, 6). Dementia severely erodes functioning and quality of life, creates burden and stress on families, and leads to institutionalization. Dementia-related costs exceed those of heart disease and cancer and often are paid directly by families (7). Therefore, preventing dementia is an urgent public health priority. Many believe that an active lifestyle may prevent cognitive decline and dementia. Findings of several reviews, primarily those looking at cohort studies, suggest that physical activity may reduce or delay the development of potential modifiable risk factors for cognitive decline, such as obesity, diabetes, and hypertension (813). However, the relationships among physical activity, other risk factors, and cognitive decline are complex and interrelated. Findings of associations from cohort studies alone cannot clarify whether physical activity affects cognitive decline directly, indirectly through the reduction of medical risk factors, or both. Previous systematic reviews of randomized controlled trials report some cognitive benefits of physical activity interventions, although the certainty and clinical importance of these findings have not always been clear (14, 15). This systematic review reports a synthesis of the evidence assessing the effectiveness of physical activity interventions in slowing cognitive decline and delaying the onset of cognitive impairment and dementia in adults without diagnosed cognitive impairments. Methods We developed and followed a standard protocol (16). Our full technical report (17) contains details on methods and findings, an analysis of studies addressing secondary prevention in adults with MCI, and an evaluation of comparative effectiveness. Data Sources and Searches We searched bibliographic databases, including MEDLINE, EMBASE, and PsycINFO via Ovid, as well as the Cochrane Library, to identify controlled trials published in any language from January 2009 through July 2017. (See Part A of the Supplement, for search strategies.) We identified studies published before 2009 by citation searching relevant systematic reviews. Supplement. Data Supplement Study Selection Two investigators independently reviewed titles and abstracts of search results and screened the full text of potentially eligible references. Disagreements about eligibility were resolved by consensus. We included randomized controlled trials of physical activity interventions with any sample size and large (n > 500) prospective quasi-experimental cohort studies with comparator groups if they enrolled adults without diagnosed cognitive impairments, had follow-up of at least 6 months, were published in English, and reported 1 of our preselected primary or intermediate outcomes. We excluded trials enrolling pure subgroups of patients with major medical conditions or conditions that may explain changes in cognitive function (namely stroke, Parkinson disease, cancer, and traumatic brain injury). Our main outcomes of interest were MCI or dementia. Intermediate outcomes included measures of cognitive function assessed by instruments that tested cognition across several domains or those that specifically tested executive function, attention, and processing speed, or memory. Intermediate outcomes were categorized as follows: broad measures intended to capture several cognitive domains that were either brief cognitive tests (category 1) or more comprehensive multidomain neuropsychological tests (category 2) and domain-specific neuropsychological tests or subscales of broader instruments that assessed executive function, attention, and processing speed (category 3) or memory (category 4). Part B of the Supplement shows a list of the intermediate outcomes reported from the studies and our categorization of those outcomes. Data Extraction and Quality Assessment One reviewer extracted the study population, treatment characteristics, and funding source from all eligible studies. Risk of bias was assessed independently by 2 investigators using an instrument developed with guidance from the Agency for Healthcare Research and Quality (AHRQ) (18). Risk of bias for each reported outcome was rated as low, medium, or high on the basis of adequacy of randomization and allocation concealment, masking, attrition, use of intention-to-treat analyses, selectiveness of outcome reporting, and confidence that results were believable given limitations. Outcomes and adverse effects were extracted from eligible trials with low or moderate risk of bias, and a second investigator checked the extraction. Data Synthesis and Analysis We grouped studies by type of physical activity intervention and analyzed results by direction of effect and statistical significance. We found it impossible to assess the clinical significance of findings of the intermediate outcomes across all studies, because many different instruments were used and we did not always find information on the degree of change in specific instrument scores or subscores that would indicate clinical importance. (Part B of the Supplement shows the information we did find about clinically important changes in specific instrument scores.) In addition, results were measured, analyzed, and reported in many different ways. When sufficient data were available (from more than 1 study or 1 study with 500 participants), 1 investigator assessed the strength of evidence for unique comparisons. These assessments were confirmed through consensus. We assessed strength of evidence by using 5 required domains: study limitations (risk of bias of eligible studies for a given comparison), directness (single, direct link between intervention and outcome), consistency (similarity of effect direction and size), precision (degree of certainty around an estimate that includes attention to small sample sizes with power to detect only large differences), and reporting bias (19). On the basis of these factors, the overall strength of evidence for each outcome from a given intervention was rated as high, moderate, low, or insufficient. Role of the Funding Source This review was funded by the National Institute on Aging and AHRQ. These agencies and members of the National Academies Committee on Preventing Dementia and Cognitive Impairment helped refine the scope and reviewed a draft report of findings. The authors are solely responsible for the content preparation, writing of the manuscript, and decision to submit the manuscript for publication. Results Of 32 eligible studies that compared interventions using physical activity components with an inactive control in adults without a cognitive impairment diagnosis (2051), 16all of which were randomized trialswere considered to have low to medium risk of bias (20, 23, 25, 29, 30, 33, 3537, 39, 40, 43, 45, 46, 48, 50). Inactive controls in the trials with low to medium risk of bias included waitlist, usual care, no-intervention, and attention (that is, education and information) groups. Most trials were government funded. Most studies enrolled older adults; some limited enrollment to men or women. Total sample sizes ranged from 42 to 1635 participants. Trials rarely reported adverse effects; those that did showed no differences between groups, with 1 exception. Intervention components, frequency, and duration varied. (Part C of the Supplement contains the literature flow diagram; part D contains evidence tables.) The Table shows overall conclusions and strength-of-evidence ratings. Details of studies considered to have low to medium risk of bias are described later. For any cognitive outcome, evidence was insufficient to draw conclusions about most interventions (aerobic training, resistance training, tai chi, physical activity with diet, and physical activity with a cognitive component). Low-strength evidence showed that multicomponent physical activity interventions of 1 to 2 years did not improve multidomain neurologic performance; executive function, attention, and processing speed; or memory compared with an attention control. Low-strength evidence showed that an intervention combining physical activity, diet, and cognitive training benefited multidomain neuropsychological test performance and executive function, attention, and processing speed compared with an attention control; however, evidence was insufficient to draw conclusions about the efficacy of this intervention on memory. Moderate-strength evidence showed that more participants in the intervention than the control groups had musculoskeletal pain. Table. Conclusions: Physical Activity Versus Inactive Comparisons in Adults Physical Activity Interventions Multicomponent Physical Activity Four trials (n= 1885) with low to medium risk of bias examined multicomponent physical activity interventions. Components included flexibility, strength, balance, endurance, and aerobic training (36, 45, 46, 50). Enrollment criteria varied by trial. Sink and colleagues (45) and Williamson and colleagues (50) enrolled sedentary adults older than 70 years, most of whom were white women. Mean Modified Mini-Mental State Examination (MMSE) scores were higher than 90 points (on a scale of 0 to 100 points). Taylor-Piliae and colleagues (46) enrolled adults, mostly white college-educated women, older than 60 years. Napoli and colleagues (36) enrolled frail, obese older adults, most of whom were white women; mean Modified MMSE score was 96 points. Interventions during the trials lasted from 6 months to 2 years. Sink and colleagues (45) (n= 1635) reported diagnostic outcomes that showed no difference in the incidence of MCI (odds ratio, 1.14 [95% CI, 0.79 to 1.62]) or dementia (odds ratio, 0.9

Evaluation and tracking of Alzheimer's disease severity using resting-state magnetoencephalography.

We have conducted multicenter clinical studies in which brain function was evaluated with brief, resting-state magnetoencephalography (MEG) scans. A study cohort of 117 AD patients and 123 elderly cognitively normal volunteers was recruited from community neurology clinics in Denver, Colorado and Minneapolis, Minnesota. Each subject was evaluated through neurological examination, medical history, and a modest battery of standard neuropsychological tests. Brain function was measured by a one-minute, resting-state, eyes-open MEG scan. Cross-sectional analysis of MEG scans revealed global changes in the distribution of relative spectral power (centroid frequency of healthy subjects = 8.24 ± 0.2 Hz and AD patients = 6.78 ± 0.25 Hz) indicative of generalized slowing of brain signaling. Functional connectivity patterns were measured using the synchronous neural interactions (SNI) test, which showed a global increase in the strength of functional connectivity (cO2 value of healthy subjects = 0.059 ± 0.0007 versus AD patients = 0.066 ± 0.001) associated with AD. The largest magnitude disease-associated changes were localized to sensors near posterior and lateral cortical regions. Part of the cohort (31 AD and 46 cognitively normal) was evaluated in an identical fashion approximately 10 months after the first assessments. Follow-up scans revealed multiple MEG scan features that correlated significantly with changes in neuropsychological test scores. Linear combinations of these MEG scan features generated an accurate multivariate model of disease progression over 10 months. Our results demonstrate the utility of brief resting-state tests based on MEG. The non-invasive, rapid and convenient nature of these scans offers a new tool for translational AD research and early phase development of novel treatments for AD.

Diffusion MRI and its Role in Neuropsychology

Diffusion Magnetic Resonance Imaging (dMRI) is a popular method used by neuroscientists to uncover unique information about the structural connections within the brain. dMRI is a non-invasive imaging methodology in which image contrast is based on the diffusion of water molecules in tissue. While applicable to many tissues in the body, this review focuses exclusively on the use of dMRI to examine white matter in the brain. In this review, we begin with a definition of diffusion and how diffusion is measured with MRI. Next we introduce the diffusion tensor model, the predominant model used in dMRI. We then describe acquisition issues related to acquisition parameters and scanner hardware and software. Sources of artifacts are then discussed, followed by a brief review of analysis approaches. We provide an overview of the limitations of the traditional diffusion tensor model, and highlight several more sophisticated non-tensor models that better describe the complex architecture of the brain’s white matter. We then touch on reliability and validity issues of diffusion measurements. Finally, we describe examples of ways in which dMRI has been applied to studies of brain disorders and how identified alterations relate to symptomatology and cognition.