Relaxation-Compensated Chemical Exchange Saturation Transfer MRI in the Brain at 7T: Application in Relapsing-Remitting Multiple Sclerosis.

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) can probe tissue biochemistry in vivo with high resolution and sensitivity without requiring exogenous contrast agents. Applying CEST MRI at ultrahigh field provides advantages of increasing spectral resolution and improving sensitivity to metabolites with faster proton exchange rates such as glutamate, a critical neurotransmitter in the brain. Prior magnetic resonance spectroscopy and CEST MRI studies have revealed altered regulation of glutamate in patients with multiple sclerosis (MS). While CEST imaging facilitates new strategies for investigating the pathology underlying this complex and heterogeneous neurological disease, CEST signals are contaminated or diluted by concurrent effects (e.g., semi-solid magnetization transfer (MT) and direct water saturation) and are scaled by the T1 relaxation time of the free water pool which may also be altered in the context of disease. In this study of 20 relapsing-remitting MS patients and age- and sex-matched healthy volunteers, glutamate-weighted CEST data were acquired at 7.0 T. A Lorentzian fitting procedure was used to remove the asymmetric MT contribution from CEST z-spectra, and the apparent exchange-dependent relaxation (AREX) correction was applied using an R1 map derived from an inversion recovery sequence to further isolate glutamate-weighted CEST signals from concurrent effects. Associations between AREX and cognitive function were examined using the Minimal Assessment of Cognitive Function in MS battery. After isolating CEST effects from MT, direct water saturation, and T1 effects, glutamate-weighted AREX contrast remained higher in gray matter than in white matter, though the difference between these tissues decreased. Glutamate-weighted AREX in normal-appearing gray and white matter in MS patients did not differ from healthy gray and white matter but was significantly elevated in white matter lesions. AREX in some cortical regions and in white matter lesions correlated with disability and measures of cognitive function in MS patients. However, further studies with larger sample sizes are needed to confirm these relationships due to potential confounding effects. The application of MT and AREX corrections in this study demonstrates the importance of isolating CEST signals for more specific characterization of the contribution of metabolic changes to tissue pathology and symptoms in MS.

Data quality assurance and control in cognitive research: Lessons learned from the PREDICT-HD study.

We discuss the strategies employed in data quality control and quality assurance for the cognitive core of Neurobiological Predictors of Huntington's Disease (PREDICT-HD), a long-term observational study of over 1,000 participants with prodromal Huntington disease. In particular, we provide details regarding the training and continual evaluation of cognitive examiners, methods for error corrections, and strategies to minimize errors in the data. We present five important lessons learned to help other researchers avoid certain assumptions that could potentially lead to inaccuracies in their cognitive data.

Distinguishing Alzheimer's disease and dementia with Lewy bodies using cognitive and olfactory measures.

OBJECTIVE: Given poor sensitivity of the diagnostic criteria in identifying dementia with Lewy bodies (DLB), the use of cognitive and olfactory measures to distinguish Alzheimer's disease (AD) from DLB was assessed. METHOD: Twenty-six patients with DLB and 60 patients with AD were administered several cognitive measures and the Brief Smell Identification Task (BSIT). RESULT: Patients with DLB performed significantly worse on the BSIT and visuoconstruction tasks than patients with AD, but significantly better on delayed recall of a word list. Sensitivity and specificity of these measures in identifying DLB are presented for each of these tasks alone and in combination. The best balance of sensitivity and specificity was found with a combination of the Hopkins Verbal Learning Test and BSIT (81% sensitivity, 90% specificity). CONCLUSIONS: These data have practical implications by providing cut scores than can be used to emphasize either specificity or sensitivity in identifying patients with DLB.

Intra-individual Variability in Prodromal Huntington Disease and Its Relationship to Genetic Burden.

The current study sought to examine the utility of intra-individual variability (IIV) in distinguishing participants with prodromal Huntington disease (HD) from nongene-expanded controls. IIV across 15 neuropsychological tasks and within-task IIV using a self-paced timing task were compared as a single measure of processing speed (Symbol Digit Modalities Test [SDMT]) in 693 gene-expanded and 191 nongene-expanded participants from the PREDICT-HD study. After adjusting for depressive symptoms and motor functioning, individuals estimated to be closest to HD diagnosis displayed higher levels of across- and within-task variability when compared to controls and those prodromal HD participants far from disease onset (F ICV(3,877)=11.25; p<.0001; F PacedTiming(3,877)=22.89; p<.0001). When prodromal HD participants closest to HD diagnosis were compared to controls, Cohen's d effect sizes were larger in magnitude for the within-task variability measure, paced timing (-1.01), and the SDMT (-0.79) and paced tapping coefficient of variation (CV) (-0.79) compared to the measures of across-task variability [CV (0.55); intra-individual standard deviation (0.26)]. Across-task variability may be a sensitive marker of cognitive decline in individuals with prodromal HD approaching disease onset. However, individual neuropsychological tasks, including a measure of within-task variability, produced larger effect sizes than an index of across-task IIV in this sample.

Dementia in multiple sclerosis: why is it rarely discussed?

Cognitive deficits in multiple sclerosis (MS) have been well studied in decades of MS research. Severe deficits are acknowledged, but the frequency is minimized in the literature, and there is a striking lack of discussion of the presence of a dementia state in MS. Possible reasons for this omission are discussed, along with an argument to define the dementia state and to provide terminology that will be palatable to patients.

Prediction of manifest Huntington's disease with clinical and imaging measures: a prospective observational study.

BACKGROUND: Although the association between cytosine-adenine-guanine (CAG) repeat length and age at onset of Huntington's disease is well known, improved prediction of onset would be advantageous for clinical trial design and prognostic counselling. We compared various measures for tracking progression and predicting conversion to manifest Huntington's disease. METHODS: In this prospective observational study, we assessed the ability of 40 measures in five domains (motor, cognitive, psychiatric, functional, and imaging) to predict time to motor diagnosis of Huntington's disease, accounting for CAG repeat length, age, and the interaction of CAG repeat length and age. Eligible participants were individuals from the PREDICT-HD study (from 33 centres in six countries [USA, Canada, Germany, Australia, Spain, UK]) with the gene mutation for Huntington's disease but without a motor diagnosis (a rating below 4 on the diagnostic confidence level from the 15-item motor assessment of the Unified Huntington's Disease Rating Scale). Participants were followed up between September, 2002, and July, 2014. We used joint modelling of longitudinal and survival data to examine the extent to which baseline and change of measures analysed separately was predictive of CAG-adjusted age at motor diagnosis. FINDINGS: 1078 individuals with a CAG expansion were included in this analysis. Participants were followed up for a mean of 5·1 years (SD 3·3, range 0·0-12·0). 225 (21%) of these participants received a motor diagnosis of Huntington's disease during the study. 37 of 40 cross-sectional and longitudinal clinical and imaging measures were significant predictors of motor diagnosis beyond CAG repeat length and age. The strongest predictors were in the motor, imaging, and cognitive domains: an increase of one SD in total motor score (motor domain) increased the risk of a motor diagnosis by 3·07 times (95% CI 2·26-4·16), a reduction of one SD in putamen volume (imaging domain) increased risk by 3·32 times (2·37-4·65), and a reduction of one SD in Stroop word score (cognitive domain) increased risk by 2·32 times (1·88-2·87). INTERPRETATION: Prediction of diagnosis of Huntington's disease can be improved beyond that obtained by CAG repeat length and age alone. Such knowledge about potential predictors of manifest Huntington's disease should inform discussions about guidelines for diagnosis, prognosis, and counselling, and might be useful in guiding the selection of participants and outcome measures for clinical trials. FUNDING: US National Institutes of Health, US National Institute of Neurological Disorders and Stroke, and CHDI Foundation.

Normative performance on the Brief Smell Identification Test (BSIT) in a multi-ethnic bilingual cohort: a Project FRONTIER study.

The Brief Smell Identification Test (BSIT) is a commonly used measure of olfactory functioning in elderly populations. Few studies have provided normative data for this measure, and minimal data are available regarding the impact of sociodemographic factors on test scores. This study presents normative data for the BSIT in a sample of English- and Spanish-speaking Hispanic and non-Hispanic Whites. A Rasch analysis was also conducted to identify the items that best discriminated between varying levels of olfactory functioning, as measured by the BSIT. The total sample included 302 older adults seen as part of an ongoing study of rural cognitive aging, Project FRONTIER. Hierarchical regression analyses revealed that BSIT scores require adjustment by age and gender, but years of education, ethnicity, and language did not significantly influence BSIT performance. Four items best discriminated between varying levels of smell identification, accounting for 59.44% of total information provided by the measure. However, items did not represent a continuum of difficulty on the BSIT. The results of this study indicate that the BSIT appears to be well-suited for assessing odor identification deficits in older adults of diverse backgrounds, but that fine-tuning of this instrument may be recommended in light of its items' difficulty and discrimination parameters. Clinical and empirical implications are discussed.

Comparison of verbal memory impairment rates in mild cognitive impairment.

There are no accepted guidelines establishing the most sensitive neuropsychological methods to define memory impairment in mild cognitive impairment (MCI). We investigated whether similar impairment rates were observed between the Hopkins Verbal Learning Test-Revised (HVLT-R) and Logical Memory (LM) in 90 patients with amnestic or amnestic plus MCI. On HVLT-R delayed recall, 80% of participants performed in the MCI range compared to only 32.2% on LM II. The same pattern was seen for both amnestic and amnestic plus subtypes. Individuals impaired on HVLT-R delayed recall performed significantly worse on LM first recall and on delayed recall of LM Story A than those not impaired. MCI patients with executive dysfunction performed significantly worse than patients with no executive impairment on both LM I and HVLT-R Total Learning, but not for delayed recall of either measure. Future studies can address the longitudinal course of impairment on these measures.

On becoming a peer reviewer for a neuropsychology journal.

The peer-review process is an invaluable service provided by the professional community, and it provides the critical foundation for the advancement of science. However, there is remarkably little systematic guidance for individuals who wish to become part of this process. This paper, written from the perspective of reviewers and editors with varying levels of experience, provides general guidelines and advice for new reviewers in neuropsychology, as well as outlining benefits of participation in this process. It is hoped that the current information will encourage individuals at all levels to become involved in peer-reviewing for neuropsychology journals.

Common blood laboratory values are associated with cognition among older inpatients referred for neuropsychological testing.

The purpose of this study was to examine the relationship between common laboratory values and cognitive functioning among 129 inpatients referred for neuropsychological evaluation. Laboratory values were recorded at admission, at the time point closest to neuropsychological evaluation, and at the time of peak metabolic derangement. Cognitive status was evaluated with the modified Mini-Mental State Exam. Patients with hyperglycemia, hypochloremia, and/or elevated creatinine at admission exhibited cognitive deficits. Patients with hyperglycemia, hyperchloremia, hypernatremia, hyperkalemia, leukocytosis, low hemoglobin, elevated blood urea nitrogen, and/or elevated creatinine at the time of peak metabolic derangement exhibited cognitive deficits. Different lab abnormalities at the time of peak metabolic derangement accounted for unique patterns of neuropsychological impairment. Lab values drawn at the time point closest to neuropsychological evaluation were not significantly associated with cognitive functioning. Results support and quantify common clinical beliefs that metabolic abnormalities are associated with global cognitive changes among elderly inpatients.

Odor identification in mild cognitive impairment subtypes.

The current study examined odor identification using the Brief Smell Identification Test (BSIT) in mild cognitive impairment (MCI) subtypes (17 "amnestic MCI", 46 "amnestic-plus MCI", and 25 "MCI other"). Performance in participants with MCI was compared to that of participants with Alzheimer's disease (AD, n=44) and healthy elderly (n=21). MCI participants performed worse than controls, but better than those with AD. MCI subtypes did not differ. The magnitude of difference between MCI participants and controls was modest, raising some question of the clinical utility of the BSIT in early detection of MCI and early differential diagnosis.

Neuropsychological correlates of self-reported depression and self-reported cognition among patients with mild cognitive impairment.

Patients with mild cognitive impairment (MCI) frequently experience significant depressive symptomatology and report cognitive disturbances. To date, no studies have examined the relationship between MCI patients' neuropsychologic functioning, self-reported depressive symptoms, and self-reported cognitive difficulties. In this study, 82 MCI patients completed a comprehensive neuropsychological evaluation that included the Beck Depression Inventory (BDI). A subset of 41 patients and informants also completed a measure of cognitive difficulties. Poorer memory functioning was associated with fewer self-reported depressive symptoms and fewer cognitive complaints.

Odor identification deficits in frontotemporal dementia: a preliminary study.

Multiple neurodegenerative disorders (e.g. Alzheimer's disease, Dementia with Lewy bodies, Parkinson's disease, and Huntington's disease) show olfactory deficits. Olfactory functioning has not been well studied in frontotemporal dementia (FTD). In the current study, individuals with FTD, Alzheimer's disease (AD), and healthy elderly controls were compared using an odor identification task. Results showed significant differences in odor identification between individuals with FTD and the healthy elderly control group. There were no differences between the FTD and AD groups. Using a cut score of 8/12, discriminant function analysis showed that the overall classification rate for the FTD and control groups was 71.4%, with a sensitivity rate of 87.5% and a specificity rate of 65%. This preliminary research demonstrates olfactory deficits in FTD, which appear to be similar in magnitude to the olfactory deficits seen in AD.

Boston naming performance distinguishes between Lewy body and Alzheimer's dementias.

Although naming impairment is common among persons with dementia, little is known about how specific error types on naming tasks may differ between dementias. Recent research has suggested that persons with dementia with Lewy bodies (DLB) have more visuospatial/visuoperceptual dysfunction than those with Alzheimer's disease (AD), which may impact their ability to correctly perceive and name objects. Our retrospective study evaluated the presence and frequency of error types among patients with DLB and AD on the Boston Naming Test (BNT). Errors on the BNT were classified into five types (i.e., visuoperceptual, semantic, phonemic, no response, and other), and performance was compared among 31 probable DLB patients and 31 probable AD patients matched for age, gender, education, and overall dementia severity. AD patients' overall performance on the BNT was significantly worse than DLB patients (p<.05). In terms of error types, DLB patients made significantly more visuoperceptual errors (p<.05) while AD patients made significantly more semantic errors (p<.001). Logistic regression revealed that the number of visuoperceptual and semantic errors significantly predicted group membership (p<.005), with an accuracy of up to 85%. Results suggest that error analysis of BNT responses may be useful in distinguishing between patients with DLB and AD.

Patient and family perceptions of the neuropsychological evaluation: how are we doing?

To assess perceptions of the neuropsychological evaluation, 349 patients and 218 significant others presenting to an academic medical center neuropsychology service were surveyed over a two year period. Thirty-seven percent of the patient surveys (n = 129) and 37% of the significant other surveys (n = 80) were returned. Overall, both patients and significant others reported being satisfied with the interview, testing, and feedback sessions. Responders were generally receptive to the recommendations made, but were more inclined to have followed recommendations regarding patient safety (63.6%) than coping or support (31.8%). Some barriers to compliance with recommendations were identified.

Presentation of Alzheimer's disease in patients with and without olfactory deficits.

Odor identification deficits are frequently reported in Alzheimer's disease (AD) but are not universal. This study examines differences in clinical presentation in AD patients with and without odor identification impairments. Ninety patients with probable AD were administered an odor identification test as part of a neuropsychological evaluation. Variables examined included demographic information, cognitive and behavioral measures, dementia severity, neuroimaging findings, and aspects of clinical history. Defining the groups with a median split, olfactory impaired and olfactory intact patients were mostly similar, though patients with impaired odor identification performance were more likely to be male, less likely to have a family history of dementia, and had worse visuospatial functioning. The differences noted raise the possibility of a clinical subtype of the disease.

Assessing olfaction in the neuropsychological exam: the relationship between odor identification and cognition in older adults.

The relationship between odor identification and cognition has not been previously well characterized. The neuroanatomy of the olfactory system and the frequent finding of olfactory dysfunction in neurodegenerative diseases suggest a likely relationship between odor identification and memory, language, and executive functioning, though previous studies have often failed to demonstrate the expected relationship. The current study examined this relationship in across a continuum of ability levels (N=100). Strongest correlations were found between odor identification and language, most aspects of memory, and a measure of general cognitive functioning. Significant but more modest correlations were seen between odor identification and attention, motor, visuospatial, and executive functions. A regression analysis revealed language as the only significant predictor of olfactory performance. These findings suggest that odor identification is most closely associated with other measures of temporo-limbic functioning. The implications of these findings, particularly in consideration of the assessment of older adults, are discussed.

Odor identification deficits in diffuse lewy body disease.

OBJECTIVES: To describe odor identification performance in patients with diffuse Lewy body disease and determine the clinical utility of odor identification tests in distinguishing diffuse Lewy body disease from Alzheimer disease. BACKGROUND: The presence of olfactory deficits, especially odor identification deficits, has been well established in both Alzheimer disease and Parkinson disease. The presence of olfactory deficits in diffuse Lewy body disease is also likely given the overlap of clinical symptoms and neuropathology with Alzheimer disease and Parkinson disease. However, odor identification abilities have not been described previously in diffuse Lewy body disease. METHODS: Nine patients from a clinic sample with diffuse Lewy body disease and nine carefully matched patients with Alzheimer disease were administered an odor identification task as part of their neuropsychologic evaluations. RESULTS: Patients with diffuse Lewy body disease performed significantly worse than patients with Alzheimer disease on the odor identification test. CONCLUSIONS: Odor identification deficits may be more prevalent and severe in people with diffuse Lewy body disease than in people with Alzheimer disease, and olfactory testing may be useful in antemortem differential diagnosis of the two disorders.

Utility of the neuropsychological evaluation in an acute medical hospital.

Although recent studies have demonstrated the importance of cognitive assessment in medical settings in general, there have been no specific studies addressing the utility of the neuropsychological evaluation in the acute inpatient hospital setting. The current study examined the use of inpatient neuropsychological evaluation by treating physicians in an acute medical hospital for patient care and discharge disposition. Participants were 100 inpatients within an urban medical center who received a neuropsychological evaluation. Results showed 78% of hospital discharge summaries included information regarding the neuropsychological evaluation, 48% referenced specific results, and 68% reported specific recommendations. Further, actual placement outcomes were consistent with the neuropsychological evaluation placement recommendations 80% of the time. The current study supports the utility of neuropsychological evaluations on overall inpatient care, and discusses ways in which the results may be used to communicate the value of neuropsychological services to medical treatment and discharge planning teams, third party payors, and medical center administrators.