Olfactory and Neuropsychological Functioning in Olfactory Reference Syndrome.

BACKGROUND: Olfactory reference syndrome (ORS) is an underrecognized, understudied, and often severe psychiatric disorder characterized by a prominent and distressing or impairing preoccupation with a false belief of emitting an offensive body odor. As this condition has only recently been recognized in the International Classification of Diseases (the 11th Edition), no empirical evidence exists about the underlying features and etiology of the disorder. OBJECTIVE: To examine the neuropsychological and olfactory functioning of individuals with ORS and address whether there is central nervous system or sensory dysfunction associated with the condition. METHODS: In this preliminary investigation, 9 consecutive participants with ORS completed a structured clinical interview and neuropsychological and olfaction evaluations. RESULTS: A proportion of individuals with ORS displayed deficits in aspects of cognitive functioning (i.e., processing speed, executive functioning, recognition memory bias for ORS-related words), olfaction functioning (i.e., odor detection and discrimination), and emotional processing. CONCLUSIONS: Based on these preliminary findings of cognitive, olfaction, and emotional processing deficits in individuals with ORS, further neuropsychological and olfaction studies are needed that better characterize this understudied patient group and address this study's limitations.

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.

Cognitive reserve and brain reserve in prodromal Huntington's disease.

Huntington disease (HD) is associated with decline in cognition and progressive morphological changes in brain structures. Cognitive reserve may represent a mechanism by which disease-related decline may be delayed or slowed. The current study examined the relationship between cognitive reserve and longitudinal change in cognitive functioning and brain volumes among prodromal (gene expansion-positive) HD individuals. Participants were genetically confirmed individuals with prodromal HD enrolled in the PREDICT-HD study. Cognitive reserve was computed as the composite of performance on a lexical task estimating premorbid intellectual level, occupational status, and years of education. Linear mixed effects regression (LMER) was used to examine longitudinal changes on four cognitive measures and three brain volumes over approximately 6 years. Higher cognitive reserve was significantly associated with a slower rate of change on one cognitive measure (Trail Making Test, Part B) and slower rate of volume loss in two brain structures (caudate, putamen) for those estimated to be closest to motor disease onset. This relationship was not observed among those estimated to be further from motor disease onset. Our findings demonstrate a relationship between cognitive reserve and both a measure of executive functioning and integrity of certain brain structures in prodromal HD individuals.

Unemployment in multiple sclerosis: the contribution of personality and disease.

BACKGROUND: Multiple sclerosis (MS) is the leading cause of neurological disability among young and middle-aged adults. One of the most devastating consequences of MS in this relatively young population group is unemployment. Although certain demographic and disease factors have been associated with employment, few studies have examined the contribution of person-specific factors, such as personality. OBJECTIVE: The goal of this study was to determine the extent to which personality, demographics, and clinical measures contribute to unemployment in MS. METHOD: A total of 101 individuals with MS who were enrolled in a clinical trial on cognition underwent a brief neuropsychological battery and completed questionnaires related to vocation, mood, fatigue, and personality. Neurological impairment was measured with the Expanded Disability Status Scale (EDSS). RESULTS: Employment status was related with disease duration, MS subtype, level of neurological impairment, fatigue, performance on measures assessing information processing speed (Symbol Digit Modalities Test (SDMT)), learning and memory (Selective Reminding Test), and the personality characteristic of persistence. Based on a forward logistic regression analysis, EDSS, SDMT, and persistence were the strongest predictors of employment status. CONCLUSIONS: These findings underscore the importance of personality on outcomes in MS and point to the need for more clinical attention and research in this area.

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.

Burden among spousal and child caregivers of patients with mild cognitive impairment.

BACKGROUND/AIMS: Patients with mild cognitive impairment (MCI) experience cognitive declines and often report significant emotional/behavioral changes. Despite this, few studies have examined the impact of MCI on caregiver burden. The purpose of this study was to confirm the presence of caregiver burden in MCI and examine the relationship between burden and patients' neuropsychological, behavioral and emotional functioning. METHODS: The current study included 51 individuals who had been diagnosed as having MCI using Petersen's criteria. The patients underwent a thorough neuropsychological evaluation and completed the Beck Depression Inventory and Cognitive Difficulties Scale. The caregivers completed the Zarit Burden Interview and the Revised Memory and Behavior Checklist. RESULTS: More than 30% of the caregivers reported clinically significant burden. Increased caregiver burden was associated with a longer course of cognitive symptoms, patient reports of worse depression and greater cognitive difficulties, and informant reports of patients having more behavior, mood and memory problems. Caregiver burden was not significantly associated with patients' neuropsychological test performance. CONCLUSION: The results highlight the importance of addressing patients' behavioral and emotional difficulties, as well as caregiver burden, as part of the clinical exam in MCI.

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.

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.

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.

Practice effects in the prediction of long-term cognitive outcome in three patient samples: a novel prognostic index.

Practice effects, defined as improvements in cognitive test performance due to repeated exposure to the test materials, have traditionally been viewed as sources of error. However, they might provide useful information for predicting cognitive outcome. The current study used three separate patient samples (older adults with mild cognitive impairments, individuals who were HIV+, individuals with Huntington's disease) to examine the relationship between practice effects and cognitive functioning at a later point. Across all three samples, practice effects accounted for as much as 31-83% of the variance in the follow-up cognitive scores, after controlling for baseline cognitive functioning. If these findings can be replicated in other patients with neurodegenerative disorders, clinicians and researchers may be able to develop predictive models to identify the individuals who are most likely to demonstrate continued cognitive decline across time. The ability to utilize practice effects data would add a simple, convenient, and non-invasive marker for monitoring an individual patient's cognitive status. Additionally, this prognostic index could be used to offer interventions to patients who are in the earliest stages of progressive neurodegenerative disorders.

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.

The impact of oculomotor functioning on neuropsychological performance in Huntington disease.

Huntington disease (HD) is a neurodegenerative condition with prominent motor (including oculomotor), cognitive, and psychiatric effects. While neuropsychological deficits are present in HD, motor impairments may impact performance on neuropsychological measures, especially those requiring a speeded response, as has been demonstrated in multiple sclerosis and schizophrenia. The current study is the first to explore associations between oculomotor functions and neuropsychological performance in HD. Participants with impaired oculomotor functioning performed worse than those with normal oculomotor functioning on cognitive tasks requiring oculomotor involvement, particularly on psychomotor speed tasks, controlling for covariates. Consideration of oculomotor dysfunction on neuropsychological performance is critical, particularly for populations with motor deficits.

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.

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.

Speedy eye movements in multiple sclerosis: association with performance on visual and nonvisual cognitive tests.

OBJECTIVE: Eye movement difficulties in multiple sclerosis (MS) are common and may influence performance on cognitive tests. The following studies examined associations between a new measure of speedy eye movement speed and visual/nonvisual cognitive tests. METHOD: In Experiment 1, MS patients (N = 71) were administered cognitive tests and the Speedy Eyes Test (SET) as a measure of purposeful speedy eye movements under timed conditions. Experiment 2 was composed of MS patients (n = 60) and a neurologically healthy comparison group (n = 31) and examined group differences in an abbreviated version of the SET. RESULTS: In both studies, slower eye movements were significantly associated with poorer performance on cognitive tests with a large effect size in Experiment 1 and a medium effect size in Experiment 2. Analyses in Experiment 2 also revealed significant group differences in an abbreviated measure of the SET, where MS patients had slower eye movements than the comparison group. CONCLUSIONS: Pending further research, the SET, a brief, inexpensive, and nontechnical measure of speedy eye movement, may serve as a visual/oculomotor indicator of cognitive impairment in multiple sclerosis.

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.

Clinical and Biomarker Changes in Premanifest Huntington Disease Show Trial Feasibility: A Decade of the PREDICT-HD Study.

There is growing consensus that intervention and treatment of Huntington disease (HD) should occur at the earliest stage possible. Various early-intervention methods for this fatal neurodegenerative disease have been identified, but preventive clinical trials for HD are limited by a lack of knowledge of the natural history of the disease and a dearth of appropriate outcome measures. Objectives of the current study are to document the natural history of premanifest HD progression in the largest cohort ever studied and to develop a battery of imaging and clinical markers of premanifest HD progression that can be used as outcome measures in preventive clinical trials. Neurobiological predictors of Huntington's disease is a 32-site, international, observational study of premanifest HD, with annual examination of 1013 participants with premanifest HD and 301 gene-expansion negative controls between 2001 and 2012. Findings document 39 variables representing imaging, motor, cognitive, functional, and psychiatric domains, showing different rates of decline between premanifest HD and controls. Required sample size and models of premanifest HD are presented to inform future design of clinical and preclinical research. Preventive clinical trials in premanifest HD with participants who have a medium or high probability of motor onset are calculated to be as resource-effective as those conducted in diagnosed HD and could interrupt disease 7-12 years earlier. Methods and measures for preventive clinical trials in premanifest HD more than a dozen years from motor onset are also feasible. These findings represent the most thorough documentation of a clinical battery for experimental therapeutics in stages of premanifest HD, the time period for which effective intervention may provide the most positive possible outcome for patients and their families affected by this devastating disease.

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.