Cognitive processing speed in multiple sclerosis clinical practice: association with patient-reported outcomes, employment and magnetic resonance imaging metrics.

BACKGROUND AND PURPOSE: To analyze the relationship between cognitive processing speed, patient-reported outcome measures (PROMs), employment and magnetic resonance imaging (MRI) metrics in a large multiple sclerosis cohort. METHODS: Cross-sectional clinical data, PROMs, employment and MRI studies within 90 days of completion of the Processing Speed Test (PST), a technology-enabled adaptation of the Symbol Digit Modalities Test, were collected. MRI was analyzed using semi-automated methods. Correlations of PST score with PROMs and MRI metrics were examined using Spearman's rho. Wilcoxon rank sum testing compared MRI metrics across PST score quartiles and linear regression models identified predictors of PST performance. Effects of employment and depression were also investigated. RESULTS: In 721 patients (mean age 47.6 ± 11.4 years), PST scores were significantly correlated with all MRI metrics, including cord atrophy and deep gray matter volumes. Linear regression demonstrated self-reported physical disability, cognitive function, fatigue and social domains (adjusted R2  = 0.44, P < 0.001) as the strongest clinical predictors of PST score, whereas that of MRI variables included T2 lesion volume, whole-brain fraction and cord atrophy (adjusted R2  = 0.42, P < 0.001). An inclusive model identified T2 lesion volume, whole-brain fraction, self-reported upper extremity function, cognition and social participation as the strongest predictors of PST score (adjusted R2  = 0.51, P < 0.001). There was significant effect modification by depression on the relationship between self-reported cognition and PST performance. Employment status was associated with PST scores independent of age and physical disability. CONCLUSION: The PST score correlates with PROMs, MRI measures of focal and diffuse brain injury, and employment. The PST score is a feasible and meaningful measure for routine multiple sclerosis care.

Multiple Sclerosis Performance Test: validation of self-administered neuroperformance modules.

BACKGROUND AND PURPOSE: The purpose was to determine the test-retest reliability, practice effects, convergent validity and sensitivity to multiple sclerosis (MS) disability of neuroperformance subtests from the patient self-administered Multiple Sclerosis Performance Test (MSPT) designed to assess low contrast vision (Contrast Sensitivity Test, CST), upper extremity motor function (Manual Dexterity Test, MDT) and lower extremity motor function (Walking Speed Test, WST) and to introduce the concept of regression-based norms to aid clinical interpretation of performance scores using the MSPT cognition test (Processing Speed Test, PST) as an example. METHODS: Substudy 1 assessed test-retest reliability, practice effects and convergent validity of the CST, MDT and WST in 30 MS patients and 30 healthy controls. Substudy 2 examined sensitivity to MS disability in over 600 MS patients as part of their routine clinic assessment. Substudy 3 compared performance on the PST in research volunteers and clinical samples. RESULTS: The CST, MDT and WST were shown to be reliable, valid and sensitive to MS outcomes. Performance was comparable to technician-administered testing. PST performance was poorer in the clinical sample compared with the research volunteer sample. CONCLUSIONS: The self-administered MSPT neuroperformance modules produce reliable, objective metrics that can be used in clinical practice and support outcomes research. Published studies which require patient voluntary consent may underestimate the rate of cognitive dysfunction observed in a clinical setting.

Effects of age, HIV, and HIV-associated clinical factors on neuropsychological functioning and brain regional volume in HIV+ patients on effective treatment.

It is yet unclear if people infected with human immunodeficiency virus (HIV+) on stable, combined antiretroviral therapies (cARTs) decline with age at the same or greater rate than healthy people. In this study, we examined independent and interactive effects of HIV, age, and HIV-related clinical parameters on neuropsychological functioning and brain regional volume in a sizable group of Polish HIV+ men receiving cART. We also estimated the impact of nadir CD4 cell count, CD4 cell count during participation in the study, duration of HIV infection, or duration of cART along with age. Ninety-one HIV+ and 95 control (HIV-) volunteers ages 23-75 completed a battery of neuropsychological tests, and 54 HIV+ and 62 HIV- of these volunteers participated in a brain imaging assessment. Regional brain volume in the cortical and subcortical regions was measured using voxel-based morphometry. We have found that HIV and older age were independently related to lower attention, working memory, nonverbal fluency, and visuomotor dexterity. Older age but not HIV was associated with less volume in several cortical and subcortical brain regions. In the oldest HIV+ participants, age had a moderating effect on the relationship between the duration of cART and visuomotor performance, such as that older age decreased speed of visuomotor performance along with every year on cART. Such results may reflect the efficacy of cART in preventing HIV-associated brain damage. They also highlight the importance of monitoring neuropsychological functioning and brain structure in HIV+ patients. This is particularly important in older patients with long adherence to cART.

HDQLIFE: development and assessment of health-related quality of life in Huntington disease (HD).

PURPOSE: Huntington disease (HD) is a chronic, debilitating genetic disease that affects physical, emotional, cognitive, and social health. Existing patient-reported outcomes (PROs) of health-related quality of life (HRQOL) used in HD are neither comprehensive, nor do they adequately account for clinically meaningful changes in function. While new PROs examining HRQOL (i.e., Neuro-QoL-Quality of Life in Neurological Disorders and PROMIS-Patient-Reported Outcomes Measurement Information System) offer solutions to many of these shortcomings, they do not include HD-specific content, nor have they been validated in HD. HDQLIFE addresses this by validating 12 PROMIS/Neuro-QoL domains in individuals with HD and by using established PROMIS methodology to develop new, HD-specific content. METHODS: New item pools were developed using cognitive debriefing with individuals with HD, and expert, literacy, and translatability reviews. Existing item banks and new item pools were field tested in 536 individuals with prodromal, early-, or late-stage HD. RESULTS: Moderate to strong relationships between Neuro-QoL/PROMIS measures and generic self-report measures of HRQOL, and moderate relationships between Neuro-QoL/PROMIS and clinician-rated measures of similar constructs supported the validity of Neuro-QoL/PROMIS in individuals with HD. Exploratory and confirmatory factor analysis, item response theory, and differential item functioning analyses were utilized to develop new item banks for Chorea, Speech Difficulties, Swallowing Difficulties, and Concern with Death and Dying, with corresponding six-item short forms. A four-item short form was developed for Meaning and Purpose. CONCLUSIONS: HDQLIFE encompasses both validated Neuro-QoL/PROMIS measures, as well as five new scales in order to provide a comprehensive assessment of HRQOL in HD.

X-Ray spectra and electronic correlations of FeSe(1-x)Te(x).

Critical issues concerning emerging Fe-based superconductors include the degree of electron correlation and the origin of the superconductivity. X-Ray absorption spectra (XAS) and resonant inelastic X-ray scattering spectra (RIXS) of FeSe(1-x)Te(x) (x = 0-1) single crystals were obtained to study their electronic properties that relate to electron correlation and superconductivity. The linewidth of Fe L(2,3)-edges XAS of FeSe(1-x)Te(x) is narrower than that of Fe-pnictides, revealing the difference between their hybridization effects and localization character and those of other Fe-pnictides. While no significant differences exist between the Fe L-edge XAS and RIXS of FeSe(1-x)Te(x) and those of Fe-pnictides, Se K-edge and Te K-edge XAS exhibit substantial edge shift, suggesting that the superconductivity in an Fe-Se superconductor is strongly associated with the ligand states. A comparison of the Se K-edge and Te K-edge spectra reveals that the charge transfer may occur between Se and Te. Given the Coulomb interaction and the bandwidth, the spectral results indicate that FeSe(1-x)Te(x) is unlikely to be a weakly correlated system unlike the Fe-pnictides of the "1111" and "122" families. The spectral results further demonstrate that superconductivity in this class of Fe-based compounds is strongly associated with the ligand 4p hole state.

Semantic memory activation in amnestic mild cognitive impairment.

Cognitively intact older individuals at risk for developing Alzheimer's disease frequently show increased functional magnetic resonance imaging (fMRI) brain activation presumably associated with compensatory recruitment, whereas mild cognitive impairment (MCI) patients tend not to show increased activation presumably due to reduced neural reserve. Previous studies, however, have typically used episodic memory activation tasks, placing MCI participants at a performance disadvantage relative to healthy elders. In this event-related fMRI study, we employed a low effort, high accuracy semantic memory task to determine if increased activation of memory circuits is preserved in amnestic MCI when task performance is controlled. Fifty-seven participants, aged 65-85 years, comprised three groups (n = 19 each): amnestic MCI patients; cognitively intact older participants at risk for developing Alzheimer's disease based on having at least one ApoE epsilon4 allele and a positive family history of Alzheimer's disease (At Risk); and cognitively intact participants without Alzheimer's disease risk factors (Control). fMRI was conducted on a 3T MR scanner while participants performed a famous name discrimination task. Participants also underwent neuropsychological testing outside the scanner; whole brain and hippocampal atrophy were assessed from anatomical MRI scans. The three groups did not differ on demographic variables or on fame discrimination performance (>87% correct for all groups). As expected, the amnestic MCI participants demonstrated reduced episodic memory performance. Spatial extent of activation (Fame--Unfamiliar subtraction) differentiated the three groups (Control = 0 ml, At Risk = 9.7 ml, MCI = 34.7 ml). The MCI and At Risk groups showed significantly greater per cent signal change than Control participants in 8 of 14 functionally defined regions, including the medial temporal lobe, temporoparietal junction, and posterior cingulate/precuneus. MCI participants also showed greater activation than Controls in two frontal regions. At Risk, but not MCI, participants showed increased activity in the left hippocampal complex; MCI participants, however, evidenced increased activity in this region when hippocampal atrophy was controlled. When performance is equated, MCI patients demonstrate functional compensation in brain regions subserving semantic memory systems that generally equals or exceeds that observed in cognitively intact individuals at risk for Alzheimer's disease. This hyperactivation profile in MCI is even observed in the left hippocampal complex, but only when the extent of hippocampal atrophy is taken into consideration.

Cryptogenic liver disease in HIV-seropositive men.

OBJECTIVES: In the era of highly active antiretroviral therapy (HAART), liver disease has become a leading cause of morbidity and mortality in HIV-seropositive individuals. Although liver disease is commonly caused by viral co-infection, it has also been described in patients without viral hepatitis. In this study, we determined clinical factors associated with the development of cryptogenic liver disease in HIV-infected individuals. METHODS: HIV-seropositive and -seronegative patients undergoing evaluation for liver transplantation were selected if they met clinical criteria for cryptogenic liver disease. Clinical data were collected retrospectively, and radiological and histological data were reviewed separately. RESULTS: Nine HIV-seropositive individuals were compared with 41 HIV-seronegative patients with cryptogenic liver disease. Only one HIV-seropositive patient (11%) had cirrhosis, compared to 39 HIV-seronegative patients (93%) (P<0.001). Three HIV-infected patients (33%) had histological evidence of nodular regenerative hyperplasia. HIV-seropositive patients had significantly lower body mass indices, and lower Child-Pugh-Turcotte and Model for Endstage Liver Disease scores than HIV-seronegative patients (P<0.05). CONCLUSIONS: Advanced cryptogenic liver disease in HIV-infected patients is infrequently caused by cirrhosis, and more frequently by nodular regenerative hyperplasia. This disease entity may become more common in the HAART era, and may contribute to an increased morbidity in HIV-infected individuals.

BLT2 is expressed in PanINs, IPMNs, pancreatic cancer and stimulates tumour cell proliferation.

Pancreatic cancer has an abysmal prognosis. Targets for early detection, prevention and therapy are desperately needed. Inflammatory pathways have an important impact on tumour growth and progression. Expression of BLT2 (the second leukotriene B(4) receptor) was investigated by real-time RT-PCR and immunohistochemistry. Cell proliferation was studied after stable transfection with BLT2, after treatment with siRNA and Compound A as an agonist. BLT2 is expressed in all pancreatic cancer cell lines. Results from real-time RT-PCR revealed significant overexpression of BLT2 in malignant intraductal papillary mucinous neoplasias (IPMNs) and pancreatic adenocarcinoma. Intense staining was evident in IPMNs, infiltrating tumour cells and advanced pancreatic intraepithelial neoplasias (PanINs) but not in normal ductal cells. Overexpression of BLT2 as well as stimulation of Colo357, Panc-1 and AsPC1 cells with Compound A caused a significant increase in tumour cell proliferation, an effect reversed after siRNA treatment. This study demonstrates for the first time the expression of BLT2 in the pancreas and overexpression in pancreatic cancers and malignant IPMNs in particular. Upregulation of BLT2 is already evident in precursor lesions (PanINs, IPMNs). Overexpression of this receptor leads to significant growth stimulation. Therefore, we suggest BLT2 as a new target for chemoprevention and therapy for pancreatic cancer.

The evolution of brain activation during temporal processing.

Timing is crucial to many aspects of human performance. To better understand its neural underpinnings, we used event-related fMRI to examine the time course of activation associated with different components of a time perception task. We distinguished systems associated with encoding time intervals from those related to comparing intervals and implementing a response. Activation in the basal ganglia occurred early, and was uniquely associated with encoding time intervals, whereas cerebellar activation unfolded late, suggesting an involvement in processes other than explicit timing. Early cortical activation associated with encoding of time intervals was observed in the right inferior parietal cortex and bilateral premotor cortex, implicating these systems in attention and temporary maintenance of intervals. Late activation in the right dorsolateral prefrontal cortex emerged during comparison of time intervals. Our results illustrate a dynamic network of cortical-subcortical activation associated with different components of temporal information processing.

Soluble TREM2 and biomarkers of central and peripheral inflammation in neurodegenerative disease.

Alzheimer's disease (AD) has been genetically and pathologically associated with neuroinflammation. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor involved in innate immunity. TREM2 rare protein coding genetic variants have been linked to AD. A soluble TREM2 (sTREM2) cleavage product is elevated in AD. It is unclear whether there is a relationship between elevated sTREM2 and markers of inflammation. The hypothesis of this investigation was that central and peripheral inflammation play a role in sTREM2 levels in AD. A consistent association of peripheral or central markers of inflammation and CSF sTREM2 levels was not found, suggesting a limited impact of general inflammation on sTREM2 levels. An association between peripheral sTREM2 levels and CSF sTREM2, as well as an association between CSF sTREM2 and a marker of blood brain barrier integrity, was observed in AD, suggesting a potential role of peripheral TREM2 in central TREM2 biology.

Outcomes after pancreatectomy for intraductal papillary mucinous neoplasms of the pancreas: an institutional experience.

PURPOSE: To evaluate the experience with pancreatectomy for intraductal papillary mucinous neoplasm (IPMN) at a single academic institution. METHODS: A prospective pancreatic database was reviewed and identified 43 patients with IPMN who were managed operatively. Clinicopathologic features and predictors of outcome were examined. The World Health Organization pathologic classification of IPMN was utilized. RESULTS: IPMN was diagnosed in 21% of patients who underwent pancreatic resection for solid or cystic mass lesions. Ninety-five percent of patients were symptomatic. Patients were managed with total pancreatectomy, pancreaticoduodenectomy, distal pancreatectomy, central pancreatectomy, or enucleation. Nine patients had adenomas, 14 had borderline neoplasms, 10 had carcinoma in situ, and 9 had invasive carcinoma. Overall, 23 patients (53%) had lesions with main duct involvement. Frozen section transection margins were positive for malignancy in 2 patients. With a mean follow-up of 17 months, the 5-year disease-specific survival for patients with main duct involvement was 67%. The 5-year disease-specific survival for patients with benign lesions was 100%, and 61% for patients with malignant lesions (P = .02). The presence of symptoms, increased CA 19-9, and tumor size were not predictive of malignancy. Increased serum bilirubin concentrations were predictive of malignancy (P = .03). Main duct involvement was also associated with malignancy (P < .02). CONCLUSIONS: Cancer is found in 65% of patients with IMPN involving the main duct. Based on our data, patients with symptomatic, main duct involvement, especially those with an increased serum bilirubin, should be offered resection. Alternatively, patients with side branch IPMN may be managed conservatively.

Neural systems underlying the recognition of familiar and newly learned faces.

Memory for famous faces can be used to examine the neural systems underlying retrieval from long-term memory. To date, there have been a limited number of functional neuroimaging investigations examining famous face recognition. In this study, we compared recognition of famous faces to recognition of newly learned faces. Whole-brain, event-related functional magnetic resonance imaging was used to image regional changes in neural activity in 11 subjects during the encoding of unfamiliar faces and during familiarity judgments for: (1) newly learned faces, (2) unfamiliar face distractors, and (3) famous faces. Image analyses were restricted to correct recognition trials. Recognition accuracy and response time to famous and recently learned faces were equivalent. Recognition of famous faces was associated with a widespread network of bilateral brain activations involving the prefrontal, lateral temporal, and mesial temporal (hippocampal and parahippocampal regions) regions compared to recognition of recently encoded faces or unfamiliar faces seen for the first time. Findings are discussed in relation to current proposals concerning the neural regions thought to participate in long-term memory retrieval and, more specifically, in relation to retrieval of information from the person identity semantic system.

Relationship between finger movement rate and functional magnetic resonance signal change in human primary motor cortex.

Functional magnetic resonance imaging (FMRI) is a noninvasive technique for mapping regional brain changes in response to sensory, motor, or cognitive activation tasks. Interpretation of these activation experiments may be confounded by more elementary task parameters, such as stimulus presentation or movement rates. We examined the effect of movement rate on the FMRI response recorded from the contralateral primary motor cortex. Four right-handed healthy subjects performed flexion-extension movements of digits 2-5 of the right hand at rates of 1, 2, 3, 4, or 5 Hz. Results of this study indicated a positive linear relationship between movement rate and FMRI signal change. Additionally, the number of voxels demonstrating functional activity increased significantly with faster movement rates. The magnitude of the signal change at each movement rate remained constant over the course of three 8-min scanning series. These findings are similar to those of previous rate studies of the visual and auditory system performed with positron emission tomography (PET) and FMRI.

Effects of methylphenidate on functional MRI blood-oxygen-level-dependent contrast.

OBJECTIVE: The authors' goal was to determine potential hemodynamic consequences of methylphenidate on functional magnetic resonance imaging (MRI) blood-oxygen-level-dependent (BOLD) contrast. METHOD: BOLD and perfusion changes were recorded from the motor cortex of six healthy subjects while they performed flexion-extension movements of the right index finger (finger tapping) at varying rates before and after oral methylphenidate administration. RESULTS: Functional MRI signals increased monotonically with faster movement rates. Subjects' heart rates increased modestly after methylphenidate administration, but no changes in finger tapping performance or functional MRI signals were observed. CONCLUSIONS: Methylphenidate does not alter BOLD neural-hemodynamic coupling. Consequently, functional MRI can be used to map neural systems that subserve cognitive operations (e.g., attention and executive processes) in subjects taking methylphenidate.

Nicotine-induced limbic cortical activation in the human brain: a functional MRI study.

OBJECTIVE: Nicotine is a highly addictive substance, and cigarette smoking is a major cause of premature death among humans. Little is known about the neuropharmacology and sites of action of nicotine in the human brain. Such knowledge might help in the development of new behavioral and pharmacological therapies to aid in treating nicotine dependence and to improve smoking cessation success rates. METHOD: Functional magnetic resonance imaging, a real-time imaging technique, was used to determine the acute CNS effects of intravenous nicotine in 16 active cigarette smokers. An injection of saline followed by injections of three doses of nicotine (0.75, 1.50, and 2.25 mg/70 kg of weight) were each administered intravenously over 1-minute periods in an ascending, cumulative-dosing paradigm while whole brain gradient-echo, echo-planar images were acquired every 6 seconds during consecutive 20-minute trials. RESULTS: Nicotine induced a dose-dependent increase in several behavioral parameters, including feelings of "rush" and "high" and drug liking. Nicotine also induced a dose-dependent increase in neuronal activity in a distributed system of brain regions, including the nucleus accumbens, amygdala, cingulate, and frontal lobes. Activation in these structures is consistent with nicotine's behavior-arousing and behavior-reinforcing properties in humans. CONCLUSIONS: The identified brain regions have been previously shown to participate in the reinforcing, mood-elevating, and cognitive properties of other abused drugs such as cocaine, amphetamine, and opiates, suggesting that nicotine acts similarly in the human brain to produce its reinforcing and dependence properties.

Guidelines for neuropsychological research in multiple sclerosis.

Acquisition of scientific information regarding the neuropsychological aspects of multiple sclerosis has been hampered by studies using small, inadequately described patient and control samples and a wide array of cognitive test procedures that hinder multicenter data pooling. Based on a review of key issues of clinical need and experimental interest, research guidelines are proposed for investigations in this burgeoning research area. The guidelines include suggestions for sampling methods, population characterization, and control groups as well as a recommended core battery of neuropsychological tests for use in this population. It is hoped that these guidelines will advance knowledge about the neuropsychology of multiple sclerosis by helping to promote sound experimental design, facilitate cross-study comparison, and encourage multicenter collaborative efforts.

Memory disturbance in chronic progressive multiple sclerosis.

Forty-four patients with chronic progressive multiple sclerosis (MS) were compared with age- and education-matched control groups on a battery of clinical and experimental memory measures. Patients with MS performed substantially below the control groups on both immediate learning and delayed recall tasks, particularly in the retrieval of spatial information. The MS sample was subdivided into three groups using a cluster analytic procedure. One group (N = 9) performed well below expectations on memory tasks, exhibited signs of global cognitive disturbance, and had an atypical personality adjustment, characterized by irritability, social withdrawal, and apathy. A second group (N = 19) showed mild memory disturbance, associated with a greater use of psychotropic medications and a higher incidence of reactive depression. A third group (N = 16) performed normally on memory measures. The three groups of patients with MS did not differ in length or overall severity of illness.

Neuropsychological test findings in subjects with leukoaraiosis.

Focal periventricular white-matter changes (leukoaraiosis) have been identified incidentally on brain imaging in normal healthy individuals and more commonly in the elderly and in hypertensive individuals. It has been suggested that leukoaraiosis represents the early stages of Binswanger's leukoencephalopathy, a dementing process thought to be related to hypertensive cerebrovascular disease. To test this hypothesis, extensive neuropsychological tests were administered to 50 consecutive normotensive, middle-aged, healthy volunteers. Ten subjects (20%) had white-matter changes on magnetic resonance scans; 40 subjects (80%) had normal scans. The differences observed on neuropsychological testing between subjects with and without leukoaraiosis were not significant. While this study argues against a link between leukoaraiosis and dementia, prospective longitudinal studies are needed to determine the value of leukoaraiosis in predicting future cognitive decline.

Cerebral disconnection in multiple sclerosis. Relationship to atrophy of the corpus callosum.

Left ear suppression to dichotically presented verbal stimuli has been observed in patients with multiple sclerosis (MS). Rubens and coworkers have suggested that a disconnection of the auditory callosal pathways may account for this finding. To examine this proposal, we compared the performance of 28 MS patients with significant corpus callosum atrophy (CCA) on midsagittal magnetic resonance scans, 16 MS patients without significant CCA, and 64 demographically matched normal control subjects on two laterality tasks: verbal dichotic listening (consonant-vowel syllables) and tachistiscopic object-naming latency. Results indicated that left ear suppression was found only in the MS patients with CCA. Likewise, patients in the MS group with CCA were slow in responding to stimuli presented in the left visual field; this effect was not observed in patients without CCA. These findings support the hypothesis that efficiency of cross-callosal information flow is reduced in MS patients with CCA.

Lateralized human brain language systems demonstrated by task subtraction functional magnetic resonance imaging.

OBJECTIVE: To develop a procedure for noninvasive measurement of language lateralization with functional magnetic resonance imaging (MRI). DESIGN: Functional neuroimaging using time-series echo-planar MRI. SETTING: University medical center research facility. SUBJECTS: Five healthy, right-handed, young adults. MAIN OUTCOME MEASURES: Number of MRI voxels in left and right hemispheres showing task-related signal increases during two contrasting auditory processing tasks. The nonlinguistic task involved processing of pure tones, while the linguistic task involved processing of single words based on semantic content. RESULTS: The pure-tone processing task activated temporal lobe auditory areas and dorsolateral frontal regions bilaterally. Using this task as a control condition, the semantic processing task resulted in lateralized activity in distributed regions of the left hemisphere. A significant effect of task on intrahemispheric activity pattern was demonstrated in every subject. Results were reproduced in preliminary studies of test-retest reliability. CONCLUSIONS: The results demonstrate the lateralized anatomy of semantic linguistic systems in contrast to non-linguistic auditory sensory processors and introduce a task subtraction technique adapted for functional MRI as a noninvasive measure of language lateralization.