Magnetic resonance imaging measures of brain atrophy from the EXPEDITION3 trial in mild Alzheimer's disease.

INTRODUCTION: Solanezumab is a humanized monoclonal antibody that preferentially binds to soluble amyloid ß and promotes its clearance from the brain in preclinical studies. The objective of this study was to assess the effect of solanezumab in slowing global and anatomically localized brain atrophy as measured by volumetric magnetic resonance imaging (MRI). METHODS: In the EXPEDITION3 phase 3 trial, participants with mild Alzheimer's disease were randomized to receive intravenous infusions of either 400 mg of solanezumab or placebo every 4 weeks for 76 weeks. Volumetric MRI scans were acquired at baseline and at 80 weeks from 275 MRI facilities using a standardized imaging protocol. A subset of 1462 patients who completed both MRI and 14-item Alzheimer's Disease Assessment Scale-Cognitive Subscale assessments at both time points were selected for analysis. Longitudinal MRI volume changes were analyzed centrally by tensor-based morphometry with a standard FreeSurfer brain parcellation. Prespecified volumetric measures, including whole brain and ventricles, along with anatomically localized regions in the temporal, parietal, and frontal lobes were evaluated in those participants. RESULTS: Group-mean differences in brain atrophy rates were directionally consistent across a number of brain regions but small in magnitude (1.3-6.9% slowing) and not statistically significant when corrected for multiple comparisons. The annualized rates of change of the volumetric measures and the correlation of these changes with cognitive changes in placebo-treated subjects were similar to those reported previously. DISCUSSION: In the EXPEDITION3 trial, solanezumab did not significantly slow down rates of global or anatomically localized brain atrophy. Brain volume changes and their relationship to cognition were consistent with previous reports.

Amyloid-related imaging abnormalities from trials of solanezumab for Alzheimer's disease.

INTRODUCTION: Solanezumab, a humanized monoclonal antibody that binds soluble amyloid beta peptide, is being developed for treatment of Alzheimer's disease (AD). METHODS: Patients (n = 2042) with mild and moderate AD were randomized 1:1 to 400-mg solanezumab or placebo infusion every 4 weeks for 80 weeks and 1457 patients entered an open-label extension. Magnetic resonance imaging scans monitored for amyloid-related imaging abnormalities-edema/effusion (ARIA-E) and amyloid-related imaging abnormalities-hemorrhage/hemosiderin deposition. RESULTS: Sixteen patients (solanezumab, n = 11; placebo, n = 5) developed ARIA-E during the double-blind phase, and 7 patients developed ARIA-E during the open-label extension as of July 31, 2014. Unique cases are discussed including solanezumab patients who were given solanezumab, while ARIA-E was present and a patient who developed ARIA-E during placebo treatment and again during solanezumab treatment. DISCUSSION: Asymptomatic ARIA-E was detected in solanezumab-treated and placebo-treated AD patients. ARIA-E occurs infrequently during solanezumab and placebo treatments but may occur repeatedly in some patients.

Deformation-based atrophy computation by surface propagation and its application to Alzheimer's disease.

Obtaining regional volume changes from a deformation field is more precise when using simplex counting (SC) compared with Jacobian integration (JI) due to the numerics involved in the latter. Although SC has been proposed before, numerical properties underpinning the method and a thorough evaluation of the method against JI is missing in the literature. The contributions of this paper are: (a) we propose surface propagation (SP)-a simplification to SC that significantly reduces its computational complexity; (b) we will derive the orders of approximation of SP which can also be extended to SC. In the experiments, we will begin by empirically showing that SP is indeed nearly identical to SC, and that both methods are more stable than JI in presence of moderate to large deformation noise. Since SC and SP are identical, we consider SP as a representative of both the methods for a practical evaluation against JI. In a real application on Alzheimer's disease neuroimaging initiative data, we show the following: (a) SP produces whole brain and medial temporal lobe atrophy numbers that are significantly better than JI at separating between normal controls and Alzheimer's disease patients; (b) SP produces disease group atrophy differences comparable to or better than those obtained using FreeSurfer, demonstrating the validity of the obtained clinical results. Finally, in a reproducibility study, we show that the voxel-wise application of SP yields significantly lower variance when compared to JI.

Amyloid PET Screening for Enrichment of Early-Stage Alzheimer Disease Clinical Trials: Experience in a Phase 1b Clinical Trial.

Amyloid positron emission tomography (PET) imaging is being investigated as a screening tool to identify amyloid-positive patients as an enrichment strategy for Alzheimer disease (AD) clinical trial enrollment. In a multicenter, phase 1b trial, patients meeting clinical criteria for prodromal or mild AD underwent florbetapir PET scanning at screening. PET, magnetic resonance imaging, and coregistered PET/magnetic resonance imaging scans were reviewed by 2 independent readers and binary visual readings tabulated. Semiquantitative values of cortical to whole cerebellar standard uptake value ratios were computed (threshold 1.10). Of 278 patients with an evaluable PET scan, 170 (61%) and 185 (67%) were amyloid-positive by visual reading and quantitative analysis, respectively; 39% were excluded from the study due to an amyloid-negative scan based on visual readings. More ApoE ε4 carriers than noncarriers were amyloid-positive (80% vs. 43%). Comparison of visual readings with quantitative results identified 21 discordant cases (92% agreement). Interreader and intrareader agreements from visual readings were 98% and 100%, respectively. Amyloid PET imaging is an effective and feasible screening tool for enrollment of amyloid-positive patients with early stages of AD into clinical trials.

Magnetic resonance spectroscopy markers of disease progression in multiple sclerosis.

IMPORTANCE: Predicting disease evolution is becoming essential for optimizing treatment decision making in multiple sclerosis (MS). Multiple sclerosis pathologic damage typically includes demyelination, neuro-axonal loss, and astrogliosis. OBJECTIVE: To evaluate the potential of magnetic resonance markers of central nervous system injury to predict brain-volume loss and clinical disability in multiple sclerosis. DESIGN, SETTING, AND PARTICIPANTS: Participants were selected from the Multiple Sclerosis Center at the University of California-San Francisco. The preliminary data set included 59 patients with MS and 43 healthy control individuals. The confirmatory data set included 220 patients from an independent, large genotype-phenotype research project. MAIN OUTCOMES AND MEASURES: Baseline N-acetylaspartate (NAA) level, myo-inositol (mI) in normal-appearing white and gray matter, myelin water fraction in normal-appearing white matter, markers of axonal damage, astrogliosis, and demyelination were evaluated as predictors in a preliminary data set. Potential predictors were subsequently tested for replication in a confirmatory data set. Clinical scores and percentage of brain-volume change were obtained annually over 4 years as outcomes. Predictors of outcomes were assessed using linear models, linear mixed-effects models, and logistic regression. RESULTS: N-acetylaspartate and mI both had statistically significant effects on brain volume, prompting the use of the mI:NAA ratio in normal-appearing white matter as a predictor. The ratio was a predictor of brain-volume change in both cohorts (annual slope in the percentage of brain-volume change/unit of increase in the ratio: -1.68; 95% CI, -3.05 to -0.30; P = .02 in the preliminary study cohort and -1.08; 95% CI, -1.95 to -0.20; P = .02 in the confirmatory study cohort). Furthermore, the mI:NAA ratio predicted clinical disability (Multiple Sclerosis Functional Composite evolution: -0.52 points annually, P < .001; Multiple Sclerosis Functional Composite sustained progression: odds ratio, 2.76/SD increase in the ratio; 95% CI, 1.32 to 6.47; P = .01) in the preliminary data set and predicted Multiple Sclerosis Functional Composite evolution (-0.23 points annually; P = .01), Expanded Disability Status Scale evolution (0.57 points annually; P = .04), and Expanded Disability Status Scale sustained progression (odds ratio, 1.46; 95% CI, 1.10 to 1.94; P = .009) in the confirmatory data set. Myelin water fraction did not show predictive value. CONCLUSIONS AND RELEVANCE: The mI:NAA ratio in normal-appearing white matter has consistent predictive power on brain atrophy and neurological disability evolution. The combined presence of astrogliosis and axonal damage in white matter has cardinal importance in disease severity.

Prevalence of asymptomatic vasogenic edema in pretreatment Alzheimer's disease study cohorts from phase 3 trials of semagacestat and solanezumab.

BACKGROUND: Cerebral vasogenic edema (VE) has been reported to occur during antiamyloid immunotherapy. VE may be associated with central nervous system pathology with blood-brain barrier disruptions; however, less is known about the prevalence of naturally occurring VE in patients with Alzheimer's disease (AD). METHODS: Fluid-attenuated inversion recovery imaging sequences were obtained from four ongoing multicenter, randomized, double-blind, placebo-controlled, phase 3 trials in patients with mild-to-moderate AD. The first set of baseline scans was from patients in volumetric magnetic resonance imaging addenda in the Interrupting Alzheimer's Dementia by EvaluatiNg Treatment of Amyloid PaThologY (IDENTITY) studies examining semagacestat, a γ-secretase inhibitor (cohort 1, n = 621). The second set of baseline scans was from the EXPanding alzhEimer's Disease InvestigaTIONs (EXPEDITION) studies examining solanezumab, an anti-Aß monoclonal antibody (cohort 2, n = 2141). Readers were blinded to patient-identifying information and future treatment. A third set of baseline scans was from the first 700 patients who underwent protocol-specified magnetic resonance imaging before randomization in the EXPEDITION studies (cohort 3). The analysis used three neuroradiologists: two performed independent primary interpretations and the third was the adjudicator. Readers were blinded to patient information, treatment, protocol, and time point. RESULTS: Four cases of asymptomatic VE were detected at baseline/screening. Two VE cases were due to underlying extra-axial mass lesions. The third VE case was associated with numerous microhemorrhages in keeping with cerebral amyloid angiopathy-related inflammation or Aß-related angiitis. The final VE case demonstrated localized sulcal fluid-attenuated inversion recovery imaging hyperintensity. No VE was detected in cohort 3 by readers blinded to patient baseline status. CONCLUSIONS: VE seems to be rare at baseline in patients with AD in clinical trials, 2 of 2,762 associated with AD. Additional cohorts should be evaluated to support these findings.

Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study).

INTRODUCTION: The aim of the study was to assess the clinical efficacy, safety, and disease-modification effects of tramiprosate (homotaurine, ALZHEMED(TM)) in mild-to-moderate Alzheimer's disease (AD). MATERIAL AND METHODS: Double-blind, placebo-controlled, randomized trial in 67 clinical centres across North America. Patients aged ≥ 50 years, with mild-to-moderate AD (Mini-Mental State Examination score between 16 and 26) and on stable doses of cholinesterase inhibitors, alone or with memantine. INTERVENTION: 78-week treatment with placebo, tramiprosate 100 mg or tramiprosate 150 mg BID. MEASUREMENTS: Alzheimer Disease Assessment Scale - cognitive subscale (ADAS-cog) and Clinical Dementia Rating - Sum of Boxes (CDR-SB) assessments were performed at baseline and every 13 weeks. Baseline and 78-week magnetic resonance imaging (MRI) hippocampus volume (HV) measurements were conducted in a subgroup of patients. RESULTS: A total of 1,052 patients were enrolled and 790 (75.1%) completed the 78-week trial. Patient discontinuation and reasons for withdrawal were similar across groups. Planned analyses did not reveal statistically significant between-group differences. Lack of adequate statistical validity of the planned analysis models led to the development of revised predictive models. These adjusted models showed a trend toward a treatment effect for ADAS-cog (P = 0.098) and indicated significantly less HV loss for tramiprosate 100 mg (P = 0.035) and 150 mg (P = 0.009) compared to placebo. The incidence of adverse events was similar across treatment groups. CONCLUSIONS: The primary planned analyses did not show a significant treatment effect, but were confounded by unexplained variance. Post-hoc analyses showed a significant treatment-related reduction in HV loss. However, there was only a trend towards slowing of decline on the ADAS-cog and no slowing of decline on the CDR-SB. These results must be interpreted in consideration of the limitations of clinical and disease-modification outcome measures and their relationship, the heterogeneity of the disease and the impact of confounding demographic and clinical variables.

Multislice brain myelin water fractions at 3T in multiple sclerosis.

PURPOSE: To evaluate a multislice nonlinearly-spaced 12-echo imaging sequence at 3T covering the supratentorial brain for the quantification of myelin water fraction (MWF) in multiple sclerosis (MS) patients. METHODS: Eighty-nine patients with, or at risk of, MS (69 relapsing remitting MS [RRMS], 7 secondary progressive MS [SPMS], 13 clinically isolated syndrome [CIS]) and 28 controls were studied. Twelve-echo datasets were acquired using a multislice T2 prep spiral imaging sequence and were fitted using a nonnegative least squares algorithm. The mean MWF within normal appearing white matter (NAWM), contrast-enhancing (CE), and nonenhancing T2 lesions were calculated. RESULTS: Mean MWF in white matter for controls was 11.3%. Mean MWF was significantly reduced in NAWM of MS patients (10.6%, P= .004) relative to controls. SPMS/RRMS patients with disease duration >5 years (10.3%) had lower MWF compared to CIS/RRMS with disease duration

Measurement of in vivo multi-component T2 relaxation times for brain tissue using multi-slice T2 prep at 1.5 and 3 T.

The objective of this study was to implement a clinically relevant multi-slice multi-echo imaging sequence in order to quantify multi-component T2 relaxation times for normal volunteers at both 1.5 and 3 T. Multi-echo data were fitted using a nonnegative least square algorithm. Twelve echo data with nonlinear echo sampling were acquired using a receive-only eight-channel phased array coil and volume head coil for phantoms and normal volunteers, and compared to 32-echo data with linear echo sampling. It was observed that the performance of the 180 degrees refocusing trains was more spatially uniform for the receive-only eight-channel phased array coil than for the head coil, particularly at 3 T. The phantom study showed that the estimated T2 relaxation times were accurate and reproducible for both single- and multi-slice acquisition from a commercial phantom with known T2 relaxation times. Short T2 components (T2 <50 ms) were mainly observed within the white matter for normal volunteers, and the fraction of short T2 water components (i.e., myelin water) was 7-12% of total water. It was observed that the calculated myelin water fraction map from the nonlinearly sampled 12-echo data was comparable with that from the linearly sampled 32-echo data. Quantification of T2 relaxation times from multi-slice images was accomplished with a clinically acceptable scan times (16 min) for normal volunteers by using a nonselective T2 prep imaging sequence. The use of the eight-channel head coil involved more accurate quantification of T2 relaxation times particularly when the number of echoes was limited.

Quantitative apparent diffusion coefficients and T2 relaxation times in characterizing contrast enhancing brain tumors and regions of peritumoral edema.

PURPOSE: To investigate the potential value and relationship of in vivo quantification of apparent diffusion coefficients (ADCs) and T2 relaxation times for characterizing brain tumor cellularity and tumor-related edema. MATERIALS AND METHODS: A total of 26 patients with newly diagnosed gliomas, meningiomas, or metastases underwent diffusion-weighted and six-echo multisection T2-preparation imaging. Regions of interest (ROIs) were drawn on conventional MR images to include tumor (as defined by contrast agent enhancement) and immediate and peripheral edema. Areas of necrosis were excluded. Median values of ADCs and T2 in the ROIs were calculated. RESULTS: ADCs for gliomas were similar to those for meningiomas or metastases in all regions. Tumor T2 values for gliomas (159.5+/-30.6 msec) were significantly higher than those for meningiomas or metastases (125.0+/-31.1 msec; P=0.005). Immediate-edema T2 values for meningiomas or metastases (226.0+/-44.1 msec) were significantly higher than those for gliomas (203.5+/-32.8 msec; P=0.033). Peripheral-edema T2 values for gliomas (219.5+/-41.9 msec) were similar to those for meningiomas or metastases (202.5+/-26.5 msec; P=0.377). Both immediate- and peritumoral-edema ADCs and T2 values were significantly higher than those in tumor for both tumor types. ADCs and T2 values from all regions correlated significantly for gliomas (r=0.95; P<0.0001) and for meningiomas or metastases (r=0.81; P<0.0001). CONCLUSION: The higher immediate-edema T2 values for nonglial tumors than for gliomas suggest tumor-related edema (vasogenic vs. infiltrated) can be further characterized by using T2 values. There were significant correlations between ADC and T2 values.

Corpus callosum axonal injury in multiple sclerosis measured by proton magnetic resonance spectroscopic imaging.

BACKGROUND: Axonal damage has been observed in normal-appearing white matter (NAWM) for patients with multiple sclerosis (MS). OBJECTIVES: To investigate changes in brain metabolite ratios in a region of normal-appearing corpus callosum (CC) for patients with MS and to test its relationship to changes in other regions of NAWM. DESIGN AND METHODS: Data were collected from 24 patients with MS and 15 control subjects. Two-dimensional proton magnetic resonance spectroscopic imaging was performed centered at the CC. Regions of interest from normal-appearing CC were manually segmented using anatomical images. The NAWM outside the CC region was segmented based on the signal intensity in T1- and T2-weighted images. RESULTS: The N-acetylaspartate-creatine-phosphocreatine ratio was lower in both regions for patients with secondary progressive MS compared with the controls; the N-acetylaspartate-creatine-phosphocreatine was lower only in the normal-appearing CC region for patients with relapsing-remitting MS (P<.001) compared with the controls. The ratio of choline-containing compound compared with the creatine-phosphocreatine ratio was also lower in the region of normal-appearing CC for patients with relapsing-remitting MS (P =.003) compared with the controls. There was a correlation between the N-acetylaspartate-creatine-phosphocreatine ratio in the normal-appearing CC and T1 lesions (r = -0.53, P =.01) for all patients. CONCLUSIONS: The CC was a more sensitive location for depicting axonal injury than other regions of NAWM. A correlation between the reduction of the N-acetylaspartate-creatine-phosphocreatine ratio in the normal-appearing CC and the T1 lesions may suggest that transection of axons in lesions may cause distant axonal damage and/or dysfunction that are expressed and more sensitively detectable in the CC.

Survival analysis in patients with glioblastoma multiforme: predictive value of choline-to-N-acetylaspartate index, apparent diffusion coefficient, and relative cerebral blood volume.

PURPOSE: To investigate the potential value of pre-external-beam radiation therapy (XRT) choline-to-NAA (N-acetylaspartate) index (CNI), apparent diffusion coefficient (ADC), and relative cerebral blood volume (rCBV) for predicting survival in newly diagnosed patients with glioblastoma multiforme (GBM). MATERIALS AND METHODS: Twenty-eight patients with GBM were studied using in vivo proton magnetic resonance spectroscopic imaging (1H MRSI) and diffusion- and perfusion-weighted imaging after surgery but prior to XRT. Patients were categorized on the basis of their volumes of morphologic and metabolic abnormalities (volume of CNI > or = 2 and CNI values), normalized ADC (nADC), or rCBV values within the T1 contrast-enhancing and T2 regions. The median survival time was compared. RESULTS: A significantly shorter median survival time was observed for patients with a large volume of metabolic abnormality than for those with a small abnormality (12.0 and 17.1 months, respectively, P = 0.002). A similar pattern was observed for patients with a low mean nADC value compared to those with high mean nADC value within the T2 region (11.2 and 21.7 months, respectively, P = 0.004). A shorter median survival time was also observed for patients with contrast-enhancing residual disease than for those without the presence of contrast enhancement with marginal significance. CONCLUSION: The pre-XRT volume of the metabolic abnormality and the nADC value within the T2 region may be valuable in predicting outcome for patients with GBM.

3D MRSI for resected high-grade gliomas before RT: tumor extent according to metabolic activity in relation to MRI.

PURPOSE: To evaluate the presence of residual disease after surgery but before radiotherapy (RT) in patients with high-grade glioma by MRI and magnetic resonance spectroscopy imaging (MRSI) and to estimate the impact of MRSI on the definition of postoperative target volumes for RT treatment planning. METHODS AND MATERIALS: Thirty patients (27 glioblastoma multiforme, 3 Grade III astrocytoma) underwent MRI and MRSI within 4 weeks after surgery but before the initiation of RT. The MRI data were manually contoured; the regions of interest included T(2)-weighted hyperintensity (T(2)), T(1)-weighted contrast enhancement (T(1)), and the resection cavity (RC). Levels of choline and N-acetyl-aspartate (NAA) in the three-dimensional MRSI data were analyzed on the basis of a choline-to-N-acetyl-aspartate index (CNI). The CNI and other metabolic indexes were superimposed on the MRI data as three-dimensional contours. Composite, conjoint, and disjoint volumes were defined for T(1) and T(2), with/without RC, and within the CNI contour, corresponding to a value of 2. In addition, follow-up MRI studies were examined for new onset contrast enhancement and compared with the initial spectroscopic findings obtained before RT. RESULTS: Substantial variation was found in the spatial relationship between the MRI and MRSI volumes. Ten patients had no contrast enhancement after surgery, and MRSI revealed abnormal metabolic activity in 8 of 10, averaging 20 cm(3) and extending 11-36 mm beyond the RC. In 20 patients with contrast-enhancing lesions, substantial variation was found between T(1) and CNI2; metabolic activity fell outside the contrast enhancement in 19 patients, averaging 21 cm(3) and extending 8-33 mm beyond the contrast enhancement. For all patients, the T(2) encompassed most of the metabolic volume. However, the CNI2 extended beyond the T(2) in 6 of 10 patients without contrast enhancement (mean, 8 cm(3); maximum, 15-23 mm) and in 13 of 20 patients with contrast enhancement (mean, 7 cm(3); maximum, 8-22 mm), representing an increase in the T(2) volume by as much as 180% (median 13%) and 86% (median 14%) for non-contrast-enhancing and contrast-enhancing patients, respectively. Preliminary evaluation of the MRI follow-up examinations revealed correspondence of areas of new contrast enhancement with initial MRSI abnormalities in 8 of 10 non-contrast-enhancing patients. In addition, CNI volumes correlated inversely with the time to onset of new contrast enhancement. CONCLUSION: MRSI is a valuable diagnostic tool for the assessment of residual disease after surgical resection in high-grade glioma. The incorporation of areas of metabolic abnormality into treatment planning for postoperative patients would produce different sizes and shapes of target volumes for both primary and boost volumes. It also may encourage the use of nonuniform margins to define the extent of tumor cell infiltration, rather than the current use of uniform margins.

Identification of MRI and 1H MRSI parameters that may predict survival for patients with malignant gliomas.

Although MR imaging (MRI) and MR spectroscopic imaging (MRSI) have been applied in the diagnosis and treatment planning for brain tumors, their prognostic significance has not yet been determined. The goal of this study was to identify pre-treatment MRI and MRSI parameters for patients with malignant glioma that may be useful in predicting survival. Two populations of patients with newly-diagnosed malignant glioma were examined with MRI and three-dimensional proton ((1)H) MRSI. Thirty-nine patients (22 grade 3 and 17 glioblastoma multiforme, GBM) were studied prior to surgery, and 33 GBM patients were studied after surgery but prior to treatment with radiation and chemotherapy. Signal intensities of choline (Cho), creatine (Cr), N-acetyl aspartate (NAA), and lactate/lipid (LL) were estimated from the spectra. Recursive partitioning methods were applied to parameters that included age, histological grade, MRI and MRSI variables to generate survival trees. Patients were grouped into high and low risk categories and the corresponding Kaplan-Meier curves were plotted for comparison between groups. The parameters that were selected by recursive partitioning as being predictive of poor outcome were older age, larger contrast enhancement, higher Cho-to-Cr, higher Cho-to-NAA, higher LL and lower Cr-to-NAA abnormalities. The survival functions were significantly different between the sub-groups of patients obtained from the survival tree for both pre-surgery and post-surgery data. The results of this study suggest that pre-treatment MRI and three-dimensional (1)H-MRSI provide information that predicts outcome for patients with malignant gliomas and have drawn attention to variables that should be examined prospectively in future studies using these techniques.

Directional diffusion in relapsing-remitting multiple sclerosis: a possible in vivo signature of Wallerian degeneration.

PURPOSE: To examine the role of directional dependence of the apparent diffusion coefficients in the evaluation of normal-appearing brain regions of patients with relapsing-remitting multiple sclerosis. MATERIALS AND METHODS: The role of diffusion tensor eigenvalues was investigated in the normal-appearing brain regions for 18 patients with relapsing-remitting multiple sclerosis and 15 age-matched normal controls. RESULTS: The isotropic apparent diffusion was increased in all regions. However, reduced anisotropy was significant only in regions with high anisotropy, including the corpus callosum and the internal capsule, and was due to increased diffusion tensor eigenvalues corresponding to diffusion transverse to the fibers without significant increase along the fibers. This characteristic pattern of changes in diffusion tensor eigenvalues has been observed previously in cases of Wallerian degeneration. Low-anisotropy regions corresponded to gray matter and gray/white interface regions. Since fiber tract orientations are not determined for regions of low anisotropy, this characteristic pattern of diffusion change is not detectable in these regions. CONCLUSION: Examination of diffusion tensor eigenvectors may provide insight into the changes observed in diffusion and a signature of Wallerian degeneration in the normal-appearing white matter of relapsing-remitting multiple sclerosis patients.

Dissociating perceptual and conceptual implicit memory in multiple sclerosis patients.

Previous studies indicate that Multiple Sclerosis (MS) patients exhibit deficits in tests of explicit memory such as free recall, but show normal priming on implicit tests of memory such as word stem completion. However, the memory performance of patients with different MS disease subtypes has not been fully examined. In the current study, memory was assessed in Primary Progressive (PPMS), Relapsing Remitting (RRMS), and Secondary Progressive (SPMS) MS subgroups. Explicit memory as well as perceptual and conceptual implicit memory were examined using free recall, word fragment completion, and exemplar generation tests, respectively. All three groups of MS patients exhibited free recall deficits and normal priming on the exemplar generation test. However, the PPMS group exhibited a deficit in word fragment completion priming, whereas the RRMS and SPMS groups exhibited normal levels of priming on this task. Lesion load was assessed using magnetic resonance imaging and was negatively correlated with explicit memory performance, but it did not account for the observed deficits in perceptual implicit memory. The results indicate that PPMS patients exhibit a pattern of memory impairment that is distinct from that of the RRMS and SPMS groups. Moreover, the results indicate that perceptual implicit memory can be neurologically dissociated from conceptual implicit memory.