Differential effects of Alzheimer\u27s disease and Huntington\u27s disease on the performance of mental rotation

he ability to spatially rotate a mental image was compared in patients with Alzheimer\u27s disease (AD; n = 18) and patients with Huntington\u27s disease (HD; n = 18). Compared to their respective age-matched normal control (NC) group, the speed, but not the accuracy, of mental rotation abnormally decreased with increasing angle of orientation for patients with HD. In contrast, the accuracy, but not the speed, of rotation abnormally decreased with increasing angle of orientation for patients with AD. Additional analyses showed that these unique patterns of performance were not attributable to different speed/accuracy trade-off sensitivities. This double dissociation suggests that the distinct brain regions affected in the two diseases differentially contribute to speed and accuracy of mental rotation. Specifically, the slowing exhibited by HD patients may be mediated by damage to the basal ganglia, whereas the spatial manipulation deficit of AD patients may reflect pathology in parietal and temporal lobe association cortices important for visuospatial processing. (JINS, 2005, 11, 30–39.

Measurement of T1 of the ultrashort T2* components in white matter of the brain at 3T.

Recent research demonstrates that white matter of the brain contains not only long T2 components, but a minority of ultrashort T2* components. Adiabatic inversion recovery prepared dual echo ultrashort echo time (IR-dUTE) sequences can be used to selectively image the ultrashort T2* components in white matter of the brain using a clinical whole body scanner. The T2*s of the ultrashort T2* components can be quantified using mono-exponential decay fitting of the IR-dUTE signal at a series of different TEs. However, accurate T1 measurement of the ultrashort T2* components is technically challenging. Efficient suppression of the signal from the majority of long T2 components is essential for robust T1 measurement. In this paper we describe a novel approach to this problem based on the use of IR-dUTE data acquisitions with different TR and TI combinations to selectively detect the signal recovery of the ultrashort T2* components. Exponential recovery curve fitting provides efficient T1 estimation, with minimized contamination from the majority of long T2 components. A rubber phantom and a piece of bovine cortical bone were used for validation of this approach. Six healthy volunteers were studied. An averaged T2* of 0.32 ± 0.09 ms, and a short mean T1 of 226 ± 46 ms were demonstrated for the healthy volunteers at 3T

Comparisons of neurodegenerative disease biomarkers across different biological fluids from patients with Huntingtons disease.

Fluid biomarkers play important roles in many aspects of neurodegenerative diseases, such as Huntingtons disease (HD). However, a main question relates to how well levels of biomarkers measured in CSF are correlated with those measured in peripheral fluids, such as blood or saliva. In this study, we quantified levels of four neurodegenerative disease-related proteins, neurofilament light (NfL), total tau (t-tau), glial fibrillary acidic protein (GFAP) and YKL-40 in matched CSF, plasma and saliva samples from Huntingtin (HTT) gene-positive individuals (n = 21) using electrochemiluminescence assays. In addition, salivary levels of NfL, t-tau, and GFAP were quantified from a larger cohort (n = 95). We found both positive and negative correlations in the levels of these biomarkers among different biofluids. Most notably, in contrast to the significant positive correlations observed between CSF and plasma levels for NfL and GFAP, we detected significant negative correlations between the CSF and saliva levels of NfL and GFAP. With regard to clinical measures, both plasma and CSF levels of NfL were significantly positively correlated with Total Motor Score and chorea, whereas saliva levels of NfL showed significant correlations in the opposite direction. Additional correlations between salivary biomarkers with clinical data, adjusting for age, sex and CAG repeat length, confirmed that salivary NfL was significantly negatively associated with chorea scores in manifest HD, but not premanifest (PM), individuals. In contrast, salivary t-tau was positively associated with measures of cognition in PM participants. These findings suggest that salivary levels of NfL and t-tau proteins may exemplify non-invasive biomarkers for disease symptoms at different stages of illness. Further, these findings highlight the notion that different forms of disease proteins exist in different biological fluids

The relationship between dementia severity and rest/activity circadian rhythms

Patients with dementia have been shown to have disturbed sleep/wake rhythms. There is evidence of impairment in endogenous generation of rhythms and deficient environmental cues in this population. This study sought to examine patterns of rest/activity rhythms as they relate to dementia severity. Three days of actigraphy were collected from 150 nursing-home patients with dementia and used to compute rhythm parameters. Dementia severity was estimated with the Mini-Mental State Examination (MMSE). The relationship between rhythm parameters and dementia severity was examined. Rhythm parameters were not associated with dementia in the sample as a whole, but relationships emerged when the sample was divided on the basis of overall rhythm robustness (F-statistic). Within the group with less robust rhythms, those with stronger rhythms had less severe dementia. In the group with more robust rhythms, milder dementia was associated with having an earlier acrophase (timing of the peak of the rhythm) and narrower peak of the rhythm (shorter duration of peak activity). These results suggested a three-stage model of rest/activity rhythm changes in dementia in which dementia patients have a rapid decline in rhythmicity followed by a slight return to stronger rhythms. In the later stages of dementia, rhythms decline even further

The Impact of Cognitive Deficits and Spasticity on Driving Simulator Performance in Multiple Sclerosis

Multiple sclerosis (MS) is a demyelinating disease that can result in numerous sequelae. Although spasticity and cognitive dysfunction are common in MS, few studies have examined the impact of both factors on driving abilities in persons with physical impairments. The present study assessed driving performance in control participants and MS patients with documented spasticity using two brief simulations designed to measure lane tracking (under high cognitive load) and car following behavior. Seventeen MS patients and 9 controls participated in the study. The MS cohort exhibited a broad range of cognitive functioning (normal to significant impairment) and disability (Expanded Disability Status Scale scores of 3.0 to 7.5). Eight of the MS patients had significant spasticity in their right knee based upon the Modified Ashworth Spasticity Scale. MS patients had greater difficulty than controls on the simulations, particularly on the car following task. MS participants also tended to drive at higher speeds than the control participants. Within the MS cohort, cognitive dysfunction was most strongly associated with lane tracking decrements, whereas the possible relationship between cognitive function and car following behavior was eclipsed by lower limb spasticity. Spastic individuals had greater difficulty mirroring speed changes in the lead car, and were approximately one second slower in responding to its accelerations and decelerations. The current simulations provide important data regarding the impact various MS sequelae may have on driving performance, and may ultimately lead to clinical recommendations regarding specific driving behaviors and their associated risks

Clinical evaluation of white matter lesions on 3D inversion recovery ultrashort echo time MRI in multiple sclerosis

BackgroundWe clinically evaluated the quality of white matter lesions (WML) of the cerebrum on 3D inversion recovery ultrashort echo time (IR-UTE) magnetic resonance imaging (MRI) in multiple sclerosis (MS) patients.MethodsForty-nine patients with MS were included in this study. A 3T MRI scanner was used. Two radiologists (readers) evaluated the quality of WML on IR-UTE images using a three-point Likert scale (1-good quality, 2-moderate quality, 3-insufficient quality). They also rated other WML-related factors potentially influencing WML quality using another three-point Likert scale (1-no/minor impact, 2-moderate impact, 3-high impact). Another reader rated the presence of WML on IR-UTE to evaluate the diagnostic value (right/false positive and false negative) of IR-UTE in detecting WML. Signal intensity ratios (SIRs) derived from WML signal intensities and WML sizes were also determined and analyzed.ResultsTwo hundred and seventy-five MS lesions were evaluated. 87% of the lesions were rated Likert 1 on IR-UTE (P<0.01). WML rated Likert 2 and 3 presented near the grey matter (GM) in 58% of the cases (n=21), with 14 lesions being ≤2 mm (P=0.03). 62.5% of the WML rated Likert 2/3 were in the temporal lobe (P=0.02). The mean SIR of WML on IR-UTE was 1.14±0.22, while the mean SIR on fluid-attenuated inversion recovery (FLAIR) was 6.97±1.88. There was no significant correlation of SIRs between IR-UTE and FLAIR (R=0.14, P=0.245). 92.4% of the WML were correctly detected on IR-UTE (n=254). 19 out of the 21 false positive/negative rated WML were located near the GM or in the temporal lobe. WML presented 7.7% smaller in mean on IR-UTE compared to FLAIR. Factors affecting WML quality with a moderate or high impact (Likert 2 and 3) were not found.ConclusionsMost WML are clearly detectable on IR-UTE sequences. The main limitations are WML in the temporal lobe and near the GM

LASSI-L detects early cognitive changes in pre-motor manifest Huntington’s disease: a replication and validation study

Background and objectivesCognitive decline is an important early sign in pre-motor manifest Huntington’s disease (preHD) and is characterized by deficits across multiple domains including executive function, psychomotor processing speed, and memory retrieval. Prior work suggested that the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L)–a verbal learning task that simultaneously targets these domains - could capture early cognitive changes in preHD. The current study aimed to replicate, validate and further analyze the LASSI-L in preHD using larger datasets.MethodsLASSI-L was administered to 50 participants (25 preHD and 25 Healthy Controls) matched for age, education, and sex in a longitudinal study of disease progression and compared to performance on MMSE, Trail A & B, SCWT, SDMT, Semantic Fluency (Animals), and CVLT-II. Performance was then compared to a separate age-education matched-cohort of 25 preHD participants. Receiver operating curve (ROC) and practice effects (12 month interval) were investigated. Group comparisons were repeated using a preHD subgroup restricted to participants predicted to be far from diagnosis (Far subgroup), based on CAG-Age-Product scaled (CAPs) score. Construct validity was assessed through correlations with previously established measures of subcortical atrophy.ResultsPreHD performance on all sections of the LASSI-L was significantly different from controls. The proactive semantic interference section (PSI) was sensitive (p = 0.0001, d = 1.548), similar across preHD datasets (p = 1.0), reliable on test–retest over 12 months (spearman rho = 0.88; p = <0.00001) and associated with an excellent area under ROC (AUROC) of 0.855. In the preHD Far subgroup comparison, PSI was the only cognitive assessment to survive FDR < 0.05 (p = 0.03). The number of intrusions on PSI was negatively correlated with caudate volume.DiscussionThe LASSI-L is a sensitive, reliable, efficient tool for detecting cognitive decline in preHD. By using a unique verbal learning test paradigm that simultaneously targets executive function, processing speed and memory retrieval, the LASSI-L outperforms many other established tests and captures early signs of cognitive impairment. With further longitudinal validation, the LASSI-L could prove to be a useful biomarker for clinical research in preHD

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead