Rehabilitation Institute of Michigan

Mild cognitive impairment is common in nondemented Parkinson's disease (PD) patients and may be a harbinger of dementia. In view of its importance, the Movement Disorder Society commissioned a task force to delineate diagnostic criteria for mild cognitive impairment in PD. The proposed diagnostic criteria are based on a literature review and expert consensus. This article provides guidelines to characterize the clinical syndrome and methods for its diagnosis. The criteria will require validation, and possibly refinement, as additional research improves our understanding of the epidemiology, presentation, neurobiology, assessment, and long-term course of this clinical syndrome. These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage.

Previously, we reported that one individual who had a motor complete, but sensory incomplete spinal cord injury regained voluntary movement after 7 months of epidural stimulation and stand training. We presumed that the residual sensory pathways were critical in this recovery. However, we now report in three more individuals voluntary movement occurred with epidural stimulation immediately after implant even in two who were diagnosed with a motor and sensory complete lesion. We demonstrate that neuromodulating the spinal circuitry with epidural stimulation, enables completely paralysed individuals to process conceptual, auditory and visual input to regain relatively fine voluntary control of paralysed muscles. We show that neuromodulation of the sub-threshold motor state of excitability of the lumbosacral spinal networks was the key to recovery of intentional movement in four of four individuals diagnosed as having complete paralysis of the legs. We have uncovered a fundamentally new intervention strategy that can dramatically affect recovery of voluntary movement in individuals with complete paralysis even years after injury.

Summ a r yPersons with motor complete spinal cord injury, signifying no voluntary movement or sphincter function below the level of injury but including retention of some sensation, do not recover independent walking.We tested intense locomotor treadmill training with weight support and simultaneous spinal cord epidural stimulation in four patients 2.5 to 3.3 years after traumatic spinal injury and after failure to improve with locomotor training alone.Two patients, one with damage to the mid-cervical region and one with damage to the high-thoracic region, achieved over-ground walking (not on a treadmill) after 278 sessions of epidural stimulation and gait training over a period of 85 weeks and 81 sessions over a period of 15 weeks, respectively, and all four achieved independent standing and trunk stability.One patient had a hip fracture during training.(Funded by the Leona M. and Harry B. Helmsley Charitable Trust and others; ClinicalTrials.govnumber, NCT02339233.)T here are estimated to be 1,275,000 persons with paralysis from spinal cord injury in the United States. 1 These patients indicate in surveys that walking and standing are highly desirable goals. 2 We have previously shown that epidural stimulation of the spinal cord and simultaneous intense rehabilitation may allow the restoration of some volitional movement below the level of spinal injury 3,4 and may result in the ability to stand independently.5,6 We report here recovery of independent walking over ground, not on a treadmill, in two of four patients with motor complete paralysis, with the use of a program that combines customized epidural spinal cord stimulation and intense training in standing and stepping.The study was approved by the institutional review board at the University of Louisville and was conducted in accordance with the Declaration of Helsinki.All the patients provided written informed consent.All the authors vouch for the completeness and accuracy of the data and the reporting of adverse events and for the adherence of the study to the protocol, available with the full text of this article at NEJM.org.Medtronic provided the epidural electrode arrays, neurostimulators, programming devices, and recharging units to the Kentucky Spinal Cord Injury Research Center at the University of Louisville.There was no other industry involvement, and no funds were given by Medtronic to the institution, investigators, or research participants.The delay between active intervention for the first patient (November 11, 2014) and registration of the study (January 12, 2015) is explained in the Supplementary Appendix, available at NEJM.org.

Glutathione peroxidase, a selenium-containing enzyme, is believed to protect cells from the toxicity of hydroperoxides. The physiological role of this enzyme has previously been implicated mainly using animals fed with a selenium-deficient diet. Although selenium deficiency also affects the activity of several other cellular selenium-containing enzymes, a dramatic decrease of glutathione peroxidase activity has been postulated to play a role in the pathogenesis of a number of diseases, particularly those whose progression is associated with an overproduction of reactive oxygen species, found in selenium-deficient animals. To further clarify the physiological relevance of this enzyme, a model of mice deficient in cellular glutathione peroxidase (GSHPx-1), the major isoform of glutathione peroxidase ubiquitously expressed in all types of cells, was generated by gene-targeting technology. Mice deficient in this enzyme were apparently healthy and fertile and showed no increased sensitivity to hyperoxia. Their tissues exhibited neither a retarded rate in consuming extracellular hydrogen peroxide nor an increased content of protein carbonyl groups and lipid peroxidation compared with those of wild-type mice. However, platelets from GSHPx-1-deficient mice incubated with arachidonic acid generated less 12-hydroxyeicosatetraenoic acid and more polar products relative to control platelets at a higher concentration of arachidonic acid, presumably reflecting a decreased ability to reduce the 12-hydroperoxyeicosatetraenoic acid intermediate. These results suggest that the contribution of GSHPx-1 to the cellular antioxidant mechanism under normal animal development and physiological conditions and to the pulmonary defense against hyperoxic insult is very limited. Nevertheless, the potential antioxidant role of this enzyme in protecting cells and animals against the pathogenic effect of reactive oxygen species in other disorders remains to be defined. The knockout mouse model described in this report will also provide a new tool for future study to distinguish the physiological role of this enzyme from other selenium-containing proteins in mammals under normal and disease states.

Adriamycin (ADR) is a potent anticancer drug known to cause severe cardiac toxicity. Although ADR generates free radicals, the role of free radicals in the development of cardiac toxicity and the intracellular target for ADR-induced cardiac toxicity are still not well understood. We produced three transgenic mice lines expressing increased levels of human manganese superoxide dismutase (MnSOD), a mitochondrial enzyme, as an animal model to investigate the role of ADR-mediated free radical generation in mitochondria. The human MnSOD was expressed, functionally active, and properly transported into mitochondria in the heart of transgenic mice. The levels of copper-zinc SOD, catalase, and glutathione peroxidase did not change in the transgenic mice. Electron microscopy revealed dose-dependent ultrastructural alterations with marked mitochondrial damage in nontransgenic mice treated with ADR, but not in the transgenic littermates. Biochemical analysis indicated that the levels of serum creatine kinase and lactate dehydrogenase in ADR-treated mice were significantly greater in nontransgenic than their transgenic littermates expressing a high level of human MnSOD after ADR treatment. These results support a major role for free radical generation in ADR toxicity as well as suggesting mitochondria as the critical site of cardiac injury.

In previous studies of attentional focus effects, investigators have measured performance outcome. Here, however, the authors used electromyography (EMG) to determine whether difference between external and internal foci would also be manifested at the neuromuscular level. In 2 experiments, participants (N=11, Experiment 1; N=12, Experiment 2) performed biceps curls while focusing on the movements of the curl bar (external focus) or on their arms (internal focus). In Experiment 1, movements were performed faster under external than under internal focus conditions. Also, integrated EMG (iEMG) activity was reduced when performers adopted an external focus. In Experiment 2, movement time was controlled through the use of a metronome, and iEMG activity was again reduced under external focus conditions. Those findings are in line with the constrained action hypothesis (G. Wulf, N. McNevin, & C. H. Shea, 2001), according to which an external focus promotes the use of more automatic control processes.

OBJECTIVE: This study examined predictors of family dysfunction and caregiver distress among 60 pairs of persons who sustained a traumatic brain injury and their caregivers. DESIGN: A cross-sectional design that used hierarchical multiple regression analyses evaluated the relative influences of time since injury, awareness of deficit, and neurobehavioral and neuropsychological functioning of the person with injury, and caregiver perceived social support. RESULTS: The predictor model accounted for 52% of the variance in family dysfunction and 39% in caregiver psychological distress. Neurobehavioral disturbance in the person with injury was the strongest predictor of caregiver distress. Social support showed a direct and linear relationship to family functioning, and it was the strongest predictor of family functioning. Social support was a powerful moderator of caregiver psychological distress. In the absence of adequate social support, caregiver distress increased with longer time after injury, cognitive dysfunction, and unawareness of deficit in care recipients, whereas these characteristics were not associated with distress among caregivers with adequate social support. CONCLUSIONS: Rehabilitation professionals should stress the importance of caregivers and families of persons with TBI seeking and obtaining adequate social support.

Lesions in the hippocampus (HC), the entorhinal cortex (EC), and the prefrontal cortex (PFC) are associated with impairment of episodic memory; reduced HC volume is linked to memory declines in dementia; and decline in EC volume predicts progression from mild cognitive impairment to dementia. However, in healthy adults, the relationship between memory and regional volumes is unclear, and no data are available on the relationship of longitudinal regional shrinkage to memory performance in a cognitively intact population. The objective of this study was to examine whether shrinkage of the EC, HC, and PFC over a 5 year period can predict declarative memory performance in healthy adults. The volumes of three brain regions were measured on magnetic resonance images that were acquired twice, 5 years apart. Multiple measures of episodic memory were administered at follow-up. Results indicated that the volume of HC and PFC (but not EC) correlated with age at baseline and follow-up. However, after age differences in memory were taken into account, none of the regional volumes was associated with memory performance at follow-up. In contrast, greater annual rate of shrinkage in EC (but not HC or PFC) predicted poorer memory performance. Thus, in a healthy and educated population, even mild age-related shrinkage of the EC may be a sensitive predictor of memory decline.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor in eukaryotic cells that alters gene expression in response to the environmental contaminant 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD). In 5L hepatoma cells, TCDD induces a G1 cell cycle arrest through a mechanism that involves the AhR. The retinoblastoma tumor suppressor protein (pRb) controls cell cycle progression through G1 in addition to promoting differentiation. We examined whether the human AhR or its dimerization partner, the AhR nuclear translocator, interacts with pRb as a basis of the TCDD-induced cell cycle arrest. In vivo and in vitro assays reveal a direct interaction between pRb and the AhR but not the AhR nuclear translocator protein. Binding between the AhR and pRb occurs through two distinct regions in the AhR. A high affinity site lies within the N-terminal 364 amino acids of the AhR, whereas a lower affinity binding region colocalizes with the glutamine-rich transactivation domain of the receptor. AhR ligand binding is not required for the pRb interaction per se, although immunoprecipitation experiments in 5L cells reveal that pRb associates preferentially with the liganded AhR, consistent with a requirement for ligand-induced nuclear translocation. These observations provide a mechanistic insight into AhR-mediated cell cycle arrest and a new perspective on TCDD-induced toxicity.

Locomotor training using body weight support on a treadmill and manual assistance is a promising rehabilitation technique following neurological injuries, such as spinal cord injury (SCI) and stroke. Previous robots that automate this technique impose constraints on naturalistic walking due to their kinematic structure, and are typically operated in a stiff mode, limiting the ability of the patient or human trainer to influence the stepping pattern. We developed a pneumatic gait training robot that allows for a full range of natural motion of the legs and pelvis during treadmill walking, and provides compliant assistance. However, we observed an unexpected consequence of the device's compliance: unimpaired and SCI individuals invariably began walking out-of-phase with the device. Thus, the robot perturbed rather than assisted stepping. To address this problem, we developed a novel algorithm that synchronizes the device in real-time to the actual motion of the individual by sensing the state error and adjusting the replay timing to reduce this error. This paper describes data from experiments with individuals with SCI that demonstrate the effectiveness of the synchronization algorithm, and the potential of the device for relieving the trainers of strenuous work while maintaining naturalistic stepping.

Intrathecal baclofen infusion has demonstrated effectiveness in decreasing spasticity of spinal origin. Oral antispasticity medication is minimally effective or not well tolerated in cerebral palsy. This study assessed the effectiveness of intrathecal baclofen in reducing spasticity in cerebral palsy. Candidates were screened by randomized, double-blind, intrathecal injections of baclofen and placebo. Responders were defined as those who experienced an average reduction of 1.0 in the lower extremities on the Ashworth Scale for spasticity. Responders received intrathecal baclofen via the SynchroMed System and were followed for up to 43 months. Fifty-one patients completed screening and 44 entered open-label trials. Lower-extremity spasticity decreased from an average baseline score of 3.64 to 1.90 at 39 months. A decrease in upper extremity spasticity was evidenced over the same study period. Forty-two patients reported adverse events. Most common reports were hypotonia, seizures (no new onset), somnolence, and nausea or vomiting. Fifty-nine percent of the patients experienced procedural or system-related events. Spasticity in patients with cerebral palsy can be treated effectively by continuous intrathecal baclofen. Adverse events, although common, were manageable.

In this article, the authors review recent studies on 3 factors that have been shown to affect the learning of motor skills-the performer's attentional focus, self-control, and practice in dyads-and discuss their implications for rehabilitation. Research has shown that directing learners' attention to the effects of their movements can be more beneficial for learning than directing their attention to the details of their own actions. Furthermore, giving learners some control over the training regimen has been found to enhance learning, unlike prescriptive training protocols that dictate when feedback will be delivered, how often, and the order that tasks will be practiced. Finally, not only can practice in dyads (or larger groups) reduce the costs of training, but it can also result in more effective learning than individual practice sessions. The incorporation of these factors into rehabilitation practice can potentially enhance the effectiveness and efficiency of rehabilitation.

OBJECTIVES: To assess the likely effects of the 1996 Health Insurance Portability and Accessibility Act (HIPAA), based on small firms' experiences under state small group insurance reforms that were similar in design to HIPAA. METHODS: Data on 17,818 small businesses (range, 2-50 employees) nationwide from the 1994 National Employer Health Insurance Survey were analyzed to examine the effects of state small group reforms on the following: (1) employers' provision of coverage; (2) the percentage of workers in insured firms who were covered by plans; and (3) insurer practices of "enrollee exclusion." Logistic regression models were estimated and used to quantify the marginal effects of state small-group reform. Reform effects were examined for all small firms, for small firms by size category, and for small firms in redlined industries. RESULTS: Under full reform for at least 3 years (full reform includes guaranteed issue and renewal, portability, limits on pre-existing condition waits, and rating restrictions), employers were slightly more likely to sponsor health plans; however, employee participation in employer plans was no higher and the prevalence of enrollee-exclusion provisions was unchanged. Businesses in redlined industries clearly benefitted from all types of small group reform. For other subgroups of businesses, however, there were advantages and disadvantages associated with reforms, which varied with the scope of the measures and time since their implementation. CONCLUSION: Widespread small group reform may eventually help raise the proportion of small firms that sponsor health benefits, but not by much.

Objective: The characteristics of the Disability Rating Scale (DRS), Functional Independence Measure (FIM), Functional Independence Measure and Functional Assessment Measure (FIM+FAM), and Community Integration Questionnaire (CIQ) are examined, especially in regard to a “celling effect” after rehabilitation discharge (ie, how well each of the instruments detects meaningful change in level of function). Design: Data were collected prospectively at admission and discharge from acute inpatient rehabilitation and at years 1 and 2 after injury (the CIQ was collected only at years 1 and 2). Analyses are reported on a subsamplc of cases with listwise deletion, although the analyses were also done using all data available, and results compared to ensure stability of findings between samples. Setting: National database of the four Traumatic Brain Injury (TBI) Model Systems in San Jose, Calif; Detroit, Mich; Richmond, Va; and Houston, Tex. Patients: All consenting patients with TBI age 16 and older admitted to a Model System within 24 hours of Injury and receiving inpatient rehabilitation within the Model System qualified for the study. Data on 612 individuals were collected, with a minimum of 80 cases having complete data over time. Main Outcome Measures: The DRS, FIM, FIM+FAM, and CIQ. Results: There is a substantial ceiling effect of the FIM, even by inpatient rehabilitation discharge (ie, one half of the cases have an average score of 6 to 7 [“independent or modified independence—no helper] across the 18 FIM Items). The FIM+FAM shows a ceiling effect In one third of the cases. The DRS shows less ceiling effect at discharge, 1 year, and 2 years than the FIM or the FIM+FAM. CIQ scores have a ceiling effect on home and social integration subscales when compared with scores from a sample of individuals without disabilities. The productivity subscale remains well below the norm. Conclusions: Celling effects for the FIM, FIM+FAM, and two of the three CIQ subscales indicate that these measures are not as sensitive to changes, especially in the community, as may be needed to assess progress in areas most commonly causing dysfunction for the TBI population. More emphasis must be placed on improved measurement of relevant goals in the postacute and home settings with brief and precise scales

Dynamic tests of trunk strength and lifting capacity have become more popular in recent years, offering certain advantages over static isometric tests in measuring patient progress in functional restoration programs for spinal disorders. However, equipment for performing such tests is expensive to buy, complex to run, and requires technical expertise and clinical volume unavailable in most physician offices. In this study, a new dynamic test known as Progressive Isoinertial Lifting Evaluation (PILE) is described, which draws upon prior psychophysical and isoinertial methods. An industrial sample of 61 male and 31 female incumbent workers were tested using the PILE, and a variety of anthropometric normalizing factors were evaluated. The isolation of an "Adjusted Weight" (AW) normalizing factor is documented, after which normative data are presented for male and female workers utilizing lumbar (0-30 inches) and cervical (30-54 inches) dynamic protocols.

Anthracyclines are antitumor agents the main clinical limitation of which is cardiac toxicity. The mechanism of this cardiotoxicity is thought to be related to generation of oxidative stress, causing lethal injury to cardiac myocytes. Although protein and lipid oxidation have been documented in anthracycline-treated cardiac myocytes, DNA damage has not been directly demonstrated. This study was undertaken to determine whether anthracyclines induce cardiac myocyte DNA damage and whether this damage is linked to a signaling pathway culminating in cell death. H9c2 cardiac myocytes were treated with the anthracycline doxorubicin at clinically relevant concentrations, and DNA damage was assessed using the alkaline comet assay. Doxorubicin induced DNA damage, as shown by a significant increase in the mean tail moment above control, an effect ameliorated by inclusion of a free radical scavenger. Repair of DNA damage was incomplete after doxorubicin treatment in contrast to the complete repair observed in H2O2-treated myocytes after removal of the agent. Immunoblot analysis revealed that p53 activation occurred subsequent in time to DNA damage. By a fluorescent assay, doxorubicin induced loss of mitochondrial membrane potential after p53 activation. Chemical inhibition of p53 prevented doxorubicin-induced cell death and loss of mitochondrial membrane potential without preventing DNA damage, indicating that DNA damage was proximal in the events leading from doxorubicin treatment to cardiac myocyte death. Specific doxorubicin-induced DNA lesions included oxidized pyrimidines and 8-hydroxyguanine. DNA damage therefore appears to play an important early role in anthracycline-induced lethal cardiac myocyte injury through a pathway involving p53 and the mitochondria.

Glutathione peroxidase 1 (GPX-1) is a selenium-dependent enzyme with antioxidant properties. Previous investigations determined that mice deficient in selenium developed myocarditis when infected with a benign strain of coxsackievirus B3 (CVB3/0). To determine whether this effect was mediated by GPX-1, mice with a disrupted Gpx1 gene (Gpx1-/-) were infected with CVB3/0. Gpx1-/- mice developed myocarditis after CVB3/0 infection, whereas infected wild-type mice (Gpx1+/+) were resistant. Sequencing of viruses recovered from Gpx1(-/-)-infected mice demonstrated seven nucleotide changes in the viral genome, of which three occurred at the G residue, the most easily oxidized base. No changes were found in virus isolated from Gpx1+/+ mice. These results demonstrate that GPX-1 provides protection against viral-induced damage in vivo due to mutations in the viral genome of a benign virus.

Although automobiles remain the transportation of choice for many older adults, late-life cognitive impairment and dementia often impair the ability to drive safely. However, there is no commonly used method of assessing dementia severity in relation to driving, no consensus on the assessment of older drivers with cognitive impairment, and no gold standard for determining driving fitness. Yet clinicians are called on by patients, their families, other health professionals, and often their state's Department of Motor Vehicles to assess their patients' fitness to drive and to make recommendations about driving privileges. This article describes the challenges of driving with cognitive impairment for both the patient and caregiver, summarizes the literature on dementia and driving, discusses evidence-based assessment of fitness to drive, and addresses important ethical and legal issues. It also describes the role of physician assessment, referral for neuropsychological testing, screening for functional ability, tools to assess dementia severity, driving evaluation clinics, and Department of Motor Vehicles referrals that may assist with evaluation. Lastly, it discusses mobility counseling (eg, exploration of transportation alternatives), because health professionals need to address this important issue for older adults who lose the ability to drive. The application of a comprehensive, interdisciplinary approach to the older driver with cognitive impairment will have the best opportunity to enhance patients' social connectedness and quality of life while meeting their psychological and medical needs and maintaining personal and public safety.

BACKGROUND AND PURPOSE: The use of locomotor training with a body-weight-support system and treadmill (BWST) and manual assistance has increased in rehabilitation. The purpose of this case report is to describe the process for retraining walking in a person with an incomplete spinal cord injury (SCI) using the BWST and transferring skills from the BWST to overground assessment and community ambulation. CASE DESCRIPTION: Following discharge from rehabilitation, a man with an incomplete SCI at C5-6 and an American Spinal Injury Association (ASIA) Impairment Scale classification of D participated in 45 sessions of locomotor training. OUTCOMES: Walking speed and independence improved from 0.19 m/s as a home ambulator using a rolling walker and a right ankle-foot orthosis to 1.01 m/s as a full-time ambulator using a cane only for community mobility. Walking activity (mean+/-SD) per 24 hours increased from 1,054+/-543 steps to 3,924+/-1,629 steps. DISCUSSION: In a person with an incomplete SCI, walking ability improved after locomotor training that used a decision-making algorithm and progression across training environments.

OBJECTIVE: To assess insomnia in a rehabilitation population, the authors examined the utility and validity of the Pittsburgh Sleep Quality Index (PSQI). The assessment of insomnia is relevant to the treatment of traumatic brain injury at the postacute level and routine screening for insomnia may be enhanced by the availability of a standardized, conveniently used, self-report sleep questionnaire. DESIGN: The authors prospectively studied 91 consecutive patients with traumatic brain injury who were admitted to an outpatient neurorehabilitation program. Besides administering the PSQI, Beck Depression Inventory, Epworth Sleepiness Scale, and Multidimensional Pain Inventory, sleep diary and interview data were obtained and used to divide subjects into insomnia and noninsomnia groups according to the criteria established by the Diagnostic and Statistical Manual of Mental Disorders, ed 4. RESULTS: Sensitivity and specificity rates to the clinical diagnosis of insomnia were 93% and 100%, respectively, for a PSQI Global Score of >8, and 83% and 100% for a diagnosis of insomnia based exclusively on PSQI-derived sleep variable data. Sleep diary data provided concurrent validity for PSQI estimates of sleep-onset latency, sleep duration, and sleep efficiency. The Beck Depression Inventory, Epworth Sleepiness Scale, and Multidimensional Pain Inventory established concurrent validity for individual PSQI items pertaining to mood, hypersomnia, and pain disturbance. CONCLUSION: The PSQI was demonstrated to be a valid and useful screening tool for assessing insomnia among postacute patients with traumatic brain injury.