Gait dyspraxia as a clinical marker of cognitive decline in Down syndrome: A review of theory and proposed mechanisms.

Down syndrome (DS) is the most common genetic cause of intellectual disability in children. With aging, DS is associated with an increased risk for Alzheimer's disease (AD). The development of AD neuropathology in individuals with DS can result in further disturbances in cognition and behavior and may significantly exacerbate caregiver burden. Early detection may allow for appropriate preparation by caregivers. Recent literature suggests that declines in gait may serve as an early marker of AD-related cognitive disorders; however, this relationship has not been examined in individuals with DS. The theory regarding gait dyspraxia and cognitive decline in the general population is reviewed, and potential applications to the population with individuals with DS are highlighted. Challenges and benefits in the line of inquiry are discussed. In particular, it appears that gait declines in aging individuals with DS may be associated with known declines in frontoparietal gray matter, development of AD-related pathology, and white matter losses in tracts critical to motor control. These changes are also potentially related to the cognitive and functional changes often observed during the same chronological period as gait declines in adults with DS. Gait declines may be an early marker of cognitive change, related to the development of underlying AD-related pathology, in individuals with DS. Future investigations in this area may provide insight into the clinical changes associated with development of AD pathology in both the population with DS and the general population, enhancing efforts for optimal patient and caregiver support and propelling investigations regarding safety/quality of life interventions and disease-modifying interventions.

WDR81 is necessary for purkinje and photoreceptor cell survival.

The gene encoding the WD repeat-containing protein 81 (WDR81) has recently been described as the disease locus in a consanguineous family that suffers from cerebellar ataxia, mental retardation, and quadrupedal locomotion syndrome (CAMRQ2). Adult mice from the N-ethyl-N-nitrosourea-induced mutant mouse line nur5 display tremor and an abnormal gait, as well as Purkinje cell degeneration and photoreceptor cell loss. We have used polymorphic marker mapping to demonstrate that affected nur5 mice carry a missense mutation, L1349P, in the Wdr81 gene. Moreover, homozygous nur5 mice that carry a wild-type Wdr81 transgene are rescued from the abnormal phenotype, indicating that Wdr81 is the causative gene in nur5. WDR81 is expressed in Purkinje cells and photoreceptor cells, among other CNS neurons, and like the human mutation, the nur5 modification lies in the predicted major facilitator superfamily domain of the WDR81 protein. Electron microscopy analysis revealed that a subset of mitochondria in Purkinje cell dendrites of the mutant animals displayed an aberrant, large spheroid-like structure. Moreover, immunoelectron microscopy and analysis of mitochondrial-enriched cerebellum fractions indicate that WDR81 is localized in mitochondria of Purkinje cell neurons. Because the nur5 mouse mutant demonstrates phenotypic similarities to the human disease, it provides a valuable genetic model for elucidating the pathogenic mechanism of the WDR81 mutation in CAMRQ2.

Gait and balance disorders in Parkinson's disease: impaired active braking of the fall of centre of gravity.

Gait and balance disorders are common in Parkinson's disease (PD), but its pathophysiology is still poorly understood. Step length, antero-posterior, and vertical velocities of the center of gravity (CG) during gait initiation were analyzed in 32 controls and 32 PD patients, with and without levodopa, using a force platform. Brain volumes and mesencephalic surface area were measured in PD patients. During the swing limb period, controls showed a fall in the CG, which was reversed before foot-contact indicating active braking of the CG fall. In PD patients, without levodopa, step length and velocity were significantly reduced and no braking occurred before foot-contact in 22 patients. With levodopa, step length and velocity increased in all patients and 7 patients improved their braking capacity. PD patients with normal braking (n = 17) had significantly lower gait and balance disorder scores and higher normalized-mesencephalic surface areas compared to patients with impaired braking (n = 15). The decreased step length and velocity, characteristic of PD, mainly result from degeneration of central dopaminergic systems. The markedly decreased braking capacity observed in half the PD patients contributes to their gait disorders and postural instability, perhaps as a result of nondopaminergic lesions, possibly at the mesencephalic level.

Gait apraxia: further clues to localization.

BACKGROUND/AIMS: Gait apraxia characterized primarily by gait ignition failure has been linked to lesions involving the dorsomedial frontal lobes, but the precise locus within this general region has not been determined. It has previously been hypothesized by Thompson and Marsden that disease, disconnection, or dysfunction of supplementary motor area (SMA) may account for the similarities in the gait disorders observed in Binswanger's disease, hydrocephalus, frontal lobe lesions, and Parkinson's disease. We reevaluate this hypothesis. METHODS: Clinical description and MRI of 2 subjects with gait apraxia characterized primarily by gait ignition failure. RESULTS: Both subjects had incapacitating gait disorders characterized by particular difficulty with initiating gait and making turns. Both had MRI-demonstrated lesions of the SMA region, parasagittal convexity premotor cortex, or subjacent white matter bilaterally, one due to primary CNS lymphoma, one due to a lobar atrophy. CONCLUSIONS: In both these cases, the lesions were substantially more limited and focal than any reported heretofore in the literature on gait apraxia or freezing of gait. The clinicopathologic correlation in these cases provides partial support for the Thompson and Marsden hypothesis, but also may implicate parasagittal convexity premotor cortex in the genesis of gait apraxia.

Gait and dementia: moving beyond the notion of gait apraxia.

Highest level gait disorders are produced by pathology in one or more structures in the cortical-basal ganglia-thalamocortical loop, which plays an important role in producing movements and postural synergies that meet personal desires and environmental constraints. Virtually all patients with dementia have pathology in one or more components of this loop, so highest level gait disorders are common in patients with dementia. The terminology surrounding these gait disorders is unnecessarily complex and too heavily influenced by the controversial concept of gait apraxia. Straightforward descriptive diagnostic criteria are needed. To this end, four core clinical features of highest level gait disorders are proposed: 1) inappropriate (counterproductive) or bizarre limb movement, postural synergies, and interaction with the environment, 2) qualitatively variable performance, influenced greatly by the environment and emotion, 3) hesitation and freezing, and 4) absent or inappropriate (counterproductive) rescue reactions. These core features follow logically from the physiology of the cortical-basal ganglia-thalamocortical loop and should be regarded as signs of pathology in this loop. A clinical rating scale based on these features should be developed to facilitate clinical diagnosis and clinicopathological correlation, while avoiding the ambiguities and controversies of gait apraxia.

Isolated frontal disequilibrium as presenting form of anti-Hu paraneoplastic encephalomyelitis.

Anti-Hu encephalomyelitis is one of the most frequent paraneoplastic syndromes, classically presenting with diffuse neurological involvement. We report a 69-year-old man presenting with a three-month isolated, progressive gait disorder with normal neurological examination, except for loss of balance and gait failure reminding frontal disequilibrium, only accompanied by a very mild rigidity of his right foot. MRI of the brain showed hyperintensities in both amygdale and left putamen. EMG study showed no abnormal continuous spontaneous fiber activity. Because of fast progression and MRI findings, anti-Hu antibodies were tested, resulting positive. Mediastinal biopsy of two adenopathies detected by body-PET, confirmed an oat-cell carcinoma. The patient received oral steroids and oncological therapy. One year later, the tumor is in remission. His gait and abnormal posture of right leg are normal. Only mild residual hyperintensities persist on follow-up MRI. A paraneoplastic syndrome should be considered in the differential diagnosis of subacute, fast progressive gait disorders.

[Multi-infarct disorder presenting as corticobasal degeneration (DCB): vascular pseudo-corticobasal degeneration?]. / Infarctus cérébraux multiples se présentant comme une dégénérescence cortico-basale: pseudo dégénérescence cortico-basale vasculaire?

We report on five patients with a clinical presentation of corticobasal degeneration (CBD), including gradually progressive, asymmetric, L-DOPA-resistant parkinsonism associated variously with apraxia, focal action myoclonus, focal dystonia, cortical sensory loss and alien limb phenomenon. Some patients also presented an atypical CBD clinical history or signs - notably sudden onset. The disease was however not suggestive of another diagnosis. Magnetic resonance imaging of the brain revealed extensive vascular lesions. Only five similar cases have been published to our knowledge. Although we cannot exclude underlying CBD pathology, our cases illustrate the fact that multi-infarct pathology can masquerade as CBD or alter the clinical phenotype of the disease.

Autopsy case of pure akinesia showing pallidonigro-luysian atrophy.

A 60-year-old man developed levodopa-resistant pure akinesia. The patient gradually became more akinetic without accompanying gaze palsies, nuchal dystonia, or other parkinsonian features such as rigidity or tremor. At the age of 71, he died of bronchopneumonia. Neuropathologically, bilateral marked neuronal loss and gliosis were restrictedly observed in the globus pallidus, substantia nigra and corpus luysii, whereas mild gliosis without neuronal loss was found in the brain stem. With Gallyas-Braak silver stain, numerous argyrophilic fibrous structures partly surrounding glial nuclei were observed in the three major affected regions. With Bodian stain, however, they were rarely recognized. The structures were partly positive for tau protein. Rare neurofibrillary tangles were found in the three areas and brain stem. They were relatively more numerous but still sparse in the hippocampus and the parahippocampus. The present case was diagnosed as having pallidonigro-luysian atrophy based on two characteristic findings: (i) the distribution of lesions showing neuronal loss with gliosis; and (ii) significant presence of tau-positive argyrophilic fibrous structures related to glia but with the absence of neurofibrillary tangles in the major affected regions and the brain stem. As our present case uniquely showed pure akinesia for the whole clinical course, it is noteworthy to report it here with a full neuropathological evaluation. In addition, a moderate number of diffuse plaques positive for beta-amyloid were distributed in the thalamus.

Apraxia de la marcha: una secuela adquirida de evolución desfavorable / Apraxia of gait: an acquired sequela with a poor prognosis

Introducción. La apraxia de la marcha es una entidad que no se tiene en cuenta en la práctica de la Neurología infantil. Casos clínicos. Se presentan dos pacientes pediátricos que, tras adquirir la marcha, y a consecuencia de un proceso agudo, perdieron la capacidad de caminar, sin que las intensivas técnicas de rehabilitación hayan podido ayudarles a lo largo de varios años. Las lesiones eran heterogéneas en ambos casos, ya que en el primero resultó afectad la corteza precentral y paracentral a consecuencia de un proceso inflamatorio de tipo encefalítico, y en el otro, los núcleos de la base cerebral y los hipocampos, a consecuencia de una situación de casi ahogamiento a la edad de 15 meses. Conclusión. Se discuten los mecanismos atribuidos a estos trastornos y se hace hincapié en su mal pronóstico a largo plazo

Introduction. Gait apraxia is not used to be considered as a diagnostic entitiy in Pediatric Neurology. Case reports. We present two pediatric patients that, after to have acquired normal gait and in consequence of a acute process, they lost the capacity to walk. In spite of intensive rehabilitation treatement hold along various years, they had not been able to help them. Both injury were very dissimilar; in one of them was affected the precentral and paracentral cortex in consequence of an encephalitic process. In the other, the basal ganglia and the hippocampus after a situation of near-drowning at the age of 15 months. Conclusion. The mechanism of this disorder is discussed and emphasis is done in its badly long-term prognosis

Late-onset autosomal recessive limb-girdle muscular dystrophy with rimmed vacuoles.

We report on two siblings with late-onset, limb-girdle muscular dystrophy (LGMD) inherited in an autosomal recessive manner. The LGMD was characterized by many rimmed vacuoles and reduced expression of the laminin beta1 chain in skeletal muscle. Both patients developed a progressive wasting and weakness of limb-girdle muscles in the late forties or early fifties; their facial, ocular, bulbar, and cardiac muscles were not involved. Histopathology of skeletal muscles biopsies showed typical dystrophic changes with many rimmed vacuoles. The immunoreactivity of the laminin beta1 chain was reduced in the muscle fibers, while dystrophin, sarcoglycans, beta-dystroglycan, dysferlin, and other laminin components were normally expressed. A mutation search revealed that no mutation existed in the coding region of the calpain 3, telethonin and UDP-N-acetylglucosamine 2-epimerase/N-acetylmanosamine kinase (GNE) genes. We conclude that this autosomal recessive LGMD is unknown and characterized by its late onset, rimmed vacuoles and reduction of the laminin beta1 chain in muscle fibers.

A prospective study of cerebral white matter abnormalities in older people with gait dysfunction.

OBJECTIVES: The authors previously reported cross-sectional data suggesting a relationship between cerebral white matter hyperintensities (WMH) and gait and balance dysfunction in older people. There have been no longitudinal MRI studies to address this issue. The current study compared progression of WMH in subjects with gait and balance dysfunction with that in healthy subjects. METHODS: Two brain MRI were performed on 70 healthy, ambulatory subjects (mean baseline age 79, range 74 to 88) with no identifiable neurologic disease. The mean time between MRI was 4 years. Gait and balance were quantified using the Tinetti Balance and Mobility Scale, and falls were documented each year. On T2-weighted MRI, total hyperintense volume (HV) within three periventricular levels was estimated using the Cavalieri principle, and WMH were graded (0 to 4) using an established semiquantitative scale. RESULTS: Compared with those with normal gait and balance, subjects whose Tinetti scores dropped markedly (> 4 points) between first and second MRI showed a significantly greater mean increase in HV during follow-up. The larger group of subjects with an abnormal Tinetti score (< 24) at the time of second MRI showed a significantly greater mean increase in HV, compared with those with normal gait and balance at follow-up. Subjects with marked WMH at baseline showed significantly greater increase in HV over time. Subjects with abnormal Tinetti scores had significantly more falls than subjects with normal Tinetti scores. CONCLUSIONS: Some older people develop gait and balance dysfunction that is associated with gradual onset of cerebral white matter disease.