Late-onset Cerebellar Degeneration Research Articles

EFFICACY OF PNEUMOMASSAGE IN THE COMPREHENSIVE TREATMENT OF POLYNEUROPATHIES OF VARIOUS ORIGINS

Objective : to evaluate the efficacy of limb pneumomassage as one of the components of comprehensive treatment for patients with polyneuropathies of various origins. Material and methods . This study included 77 patients (36 men and 41 women) with limb polyneuropathies treated in the Department of Neurology, Alexander-Mariinsky Regional Clinical Hospital. The mean age of women was 64 ± 9.6 years, while the mean age of men was 58 ± 7.4 years. All study participants were divided into 5 groups depending on the causes of their limb polyneuropathy. Group 1 included 30 patients (14 men and 16 women) with axonal polyneuropathies plus sensologic syndrome, ataxia, toxic polyneuropathies, diabetic polyneuropathies, and chronic inflammatory demyelinating polyneuropathies. Group 2 comprised 16 patients (6 men and 10 women) with multiple sclerosis plus lower paraparesis, cerebellar ataxia. Group 3 included 11 patients (7 men and 4 women) with discogenic vascular myelopathy of the thoracic and lumbosacral spine plus paraparesis and gait disorders. Group 4 comprised 10 patients (4 men and 6 women) after ischemic strokes with hemiparesis. Group 5 was composed of 10 patients (5 men and 5 women) with hereditary diseases, including Charcot-Marie-Tooth disease, CurschmannBatten-Steinert syndrome plus tetraparesis, late-onset cerebellar degeneration with ataxia. All patients received pharmacotherapy that included vascular, neuroprotective, analgesic, antioxidant, and immunomodulatory agents, as well as exercise therapy, acupuncture, and limb pneumomassage. The control group included 21 patients (11 men and 10 women) with polyneuropathies of various origins, who received standard treatment without pneumomassage. The STATISTICA-16 software was used for data amalysis. We performed correlation analysis and calculated Pearson correlation coefficients. R esults . We found that limb pneumomassage improved the condition of patients with metabolic, toxic, and inflammatory polyneuropathies. However, limb pneumomassage was ineffective in patients with hereditary polyneuropathies due to more significant and irreversible lesions of the nervous system.

Gaze-evoked nystagmus induced by alcohol intoxication.

The cerebellum is the core structure controlling gaze stability. Chronic cerebellar diseases and acute alcohol intoxication affect cerebellar function, inducing, among others, gaze instability as gaze-evoked nystagmus. Gaze-evoked nystagmus is characterized by increased centripetal eye-drift. It is used as an important diagnostic sign for patients with cerebellar degeneration and to assess the 'driving while intoxicated' condition. We quantified the effect of alcohol on gaze-holding using an approach allowing, for the first time, the comparison of deficits induced by alcohol intoxication and cerebellar degeneration. Our results showed that alcohol intoxication induces a two-fold increase of centripetal eye-drift. We establish analysis techniques for using controlled alcohol intake as a model to support the study of cerebellar deficits. The observed similarity between the effect of alcohol and the clinical signs observed in cerebellar patients suggests a possible pathomechanism for gaze-holding deficits. Gaze-evoked nystagmus (GEN) is an ocular-motor finding commonly observed in cerebellar disease, characterized by increased centripetal eye-drift with centrifugal correcting saccades at eccentric gaze. With cerebellar degeneration being a rare and clinically heterogeneous disease, data from patients are limited. We hypothesized that a transient inhibition of cerebellar function by defined amounts of alcohol may provide a suitable model to study gaze-holding deficits in cerebellar disease. We recorded gaze-holding at varying horizontal eye positions in 15 healthy participants before and 30min after alcohol intake required to reach 0.6‰ blood alcohol content (BAC). Changes in ocular-motor behaviour were quantified measuring eye-drift velocity as a continuous function of gaze eccentricity over a large range (±40deg) of horizontal gaze angles and characterized using a two-parameter tangent model. The effect of alcohol on gaze stability was assessed analysing: (1) overall effects on the gaze-holding system, (2) specific effects on each eye and (3) differences between gaze angles in the temporal and nasal hemifields. For all subjects, alcohol consumption induced gaze instability, causing a two-fold increase [2.21 (0.55), median (median absolute deviation); P=0.002] of eye-drift velocity at all eccentricities. Results were confirmed analysing each eye and hemifield independently. The alcohol-induced transient global deficit in gaze-holding matched the pattern previously described in patients with late-onset cerebellar degeneration. Controlled intake of alcohol seems a suitable disease model to study cerebellar GEN. With alcohol resulting in global cerebellar hypofunction, we hypothesize that patients matching the gaze-holding behaviour observed here suffered from diffuse deficits in the gaze-holding system as well.

Gaze holding deficits discriminate early from late onset cerebellar degeneration.

The vestibulo-cerebellum calibrates the output of the inherently leaky brainstem neural velocity-to-position integrator to provide stable gaze holding. In healthy humans small-amplitude centrifugal nystagmus is present at extreme gaze-angles, with a non-linear relationship between eye-drift velocity and eye eccentricity. In cerebellar degeneration this calibration is impaired, resulting in pathological gaze-evoked nystagmus (GEN). For cerebellar dysfunction, increased eye drift may be present at any gaze angle (reflecting pure scaling of eye drift found in controls) or restricted to far-lateral gaze (reflecting changes in shape of the non-linear relationship) and resulting eyed-drift patterns could be related to specific disorders. We recorded horizontal eye positions in 21 patients with cerebellar neurodegeneration (gaze-angle=±40°) and clinically confirmed GEN. Eye-drift velocity, linearity and symmetry of drift were determined. MR-images were assessed for cerebellar atrophy. In our patients, the relation between eye-drift velocity and gaze eccentricity was non-linear, yielding (compared to controls) significant GEN at gaze-eccentricities≥20°. Pure scaling was most frequently observed (n=10/18), followed by pure shape-changing (n=4/18) and a mixed pattern (n=4/18). Pure shape-changing patients were significantly (p=0.001) younger at disease-onset compared to pure scaling patients. Atrophy centered around the superior/dorsal vermis, flocculus/paraflocculus and dentate nucleus and did not correlate with the specific drift behaviors observed. Eye drift in cerebellar degeneration varies in magnitude; however, it retains its non-linear properties. With different drift patterns being linked to age at disease-onset, we propose that the gaze-holding pattern (scaling vs. shape-changing) may discriminate early- from late-onset cerebellar degeneration. Whether this allows a distinction among specific cerebellar disorders remains to be determined.

Loss of Clcc1 results in ER stress, misfolded protein accumulation, and neurodegeneration.

Folding of transmembrane and secretory proteins occurs in the lumen of the endoplasmic reticulum (ER) before transportation to the cell surface and is monitored by the unfolded protein response (UPR) signaling pathway. The accumulation of unfolded proteins in the ER activates the UPR that restores ER homeostasis by regulating gene expression that leads to an increase in the protein-folding capacity of the ER and a decrease in the ER protein-folding load. However, prolonged UPR activity has been associated with cell death in multiple pathological conditions, including neurodegeneration. Here, we report a spontaneous recessive mouse mutation that causes progressive cerebellar granule cell death and peripheral motor axon degeneration. By positional cloning, we identify the mutation in this strain as a retrotransposon insertion in the Clcc1 gene, which encodes a putative chloride channel localized to the ER. Furthermore, we demonstrate that the C3H/HeSnJ inbred strain has late onset cerebellar degeneration due to this mutation. Interestingly, acute knockdown of Clcc1 expression in cultured cells increases sensitivity to ER stress. In agreement, GRP78, the major HSP70 family chaperone in the ER, is upregulated in Clcc1-deficient granule cells in vivo, and ubiquitinated proteins accumulate in these neurons before their degeneration. These data suggest that disruption of chloride homeostasis in the ER disrupts the protein-folding capacity of the ER, leading to eventual neuron death.

The contribution of the cerebellum to cognition in Spinocerebellar Ataxia Type 6.

This study sought evidence for a specific cerebellar contribution to cognition by characterising the cognitive phenotype of Spinocerebellar Ataxia Type 6 (SCA-6); an autosomal dominant genetic disease which causes a highly specific late-onset cerebellar degeneration. A comprehensive neuropsychological assessment was administered to 27 patients with genetically confirmed SCA-6. General intellectual ability, memory and executive function were examined using internationally standardised tests (Wechsler Adult Intelligence Scale-III, Wechsler Memory Scale-III, Delis and Kaplan Executive Function System, Brixton Spatial Anticipation test). The patient group showed no evidence of intellectual or memory decline. However, tests of executive function involving skills of cognitive flexibility, inhibition of response and verbal reasoning and abstraction demonstrated significant impairment at the group level with large effect sizes. The results demonstrate an executive deficit due to SCA-6 that can be conceptualised as parallel to the motor difficulties suffered by these patients: the data support a role for the cerebellum in the regulation and coordination of cognitive, as well as motor processes that is relevant to individual performance.

The Contribution of the Cerebellum to Cognition in Spinocerebellar Ataxia Type 6

This study sought evidence for a specific cerebellar contribution to cognition by characterising the cognitive phenotype of Spinocerebellar Ataxia Type 6 (SCA-6); an autosomal dominant genetic disease which causes a highly specific late-onset cerebellar degeneration. A comprehensive neuropsychological assessment was administered to 27 patients with genetically confirmed SCA-6. General intellectual ability, memory and executive function were examined using internationally standardised tests (Wechsler Adult Intelligence Scale-III, Wechsler Memory Scale-III, Delis and Kaplan Executive Function System, Brixton Spatial Anticipation test). The patient group showed no evidence of intellectual or memory decline. However, tests of executive function involving skills of cognitive flexibility, inhibition of response and verbal reasoning and abstraction demonstrated significant impairment at the group level with large effect sizes. The results demonstrate an executive deficit due to SCA-6 that can be conceptualised as parallel to the motor difficulties suffered by these patients: the data support a role for the cerebellum in the regulation and coordination of cognitive, as well as motor processes that is relevant to individual performance.

MRE11 mutations and impaired ATM-dependent responses in an Italian family with ataxia-telangiectasia-like disorder.

Hypomorphic mutations of the MRE11 gene are the hallmark of the radiosensitive ataxia-telangiectasia-like disorder (ATLD). Here, we describe a new family with two affected siblings, ATLD5 and ATLD6, now aged 37 and 36, respectively. They presented with late onset cerebellar degeneration slowly progressing until puberty and absence of telangiectasias, and were cancer-free. Both patients were wild-type for ATM and NBS1, but compound heterozygotes for MRE11 gene mutations [1422C-->A, T481K; 1714C-->T, R571X]. The 1422C-->A allele was inherited from the mother, whereas the 1714C-->T, allele paternally inherited, was apparently null as a result of nonsense-mediated mRNA decay (NMD). Interestingly, the 1714C-->T mutation is the same as previously identified in an unrelated English ATLD family (probands ATLD3 and ATLD4), suggesting an important role for NMD in saving potentially lethal mutations. Lymphoblastoid cell lines (LCLs) derived from ATLD5 and ATLD6 were normal for ATM, but defective for Mre11, Rad50 and Nbs1 (the MRN complex) protein expression. Their response to gamma-radiation was abnormal, as evidenced by the enhanced radiosensitivity, attenuated autophosphorylation of ATM-S1981 and phosphorylation of the ATM targets p53-S15 and Smc1-S966, failure to form Mre11 nuclear foci and defective G1 checkpoint arrest. The fibroblasts, but not LCLs, from ATLD5 and ATLD6 showed an impaired ATM-dependent Chk2 phosphorylation. These findings further underscore the interconnection between ATM activity and MRN function, which rationalizes the clinical similarity between ataxia-telangiectasia (A-T) and ATLD.

Effects of hyperventilation on fast goal-directed limb movements in spinocerebellar ataxia type 6.

It has been shown previously that hyperventilation modifies the features of the nystagmus in cerebellar patients (Walker and Zee, 1999). It has been hypothesized that hyperventilation influences the oculomotor control through a metabolic effect on cerebellar calcium channels, which play a critical role in the firing behaviour of neuronal populations in the cerebellum. This hypothesis has been tested here by analysing fast goal-directed limb movements before and after hyperventilation in spinocerebellar ataxia type 6 (SCA-6), a disease associated with a polyglutamine expansion in the alpha 1-A voltage-dependent calcium channel. Cerebellar hypermetria associated with fast distal single-joint movements was found to be increased following hyperventilation in patients presenting SCA-6 but remained unchanged in patients with idiopathic late-onset cerebellar degeneration (ILOCA). This is a new provocative test to enhance distal dysmetria in SCA-6. The present results strengthen the hypothesis of Walker and Zee. It is suggested that hyperventilation enhances the defective calcium transfers in SCA-6, resulting in an impairment of the calcium influx in particular into Purkinje cells involved in the control of fast goal-directed voluntary movements.

Cerebellar hypermetria associated with a selective decrease in the rate of rise of antagonist activity.

Classically, cerebellar hypermetria observed during fast and accurate movements is ascribed to a delayed onset of the electromyographic activity of the antagonist muscle. We describe here 3 patients presenting a late-onset cerebellar degeneration and exhibiting a hypermetria during their fast and accurate movements in spite of a normal onset latency of the antagonist activity. Hypermetria was found to be due to a slower rate of rise of the antagonist activity.

The antioxidant butylated hydroxytoluene can retard cerebellar degeneration induced transplacentally by a single low dosage of N‐methyl‐n‐nitrosourea

Late-onset cerebellar degeneration can be induced transplacentally in mice by a single low-dose (1 mg/kg) injection of the direct-acting DNA alkylating agent N-methyl-N-nitrosourea (MNU) on day 16 of pregnancy. The offspring develop a mild ataxia that manifests by 12-16 weeks of age postnatally when the animals are challenged with a motor coordination task. Morphological evidence of degeneration includes pyknosis of Purkinje cells and abnormal foliation patterns. Additionally, these animals demonstrate a progressive retinopathy characterized by thinning of the nuclear and plexiform layers of the retina. Efforts to retard the cerebellar degeneration were undertaken in the present study. MNU-exposed and control animals were fed a standard mouse chow diet supplemented with 0.75% butylated hydroxytoluene (BHT), an antioxidant. This supplementation commenced 24 h following exposure to the teratogen and continued throughout the life of the offspring. A second group of MNU-exposed and control mice were fed a non-BHT-supplemented, standard Purina mouse chow diet. Quantitative histological evaluation of cerebellar coronal sections indicated that by 4 weeks of age BHT-fed, MNU-exposed mice had significantly fewer pyknotic Purkinje cells than non-BHT-fed, MNU-exposed animals. This was true for the vermal, paravermal, and lateral areas of the cerebellum. The findings suggest the usefulness of teratogenic models of degenerative diseases for the testing of potential intervention strategies.

Late-onset cerebellar degeneration in mice induced transplacentally by methylnitrosourea.

A late-onset degenerative disease in the cerebellum was produced in the offspring of mice exposed to 1 mg/kg of the direct-acting DNA alkylating agent methylnitrosourea (MNU) on day 16 of gestation. This intrauterine exposure to MNU also provoked a progressive retinal degeneration that was described elsewhere. Mild ataxia in the MNU-exposed animals was expressed by 20 weeks of age. Although animals appeared normal in the immediate post-natal period, quantitative histological evaluation of cerebellar coronal sections indicated that MNU-exposed animals had a significantly greater number of pyknotic Purkinje cells than age-matched controls. The number of pyknotic Purkinje cells declined with age in the drug exposed animals; however, the percentage of pyknotic Purkinje cells to total number of Purkinje cells still was greater in MNU-induced animals at 36 weeks than in controls, suggesting that a slow degenerative process was ongoing in the MNU-exposed animals. Furthermore, the folia were grossly disrupted in 90% of the older MNU-exposed animals (ages greater than 12 weeks), suggesting permanent cerebellar disruption macroscopically. Such intrauterine exposure to low doses of alkylating agents may be potentially useful in modeling degenerative neuronal diseases.

Brain-stem auditory evoked potentials in patients with multiple system atrophy with progressive autonomic failure (SHY-drager syndrome)

Brain stem potentials from three groups of patients, namely those with pure progressive autonomic failure, Parkinson's disease and multisystem atrophy with progressive autonomic failure (Shy-Drager syndrome) were compared with each other and a group of normal subjects. In virtually all the patients with multisystem atrophy with progressive autonomic failure the brain stem potentials were abnormal in contrast to normal findings with Parkinson's disease. The closely associated group of patients with progressive autonomic failure alone also revealed no abnormalities of the BAEP. This separation of the two groups, Parkinson's disease and progressive autonomic failure from multisystem atrophy with progressive autonomic failure is important clinically as multiple system atrophy of the Shy-Drager type has extra-pyramidal features closely resembling Parkinsonism or a late onset cerebellar degeneration. From the abnormalities of the brain stem response in multisystem atrophy with progressive autonomic failure, it is clear that some disruption of the auditory pathway occurs in the ponto-medullary region as in nearly all patients there is a significant delay or reduction in the amplitude of components of the response generated beyond this region. The most likely area involved is the superior olivary complex.