Urinary symptoms and urodynamic findings in patients with Machado–Joseph disease

The study evaluated the prevalence of clinical and urodynamic findings in the lower urinary tract of patients with Machado–Joseph (MJ) disease. One hundred twenty-two patients were retrospectively evaluated; 17 (13.9%) presented lower urinary tract dysfunction, 10 of them were women. The average age was 41.6 years. Urgency was found in 15 patients and incontinence in nine. The urodynamic study showed detrusor overactivity in eight patients, areflexia in one, and four with normal detrusor contractility. Bladder sensitivity was abnormal in six, bladder capacity was decreased in one, urine flow decreased in 13, post-voiding residue was greater than 100 ml in nine. We could not find sphincter dyssynergia. The average cytosine–adenine–guanine (CAG) repetition was higher in patients with abnormal detrusor contraction (89.9) than in patients with normal urodynamics (68.2) (p = 0.03). There was no statistical significance when comparing the averages of replicates for people with and without urgency urinary incontinence (p = 0.27 and p = 0.5, respectively). The rate of lower urinary tract dysfunction in patients with MJ disease was around 14%. The urodynamic study showed predominance of detrusor overactivity and urgency as the most common symptom. We found an association between the total number of CAG repetitions and changes in detrusor contractility.     

Excessive fragmentary myoclonus in Machado–Joseph disease

ObjectiveMachado–Joseph disease (MJD) is a neurodegenerative disease which usually presents several clinical findings including cerebellar ataxia and other extracerebellar features, such as Parkinsonism, dystonia, peripheral neuropathy, and lower motor neuron disease. Some data have demonstrated a high frequency of sleep disorders in these patients, including excessive daytime sleepiness (EDS), insomnia, obstructive sleep apnea (OSA), rapid eye movement (REM) sleep behavior disorder (RBD), and restless legs syndrome (RLS). Herein, we aimed to describe the high frequency of excessive fragmentary myoclonus (EFM) in MJD.Materials and methodsWe recruited 44 patients with MJD and 44 healthy controls. All participants underwent an all-night polysomnography (PSG). EFM was evaluated and defined in accordance to the criteria of the American Academy of Sleep Medicine.ResultsHalf of the MJD patients (n = 22) had EFM diagnosed through PSG, though no healthy control participant presented this finding (P < .0001). In the MJD group, older participants and men had a higher frequency of EFM. There was no correlation between EFM and the following data: body mass index (BMI), apnea–hypopnea index (AHI), EDS, loss of atonia during REM sleep, periodic limb movements during sleep (PLMS), RLS, RBD, ataxia severity, the number of cytosine–adenine–guanine trinucleotide (CAG) repeats, disease duration, sleep efficiency, sleep fragmentation, and sleep stage percentages between patients with or without EFM.ConclusionEFM is highly prevalent in patients with MJD. Our study demonstrates that EFM must be included in the clinical spectrum of sleep disorders in MJD patients.     

Sleep disorders in Machado–Joseph disease: A dopamine transporter imaging study

ObjectivesSleep disorders, especially restless legs syndrome (RLS) and rapid eye movement sleep behavior disorder (RBD), are common in spinocerebellar ataxia type 3 or Machado–Joseph disease (MJD), and a possible underlying dopaminergic dysfunction is implicated. This study assessed the relationship between sleep disorders in MJD and dopamine transporter (DAT) densities.Patients and methodsTwenty-two patients with MJD and twenty healthy subjects were enrolled in this study. MJD patients underwent clinical sleep evaluation and polysomnography. SPECT with [^99mTc]-TRODAT-1, was performed in all subjects.ResultsDAT densities were significantly reduced in MJD group when compared to controls. No significant correlation was found between DAT densities and RLS or RBD in MJD.ConclusionOur study failed to demonstrate a clear correlation between sleep disorders and DAT densities in MJD patients, hence suggesting that extrastriatal and non-presynaptic dopamine pathways could be implicated in MJD-related sleep disorders.     

Involvement of Onuf’s nucleus in Machado–Joseph disease: a morphometric and immunohistochemical study

Machado–Joseph disease (MJD) is an autosomal dominant neurodegenerative disease caused by an expansion of CAG repeats in the MJD1 gene, in which lower urinary tract dysfunction is known to be the most commonly encountered autonomic failure. However, it remains unclear whether Onuf’s nucleus (ON), which plays major roles in the micturition reflex and voluntary continence, degenerates during the disease process. In the present study, we conducted a morphometric and immunohistochemical study of ON, together with the lateral nuclear group (LNG) of the sacral anterior horns, in seven patients with MJD. When compared with controls, the number of lower motor neurons in both ON and LNG was significantly smaller in the MJD patients, the former being inversely correlated with the size of the expanded CAG repeats. Notably, MJD patients with a large CAG-repeat expansion showed an ON-predominant pattern of neuronal loss, while in the remaining patients, ON and LNG were affected to a similar degree, or rather an LNG-predominant pattern of neuronal loss was evident. Moreover, when adjusted for age, the degree of neuronal loss in both ON and LNG was significantly correlated with the extent of expansion of the CAG repeats. In MJD, the remaining lower motor neurons in ON often exhibited ataxin-3- or 1C2-immunoreactive (ir) neuronal intranuclear inclusions, while no pTDP-43-ir neuronal cytoplasmic inclusions were present in these neurons. In conclusion, the present findings strongly suggest that neuronal loss in ON, the degree of which is highly influenced by the extent of expansion of CAG repeats, is a consistent feature in MJD.     

Selective occurrence of TDP-43-immunoreactive inclusions in the lower motor neurons in Machado–Joseph disease

Pathological transactivation-responsive DNA-binding protein 43 (TDP-43) has been identified as a component of ubiquitinated inclusions in frontotemporal lobar degeneration with motor neuron disease, as well as in sporadic and some forms of familial amyotrophic lateral sclerosis. To clarify whether pathological TDP-43 is present in other neurodegenerative diseases involving the motor neuron system, we immunohistochemically examined the brain and spinal cord affected by two CAG repeat (polyglutamine) diseases, Machado–Joseph disease (MJD) and spinal and bulbar muscular atrophy (SBMA), using polyclonal antibody against TDP-43. In all the MJD cases, TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs), although few in number, were found only in the lower motor neurons in the brainstem and spinal cord. TDP-43-ir NCIs appeared as linear wisp-like, skein-like, or thick, somewhat rod-like bodies. These inclusions were also visualized with antibodies against phosphoserines 409 and 410 of TDP-43, and ubiquitin, but were not recognized by antibody against expanded polyglutamine stretches or ataxin-3. The ultrastructure of the TDP-43-ir NCIs was similar to that of the inclusions seen in sporadic ALS, consisting of bundles of parallel filaments. None of the SBMA cases showed abnormal TDP-43 immunoreactivity in any of the regions examined. Immunoblot analysis failed to recognize hyperphosphorylated TDP-43 at ~23 kDa in two MJD cases examined. However, the immunohistochemical findings strongly suggested that in MJD, in addition to the polyglutamine-dependent disease process, TDP-43-related pathogenesis is associated with degeneration and death of the lower motor neurons.     

Neurophysiological Studies and Non-Motor Symptoms Prior to Ataxia in a Patient with Machado–Joseph Disease: Trying to Understand the Natural History of Brain Degeneration

Spinocerebellar ataxia type 3 or Machado–Joseph disease is the most common spinocerebellar ataxia. In this neurological disease, anatomical, physiological, clinical, and functional neuroimaging demonstrate a degenerative process besides the cerebellum. We performed neurophysiological and neuroimaging studies—polysomnography, transcranial sonography, vestibular-evoked myogenic potential, single-photon emission computed tomography (SPECT) with ^99mTc-TRODAT-1, and a formal neuropsychological evaluation in a patient with sleep complaints and positive testing for Machado–Joseph disease, without cerebellar atrophy, ataxia, or cognitive complaints. Polysomnography disclosed paradoxical high amplitude of submental muscle, characterizing REM sleep without atonia phenomenon. Transcranial sonography showed hyperechogenicity of the substantia nigra. There was an absence of vestibular-evoked myogenic potentials on both sides in the patient under study, in opposite to 20 healthy subjects. Brain imaging SPECT with ^99mTc-TRODAT-1 demonstrated a significant lower DAT density than the average observed in six healthy controls. Electroneuromyography was normal. Neuropsychological evaluation demonstrated visuospatial and memory deficits. Impairment of midbrain cholinergic and pontine noradrenergic systems, dysfunction of the pre-synaptic nigrostriatal system, changes in echogenicity of the substantia nigra, and damage to vestibulo-cervical pathways are supposed to occur previous to cerebellar involvement in Machado–Joseph disease.     

Current pharmacotherapy and putative disease-modifying therapy for Alzheimer’s disease

Alzheimer’s disease (AD) is an age-related neurodegenerative disease of the central nervous system correlated with the progressive loss of cognition and memory. β-Amyloid plaques, neurofibrillary tangles and the deficiency in cholinergic neurotransmission constitute the major hallmarks of the AD. Two major hypotheses have been implicated in the pathogenesis of AD namely the cholinergic hypothesis which ascribed the clinical features of dementia to the deficit cholinergic neurotransmission and the amyloid cascade hypothesis which emphasized on the deposition of insoluble peptides formed due to the faulty cleavage of the amyloid precursor protein. Current pharmacotherapy includes mainly the acetylcholinesterase inhibitors and N-methyl-d-aspartate receptor agonist which offer symptomatic therapy and does not address the underlying cause of the disease. The disease-modifying therapy has garnered a lot of research interest for the development of effective pharmacotherapy for AD. β and γ-Secretase constitute attractive targets that are focussed in the disease-modifying approach. Potentiation of α-secretase also seems to be a promising approach towards the development of an effective anti-Alzheimer therapy. Additionally, the ameliorative agents that prevent aggregation of amyloid peptide and also the ones that modulate inflammation and oxidative damage associated with the disease are focussed upon. Development in the area of the vaccines is in progress to combat the characteristic hallmarks of the disease. Use of cholesterol-lowering agents also is a fruitful strategy for the alleviation of the disease as a close association between the cholesterol and AD has been cited. The present review underlines the major therapeutic strategies for AD with focus on the new developments that are on their way to amend the current therapeutic scenario of the disease.     

Cell replacement therapy for Parkinson's disease: how close are we to the clinic?

Cell replacement therapy (CRT) offers great promise as the future of regenerative medicine in Parkinson′s disease (PD). Three decades of experiments have accumulated a wealth of knowledge regarding the replacement of dying neurons by new and healthy dopaminergic neurons transplanted into the brains of animal models and affected patients. The first clinical trials provided the proof of principle for CRT in PD. In these experiments, intrastriatal transplantation of human embryonic mesencephalic tissue reinnervated the striatum, restored dopamine levels and showed motor improvements. Sequential controlled studies highlighted several problems that should be addressed prior to the wide application of CRT for PD patients. Moreover, owing to ethical and practical problems, embryonic stem cells require replacement by better-suited stem cells. Several obstacles remain to be surpassed, including identifying the best source of stem cells for A9 dopaminergic neuron generation, eliminating the risk of tumor formation and the development of graft-induced dyskinesias, and standardizing dopaminergic cell production in order to enable clinical application. In this article, we present an update on CRT for PD, reviewing the research milestones, various stem cells used and tailored differentiation methods, and analyze the information gained from the clinical trials.     

Altered Heart Rate Control in Response to Postural Change in Patients with Machado–Joseph Disease (SCA3)

To assess heart rate (HR) regulation in Machado–Joseph disease (MJD), we evaluated HR variability at rest and the initial HR response to standing suddenly in 13 MJD patients and 26 normal control subjects. A head-up tilt (HUT) test involving the monitoring of blood pressure, HR, and cerebral oxy/deoxyhemoglobin concentration was also performed in each participant. There was no significant difference in HR variability at rest between the two groups, but the transient HR rise just after standing suddenly in the MJD group was significantly less than that in the control group (p < 0.01). The HUT test, where each participant was gradually tilted upward, induced a significantly greater HR increase in the MJD group compared with the controls (p < 0.01), while there were no significant differences in the blood pressure and cerebral oxygenation changes between the two groups. In our MJD study, the transient HR rise just after standing suddenly was diminished, and HR markedly increased during sustained orthostatic stress.