Inherited polyneuropathy in Leonberger dogs: A mixed or intermediate form of Charcot‐Marie‐Tooth disease?

A spontaneous distal, symmetrical polyneuropathy in related Leonberger dogs with onset between 1 to 9 years of age was characterized clinically, electrophysiologically, histologically, and morphometrically. Exercise intolerance and weakness was associated with a high-steppage pelvic-limb gait, a loss or change in the pitch of the bark, and dyspnea. Neurological examination revealed marked atrophy of the distal limb muscles, depressed spinal and cranial nerve reflexes, and weak or absent movement of the laryngeal and pharyngeal muscles. Electrophysiological evaluation was consistent with denervation and was characterized by loss or marked attenuation of compound muscle action potentials and slowed motor nerve conduction velocity. Muscle biopsy specimens showed neurogenic atrophy. Chronic nerve fiber loss associated with decreased myelinated fiber density and a shift of the axonal size-frequency distribution toward smaller fibers was the predominant finding in peripheral nerve specimens. Pedigree analysis of a large multigenerational family, including nine sibships with at least one affected individual, suggested X-linked inheritance. Mutational and linkage analysis of this family may aid in identification of the chromosomal loci and gene responsible for this inherited axonal neuropathy. Further characterization of this inherited axonal neuropathy may establish the Leonberger dog as a spontaneous animal model of inherited axonal neuropathy and possibly lead to the discovery of a new gene or genes associated with axonal variants.     

Symptomatic Charcot–Marie‐Tooth? A pair of concordant monozygotic twins

BACKGROUND: A pair of monozygotic twin brothers were referred due to hereditary peripheral neuropathy resembling late onset Charcot-Marie-Tooth (CMT). AIM OF THE STUDY: Diagnostic classification of the twin pair. METHOD: Clinical, neurological, genetical and neurophysiological examination, and molecular genetic testing. RESULTS: The clinic and neurophysiology was compatible with CMT disease with late onset. Molecular genetic analysis excluded mutations in PMP22, connexin32, MPZ, LITAF and MFNZ genes, as well as duplication and deletion of PMP22. CONCLUSIONS: The twins were employed in PVC production and developed symptoms after 14 years of massive exposure. We think that the heavy exposure to various neurotoxic compounds caused symptoms that mimic late-onset CMT. However, the twins had distal dysesthesia which is unusual in inherited neuropathies. This illustrates the importance of an occupational history even in the molecular genetic era.     

Testing overwork weakness in Charcot‐Marie‐tooth disease: Is it true or false?

The occurrence of the overwork weakness (OW) in Charcot‐Marie‐tooth (CMT) disease has been debated for a long time. Especially at the hands level, it is still unclear as to whether OW occurs. Contrasting results may relate to the different muscle groups evaluated and the instruments used. We concentrated to the upper limbs (UL). We recruited 120 subjects, 60 CMT patients and 60 normal controls and evaluated the strength of the tripod pinch and of the hand‐grip with a dynamometer, the opposition ability with the thumb opposition test (TOT) and applied an innovative instrumental testing of hand function using the sensor engineered glove test (SEGT), which previously demonstrated its sensitiveness to measure severity of hands dysfunction in CMT patients. In CMT patients, TOT scores were significantly higher in the non‐dominant hand (NDH) compared to dominant hand (DH), strength in the NDH was slightly but not significantly better than the DH. Finally, SEGT results were similar between the NDH and DH, whereas in normal controls the DH performed better. In conclusion, this study supports the existence of the overwork weakness in CMT. We can speculate that the dexterity and overall ability of the hands appear more impaired in the DH as a result of a weakness and incapacity of opposition. Our results support the importance of avoiding supramaximal exercises and educating patients to prevent incorrect movements.     

Region- and age-specific changes in glutamate transport in the AβPP23 mouse model for Alzheimer's disease

Using 8- and 18-month-old AβPP23 mice, we investigated the involvement of high-affinity glutamate transporters (GLAST, GLT-1, EAAC1), vesicular glutamate transporters (VGLUT1-3) and xCT, the specific subunit of system x(c)?, in Alzheimer's disease (AD) pathogenesis. Transporter expression was studied in cortical and hippocampal tissue and linked to extracellular glutamate and glutamate reuptake activity as measured using in vivo microdialysis. In 8-month-old animals, we could not observe plaque formation or gliosis. Yet, in hippocampus as well as cortex GLAST and GLT-1 expression was decreased. Whereas in cortex this was accompanied by upregulated VGLUT1 expression, extracellular glutamate concentrations were decreased. Surprisingly, inhibiting glutamate reuptake with TBOA revealed increased glutamate reuptake activity in cortex of AβPP23 mice, despite decreased GLAST and GLT-1 expression, and resulted in status epilepticus in all AβPP23 mice, contrary to wildtype littermates. In hippocampus of 8-month-old AβPP23 mice, we observed increased EAAC1 expression besides the decrease in GLAST and GLT-1. Yet, glutamate reuptake activity was drastically decreased according to the decreased GLAST and GLT-1 expression. In 18-month-old AβPP23 mice, plaque formation and gliosis in cortex and hippocampus were accompanied by decreased GLT-1 expression. We also showed, for the first time, increased cortical expression of VGLUT3 and xCT together with a strong tendency towards increased cortical extracellular glutamate levels. VGLUT2 expression remained unaltered in all conditions. The present findings support the hypothesis that alterations in transport of glutamate, and more particular via GLT-1, may be involved in AD pathogenesis.     

Cerebellar abnormalities in Huntington's disease: A role in motor and psychiatric impairment?

The cerebellum has received limited attention in Huntington's disease (HD), despite signs of possible cerebellar dysfunction, including motor incoordination and impaired gait, which are currently attributed to basal ganglia atrophy and disrupted fronto‐striatal circuits. This study is the first to investigate a potential contribution of macro‐ and microstructural cerebellar damage to clinical manifestations of HD. T1‐ and diffusion‐weighted 3T magnetic resonance imaging (MRI) scans were obtained from 12 controls and 22 early‐stage HD participants. Manual delineation and voxel‐based morphometry were used to assess between‐group differences in cerebellar volume, and diffusion metrics were compared between groups within the cerebellar gray and white matter. Associations between these imaging measures and clinical scores were examined within the HD group. Reduced paravermal volume was detected in HD compared with controls using voxel‐based morphometry (P < 0.05), but no significant volumetric differences were found using manual delineation. Diffusion abnormalities were detected in both cerebellar gray matter and white matter. Smaller cerebellar volumes, although not significantly reduced, were significantly associated with impaired gait and psychiatric morbidity and of borderline significance with pronate/supinate‐hand task performance. Abnormal cerebellar diffusion was associated with increased total motor score, impaired saccade initiation, tandem walking, and timed finger tapping. In conclusion, atrophy of the paravermis, possibly encompassing the cerebellar nuclei, and microstructural abnormalities within the cerebellum may contribute to HD neuropathology. Aberrant cerebellar diffusion and reduced cerebellar volume together associate with impaired motor function and increased psychiatric symptoms in stage I HD, potentially implicating the cerebellum more centrally in HD presentation than previously recognized. © 2014 International Parkinson and Movement Disorder Society     

New insights into the pathophysiology of pes cavus in Charcot–Marie–Tooth disease type 1A duplication

Forefoot pes cavus is a cardinal sign of Charcot–Marie–Tooth disease (CMT). This review is focused on the pathophysiology of pes cavus in CMT1A duplication, which is the most common subtype of the disease. Assessment of foot deformities in CMT1A, their prevalence and proposed mechanisms, and recent contributions of magnetic resonance imaging studies of lower-leg and foot musculature are revised. Special attention is given to papers on foot deformities at initial stages of the disease. We conclude that pes cavus is an early and age-dependent manifestation of CMT1A duplication. Selective denervation of intrinsic foot musculature, particularly of the lumbricals, and not imbalance of lower-leg muscles, seems to be the initial mechanism causing reduced ankle flexibility and forefoot cavus deformity.     

Wheel-running in a transgenic mouse model of Alzheimer's disease: protection or symptom?

Several studies on both humans and animals reveal benefits of physical exercise on brain function and health. A previous study on TgCRND8 mice, a transgenic model of Alzheimer's disease, reported beneficial effects of premorbid onset of long-term access to a running wheel on spatial learning and plaque deposition. Our study investigated the effects of access to a running wheel after the onset of Abeta pathology on behavioural, endocrinological, and neuropathological parameters. From day 80 of age, the time when Abeta deposition becomes apparent, TgCRND8 and wildtype mice were kept with or without running wheel. Home cage behaviour was analysed and cognitive abilities regarding object recognition memory and spatial learning in the Barnes maze were assessed. Our results show that, in comparison to Wt mice, Tg mice were characterised by impaired object recognition memory and spatial learning, increased glucocorticoid levels, hyperactivity in the home cage and high levels of stereotypic behaviour. Access to a running wheel had no effects on cognitive or neuropathological parameters, but reduced the amount of stereotypic behaviour in transgenics significantly. Furthermore, wheel-running was inversely correlated with stereotypic behaviour, suggesting that wheel-running may have stereotypic qualities. In addition, wheel-running positively correlated with plaque burden. Thus, in a phase when plaques are already present in the brain, it may be symptomatic of brain pathology, rather than protective. Whether or not access to a running wheel has beneficial effects on Alzheimer-like pathology and symptoms may therefore strongly depend on the exact time when the wheel is provided during development of the disease.     

Which memory task for my mouse? A systematic review of spatial memory performance in the Tg2576 Alzheimer's mouse model

We review studies testing performance on tasks putatively tapping spatial memory in the Tg2576 mouse model of Alzheimer's disease (AD). This model exhibits age-dependent elevation of amyloid-β in the hippocampal formation and elsewhere in the brain. From 49 articles in all, we reviewed Tg2576 performance on five spatial memory tasks: the reference memory version of the Morris water maze, continuous Y-maze alternation, discrete forced-choice T-maze alternation, the radial arm water maze, and the circular platform maze (Barnes maze). Proportionally, the likelihood of detecting significant impairment in Tg2576 mice (relative to age-matched controls) was found to be: highest with the use of T-maze alternation and the radial arm water maze; intermediate when using the Morris water maze and continuous Y-maze alternation; and lowest when using the circular platform maze. These results are indicative rather than conclusive, but have implications for testing cognitive function in Tg2576 mice and, potentially, other AD rodent models. The apparent sensitivity of the T-maze alternation task and reduced sensitivity of the Morris water maze task (reference memory version) are discussed. We also consider limitations and potential improvements in assessing cognitive impairment in dementia models.     

Minocycline: A neuroprotective agent for hypoxic‐ischemic brain injury in the neonate?

Minocycline is a second-generation tetracycline and a potential neuroprotective intervention following brain injury. However, despite the recognized beneficial effects of minocycline in a multitude of adult disease states, the clinical application of minocycline in neonates is contentious. Tetracyclines, as a class, are not usually administered to neonates, but there is compelling evidence that minocycline reduces brain injury after neonatal hypoxic-ischemic brain injury. This Review focuses on the evidence for minocycline use in neonates by considering aspects of pharmacology, drug regimens, functional outcomes, and mechanisms of action.