Revisiting the Molecular Mechanism of Neurological Manifestations in Antiphospholipid Syndrome: Beyond Vascular Damage

Antiphospholipid syndrome (APS) is a multiorgan disease often affecting the central nervous system (CNS). Typically, neurological manifestations of APS include thrombosis of cerebral vessels leading to stroke and requiring prompt initiation of treatment with antiplatelet drugs or anticoagulant therapy. In these cases, alterations of the coagulation system at various levels caused by multiple effects of antiphospholipid antibodies (aPL) have been postulated to explain the vascular damage to the CNS in APS. However, several nonvascular neurological manifestations of APS have progressively emerged over the past years. Nonthrombotic, immune-mediated mechanisms altering physiological basal ganglia function have been recently suggested to play a central role in the pathogenesis of these manifestations that include, among others, movement disorders such as chorea and behavioral and cognitive alterations. Similar clinical manifestations have been described in other autoimmune CNS diseases such as anti-NMDAR and anti-VGCK encephalitis, suggesting that the spectrum of immune-mediated basal ganglia disorders is expanding, possibly sharing some pathophysiological mechanisms. In this review, we will focus on thrombotic and nonthrombotic neurological manifestations of APS with particular attention to immune-mediated actions of aPL on the vascular system and the basal ganglia

Immunity and inflammation in neurodegenerative diseases.

Immune reactions inside the central nervous system are finely regulated, thanks to the presence of several checkpoints that have the fundamental purpose to preserve this fragile tissue form harmful events. The current knowledge on the role of neuroinflammation and neuro-immune interactions in the fields of multiple sclerosis, Alzheimer's disease and Parkinson's disease is reviewed. Moreover, a focus on the potential role of both active and passive immunotherapy is provided. Finally, we propose a common perspective, which implies that, under pathological conditions, inflammation may exert both detrimental and protective functions, depending on local factors and the timing of immune activation and shutting-off systems

Below the canopy: global trends in forest vertebrate populations and their drivers

Global forest assessments use forest area as an indicator of biodiversity status, which may mask below-canopy pressures driving forest biodiversity loss and 'empty forest' syndrome. The status of forest biodiversity is important not only for species conservation but also because species loss can have consequences for forest health and carbon storage. We aimed to develop a global indicator of forest specialist vertebrate populations to improve assessments of forest biodiversity status. Using the Living Planet Index methodology, we developed a weighted composite Forest Specialist Index for the period 1970-2014. We then investigated potential correlates of forest vertebrate population change. We analysed the relationship between the average rate of change of forest vertebrate populations and satellite-derived tree cover trends, as well as other pressures. On average, forest vertebrate populations declined by 53% between 1970 and 2014. We found little evidence of a consistent global effect of tree cover change on forest vertebrate populations, but a significant negative effect of exploitation threat on forest specialists. In conclusion, we found that the forest area is a poor indicator of forest biodiversity status. For forest biodiversity to recover, conservation management needs to be informed by monitoring all threats to vertebrates, including those below the canopy

Cortical visuomotor interactions in Freezing of Gait: A TMS approach

OBJECTIVES: Altered cortical visuomotor integration has been involved in the pathophysiology of freezing of gait (FoG) in parkinsonism. The aim of this study was to assess the connections between the primary visual (V1) and motor (M1) areas with a paired-pulse, twin-coil transcranial magnetic stimulation (TMS) technique in patients with FoG. METHODS: Twelve Parkinson's disease (PD) patients suffering from levodopa-responsive-FoG (off-FoG) were compared with 12 PD patients without FoG and 12 healthy subjects of similar age/sex. In the "off" condition, visuomotor connections (VMCs) were assessed bilaterally. A conditioning stimulus over the V1 phosphene hotspot was followed at interstimulus intervals (ISIs) of 18 and 40ms by a test stimulus over M1, to elicit motor evoked potentials (MEPs) in the contralateral first dorsal interosseous muscle. RESULTS: Significant (P<0.01), bilateral effects due to VMCs were detected in all three groups, consisting of a MEP suppression at ISI 18 and 40ms. However, in PD patients with FoG, the MEP suppression was significantly (P<0.05) enhanced, both at ISI 18-40ms, in comparison with the other two groups. The phenomenon was limited to the right hemisphere. CONCLUSIONS: PD patients with FoG showed an excessive inhibitory response of the right M1 to inputs travelling from V1 at given ISIs. Right-sided alterations of the cortical visuomotor integration may contribute to the pathophysiology of FoG

Peripheral nervous system involvement in Parkinson's disease: Evidence and controversies

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Transorbital Sonography in Acute Optic Neuritis: A Case-Control Study

BACKGROUND AND PURPOSE: Acute unilateral optic neuritis is associated with a thickening of the retrobulbar portion of the optic nerve as revealed by transorbital sonography, but no comparison has been made between nerve sheath diameter and optic nerve diameter in patients with acute optic neuritis versus healthy controls. We evaluated optic nerve sheath diameter and optic nerve diameter in patients with acute optic neuritis and healthy controls and compared optic nerve sheath diameter and optic nerve diameter with visual-evoked potentials in patients. MATERIALS AND METHODS: A case-control study was performed in 2 centers. Twenty-one consecutive patients with onset of visual loss during the prior 10 days and established acute noncompressive unilateral optic neuritis were compared with 21 healthy controls, matched for sex and age (±5 years). Two experienced vascular sonographers performed the study by using B-mode transorbital sonography. Visual-evoked potentials were performed on the same day as the transorbital sonography and were evaluated by an expert neurophysiologist. Sonographers and the neurophysiologist were blinded to the status of the patient or control and to clinical information, including the side of the affected eye. RESULTS: The median optic nerve sheath diameter was thicker on the affected side (6.3 mm; interquartile range, 5.9–7.2 mm) compared with the nonaffected side (5.5 mm; interquartile range, 5.1–6.2 mm; P P P = not significant.). Both sides were thicker than those in controls (2.7 mm; interquartile range, 2.5–2.8 mm; P = .001 and .009). No correlation was found between optic nerve sheath diameter and optic nerve diameter and amplitude and latency of visual-evoked potentials in patients with optic neuritis. CONCLUSIONS: Transorbital sonography is a promising tool to support the clinical diagnosis of acute optic neuritis. Further studies are needed to define its specific role in the diagnosis and follow-up of optic neuritis

Slow (1 Hz) repetitive transcranial magnetic stimulation (rTMS) induces a sustained change in cortical excitability in patients with Parkinson's disease

Objective: Low-frequency ( lt = 1 Hz) rTMS (LF-rTMS) can reduce excitability in the underlying cortex and/or promote inhibition. In patients with Parkinson's disease (PD) several TMS elicited features of motor corticospinal physiology suggest presence of impaired inhibitory mechanisms. These include shortened silent period (SP) and slightly steeper input-output (I-O) curve of motor evoked potential (MEP) size than in normal controls. However, studies of LF-rTMS effects on inhibitory mechanisms in PD are scarce. Objective: In this companion paper to the clinical paper describing effects of four consecutive days of LF-rTMS on dyskinesia in PD (Filipovic et al., 2009), we evaluate the delayed (24 h) effects of the LF-rTMS treatment on physiological measures of excitability of the motor cortex in the same patients. There are very few studies of physiological follow up of daily rTMS treatments. Methods: Nine patients with PD in Hoehn and Yahr stages 2 or 3 and prominent medication-induced dyskinesia were studied. This was a placebo-controlled, crossover study, with two treatment arms, "real" rTMS and "sham" rTMS (placebo). In each of the treatment arms, rTMS (1800 pulses; 1 Hz rate; intensity of the real stimuli just-below the active motor threshold) was delivered over the motor cortex for four consecutive days. Motor cortex excitability was evaluated at the beginning of the study and the next day following each of the four-day rTMS series (real and sham) with patients first in the practically defined "off" state, following 12 h withdrawal of medication, and subsequently in a typical "on" state following usual morning medication dose. Results: The SP was significantly longer following real rTMS in comparison to both baseline and sham rTMS. The effect was independent from the effects of dopaminergic treatment. There was no difference in MEP size, rest and active motor threshold. The I-O curve, recorded from the relaxed muscle, showed a trend towards diminished slope in comparison to baseline, but the difference was not significant. There was no consistent correlation between prolongation of SP and concomitant reduction in dyskinesia following real rTMS. Conclusions: Low-frequency rTMS delivered over several consecutive days changes the excitability of motor cortex by increasing the excitability of inhibitory circuits. The effects persist for at least a day after rTMS. Significance: The results confirm the existence of a residual after-effect of consecutive daily applications of rTMS that might be relevant to the clinical effect that was observed in this group of patients and could be further exploited for potential therapeutic uses

Evidence of pre-synaptic dopaminergic deficit in a patient with a novel progranulin mutation presenting with atypical parkinsonism

Parkinsonism can be the presenting feature of frontotemporal dementia due to Progranulin (GRN) mutations or develop over the course of the disease, mimicking idiopathic Parkinson's disease or atypical parkinsonism. Here we report on a patient carrying a novel GRN mutation who presented with asymmetric parkinsonism and developed cognitive decline and language alterations two years later. Brain MRI showed mild asymmetric fronto-parietal atrophy. Single-photon emission computed tomography with I123 ioflupane (DAT-Scan) demonstrated reduced tracer uptake in the left putamen. Larger studies are needed to clarify whether presynaptic dopaminergic deficit is present in all GRN mutation carriers or only in those with parkinsonism