Nick Jones

Stroke: Disruption of the nNOS–PSD-95 complex is neuroprotective in models of cerebral ischemia.

Stroke: Disruption of the nNOS–PSD-95 complex is neuroprotective in models of cerebral ischemia

Alzheimer disease: plasma clusterin predicts degree of pathogenesis in AD.

Plasma levels of clusterin, a chaperone protein that regulates amyloid formation and clearance, indicate that blood-based biomarkers could identify individuals at risk of developing alzheimer disease (aD), according to a study published in Archives of General Psychiatry. “the results of this study demonstrate that this protein, which has an established role in several pathways relevant to aD, is closely associated with disease progression,” explains lead author madhav thambisetty (national institute on aging, usa). aD is a neurodegenerative disease that is associated with profound cognitive deficits, and no disease-modifying therapies are currently available for this condition. “a major hurdle to the development of effective treatments for aD is the lack of inexpensive and noninvasive methods that accurately detect early pathological changes in the brains of individuals who will eventually develop this disease,” says thambisetty. Blood-based biomarkers might represent one means of identifying and monitoring such individuals. thambisetty and colleagues used a combined proteomic and neuroimaging amyloid plaques in a transgenic mouse overexpressing human amyloid precursor protein and presenilin 1 contain amyloid-β (black arrow) and clusterin (white arrow). image provided by Dr Madhav thambisetty. approach to identify blood-based biomarkers that could accurately predict disease pathology and clinical progression in aD. the researchers found that the plasma concentration of clusterin is positively associated with atrophy in the hippocampus and entorhinal cortex—two brain regions that are affected in early stages of the disease—in patients with mild cognitive impairment or aD. Furthermore, proteomic analysis in a separate group of patients with aD revealed that clusterin levels were increased in patients deemed to have a faster rate of cognitive decline compared with patients with a slow rate of cognitive decline. using Pet imaging, the researchers also demonstrated that increased plasma clusterin concentrations were positively associated with fibrillar amyloid-β (aβ) burden in the entorhinal cortex. this result was confirmed in transgenic mice that had marked cerebral aβ deposition and cognitive defects: plasma concentrations of clusterin were higher in mice with aD-like symptoms than in wild-type animals. moreover, in these transgenic animals, cortical aβ plaques were shown to contain clusterin, and both aβ burden and clusterin deposition increased with age. “we believe that our findings are a significant advance in the field because they identify a strong signal in blood from clusterin that seems to be relevant to both pathology and symptoms in patients with aD,” says thambisetty. However, “although plasma clusterin levels do not seem to be a definitive marker for aD, the results set the stage for further directed studies of other amyloid chaperone proteins like clusterin that might be useful as blood biomarkers for aD.”

PINK1 targets dysfunctional mitochondria for autophagyin Parkinson disease.

Parkinson disease: PINK1 targets dysfunctional mitochondria for autophagy in Parkinson disease

Parkinson disease: PINK1 targets dysfunctional mitochondria for autophagy in Parkinson disease

Parkinson disease: PINK1 targets dysfunctional mitochondria for autophagy in Parkinson disease

Alzheimer disease: Risk of dementia and Alzheimer disease increases with occupational pesticide exposure

Alzheimer disease: Risk of dementia and Alzheimer disease increases with occupational pesticide exposure

Epilepsy: DBS reduces seizure frequency in refractory epilepsy

a double-blind randomized controlled trial published in Epilepsia provides evidence that deep brain stimulation (DBs) of the anterior nucleus of the thalamus can significantly reduce the monthly seizure frequency in patients with medically refractory epilepsy. the beneficial effects of DBs were shown to last for the duration of the 2 year study, indicating that the positive effects of the treatment are not associated with the surgical procedure.

Movement disorders: Imaging differentiates progressive supranuclear palsy from Parkinson disease

Movement disorders: Imaging differentiates progressive supranuclear palsy from Parkinson disease

Multiple sclerosis: Can Pittsburgh compound B PET imaging quantify demyelination in MS?

Pittsburgh compound B (PiB) could be used to quantify myelin loss in patients with multiple sclerosis (ms), according to a proof-of-concept study published in Annals of Neurology. the quantification of demyelination in this disease could “improve our understanding of the pathophysiology of ms ... and provide a means of evaluating new promyelinating strategies in future clinical trials”, says lead investigator Bruno stankoff, of university Pierre et marie Curie, Paris, France. Demyelination is one of the main features of ms and mri can detect demyelinating lesions; however, to date, no imaging technique is able to quantify demyelination or remyelination. research has shown that derivatives of the stain Congo red bind to both mylein and amyloid plaques. this finding led stankoff and colleagues to hypothesize that PiB, which is a thoflavin t derivative that binds to amyloid-β and also displays an affinity for myelin, could be used as a myelin imaging marker.

Neurodegenerative disease: CSF biomarkers differentiate between two forms of frontotemporal lobar degeneration

Neurodegenerative disease: CSF biomarkers differentiate between two forms of frontotemporal lobar degeneration

Pain: do cytokines cause pain in small-fiber neuropathy?

burning pain associated with sFn are currently unknown. Proinflammatory cytokines are typically algesic, and evidence suggests that these pleiotropic molecules might cause pain in various chronic pain conditions. to ascertain whether proinflammatory cytokines are involved in the genesis of pain in sFn, Üçeyler and colleagues quantified the cutaneous expression of cytokines in skin biopsy samples taken from the site of pain (distal calf) and at an unaffected site (proximal thigh). the researchers also analyzed blood samples taken from the patients to assess systemic cytokine gene expression. “the most significant finding of our study was that in patients with lengthdependent sFn, the gene expression of the proinflammatory cytokines interleukin (il)-6 and il-8 was significantly increased in the affected skin [compared with the unaffected skin and skin from healthy controls],” says Üçeyler. the researchers also found that patients with sFn had approximately twofold greater systemic gene expression of il-2, il-10 and transforming growth factor-β1 than had healthy controls. inflammatory cells are an important source of both anti-inflammatory and proinflammatory cytokines. nevertheless, the researchers found that macrophage and t lymphocyte numbers were similar between skin biopsy samples taken from affected and unaffected skin and between patients with sFn and controls. this result indicates that the increased cytokine expression in affected skin was not associated with the degree of inflammatory cell infiltration. the results of the Üçeyler et al. study indicate that a-δ and C fibers that are damaged in sFn might be sensitive to algogens, and elevated local proinflammatory cytokines might be one of the underlying causes of pain associated with this condition. However, “future studies with higher numbers of patients and controls are needed to confirm and extend our findings,” write the authors. the researchers now plan to use organ culture techniques to identify the cellular source of the elevated local cytokines.