Anne-Marie Duchemin

Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies

Objective: Anti-Hu antibodies (Hu-Ab) and anti-CV2/CRMP5 antibodies (CV2/CRMP5-Ab) have been identified in association with paraneoplastic neurological disorders. However, it is not clear whether these antibodies are associated with specific neurological symptoms or are only markers of anti-cancer immune reaction. Methods: To address this question, 37 patients with CV2/CRMP5-Ab and 324 patients with Hu-Ab were compared. Results: Whereas the age and sex ratio were the same between the two groups, the distribution of neurological symptoms was not. Patients with CV2/CRMP5-Ab presented more frequently cerebellar ataxia, chorea, uveo/retinal symptoms and myasthenic syndrome (Lambert–Eaton myasthenic syndrome LEMS or myasthenia gravis). They also had a better Rankin score. In contrast, dysautonomia, brainstem encephalitis and peripheral neuropathy were more frequent in patients with Hu-Ab. Limbic encephalitis occurred similarly in both groups. Small-cell lung cancer was the most frequently associated tumour in both groups of patients, while malignant thymoma was observed only in patients with CV2/CRMP5-Ab. In particular, patients with CV2/CRMP5-Ab and thymoma developed myasthenic syndrome more frequently, while patients with SCLC developed neuropathies more frequently. Chorea and myasthenic syndrome were only seen in patients with CV2/CRMP5-Ab. The median survival time was significantly longer in patients with CV2/CRMP5-Ab, and this effect was not dependent on the type of tumour. Interpretation: The data demonstrate that in patients with paraneoplastic neurological syndromes, the neurological symptoms and survival vary with both the type of associated onco-neural antibody and the type of tumour.

GM1 ganglioside induces phosphorylation and activation of Trk and Erk in brain.

We investigated the ability of GM1 to induce phosphorylation of the tyrosine kinase receptor for neurotrophins, Trk, in rat brain, and activation of possible down‐stream signaling cascades. GM1 increased phosphorylated Trk (pTrk) in slices of striatum, hippocampus and frontal cortex in a concentration‐ and time‐dependent manner, and enhanced the activity of Trk kinase resulting in receptor autophosphorylation. The ability of GM1 to induce pTrk was shared by other gangliosides, and was blocked by the selective Trk kinase inhibitors K252a and AG879. GM1 induced phosphorylation of TrkA > TrkC > TrkB in a region‐specific distribution. Adding GM1 to brain slices activated extracellular‐regulated protein kinases (Erks) in all three brain regions studied. In striatum, GM1 elicited activation of Erk2 > Erk1 in a time‐and concentration‐dependent manner. The GM1 effect on Erk2 was mimicked by other gangliosides, and was blocked by the Trk kinase inhibitors K252a and AG879. Pertussis toxin, as well as Src protein tyrosine kinase and protein kinase C inhibitors, did not prevent the GM1‐induced activation of Erk2, apparently excluding the participation of Gi and Gq/11 protein‐coupled receptors. Intracerebroventricular administration of GM1 induced a transient phosphorylation of TrkA and Erk1/2 in the striatum and hippocampus complementing the in situ studies. These observations support a role for GM1 in modulating Trk and Erk phosphorylation and activity in brain.

Involvement of collapsin response mediator proteins in the neurite extension induced by neurotrophins in dorsal root ganglion neurons.

The pattern of sensory neuron extensions and connections is established during embryonic development through complex and varied guidance cues that control motility of growth cones and neurite morphogenesis. Semaphorins and neurotrophins are molecules that act as such cues. Collapsin response mediator proteins (CRMPs) are thought to be part of the semaphorin signal transduction pathway implicated in semaphorin-induced growth cone collapse. In this report, we present evidence that CRMPs are also involved in the neurite extension controlled by neurotrophins. We found that specific antibodies and the dominant-negative mutant protein for CRMP2 both potentiated the neurite extension induced by NGF, while specific antibodies and the corresponding mutant protein for CRMP1 both abolished the neurite extension induced by NT3. Our data suggest that CRMP2 has a negative effect on neurite extension induced by NGF and CRMP1 participates in the neurite formation/extension induced by NT3. These results point to a function for CRMPs in the regulation of neurite outgrowth induced by neurotrophins in sensory neurons.

Changes in plasma nerve growth factor levels in older adults associated with chronic stress.

Evidence indicates that the actions of nerve growth factor (NGF) reach beyond the nervous system and might modulate immune function. Based on reports that blood NGF rises following the acute stress of parachute jumping, we investigated whether exposure to a chronic stressor, caregiving for a cognitively impaired spouse, could alter the levels of blood NGF. High perceived stress and depression in caregivers (vs. well-matched controls) were associated with elevated blood NGF. These data suggest that exposure to this chronic stressor can alter the concentrations of circulating NGF, and that psychological stress can induce changes in NGF concentrations in older adults.

CRMP3 is required for hippocampal CA1 dendritic organization and plasticity

In vitro studies have pointed to the collapsin response mediator proteins (CRMPs) as key regulators of neurite outgrowth and axonal differentiation. CRMP3 is expressed mostly in the nervous system during development but remains at high levels in the hippocampus of adults. To explore CRMP3 function in vivo, we generated mice with targeted disruption of the CRMP3 gene. Immunohistochemistry and Golgi staining of CA1 showed abnormal dendrite and spine morphogenesis in the hippocampus of CRMP3‐deficient mice. Apical dendrites displayed an increase in undulation and a reduction in length and branching points. Basal dendrites also exhibited a reduction in length with an alteration in soma stem distribution and an increased number of thick dendrites localized in stratum oriens (SO). Long‐term potentiation (LTP) was impaired in this area. These data indicate an important role for CRMP3 in dendrite arborization, guide‐posts navigation, and neuronal plasticity.—Quach, T. T., Massicotte, G., Belin, M. F., Honnorat, J., Glasper, E. R., Devries, A. C., Jakeman, L. B., Baudry, M., Duchemin, A. M., Kolattukudy, P. E. CRMP3 is required for hippocampal CA1 dendritic organization and plasticity. FASEB J. 22, 401–409 (2008)

Shared Decision Making and Other Variables as Correlates of Satisfaction with Health Care Decisions in a United States National Survey

OBJECTIVE The purpose of this study was to examine the relationship between shared decision-making (SDM) and satisfaction with decision (SWD) within a larger survey of patient decision-making in health care consultations. METHODS A randomly selected age-proportionate national sample of adults (aged 21-70 years) stratified on race, ethnicity, and gender (N=488) was recruited from a health research volunteer registry and completed an online survey with reference to a recent health consultation. Measures included the shared decision making-9 questionnaire (SDM-Q-9), Satisfaction With Decision (SWD) scale, sociodemographic, health, and other standardized decision-making measures. Forward selection weighted multiple regression analysis was used to model correlates of SWD. RESULTS After controlling for sociodemographic variables, SDM-Q-9 total score was associated with SWD, adjusted R(2)=.368, p<.001. Three of nine SDM-Q-9 items accounted for significant proportions of variance in SWD. CONCLUSION SDM was positively associated with SWD and was strongest for three areas of SDM: patients being helped in a health care consultation with understanding information, with treatment preference elicitation, and with weighing options thoroughly. PRACTICE IMPLICATIONS By identifying variables such as SDM that are associated with SWD, health care interventions can better target modifiable factors to enhance satisfaction and other outcomes.

Met-enkephalin and preproenkephalin mRNA changes in the striatum of the nicotine abstinence mouse.

We studied the changes of met-enkephalin (Met-Enk) content and preproenkephalin (PPE) mRNA in the striatum in a mouse model of nicotine abstinence. Nicotine, 2 mg/kg, s.c., was administered four times daily for 14 days and Met-Enk and PPE mRNA evaluated at various times (4-96 h) following drug discontinuation. Met-Enk, assayed by radioimmunoassay, was increased in the ventral (nucleus accumbens) but not dorsal (putamen/caudate) striatum, while PPE mRNA, assayed in whole striatum by Northern blotting was elevated. Both changes were seen early during withdrawal and lasted over 72 h. In situ hybridization revealed enhanced signal in the dorsal striatum, mostly laterally, and smaller increases in the rostral pole, core and shell of the nucleus accumbens. These observations indicate that during nicotine withdrawal, striatal enkephalinergic neurons undergo adaptative responses, which might contribute to the abstinence behavioral syndrome.

GM1-induced activation of phosphatidylinositol 3-kinase: involvement of Trk receptors.

J. Neurochem. (2008) 104, 1466–1477.

Nerve growth factor (NGF) and NGF mRNA change in rat uterus during pregnancy

During pregnancy, the uterus undergoes a profound sympathetic denervation. To explore whether this is associated with changes in neurotrophic factors, we assayed nerve growth factor (NGF) and NGF mRNA in the uterus of non-pregnant and pregnant rats. In the uterine horn, the concentration of NGF and its mRNA decreased during middle and late pregnancy. However, when values were corrected for the increase of uterine weight and total RNA yield during pregnancy, NGF content and mRNA per horn increased during middle and late pregnancy. Similar, but less pronounced, changes were observed in the cervix. By seven days postpartum, both parameters returned to near normal.

Tyrosine hydroxylase, aromatic L-amino acid decarboxylase and dopamine metabolism after chronic treatment with dopaminergic drugs.

Mice were treated with dopamine (DA) receptor agonist and antagonist drugs: Agonists: (+/-)-SKF 38393 ((+/-)-1-phenyl-2,3,4, 5-tetrahydro-(1H)-3-benzazepine-7,8-diol) [DA D1-like]; bromocriptine, [DA D2 selective]; quinpirole, [DA D2/D3 preferring]; (+/-)-7-hydroxy-dipropylamino-tetralin (7-OH-DPAT), [DA D3/D2 preferring], Antagonists: R(+)-SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine), [DA D1-like]; and haloperidol, [DA D2-like]. All drugs were administered intraperitoneally, two injections daily 8 h apart for 30 days. Aromatic L-amino acid decarboxylase (AAAD) and tyrosine hydroxylase (TH) activity, protein and mRNA, as well as DA metabolism were followed with time thereafter in the nigrostriatal neurons. We observed that chronic administration of D1-like agonists had no effect on TH or AAAD activity, while D2-like agonists decreased AAAD, but not TH activity. Additionally, chronic blockade of DA D2-like receptors resulted in prolonged induction of TH and AAAD, while chronic blockade of DA D1-like receptors induced changes of AAAD only. Compared to TH the induction of AAAD was longer lasting. DA metabolism was altered by chronic administration of drugs acting on DA D2-like, but not DA D1-like receptors, and in general the patterns of change did not follow those for TH or AAAD. When studied 48 h after the last dose of the chronic haloperidol schedule TH displayed tolerance to acute drug challenge. At the same time interval, there was tolerance to the enhancing effects of haloperidol and SCH 23390 on DA metabolism. The induction of AAAD by haloperidol or SCH 23990 did not appear to develop tolerance after chronic administration. These observations complement existing knowledge, and provide novel information about AAAD that may have practical importance for Parkinsons patients on L-DOPA therapy.