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Progressive neuronal loss in neurodegenerative diseases such as Parkinson's disease (PD) is associated with progressive degeneration of associated white matter tracts as measured by diffusion tensor imaging (DTI). These findings may have diagnostic and functional implications but their value in PD remains unknown. Here we analyzed longitudinal DTI data from Parkinson's Progression Markers Initiative PD patients for changes over time relative to healthy control (HC) participants. Baseline and 1-year follow-up DTI MRI data from 71 PD patients and 45 HC PPMI participants were included in the analyses. Whole-brain fractional anisotropy (FA) and mean diffusivity (MD) images were compared for baseline group differences and group-by-time interactions. Baseline and 1-year changes in DTI values were correlated with changes in DTI measures and symptom severity, respectively. At baseline, PD patients showed significantly increased FA in brainstem, cerebellar, anterior corpus callosal, inferior frontal and inferior fronto-occipital white matter and increased MD in primary sensorimotor and supplementary motor regions. Over 1 year PD patients showed a significantly stronger decline in FA compared to HC in the optic radiation and corpus callosum and parietal, occipital, posterior temporal, posterior thalamic, and vermis gray matter. Significant increases in MD were observed in white matter of the midbrain, optic radiation and corpus callosum, while gray matter of prefrontal, insular and posterior thalamic regions. Baseline brainstem FA white matter (WM) values predicted 1-year changes in FA white matter and MD gray matter values. White but not gray matter changes in both FA and MD were significantly associated with changes in symptom severity. Significant gray and white matter DTI alterations are observable at the time of PD diagnosis and expand in the first year of PD to other cortical and white matter regions. This pattern of DTI changes is in line with preclinical and neuroanatomical studies suggesting that the increased spatial spread of alpha-synuclein neuropathology is the key mechanism of PD progression. Taken together, these findings suggest that DTI may serve as a sensitive biomarker of disease progression in early-stage PD.

We evaluated the impact of baseline comorbidities on the effectiveness of duloxetine and anticonvulsants (pregabalin/gabapentin) in patients with painful diabetic neuropathy in clinical care. Outcomes from a 6-month, observational study with 2575 patients initiating/switching DPNP treatment were analyzed post-hoc. Propensity scoring was used to adjust for baseline factors influencing treatment choice in 1523 patients receiving duloxetine or anticonvulsants. Analysis of covariance models with fixed effects for baseline pain, treatment, propensity score, baseline characteristics or comorbidities, and their interaction with treatment were used to estimate LSmean effects on Brief Pain Inventory (BPI) average pain and interference scores. 89.5% of patients reported comorbidities, including hypertension (70.5%), hyperlipidemia (39.2%), and depression (24.8%). Macrovascular complications (37.0%) and ‘other chronic pain’ (41.5%), particularly joint pain had an impact on both pain treatments, i.e. less improvement of average pain and interference of pain. Better treatment responses with duloxetine vs. anticonvulsants were observed in patients with depression, those with high baseline BPI total interference score, especially general activity, and in patients with joint pain. Comorbidities such as macroangiopathy and depression as well as pain characteristics should be considered in the treatment of DPNP as they may predict the effectiveness of duloxetine and anticonvulsants.

Rationale and objective Agonists of α7 nicotinic acetylcholine receptors (nAChRs) may have therapeutic potential for the treatment of cognitive deficits. This study describes the in vitro pharmacology of the novel α7 nAChR agonist/serotonin 5-HT 3 receptor (5-HT 3 R) antagonist N -[(3 R )-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141) and its behavioral effects. Results EVP-5141 bound to α7 nAChRs in rat brain membranes ( K i  = 270 nM) and to recombinant human serotonin 5-HT 3 Rs ( K i  = 880 nM) but had low affinity for α4β2 nAChRs ( K i  > 100 μM). EVP-5141 was a potent agonist at recombinant rat and human α7 nAChRs expressed in Xenopus oocytes. EVP-5141 acted as 5-HT 3 R antagonist but did not block α3β4, α4β2, and muscle nAChRs. Rats trained to discriminate nicotine from vehicle did not generalize to EVP-5141 (0.3–30 mg kg −1 , p.o.), suggesting that the nicotine cue is not mediated by the α7 nAChR and that EVP-5141 may not share the abuse liability of nicotine. EVP-5141 (0.3–3 mg kg −1 ) improved performance in the rat social recognition test. EVP-5141 (0.3 mg kg −1 , p.o.) ameliorated scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1 mg kg −1 , i.p.) improved spatial working memory of aged (26- to 32-month-old) rats in a water maze repeated acquisition task. In addition, EVP-5141 improved both object and social recognition memory in mice (0.3 mg kg −1 , p.o.). Conclusions EVP-5141 improved performance in several learning and memory tests in both rats and mice, supporting the hypothesis that α7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits in Alzheimer's disease or schizophrenia.

Rationale and objective Agonists of α7 nicotinic acetylcholine receptors (nAChRs) may have therapeutic potential for the treatment of cognitive deficits. This study describes the in vitro pharmacology of the novel α7 nAChR agonist/ serotonin 5-H[T.sub.3] receptor (5-H[T.sub.3]R) antagonist N-[(3R)-1azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP5141) and its behavioral effects. Results EVP-5141 bound to α7 nAChRs in rat brain membranes ([K.sub.i]=270 nM) and to recombinant human serotonin 5H[T.sub.3]Rs ([K.sub.i] = 880 nM) but had low affinity for α4β2 nAChRs ([K.sub.i] > 100 µM). EVP-5141 was a potent agonist at recombinant rat and human α7 nAChRs expressed in Xenopus oocytes. EVP-5141 acted as 5-H[T.sub.3]R antagonist but did not block α3β4, α4β2, and muscle nAChRs. Rats trained to discriminate nicotine from vehicle did not generalize to EVP-5141 (0.3-30 mg [kg.sub.-1], p.o.), suggesting that the nicotine cue is not mediated by the α7 nAChR and that EVP5141 may not share the abuse liability of nicotine. EVP5141 (0.3-3mg [kg.sup.-1]) improved performance in the rat social recognition test. EVP-5141 (0.3 mg [kg.sup.-1], p.o.) ameliorated scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1 mg [kg.sup.-1],i.p.) improved spatial working memory of aged (26- to 32-month-old) rats in a water maze repeated acquisition task. In addition, EVP-5141 improved both object and social recognition memory in mice (0.3 mg [kg.sup.-1], p.o.). Conclusions EVP-5141 improved performance in several learning and memory tests in both rats and mice, supporting the hypothesis that a7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits in Alzheimer's disease or schizophrenia. Keywords α7 nAChR agonist. Radioligand binding * Xenopus oocytes * Social recognition * Object recognition * Passive avoidance * Morris water maze * Working memory * Abuse liability * EVP-5141

Prasinezumab is a monoclonal antibody to α-synuclein, a protein involved in the pathogenesis of Parkinson’s disease. In a placebo-controlled trial, prasinezumab did not slow the progression of disease over a period of 52 weeks.

Rationale and objective: Agonists of alpha 7 nicotinic acetylcholine receptors (nAChRs) may have therapeutic potential for the treatment of cognitive deficits. This study describes the in vitro pharmacology of the novel alpha 7 nAChR agonist/serotonin 5-HT sub(3) receptor (5-HT sub(3)R) antagonist N-[(3R)-1-azabicyclo[2.2.2]oct-3- yl]-6-chinolincarboxamide (EVP-5141) and its behavioral effects. Results: EVP-5141 bound to alpha 7 nAChRs in rat brain membranes (K sub( i )=270 nM) and to recombinant human serotonin 5-HT sub(3)Rs (K sub( i )=880 nM) but had low affinity for alpha 4 beta 2 nAChRs (K sub( i )>100 mu M). EVP-5141 was a potent agonist at recombinant rat and human alpha 7 nAChRs expressed in Xenopus oocytes. EVP-5141 acted as 5-HT sub(3)R antagonist but did not block alpha 3 beta 4, alpha 4 beta 2, and muscle nAChRs. Rats trained to discriminate nicotine from vehicle did not generalize to EVP-5141 (0.3-30 mg kg super(-1), p.o.), suggesting that the nicotine cue is not mediated by the alpha 7 nAChR and that EVP-5141 may not share the abuse liability of nicotine. EVP-5141 (0.3-3 mg kg super(-1)) improved performance in the rat social recognition test. EVP-5141 (0.3 mg kg super(-1), p.o.) ameliorated scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1 mg kg super(-1), i.p.) improved spatial working memory of aged (26- to 32-month-old) rats in a water maze repeated acquisition task. In addition, EVP-5141 improved both object and social recognition memory in mice (0.3 mg kg super(-1), p.o.). Conclusions: EVP-5141 improved performance in several learning and memory tests in both rats and mice, supporting the hypothesis that alpha 7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits in Alzheimer's disease or schizophrenia.

Agonists of [alpha]7 nicotinic acetylcholine receptors (nAChRs) may have therapeutic potential for the treatment of cognitive deficits. This study describes the in vitro pharmacology of the novel [alpha]7 nAChR agonist/serotonin 5-HT^sub 3^ receptor (5-HT^sub 3^R) antagonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141) and its behavioral effects. EVP-5141 bound to [alpha]7 nAChRs in rat brain membranes (K ^sub i^=270 nM) and to recombinant human serotonin 5-HT^sub 3^Rs (K ^sub i^=880 nM) but had low affinity for [alpha]4[beta]2 nAChRs (K ^sub i^>100 [mu]M). EVP-5141 was a potent agonist at recombinant rat and human [alpha]7 nAChRs expressed in Xenopus oocytes. EVP-5141 acted as 5-HT^sub 3^R antagonist but did not block [alpha]3[beta]4, [alpha]4[beta]2, and muscle nAChRs. Rats trained to discriminate nicotine from vehicle did not generalize to EVP-5141 (0.3-30 mg kg^sup -1^, p.o.), suggesting that the nicotine cue is not mediated by the [alpha]7 nAChR and that EVP-5141 may not share the abuse liability of nicotine. EVP-5141 (0.3-3 mg kg^sup -1^) improved performance in the rat social recognition test. EVP-5141 (0.3 mg kg^sup -1^, p.o.) ameliorated scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1 mg kg^sup -1^, i.p.) improved spatial working memory of aged (26- to 32-month-old) rats in a water maze repeated acquisition task. In addition, EVP-5141 improved both object and social recognition memory in mice (0.3 mg kg^sup -1^, p.o.). EVP-5141 improved performance in several learning and memory tests in both rats and mice, supporting the hypothesis that [alpha]7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits in Alzheimer's disease or schizophrenia.[PUBLICATION ABSTRACT]

Agonists of α7 nicotinic acetylcholine receptors (nAChRs) may have therapeutic potential for the treatment of cognitive deficits. This study describes the in vitro pharmacology of the novel α7 nAChR agonist/serotonin 5-HT3 receptor (5-HT3R) antagonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141) and its behavioral effects.RATIONALE AND OBJECTIVEAgonists of α7 nicotinic acetylcholine receptors (nAChRs) may have therapeutic potential for the treatment of cognitive deficits. This study describes the in vitro pharmacology of the novel α7 nAChR agonist/serotonin 5-HT3 receptor (5-HT3R) antagonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141) and its behavioral effects.EVP-5141 bound to α7 nAChRs in rat brain membranes (K i  = 270 nM) and to recombinant human serotonin 5-HT3Rs (K i  = 880 nM) but had low affinity for α4β2 nAChRs (K i  > 100 μM). EVP-5141 was a potent agonist at recombinant rat and human α7 nAChRs expressed in Xenopus oocytes. EVP-5141 acted as 5-HT3R antagonist but did not block α3β4, α4β2, and muscle nAChRs. Rats trained to discriminate nicotine from vehicle did not generalize to EVP-5141 (0.3-30 mg kg(-1), p.o.), suggesting that the nicotine cue is not mediated by the α7 nAChR and that EVP-5141 may not share the abuse liability of nicotine. EVP-5141 (0.3-3 mg kg(-1)) improved performance in the rat social recognition test. EVP-5141 (0.3 mg kg(-1), p.o.) ameliorated scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1 mg kg(-1), i.p.) improved spatial working memory of aged (26- to 32-month-old) rats in a water maze repeated acquisition task. In addition, EVP-5141 improved both object and social recognition memory in mice (0.3 mg kg(-1), p.o.).RESULTSEVP-5141 bound to α7 nAChRs in rat brain membranes (K i  = 270 nM) and to recombinant human serotonin 5-HT3Rs (K i  = 880 nM) but had low affinity for α4β2 nAChRs (K i  > 100 μM). EVP-5141 was a potent agonist at recombinant rat and human α7 nAChRs expressed in Xenopus oocytes. EVP-5141 acted as 5-HT3R antagonist but did not block α3β4, α4β2, and muscle nAChRs. Rats trained to discriminate nicotine from vehicle did not generalize to EVP-5141 (0.3-30 mg kg(-1), p.o.), suggesting that the nicotine cue is not mediated by the α7 nAChR and that EVP-5141 may not share the abuse liability of nicotine. EVP-5141 (0.3-3 mg kg(-1)) improved performance in the rat social recognition test. EVP-5141 (0.3 mg kg(-1), p.o.) ameliorated scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1 mg kg(-1), i.p.) improved spatial working memory of aged (26- to 32-month-old) rats in a water maze repeated acquisition task. In addition, EVP-5141 improved both object and social recognition memory in mice (0.3 mg kg(-1), p.o.).EVP-5141 improved performance in several learning and memory tests in both rats and mice, supporting the hypothesis that α7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits in Alzheimer's disease or schizophrenia.CONCLUSIONSEVP-5141 improved performance in several learning and memory tests in both rats and mice, supporting the hypothesis that α7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits in Alzheimer's disease or schizophrenia.