New and Noteworthy Information—September 2013

A recent case–control study provides further evidence against the Zamboni hypothesis that chronic cerebrospinal venous insufficiency is involved with multiple sclerosis (MS), researchers reported August 14 in PLOS One. The researchers randomly selected 100 patients with MS between ages 18 and 65 and 100 controls with no known history of MS or other neurologic condition. All participants underwent ultrasound imaging of the veins of the neck and the deep cerebral veins, as well as MRI of the neck veins and brain. The investigators found no evidence of reflux, stenosis, or blockage in the internal jugular veins or vertebral veins in any study participant and no evidence of reflux or cessation of flow in the deep cerebral veins in any subject.

Breastfeeding may reduce a woman’s risk of Alzheimer’s disease, according to research published online ahead of print July 23 in the Journal of Alzheimer’s Disease. Investigators collected reproductive history data from and conducted Alzheimer’s disease diagnostic interviews with a cohort of elderly British women. Analysis using Cox proportional-hazard models indicated that longer breastfeeding duration corresponded to reduced risk of Alzheimer’s disease. Women who breastfed had lower risk of Alzheimer’s disease than women who did not breastfeed. Breastfeeding practices are an important modifier of cumulative endogenous hormone exposure for mothers, according to the researchers. Future studies should consider how reproductive history leads to variation in endogenous hormone exposure and how this variation may influence the relationship between hormones and Alzheimer’s disease, the investigators concluded.

Among older adults, anemia may be associated with an increased risk of dementia, according to a study published August 6 in Neurology. Researchers studied 2,552 older adults (mean age, 76) participating in the Health, Aging, and Body Composition study and who were free of dementia at baseline. Of the total population, 392 participants had anemia at baseline. Over 11 years of follow-up, 455 participants developed dementia. An unadjusted analysis indicated that subjects with baseline anemia had an increased risk of dementia (23% vs 17%) compared with subjects without anemia. The association remained significant after adjusting for demographics, APOE ε4, baseline Modified Mini-Mental State score, comorbidities, and renal function. Additional adjustment for other anemia measures, erythropoietin, and C-reactive protein did not affect the results significantly.

The FDA has approved Trokendi XR, a once-daily extended release formulation of topiramate for the treatment of epilepsy. The agency granted a waiver for certain pediatric study requirements and a deferral for the submission of postmarketing pediatric pharmacokinetic assessments. Trokendi XR is indicated for initial monotherapy in patients ages 10 and older with partial onset or primary generalized tonic–clonic seizures. The drug also is approved as adjunctive therapy in patients ages 6 and older with partial onset or primary generalized tonic–clonic seizures, and as adjunctive therapy in patients ages 6 and older with seizures associated with Lennox–Gastaut syndrome. The product will be available in 25-, 50-, 100- and 200-mg extended-release capsules. Supernus Pharmaceuticals (Rockville, Maryland) expects to launch the product in September 2013.

The FDA has approved scored tablet and oral suspension formulations of ONFI (clobazam) CIV. ONFI is an oral antiepileptic drug of the benzodiazepine class (ie, a 1,5 benzodiazepine). The agency originally approved ONFI in 2011 as a prescription medication to treat seizures associated with Lennox–Gastaut syndrome in adults and children age 2 or older. The new oval-shaped ONFI scored tablets (10 mg and 20 mg) will replace the round, nonscored tablets and are similar in size. The new tablets contain the same ingredients as the round tablet, and the score allows patients or their caregivers to split the tablets in half. ONFI oral suspension (2.5 mg/mL) has a berry flavor. ONFI, manufactured by Lundbeck (Deerfield, Illinois), will no longer be available in a 5-mg tablet.

An incomplete circle of Willis may be more common in patients with migraine with aura than in the general population, according to research published July 26 in PLOS One. Investigators enrolled 56 migraineurs with aura, 61 migraineurs without aura, and 53 controls in an observational study. The researchers performed magnetic resonance angiography to examine subjects’ circle of Willis anatomy and measured cerebral blood flow with arterial spin–labeled perfusion MRI. An incomplete circle of Willis was significantly more common in migraineurs with aura, compared with controls (73% vs 51%). A similar trend was observed among migraineurs without aura (67% vs 51%). Compared with subjects with a complete circle of Willis, subjects with an incomplete circle had greater asymmetry in hemispheric cerebral blood flow.

Some patients with chronic pain diagnosed as fibromyalgia may have unrecognized small-fiber polyneuropathy (SFPN), according to research published online ahead of print June 7 in Pain. Investigators analyzed symptoms associated with SFPN, neurologic examinations, and pathologic and physiologic markers in 27 patients with fibromyalgia and 30 matched normal controls. Study instruments included the Michigan Neuropathy Screening Instrument (MNSI), the Utah Early Neuropathy Scale (UENS), distal-leg neurodiagnostic skin biopsies, and autonomic-function testing (AFT). Approximately 41% of skin biopsies from subjects with fibromyalgia supported a diagnosis of SFPN, compared with 3% of biopsies from control subjects. MNSI and UENS scores were higher in patients with fibromyalgia than in control subjects. Abnormal AFTs were prevalent among patients with fibromyalgia, suggesting that fibromyalgia-associated SFPN is primarily somatic, said the researchers.

High glucose levels may be a risk factor for dementia, even among persons without diabetes, according to a study published August 8 in the New England Journal of Medicine. Researchers examined 35,264 clinical measurements of glucose levels and 10,208 measurements of glycated hemoglobin levels from 2,067 participants (1,228 women) without dementia. Participants’ mean age at baseline was 76. Of the total population, 232 participants had diabetes. During a median follow-up of 6.8 years, 524 participants developed dementia (74 with diabetes). Among participants without diabetes, higher average glucose levels within the preceding five years were related to an increased risk of dementia. A glucose level of 115 mg/dL, compared with 100 mg/dL, was associated with an adjusted hazard ratio for dementia of 1.18.

A majority of Alzheimer’s disease investigators favor disclosing amyloid imaging results to participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), according to a survey published online ahead of print August 21 in Neurology. Shortly before the FDA approved the amyloid-binding radiotracer florbetapir, all ADNI investigators and personnel were asked to complete an anonymous online survey that contained fixed-choice and free-text questions. Although ADNI participants often requested amyloid imaging results, the majority of ADNI investigators (approximately 90%) did not return amyloid imaging results to the participants. Most investigators reported that if the FDA approved florbetapir, they would support the return of amyloid imaging results to participants with mild cognitive impairment and normal cognition, however. ADNI investigators emphasized the need for guidance on how to provide these results to participants.

A sudden decrease of testosterone may induce nigrostriatal pathologies in mice through a decrease in glial-derived neurotrophic factor (GDNF) mediated by inducible nitric-oxide synthase (iNOS), investigators reported in the July 19 Journal of Biological Chemistry. Levels of iNOS, glial markers, and α-synuclein were higher in the nigra of castrated male mice than in normal male mice. After castration, the level of GDNF markedly decreased in the nigra of male mice, however. Subcutaneous implantation of 5 α-dihydrotestosterone pellets reversed nigrostriatal pathologies in castrated male mice, suggesting that the male sex hormone plays a role in castration-induced nigrostriatal pathology. Castrated young male mice may be used as a simple, toxin-free, and nontransgenic animal model to study Parkinson’s disease-related nigrostriatal pathologies, thus facilitating the screening of drugs against Parkinson’s disease, said the researchers.

IV thrombolysis within 90 minutes may be associated with excellent outcomes in patients with moderate and mild stroke, according to research published online ahead of print August 22 in Stroke. Investigators prospectively collected data for consecutive ischemic stroke patients who received IV thrombolysis at 10 European stroke centers. Logistic regression analysis suggested that shorter onset-to-treatment time was significantly associated with excellent outcome. Patients with onset-to-treatment time of 90 minutes or less had lower frequency of intracranial hemorrhage. After adjusting for age, sex, admission glucose level, and year of treatment, the researchers found that onset-to-treatment time of 90 minutes or less was associated with excellent outcome in patients with NIH Stroke Scale (NIHSS) score from 7 to 12, but not in patients with baseline NIHSS score greater than 12 and baseline NIHSS 0 to 6.

A neo-substrate approach involving the adenosine triphosphate (ATP) analog kinetin triphosphate (KTP) can increase the activity of Parkinson’s disease–related mutant PINK1^G309D and PINK1^WT, according to research published on August 15 in Cell. Investigators found that the normal and mutated versions of PINK1 bind to KTP. The application of KTP precursor kinetin to cells resulted in biologically significant increases in PINK1 activity, which were manifest as higher levels of Parkin recruitment to depolarized mitochondria, reduced mitochondrial motility in axons, and lower levels of apoptosis. Kinetin could treat patients with a known PINK1 mutation and also slow disease progression in patients without a family history of the disease, said the researchers. The search for neo-substrates for kinases could provide a novel way of regulating kinase activity, they concluded.

The effect of copper on brain amyloid-β homeostasis depends on whether it is accumulated in the capillaries or in the parenchyma, researchers reported online ahead of print August 19 in Proceedings of the National Academy of Sciences. In aging mice, the accumulation of copper in brain capillaries was associated with its reduction in low-density lipoprotein receptor–related protein 1 (LRP1) and higher brain amyloid-β levels. In human brain endothelial cells, normal labile levels of copper caused the downregulation of LRP1 by inducing nitrotyrosination and subsequent proteosomal-dependent degradation, partly because of interactions between copper, cellular prion protein, and LRP1. In APP^sw/0 mice, copper downregulated LRP1 in brain capillaries and increased amyloid-b production and neuroinflammation. The effect resulted from the accumulation of copper in brain capillaries and in the parenchyma.

—Erik Greb
Senior Associate Editor

A recent case–control study provides further evidence against the Zamboni hypothesis that chronic cerebrospinal venous insufficiency is involved with multiple sclerosis (MS), researchers reported August 14 in PLOS One. The researchers randomly selected 100 patients with MS between ages 18 and 65 and 100 controls with no known history of MS or other neurologic condition. All participants underwent ultrasound imaging of the veins of the neck and the deep cerebral veins, as well as MRI of the neck veins and brain. The investigators found no evidence of reflux, stenosis, or blockage in the internal jugular veins or vertebral veins in any study participant and no evidence of reflux or cessation of flow in the deep cerebral veins in any subject.

Breastfeeding may reduce a woman’s risk of Alzheimer’s disease, according to research published online ahead of print July 23 in the Journal of Alzheimer’s Disease. Investigators collected reproductive history data from and conducted Alzheimer’s disease diagnostic interviews with a cohort of elderly British women. Analysis using Cox proportional-hazard models indicated that longer breastfeeding duration corresponded to reduced risk of Alzheimer’s disease. Women who breastfed had lower risk of Alzheimer’s disease than women who did not breastfeed. Breastfeeding practices are an important modifier of cumulative endogenous hormone exposure for mothers, according to the researchers. Future studies should consider how reproductive history leads to variation in endogenous hormone exposure and how this variation may influence the relationship between hormones and Alzheimer’s disease, the investigators concluded.

Among older adults, anemia may be associated with an increased risk of dementia, according to a study published August 6 in Neurology. Researchers studied 2,552 older adults (mean age, 76) participating in the Health, Aging, and Body Composition study and who were free of dementia at baseline. Of the total population, 392 participants had anemia at baseline. Over 11 years of follow-up, 455 participants developed dementia. An unadjusted analysis indicated that subjects with baseline anemia had an increased risk of dementia (23% vs 17%) compared with subjects without anemia. The association remained significant after adjusting for demographics, APOE ε4, baseline Modified Mini-Mental State score, comorbidities, and renal function. Additional adjustment for other anemia measures, erythropoietin, and C-reactive protein did not affect the results significantly.

The FDA has approved Trokendi XR, a once-daily extended release formulation of topiramate for the treatment of epilepsy. The agency granted a waiver for certain pediatric study requirements and a deferral for the submission of postmarketing pediatric pharmacokinetic assessments. Trokendi XR is indicated for initial monotherapy in patients ages 10 and older with partial onset or primary generalized tonic–clonic seizures. The drug also is approved as adjunctive therapy in patients ages 6 and older with partial onset or primary generalized tonic–clonic seizures, and as adjunctive therapy in patients ages 6 and older with seizures associated with Lennox–Gastaut syndrome. The product will be available in 25-, 50-, 100- and 200-mg extended-release capsules. Supernus Pharmaceuticals (Rockville, Maryland) expects to launch the product in September 2013.

The FDA has approved scored tablet and oral suspension formulations of ONFI (clobazam) CIV. ONFI is an oral antiepileptic drug of the benzodiazepine class (ie, a 1,5 benzodiazepine). The agency originally approved ONFI in 2011 as a prescription medication to treat seizures associated with Lennox–Gastaut syndrome in adults and children age 2 or older. The new oval-shaped ONFI scored tablets (10 mg and 20 mg) will replace the round, nonscored tablets and are similar in size. The new tablets contain the same ingredients as the round tablet, and the score allows patients or their caregivers to split the tablets in half. ONFI oral suspension (2.5 mg/mL) has a berry flavor. ONFI, manufactured by Lundbeck (Deerfield, Illinois), will no longer be available in a 5-mg tablet.

An incomplete circle of Willis may be more common in patients with migraine with aura than in the general population, according to research published July 26 in PLOS One. Investigators enrolled 56 migraineurs with aura, 61 migraineurs without aura, and 53 controls in an observational study. The researchers performed magnetic resonance angiography to examine subjects’ circle of Willis anatomy and measured cerebral blood flow with arterial spin–labeled perfusion MRI. An incomplete circle of Willis was significantly more common in migraineurs with aura, compared with controls (73% vs 51%). A similar trend was observed among migraineurs without aura (67% vs 51%). Compared with subjects with a complete circle of Willis, subjects with an incomplete circle had greater asymmetry in hemispheric cerebral blood flow.

Some patients with chronic pain diagnosed as fibromyalgia may have unrecognized small-fiber polyneuropathy (SFPN), according to research published online ahead of print June 7 in Pain. Investigators analyzed symptoms associated with SFPN, neurologic examinations, and pathologic and physiologic markers in 27 patients with fibromyalgia and 30 matched normal controls. Study instruments included the Michigan Neuropathy Screening Instrument (MNSI), the Utah Early Neuropathy Scale (UENS), distal-leg neurodiagnostic skin biopsies, and autonomic-function testing (AFT). Approximately 41% of skin biopsies from subjects with fibromyalgia supported a diagnosis of SFPN, compared with 3% of biopsies from control subjects. MNSI and UENS scores were higher in patients with fibromyalgia than in control subjects. Abnormal AFTs were prevalent among patients with fibromyalgia, suggesting that fibromyalgia-associated SFPN is primarily somatic, said the researchers.

High glucose levels may be a risk factor for dementia, even among persons without diabetes, according to a study published August 8 in the New England Journal of Medicine. Researchers examined 35,264 clinical measurements of glucose levels and 10,208 measurements of glycated hemoglobin levels from 2,067 participants (1,228 women) without dementia. Participants’ mean age at baseline was 76. Of the total population, 232 participants had diabetes. During a median follow-up of 6.8 years, 524 participants developed dementia (74 with diabetes). Among participants without diabetes, higher average glucose levels within the preceding five years were related to an increased risk of dementia. A glucose level of 115 mg/dL, compared with 100 mg/dL, was associated with an adjusted hazard ratio for dementia of 1.18.

A majority of Alzheimer’s disease investigators favor disclosing amyloid imaging results to participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), according to a survey published online ahead of print August 21 in Neurology. Shortly before the FDA approved the amyloid-binding radiotracer florbetapir, all ADNI investigators and personnel were asked to complete an anonymous online survey that contained fixed-choice and free-text questions. Although ADNI participants often requested amyloid imaging results, the majority of ADNI investigators (approximately 90%) did not return amyloid imaging results to the participants. Most investigators reported that if the FDA approved florbetapir, they would support the return of amyloid imaging results to participants with mild cognitive impairment and normal cognition, however. ADNI investigators emphasized the need for guidance on how to provide these results to participants.

A sudden decrease of testosterone may induce nigrostriatal pathologies in mice through a decrease in glial-derived neurotrophic factor (GDNF) mediated by inducible nitric-oxide synthase (iNOS), investigators reported in the July 19 Journal of Biological Chemistry. Levels of iNOS, glial markers, and α-synuclein were higher in the nigra of castrated male mice than in normal male mice. After castration, the level of GDNF markedly decreased in the nigra of male mice, however. Subcutaneous implantation of 5 α-dihydrotestosterone pellets reversed nigrostriatal pathologies in castrated male mice, suggesting that the male sex hormone plays a role in castration-induced nigrostriatal pathology. Castrated young male mice may be used as a simple, toxin-free, and nontransgenic animal model to study Parkinson’s disease-related nigrostriatal pathologies, thus facilitating the screening of drugs against Parkinson’s disease, said the researchers.

IV thrombolysis within 90 minutes may be associated with excellent outcomes in patients with moderate and mild stroke, according to research published online ahead of print August 22 in Stroke. Investigators prospectively collected data for consecutive ischemic stroke patients who received IV thrombolysis at 10 European stroke centers. Logistic regression analysis suggested that shorter onset-to-treatment time was significantly associated with excellent outcome. Patients with onset-to-treatment time of 90 minutes or less had lower frequency of intracranial hemorrhage. After adjusting for age, sex, admission glucose level, and year of treatment, the researchers found that onset-to-treatment time of 90 minutes or less was associated with excellent outcome in patients with NIH Stroke Scale (NIHSS) score from 7 to 12, but not in patients with baseline NIHSS score greater than 12 and baseline NIHSS 0 to 6.

A neo-substrate approach involving the adenosine triphosphate (ATP) analog kinetin triphosphate (KTP) can increase the activity of Parkinson’s disease–related mutant PINK1^G309D and PINK1^WT, according to research published on August 15 in Cell. Investigators found that the normal and mutated versions of PINK1 bind to KTP. The application of KTP precursor kinetin to cells resulted in biologically significant increases in PINK1 activity, which were manifest as higher levels of Parkin recruitment to depolarized mitochondria, reduced mitochondrial motility in axons, and lower levels of apoptosis. Kinetin could treat patients with a known PINK1 mutation and also slow disease progression in patients without a family history of the disease, said the researchers. The search for neo-substrates for kinases could provide a novel way of regulating kinase activity, they concluded.

The effect of copper on brain amyloid-β homeostasis depends on whether it is accumulated in the capillaries or in the parenchyma, researchers reported online ahead of print August 19 in Proceedings of the National Academy of Sciences. In aging mice, the accumulation of copper in brain capillaries was associated with its reduction in low-density lipoprotein receptor–related protein 1 (LRP1) and higher brain amyloid-β levels. In human brain endothelial cells, normal labile levels of copper caused the downregulation of LRP1 by inducing nitrotyrosination and subsequent proteosomal-dependent degradation, partly because of interactions between copper, cellular prion protein, and LRP1. In APP^sw/0 mice, copper downregulated LRP1 in brain capillaries and increased amyloid-b production and neuroinflammation. The effect resulted from the accumulation of copper in brain capillaries and in the parenchyma.

—Erik Greb
Senior Associate Editor

A recent case–control study provides further evidence against the Zamboni hypothesis that chronic cerebrospinal venous insufficiency is involved with multiple sclerosis (MS), researchers reported August 14 in PLOS One. The researchers randomly selected 100 patients with MS between ages 18 and 65 and 100 controls with no known history of MS or other neurologic condition. All participants underwent ultrasound imaging of the veins of the neck and the deep cerebral veins, as well as MRI of the neck veins and brain. The investigators found no evidence of reflux, stenosis, or blockage in the internal jugular veins or vertebral veins in any study participant and no evidence of reflux or cessation of flow in the deep cerebral veins in any subject.

Breastfeeding may reduce a woman’s risk of Alzheimer’s disease, according to research published online ahead of print July 23 in the Journal of Alzheimer’s Disease. Investigators collected reproductive history data from and conducted Alzheimer’s disease diagnostic interviews with a cohort of elderly British women. Analysis using Cox proportional-hazard models indicated that longer breastfeeding duration corresponded to reduced risk of Alzheimer’s disease. Women who breastfed had lower risk of Alzheimer’s disease than women who did not breastfeed. Breastfeeding practices are an important modifier of cumulative endogenous hormone exposure for mothers, according to the researchers. Future studies should consider how reproductive history leads to variation in endogenous hormone exposure and how this variation may influence the relationship between hormones and Alzheimer’s disease, the investigators concluded.

Among older adults, anemia may be associated with an increased risk of dementia, according to a study published August 6 in Neurology. Researchers studied 2,552 older adults (mean age, 76) participating in the Health, Aging, and Body Composition study and who were free of dementia at baseline. Of the total population, 392 participants had anemia at baseline. Over 11 years of follow-up, 455 participants developed dementia. An unadjusted analysis indicated that subjects with baseline anemia had an increased risk of dementia (23% vs 17%) compared with subjects without anemia. The association remained significant after adjusting for demographics, APOE ε4, baseline Modified Mini-Mental State score, comorbidities, and renal function. Additional adjustment for other anemia measures, erythropoietin, and C-reactive protein did not affect the results significantly.

The FDA has approved Trokendi XR, a once-daily extended release formulation of topiramate for the treatment of epilepsy. The agency granted a waiver for certain pediatric study requirements and a deferral for the submission of postmarketing pediatric pharmacokinetic assessments. Trokendi XR is indicated for initial monotherapy in patients ages 10 and older with partial onset or primary generalized tonic–clonic seizures. The drug also is approved as adjunctive therapy in patients ages 6 and older with partial onset or primary generalized tonic–clonic seizures, and as adjunctive therapy in patients ages 6 and older with seizures associated with Lennox–Gastaut syndrome. The product will be available in 25-, 50-, 100- and 200-mg extended-release capsules. Supernus Pharmaceuticals (Rockville, Maryland) expects to launch the product in September 2013.

The FDA has approved scored tablet and oral suspension formulations of ONFI (clobazam) CIV. ONFI is an oral antiepileptic drug of the benzodiazepine class (ie, a 1,5 benzodiazepine). The agency originally approved ONFI in 2011 as a prescription medication to treat seizures associated with Lennox–Gastaut syndrome in adults and children age 2 or older. The new oval-shaped ONFI scored tablets (10 mg and 20 mg) will replace the round, nonscored tablets and are similar in size. The new tablets contain the same ingredients as the round tablet, and the score allows patients or their caregivers to split the tablets in half. ONFI oral suspension (2.5 mg/mL) has a berry flavor. ONFI, manufactured by Lundbeck (Deerfield, Illinois), will no longer be available in a 5-mg tablet.

An incomplete circle of Willis may be more common in patients with migraine with aura than in the general population, according to research published July 26 in PLOS One. Investigators enrolled 56 migraineurs with aura, 61 migraineurs without aura, and 53 controls in an observational study. The researchers performed magnetic resonance angiography to examine subjects’ circle of Willis anatomy and measured cerebral blood flow with arterial spin–labeled perfusion MRI. An incomplete circle of Willis was significantly more common in migraineurs with aura, compared with controls (73% vs 51%). A similar trend was observed among migraineurs without aura (67% vs 51%). Compared with subjects with a complete circle of Willis, subjects with an incomplete circle had greater asymmetry in hemispheric cerebral blood flow.

Some patients with chronic pain diagnosed as fibromyalgia may have unrecognized small-fiber polyneuropathy (SFPN), according to research published online ahead of print June 7 in Pain. Investigators analyzed symptoms associated with SFPN, neurologic examinations, and pathologic and physiologic markers in 27 patients with fibromyalgia and 30 matched normal controls. Study instruments included the Michigan Neuropathy Screening Instrument (MNSI), the Utah Early Neuropathy Scale (UENS), distal-leg neurodiagnostic skin biopsies, and autonomic-function testing (AFT). Approximately 41% of skin biopsies from subjects with fibromyalgia supported a diagnosis of SFPN, compared with 3% of biopsies from control subjects. MNSI and UENS scores were higher in patients with fibromyalgia than in control subjects. Abnormal AFTs were prevalent among patients with fibromyalgia, suggesting that fibromyalgia-associated SFPN is primarily somatic, said the researchers.

High glucose levels may be a risk factor for dementia, even among persons without diabetes, according to a study published August 8 in the New England Journal of Medicine. Researchers examined 35,264 clinical measurements of glucose levels and 10,208 measurements of glycated hemoglobin levels from 2,067 participants (1,228 women) without dementia. Participants’ mean age at baseline was 76. Of the total population, 232 participants had diabetes. During a median follow-up of 6.8 years, 524 participants developed dementia (74 with diabetes). Among participants without diabetes, higher average glucose levels within the preceding five years were related to an increased risk of dementia. A glucose level of 115 mg/dL, compared with 100 mg/dL, was associated with an adjusted hazard ratio for dementia of 1.18.

A majority of Alzheimer’s disease investigators favor disclosing amyloid imaging results to participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), according to a survey published online ahead of print August 21 in Neurology. Shortly before the FDA approved the amyloid-binding radiotracer florbetapir, all ADNI investigators and personnel were asked to complete an anonymous online survey that contained fixed-choice and free-text questions. Although ADNI participants often requested amyloid imaging results, the majority of ADNI investigators (approximately 90%) did not return amyloid imaging results to the participants. Most investigators reported that if the FDA approved florbetapir, they would support the return of amyloid imaging results to participants with mild cognitive impairment and normal cognition, however. ADNI investigators emphasized the need for guidance on how to provide these results to participants.

A sudden decrease of testosterone may induce nigrostriatal pathologies in mice through a decrease in glial-derived neurotrophic factor (GDNF) mediated by inducible nitric-oxide synthase (iNOS), investigators reported in the July 19 Journal of Biological Chemistry. Levels of iNOS, glial markers, and α-synuclein were higher in the nigra of castrated male mice than in normal male mice. After castration, the level of GDNF markedly decreased in the nigra of male mice, however. Subcutaneous implantation of 5 α-dihydrotestosterone pellets reversed nigrostriatal pathologies in castrated male mice, suggesting that the male sex hormone plays a role in castration-induced nigrostriatal pathology. Castrated young male mice may be used as a simple, toxin-free, and nontransgenic animal model to study Parkinson’s disease-related nigrostriatal pathologies, thus facilitating the screening of drugs against Parkinson’s disease, said the researchers.

IV thrombolysis within 90 minutes may be associated with excellent outcomes in patients with moderate and mild stroke, according to research published online ahead of print August 22 in Stroke. Investigators prospectively collected data for consecutive ischemic stroke patients who received IV thrombolysis at 10 European stroke centers. Logistic regression analysis suggested that shorter onset-to-treatment time was significantly associated with excellent outcome. Patients with onset-to-treatment time of 90 minutes or less had lower frequency of intracranial hemorrhage. After adjusting for age, sex, admission glucose level, and year of treatment, the researchers found that onset-to-treatment time of 90 minutes or less was associated with excellent outcome in patients with NIH Stroke Scale (NIHSS) score from 7 to 12, but not in patients with baseline NIHSS score greater than 12 and baseline NIHSS 0 to 6.

A neo-substrate approach involving the adenosine triphosphate (ATP) analog kinetin triphosphate (KTP) can increase the activity of Parkinson’s disease–related mutant PINK1^G309D and PINK1^WT, according to research published on August 15 in Cell. Investigators found that the normal and mutated versions of PINK1 bind to KTP. The application of KTP precursor kinetin to cells resulted in biologically significant increases in PINK1 activity, which were manifest as higher levels of Parkin recruitment to depolarized mitochondria, reduced mitochondrial motility in axons, and lower levels of apoptosis. Kinetin could treat patients with a known PINK1 mutation and also slow disease progression in patients without a family history of the disease, said the researchers. The search for neo-substrates for kinases could provide a novel way of regulating kinase activity, they concluded.

The effect of copper on brain amyloid-β homeostasis depends on whether it is accumulated in the capillaries or in the parenchyma, researchers reported online ahead of print August 19 in Proceedings of the National Academy of Sciences. In aging mice, the accumulation of copper in brain capillaries was associated with its reduction in low-density lipoprotein receptor–related protein 1 (LRP1) and higher brain amyloid-β levels. In human brain endothelial cells, normal labile levels of copper caused the downregulation of LRP1 by inducing nitrotyrosination and subsequent proteosomal-dependent degradation, partly because of interactions between copper, cellular prion protein, and LRP1. In APP^sw/0 mice, copper downregulated LRP1 in brain capillaries and increased amyloid-b production and neuroinflammation. The effect resulted from the accumulation of copper in brain capillaries and in the parenchyma.

—Erik Greb
Senior Associate Editor