Best and Worst of Health and Healthcare – September 2015




Last month was highly prolific in Alzheimer’s disease research – pathological mechanisms were described, detection tools were evaluated, and therapeutic targets were unraveled. But it was not all about Alzheimer’s. Here is the best and worst news I came across within September.

THE BEST

A new target for morphine addiction prevention

Morphine mediates its euphoric and analgesic effects by acting on the mu-opioid receptor (MOR). MOR belongs to a family of receptors whose signaling efficiency is controlled by the regulator of G-protein signaling (RGS) proteins. A study published in Biological Psychiatry used genetically modified animal models to study the effects of the protein RGS7 as a regulator of morphine’s action through MOR signaling. Results showed that the elimination of RGS7 increased the predisposition to morphine addiction by enhancing reward, increasing analgesia, delaying tolerance, and heightening withdrawal in response to morphine administration. This study therefore suggests that RGS7 may be a potential drug target that may help reduce some of the disadvantageous side-effects of morphine.

The efficacy of early detection tools for Alzheimer’s disease

The early diagnosis of Alzheimer’s disease is of obvious importance for a timely and effective intervention in disease development. Amyloid-beta (A-beta) is a marker for Alzheimer’s disease that can be detected in the cerebrospinal fluid (CSF). A method known as amyloid PET is now also being used as a tool for Alzheimer’s disease detection. Since there are conflicting opinions on which is the best tool for detecting early-stage Alzheimer’s disease, a study published in Neurology aimed at comparing the diagnostic accuracy of CSF biomarkers and amyloid PET for diagnosing early-stage Alzheimer’s disease. There were no differences between the best CSF and PET measures and no improvement when combining them. This therefore showed that both amyloid PET and CSF biomarkers can identify early Alzheimer’s disease with high accuracy.

Tau acetylation as a new therapeutic target in Alzheimer’s disease

Tau fibrils accumulation is one of the hallmarks of Alzheimer’s disease and frontotemporal dementia (FTD). Soluble tau species are highly toxic and may be a key factor in these pathologies. An article published in Nature Medicine showed that tau acetylation is a key contributor to its toxicity and an early feature of Alzheimer’s disease in mice. In fact, tau acetylation may be one of the first signs of the pathology, even before tau fibrillary tangles are detectable. This study also showed that tau acetylation can be inhibited by salsalate a nonsteroidal anti-inflammatory drug used for the treatment of arthritis. Administration of salsalate after disease onset lowered the levels of total tau and acetylated tau, improved tau-induced memory deficits and prevented hippocampal atrophy, which is strongly linked to memory impairment. This indicates that targeting tau acetylation may be a new therapeutic strategy for Alzheimer’s disease and tau-associated dementia.

Bioenergetic demand is a vulnerability factor for dopaminergic neurons in Parkinson’s disease

One of the hallmarks of Parkinson’s disease is the selective loss of dopaminergic neurons in the substantia nigra compacta (SNc). The reason for this specificity remains a key subject of Parkinson’s disease research. Research published in Current Biology showed that SNc dopaminergic neurons differ from other, less susceptible neurons by having more complex morphological characteristics that are associated with increased mitochondrial oxidative phosphorylation and higher bioenergetic demands. As a result of this energetic burden, these neurons develop chronically elevated oxidative stress, becoming more susceptible to Parkinson’s disease. The manipulation of these morphological features was able to reduce mitochondrial oxidative phosphorylation and the vulnerability of SNc dopaminergic neurons to neurotoxic agents.

Increasing the brain clearance of A-beta in Alzheimer’s disease therapy

Increased brain accumulation of the neurotoxic amyloid-beta (A-beta) peptide is a key event in the pathogenesis of Alzheimer’s disease. Impaired clearance of A-beta from the brain via the bloodstream is a major factor in the disease process. Blood vessels in the brain have properties that strictly regulate what gets in and out of the brain; this blood-brain barrier plays an essential part in the impaired clearance of A-beta. A study published in Science Advances showed that specific components of these blood vessels (tight junction molecules) are altered in a mouse model of Alzheimer’s disease and may therefore affect the clearance of A-beta to the plasma. Indeed, this study showed that suppressing the expression of these tight junction molecules decreased the levels of A-beta in the brain while increasing its plasma levels, and enhanced cognitive function. It was also shown that A-beta itself can induce a transient decrease in the expression of those molecules, allowing its own clearance across the blood-brain barrier. This data places the modulation of tight junction molecules as a potential therapeutic approach for Alzheimer’s disease.

THE WORST

Smoking aggravates multiple sclerosis

Smoking tobacco is a risk factor for multiple sclerosis (MS). However, it is not clear whether smoking after MS diagnosis is also significantly detrimental. To determine the effect of smoking after MS diagnosis in disease progression, a study published in JAMA Neurology followed a cohort of patients with MS who smoked at diagnosis. Data showed that each additional year of smoking after diagnosis accelerated disease progression by 4.7%, and that those who carried on smoking continuously each year after diagnosis had a faster development than those who quit smoking. This study therefore showed that patients with MS should be advised to stop smoking.

Sleep and cardiovascular disease

A study published in the journal Arteriosclerosis, Thrombosis and Vascular Biology, which compared sleep patterns with preclinical signs of cardiovascular disease, showed that extreme sleep duration and poor sleep quality can be associated with an increased risk of cardiovascular disease. It was shown that markers of preclinical cardiovascular disease were highest for participants sleeping either less than 5 hours or more than 9 hours, when compared with a mean sleep duration of 7 hours. These results reinforce the importance of sleep quality and duration in cardiovascular health.

Amyloid-beta pathology may be transmissible

A letter published in Nature revealed that amyloid-beta (A-beta) pathology may be iatrogenically transmissible, i.e. transmissible through medical procedures. While performing an autopsy study of eight individuals with iatrogenic Creutzfeldt-Jakob disease (iCJD), four cases of moderate to severe A-beta pathology were also found. A-beta deposition in the grey matter was typical of that seen in Alzheimer’s disease, and A-beta deposition in blood vessel walls was characteristic of cerebral amyloid angiopathy. None of the patients had any risk factors for early-onset Alzheimer’s disease. Also, patients with other prion diseases showed no signs of A-beta pathology. This pattern of A-beta deposition was therefore consistent with iatrogenic transmission of A-beta pathology along with CJD. This raises the question of whether other iatrogenic paths of prion transmission may also be relevant to human diseases.

Antidepressant drugs disproved as effective

Work published in The BMJ aimed at reevaluating a study funded by SmithKline Beecham (now GlaxoSmithKline), that was published in 2001 and that stated that paroxetine was effective and safe for depression in adolescents. Concerns about this study had already been raised, and, in fact, the current study disproved those findings. The BMJ’s study compared the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. It was found that paroxetine and imipramine were ineffective for major depression in adolescents; in fact, that there was actually an increase in harms, including suicidal ideation and behavioral adverse effects in the paroxetine group, and cardiovascular problems in the imipramine group.

Children of smokers are more likely to also become smokers

According to research published on the American Journal of Public Health, parental and adolescent smoking and nicotine dependence may be associated. Using data from the US National Survey on Drug Use and Health, the association between parental and adolescent smoking behaviors was determined. It was found that parental current dependence was strongly associated with adolescents’ lifetime smoking; parental current nondependent smoking and former smoking were less strongly associated. Parental nicotine dependence was also associated with adolescent nicotine dependence.

References

Jaunmuktane Z, Mead S, Ellis M, Wadsworth JD, Nicoll AJ, et al (2015). Evidence for human transmission of amyloid-beta pathology and cerebral amyloid angiopathy. Nature 525: 247–250. PMID: 26354483

Kandel DB, Griesler PC, Hu MC (2015). Intergenerational Patterns of Smoking and Nicotine Dependence Among US Adolescents. Am J Public Health [Epub ahead of print] PMID: 26378847

Keaney J, Walsh DM, O’Malley T, Hudson N, Crosbie DE, et al (2015). Autoregulated paracellular clearance of amyloid-? across the blood-brain barrier. Science Advances, 1(8):e1500472

Kim CW, Chang Y, Zhao D, Cainzos-Achirica M, Ryu S et al (2015). Sleep Duration, Sleep Quality, and Markers of Subclinical Arterial Disease in Healthy Men and Women. Arterioscler Thromb Vasc Biol. [Epub ahead of print] PMID: 26359509

Le Noury J, Nardo JM, Healy D, Jureidini J, Raven M, et al (2015). Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. BMJ, 351:h4320. PMID: 26376805

Min SW, Chen X, Tracy TE, Li Y, Zhou Y, et al (2015). Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med [Epub ahead of print] PMID: 26390242

Pacelli C, Giguère N, Bourque MJ, Lévesque M, Slack RS, Trudeau LÉ (2015). Elevated Mitochondrial Bioenergetics and Axonal Arborization Size Are Key Contributors to the Vulnerability of Dopamine Neurons. Curr Biol [Epub ahead of print]. PMID: 26320949

Palmqvist S, Zetterberg H, Mattsson N, Johansson P; Alzheimer’s Disease Neuroimaging Initiative, et al (2015). Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease. Neurology [Epub ahead of print] PMID: 26354982

Ramanujam R, Hedström AK, Manouchehrnia A, Alfredsson L, Olsson T, et al (2015). Effect of Smoking Cessation on Multiple Sclerosis Prognosis. JAMA Neurol, 8:1-7. PMID: 26348720

Sutton LP, Ostrovskaya O, Dao M, Xie K, Orlandi C, et al (2015). Regulator of G-Protein Signaling 7 Regulates Reward Behavior by Controlling Opioid Signaling in the Striatum. Biological Psychiatry [Epub ahead of print] PMID: 26364547

Image via aga7ta / Shutterstock.

Sara Adaes, PhD

Sara Adaes, PhD, has been a researcher in neuroscience for over a decade. She studied biochemistry and did her first research studies in neuropharmacology. She has since been investigating the neurobiological mechanisms of pain at the Faculty of Medicine of the University of Porto, in Portugal. Follow her on Twitter @saradaes
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