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• W4236030849 abstract "Neurodegenerative Disease ManagementVol. 2, No. 3 News & ViewsFree AccessJournal Watch: Our panel of experts highlight the most important research articles across the spectrum of topics relevant to the field of neurodegenerative disease managementDag Aarsland, Anne Rosser, Alysia Battersby, Susan Fox, Lorraine Kalia, Henrik Zetterberg & Niklas MattssonDag AarslandAlzheimer’s Disease Research Center, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this author, Anne RosserNeuroscience & Mental Health Research Institute, Cardiff University, Cardiff, UKSearch for more papers by this author, Alysia BattersbyNeuroscience & Mental Health Research Institute, Cardiff University, Cardiff, UKSearch for more papers by this author, Susan FoxMovement Disorder Clinic, Toronto Western Hospital, ON, CanadaSearch for more papers by this author, Lorraine KaliaMovement Disorder Clinic, Toronto Western Hospital, ON, CanadaSearch for more papers by this author, Henrik ZetterbergInstitute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, SwedenSearch for more papers by this author & Niklas MattssonInstitute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, SwedenSearch for more papers by this authorPublished Online:18 Jun 2012https://doi.org/10.2217/nmt.12.27AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Wang HX, Wahlberg M, Karp A, Winblad B, Fratiglioni L. Psychosocial stress at work is associated with increased dementia risk in late life. Alzheimers Dement. 8(2), 114–120 (2012).Lifestyle factors are increasingly recognized in the etiology of Alzheimer’s disease and other related diseases. For example, mental, physical and social activities have all been found to decrease the risk of dementia, and potentially treatable conditions such as hypertension, hypercholesterolemia and depression are associated with increased risk. Psychosocial stress, including work-related stress, is associated with cardiovascular disease and some studies, but not all, have found an association with dementia risk. Wang et al. used data from the population-based longitudinal Kungsholmen study to test the hypothesis that psychosocial stress is associated with incident dementia, and that vascular disease could mediate the association.A total of 1473 nondemented participants who were aged 75 years or older at baseline were followed for 6 years and occupational data were collected from an informant. A validated psychosocial job exposure matrix was used to score job demands, job control and job support. The latter was treated as a potential confounder together with a range of other variables. Low job control in combination with either high or low job demand was significantly associated with an increased incidence of dementia and Alzheimer’s disease. Vascular disease did not mediate this association, which may be better explained by a stress-related increase in the activity of the glucocorticoid cascade and hippocampus atrophy. Although limitations, such as retrospectively collected job data and the long interval between career end and the start of the study, these findings may have potentially high public health relevance because of the potential to influence job stress.– Written by Dag AarslandJeong H, Cohen DE, Cui L et al. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat. Med. 18(1), 159–165 (2011); Jiang M, Wang J, Fu J et al. Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets Nat. Med. 18(1), 153–158 (2011).Calorie restriction improves disease symptoms and pathology in mouse models of Huntington’s disease (HD). At the molecular level, the benefits of calorie restriction are known to be mediated by sirtuins, an evolutionary conserved family of nicotinamide adenine dinucleotide-dependent deacetylases that regulate a cell’s transcriptional response to metabolic stress and aging processes. These two studies establish a link between HD and the sirtuin family member Sirt1. Using mouse models of HD, the authors demonstrate that phenotypes such as motor function and striatal atrophy are ameliorated by increased Sirt1 levels, but exacerbated by reduced Sirt1 levels. Sirt1 regulates its substrates, such as the neuroprotective transcription factor Foxo3a and transcriptional co-activator TORC1, by removing key acetyl groups, thereby allowing them to activate neurotrophic genes such as BDNF. The studies here demonstrate a physical interaction between mutant huntingtin protein and Sirt1, which, to the authors’ knowledge, inhibits Sirt1’s deacetylase activity and consequently prevents its substrates from activating their neuroprotective targets. This inhibition by mutant huntingtin can be overcome in vitro and in vivo by increasing Sirt1 levels. We know that Sirt1 levels can be modulated by small compounds and that these have been shown to improve metabolic symptoms in mouse models of Type 2 diabetes. Sirt1’s neuroprotective action in mouse models of HD suggests that small-molecule activators of Sirt1 may also be beneficial for HD treatment.– Written by Alysia Battersby & Anne RosserDebacker K, Frizzell A, Gleeson O, Kirkham-McCarthy L, Mertz T, Lahue RS. Histone deacetylase complexes promote trinucleotide repeat expansions. PLoS Biol. 10(2), e1001257 (2012).DNA trinucleotide repeat sequences (TRS) occur frequently in the human genome, but are thought to be generally stable because TRS expansion events, which lead to disorders such as Huntington’s disease (HD), appear to be relatively rare. By contrast, once a repeat has become abnormally expanded, further elongation appears to be a common event. Elongation of an already expanded CAG repeat can be seen in HD in the germ line (leading to earlier disease onset in subsequent generations when HD is paternally transmitted) and in somatic cells (most strikingly seen in the striatum, the area of the brain most affected in HD). The extent and distribution of somatic CAG expansions in HD suggest that they may play a role in the pathogenesis of this disorder, but to date, the mechanisms responsible for such expansion events have been unknown. In this study, the authors set out to search for such factors through the use of a mutagenesis screens in yeast. They used a (CTG)20-CAN1 reporter line, as 20 CTG repeats seem to be close to the expansion threshold in yeast, on the basis that if disruption of a gene resulted in reduced expansion, then that gene was probably important in the expansion process. They identified 11 candidates, three of which encoded for subunits of two yeast histone deacetylases (HDACs): Rpd3l and Hda1. They confirmed the role of these HDACs in the expansion process by demonstrating that knockouts of these genes and their suppression using RNAi blocked the majority of expansion events. They also showed that other HDACs play a markedly smaller role in encouraging CTG expansion. The relevance to humans was illustrated by reduced expansion rates following inhibition (using a small molecule active against HDAC3, but with some activity against HDAC1)or RNAi knockdown of the human homolog of yeast Rpd3l (HDAC3) in a cultured human astrocyte line that supports CTG expansion in vitro. In yeast they have gone on to show that these events are mediated, at least in part, through the nucleases Sae2 and Mre11. There is current interest in the therapeutic application of HDAC inhibitors for therapy in HD following the demonstration of a beneficial effect on the phenotype of HD mice, which is thought to be effected through their modification of the transcriptional abnormalities in HD. These results strongly suggest a second mechanism through modification of TRS expansion rates. It should be considered that a reduction in somatic expansion rates may take years rather than months to translate into a slowing of the HD phenotype, and this, of course, has major implications for the design of clinical trials.– Written by Anne RosserKachroo A, Schwarzschild MA. Adenosine A2A receptor gene disruption protects in an α-synuclein model of Parkinson’s disease. Ann. Neurol. 71(2), 278–282 (2012).Nondopaminergic neurotransmitter systems are becoming well recognized as important contributors to the symptomatology as well as the pathogenesis of Parkinson’s disease (PD). A potential role for adenosine was first suggested by epidemiological studies demonstrating that the risk of PD was reduced in people who consumed moderate doses of coffee (i.e., caffeine, a nonspecific adenosine A2A receptor [A2AR] antagonist). Preclinical studies have examined the effects of the adenosine system on neurodegeneration using animal models of PD induced by acute toxin administration (e.g., MPTP). These studies suggest neuroprotection by A2AR blockade or knockout of A2AR.This recent study reports on the effects of an A2AR knockout in a genetic mouse model in which progressive neurodegeneration is induced over 20–24 months by expression of human α-synuclein harboring disease-causing mutations (A53T/A30P). This type of approach may be a better model of the neurodegenerative process occurring in human PD compared with the acute loss of dopaminergic neurons induced by MPTP. Mice expressing both A2ARs and human mutant α-synuclein showed a reduction in striatal dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid, compared with mice expressing A2ARs and either no human α-synuclein or wild-type human α-synuclein. This was associated with a decrease in the number of dopaminergic neurons within the substantia nigra pars compacta. Interestingly, knockout mice that did not express A2AR but expressed human mutant α-synuclein displayed no statistically significant reduction in striatal dopamine and no loss of nigral neurons.This study provides support for the hypothesis that A2AR signaling plays a role in dopaminergic neurodegeneration in PD. A shortcoming includes the lack of investigation into behavioral correlates in this study. Furthermore, the mechanism by which A2AR signaling contributes to neuronal death remains to be elucidated. Regardless, A2AR antagonists may be promising candidates for future neuroprotective trials for PD and currently, the specific A2AR antagonist, preladenant, is in Phase III studies with others in development.– Written by Susan Fox& Lorraine KaliaLi F, Harmer P, Fitzgerald K et al. Tai chi and postural stability in patients with Parkinson’s disease. N. Engl. J. Med. 366(6), 511–519 (2012).Dopaminergic drugs are the mainstay of treatment for Parkinson’s disease (PD). However, certain symptoms such as postural instability, gait impairment and falls can be resistant to pharmacological treatment. Various nonpharmacological strategies including rehabilitative therapies and exercise programs are emerging as useful adjuncts to the medical management of PD. Tai chi is a balance-based exercise derived from the Chinese martial art. Prior small studies investigating tai chi or qigong, a similar form of exercise, suggest that these exercise programs may improve some motor symptoms of PD. However, to date, no well controlled, large randomized controlled trials have been performed in this population.This large-scale randomized controlled trial examined, as its primary outcome, whether a modified tai chi program could improve laboratory indicators of postural stability (maximum excursion and directional control). Unified Parkinson’s Disease Rating Scale (UPDRS) III motor subscale scores, number of falls and quantitative measures of strength, mobility, balance and gait were secondary outcomes. A total of 195 eligible patients with mild-to-moderate PD were randomized to tai chi or to one of two control exercise programs (resistance-based exercise or low-impact stretching). Patients participated in a 60-min class twice-weekly for 6 months. Upon completion of the programs, the tai chi group performed better than the other groups on the primary outcome measures in the ‘on’ state. The tai chi group also performed better than the stretching group on all secondary outcomes, including UPDRS III (mean change from baseline: -6.4 vs -1.4 points) and fall frequency (0.22 vs 0.62 falls per participant month). There were no statistically significant differences between the tai chi and resistance exercise groups for UPDRS III, fall frequency or most of the other secondary outcomes. The benefits from tai chi were maintained 3 months after completion of the intervention. There were no major adverse events for any of the exercise programs.Several studies have investigated the benefits of exercise in PD, but this is one of the few high-quality studies to date. An inherent limitation of this study and others assessing exercise in PD is the inability to blind patients to the intervention. The results for the primary outcome measures of this trial suggest that tai chi improves stability compared with the other exercise programs tested, although it is unclear whether these results are clinically significant. A reduction in the UPDRS III scores of >5.0 points and a lower incidence of falls for both the tai chi and resistance exercise groups probably represent clinically meaningful outcomes, suggesting that more intensive exercise programs, compared with low-impact stretching, may be useful adjuncts to medical treatment in PD.– Written by Susan Fox& Lorraine KaliaTarawneh R, Lee J-M, Ladenson J-H et al. CSF VILIP-1 predicts rates of cognitive decline in early Alzheimer disease. Neurology 78(10), 709–719 (2012).VILIP-1 is a highly expressed neuronal calcium-sensor protein that has demonstrated utility as a marker of neuronal injury. This candidate marker of Alzheimer’s disease (AD) was originally identified by its brain-specific expression pattern and by being measurable in the cerebrospinal fluid (CSF). CSF levels of VILIP-1 are elevated in patients with AD and correlate with CSF levels of the well-established biomarker for cortical axonal degeneration, total-tau (T-tau) [1]. In a recent investigation, Tarawneh and colleagues demonstrate that CSF levels of VILIP-1 predict the rate of future cognitive decline in patients at risk of AD dementia. The data suggest that high CSF levels of VILIP-1 indicate intense neuronal degeneration at the time of sampling and that the levels predict future clinical signs of brain deterioration as reflected by psychometric scores of cognitive decline. This feature of VILIP-1 resembles that of CSF T-tau: higher CSF levels suggest more intense brain degeneration in individuals with AD and the more severe their cognitive symptoms. But do we need another biomarker of the clinical effects of neuronal degeneration in AD? Yes. We need biomarkers that are easy to measure in a standardized manner. T-tau, with its many isoforms, may not be optimal from that perspective. If we are lucky, VILIP-1 may be easier. In the meantime, the study by Tarawneh and coworkers is good news for the AD field. Now, we have two biomarkers that reflect disease intensity and predict the rate of cognitive decline as a consequence of the disease. A successful disease-modifying drug against AD should reduce the CSF levels of both VILIP-1 and T-tau. What the field urgently needs is a clue as to the degree of reduction that is clinically relevant.– Written by Henrik ZetterbergBalasa M, Vidal-Piñeiro D, Lladó A et al.PSEN1 mutation carriers present lower cerebrospinal fluid amyoid-β42 levels than sporadic early onset Alzheimer’s disease patients but no differences in neuronal injury biomarkers. J. Alzheimers Dis. doi:10.3233/JAD-2012-111949 (2012) (Epub ahead of print).The amyloid cascade hypothesis, which emphasizes abnormal metabolism of the peptide amyloid-β42 (Aβ42) as a core pathogenic event in Alzheimer’s disease (AD), is largely based on findings in the small subgroup of patients with hereditary autosomal dominant forms of the disease. Despite this, relatively few studies have compared familial AD (FAD) patients with non-Mendelian sporadic AD (SAD) patients, which make up the vast majority of AD patients (>99%). Such studies may not only serve to prove the applicability of the amyloid cascade hypothesis in SAD patients, but may also highlight the important mechanistical differences between FAD and SAD. The obvious reason for the lack of such comparative studies is the rarity of FAD patients. In a recent paper in the Journal of Alzheimer’s Disease, Balasa and co-authors report a study on cerebrospinal fluid (CSF) and MRI biomarkers in SAD and FAD. They found that FAD patients, carrying different mutations in the presenilin-1 gene, had lower CSF Aβ42 levels than SAD patients (both groups, as expected, had lower CSF Aβ42 than controls). They interpreted this finding as evidence of increased brain Aβ42 load in FAD than in SAD, which is also supported by previous neuropathological studies. However, there were no significant differences between FAD and SAD in the axonal injury markers CSF total-tau and phosphorylated tau, or in the MRI measurement of atrophy. From this, the authors conclude that axonal injury is likely to be independent of the severity of the Aβ42 abnormalities, supporting the Aβ42 trigger hypothesis, which states that Aβ42 plays a less important role once the neurodegenerative process has been initiated. As results from Phase III clinical trials on disease-modifying drugs directed against Aβ42 accumulates during the coming years, we will learn if this also has an impact on treatment outcome from this class of drugs.– Written by Niklas MattssonJack CR Jr, Vemuri P, Wiste HJ et al. Shapes of the trajectories of 5 major biomarkers of Alzheimer disease. Arch. Neurol. doi:10.1001/archneurol.2011.3405 (2012) (Epub ahead of print).Cerebrospinal fluid and imaging biomarkers are becoming increasingly important in Alzheimer’s disease (AD) research for designing clinical trials and for diagnosing patients in clinical practice. A common belief, supported by an increasing number of studies, is that the development of AD-specific biomarker profiles reflecting the disease hallmarks precedes and parallels the clinical symptoms. Detailed data on the biomarkers’ trajectories during the span of the disease would be useful both to optimize diagnostic cut-offs and to detect treatment-induced biomarker responses. In a recent study, Jack and coauthors approached this important question by utilizing large data sets from the Alzheimer’s Disease Neuroimaging Initative cohort and the Mayo Clinic. The authors investigated the relationships between the major established AD biomarkers and cognitive function, estimated by the Mini-Mental State Examination (MMSE) score, controlling for age and APOE ε4 status. Generally, they found that baseline biomarker values were more abnormal in subjects with low MMSE scores, and that biomarkers changed longitudinally with worsening MMSE score. However, as the authors acknowledge, this type of study is limited by floor and ceiling effects of the cognitive scoring itself. Also, the study subjects need to be followed for a significant period of time to accurately model the change of biomarkers in a disease such as AD, which is believed to be developed over decades. Despite these limitations, the study provides clues to the relationship between biomarker development and disease progression in AD, and can serve as an important template for future studies with more longitudinal data.– Written by Niklas MattssonFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Reference1 Lee JM, Blennow K, Andreasen N et al. The brain injury biomarker VLP-1 is increased in the cerebrospinal fluid of Alzheimer’s disease patients. Clin. Chem.54,1617–1623 (2008).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetails Vol. 2, No. 3 Follow us on social media for the latest updates Metrics Downloaded 234 times History Published online 18 June 2012 Published in print June 2012 Information© Future Medicine LtdFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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