Thanks jelchertjr ! This reminds me about the paper below. There are some 100M essential tremor patients in the world.
Mov Disord. 2013 Feb;28(2):196-200. doi: 10.1002/mds.25263. Epub 2012 Dec 12.
Brain iron deposition in essential tremor: a quantitative 3-Tesla magnetic resonance imaging study.
Novellino F1, Cherubini A, Chiriaco C, Morelli M, Salsone M, Arabia G, Quattrone A.
Studies have demonstrated brain iron deposition in neurodegenerative disease and in normal aging. Data on this topic are lacking in essential tremor (ET). The aim of our study was to investigate brain iron content in patients with ET, using quantitative magnetic resonance imaging (MRI) T2*-relaxometry. We enrolled 24 patients with ET and 25 age-matched healthy controls. Subjects were examined using a 3T MRI scanner. The protocol included conventional MRI sequences and quantitative T2*-relaxometry. Whole-brain voxel-based analyses showed significant differences in T2* values in bilateral globus pallidus, substantia nigra, and in right dentate nucleus (P
Metallomics. 2016 Jul 11. [Epub ahead of print]
Metallo-pathways to Alzheimer's disease: lessons from genetic disorders of copper trafficking.
Greenough MA1, Ramírez Munoz A1, Bush AI1, Opazo CM1.
1The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria 3010, Australia. email@example.com.
Copper is an essential metal ion that provides catalytic function to numerous enzymes and also regulates neurotransmission and intracellular signaling. Conversely, a deficiency or excess of copper can cause chronic disease in humans. Menkes and Wilson disease are two rare heritable disorders of copper transport that are characterized by copper deficiency and copper overload, respectively. Changes to copper status are also a common feature of several neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). In the case of AD, which is characterized by brain copper depletion, changes in the distribution of copper has been linked with various aspects of the disease process; protein aggregation, defective protein degradation, oxidative stress, inflammation and mitochondrial dysfunction. Although AD is a multifactorial disease that is likely caused by a breakdown in multiple cellular pathways, copper and other metal ions such as iron and zinc play a central role in many of these cellular processes. Pioneering work by researchers who have studied relatively rare copper transport diseases has shed light on potential metal ion related disease mechanisms in other forms of neurodegeneration such as AD.
Of 7130 participants (2879 [40.4%] men; overall mean [SD] age, 79.9 [6.9] years), 865 reported a history of TBI with LOC. In 45 190 person-years of follow-up, 1537 incident cases of dementia and 117 of PD were identified. No association was found between TBI with LOC and incident dementia (ACT: HR for TBI with LOC less than1 hour, 1.03; 95% CI, 0.83-1.27; HR for TBI with LOC more than1 hour, 1.18; 95% CI, 0.77-1.78; ROS and MAP: HR for TBI with LOC less than1 hour, 0.87; 95% CI, 0.58-1.29; HR for TBI with LOC more than 1 hour, 0.84; 95% CI, 0.44-1.57) or AD (findings similar to those for dementia). Associations were found for TBI with LOC and incident PD in ACT (HR for TBI with LOC more than1 hour, 3.56; 95% CI, 1.52-8.28) and progression of parkinsonian signs in ROS and MAP (odds ratio [OR] for TBI with LOC less than1 hour, 1.65; 95% CI, 1.23-2.21; OR for TBI with LOC more than1 hour, 2.23; 95% CI, 1.16-4.29). Traumatic brain injury with LOC was associated with Lewy bodies (any Lewy body in ACT: RR for TBI with LOC more than1 hour, 2.64; 95% CI, 1.40-4.99; Lewy bodies in substantia nigra and/or locus ceruleus in ACT: RR for TBI with LOC more than1 hour, 3.30; 95% CI, 1.71-6.38; Lewy bodies in frontal or temporal cortex in ACT: RR for TBI with LOC 1 hour, 5.73; 95% CI, 2.18-15.0; ROS and MAP: RR for TBI with LOC ≤1 hour, 1.64; 95% CI, 1.00-2.70; pooled RR for TBI with LOC less than1 hour, 1.59; 95% CI, 1.06-2.39) and microinfarcts (any cortical microinfarct in ROS and MAP: RR for TBI with LOC more than 1 hour, 2.12; 95% CI, 1.12-4.01; pooled RR for TBI with LOC more than 1 hour, 1.58; 95% CI, 1.06-2.35).
Conclusions and Relevance:
Pooled clinical and neuropathologic data from 3 prospective cohort studies indicate that TBI with LOC is associated with risk for Lewy body accumulation, progression of parkinsonism, and PD, but not dementia, AD, neuritic plaques, or neurofibrillary tangles.
JAMA Neurol. 2016 Jul 11. doi: 10.1001/jamaneurol.2016.1948. [Epub ahead of print]
Association of Traumatic Brain Injury With Late-Life Neurodegenerative Conditions and Neuropathologic Findings.
Crane PK1, Gibbons LE1, Dams-O'Connor K2, Trittschuh E3, Leverenz JB4, Keene CD5, Sonnen J6, Montine TJ7, Bennett DA8, Leurgans S8, Schneider JA9, Larson EB10.
The late effects of traumatic brain injury (TBI) are of great interest, but studies characterizing these effects are limited.
To determine whether TBI with loss of consciousness (LOC) is associated with an increased risk for clinical and neuropathologic findings of Alzheimer disease (AD), Parkinson disease (PD), and other dementias.
Design, Setting, and Participants:
This study analyzed data from the Religious Orders Study (ROS), Memory and Aging Project (MAP), and Adult Changes in Thought study (ACT). All ROS and MAP participants and a subset of ACT participants consent to autopsy. Studies performed annual (ROS and MAP) or biennial (ACT) cognitive and clinical testing to identify incident cases of dementia and AD. The 7130 participants included members of a Seattle-area health care delivery system (ACT), priests and nuns living in orders across the United States (ROS), and Chicago-area adults in retirement communities (MAP). Of these, 1589 underwent autopsy. Primary hypothesis was that TBI with LOC would be associated with increased risk for AD and neurofibrillary tangles. Data were accrued from 1994 to April 1, 2014.
Self-reported TBI when the participant was free of dementia, categorized as no more than 1 vs more than 1 hour of LOC.
Main Outcomes and Measures:
Clinical outcomes included incident all-cause dementia, AD, and PD in all studies and incident mild cognitive impairment and progression of parkinsonian signs in ROS and MAP. Neuropathologic outcomes included neurofibrillary tangles, neuritic plaques, microinfarcts, cys
Most of conference papers are today presented as posters, usually no PowerPoint but only a poster and the authors explaining the results. The presentation by Prof Masters "An Exploratory Molecular Imaging Study Targeting Aβ with a Novel 8-OH Quinoline in Alzheimer’s Disease (The PBT2-204 IMAGINE Study)" will most likely explain more about the Imagine study results which been found by exploring after the primary results were published. Because the placebo group behaved in an unexpected way I would think that he will present comparison between AIBL population and PBT2 treated patients ( 1+ 1 year follow up. He perhaps could also present results in which the original pictures (as MRI) are evaluated or measured by a more accurate method ( texture analysis as a posible example ?). But we need to wait to see the poster. Before that it is only guessing and to guess what a top scientist will tell in his presentation is impossible, they have always real news.
2y ago in Stockholm Masters presented a very nice talk and I would say that he will again present a great paper and most likely it will be good news for Prana and PBT2. Without good news Prana and Masters would not go to the conference at all.
Transl Psychiatry. 2016 Jun 14;6(6):e838. doi: 10.1038/tp.2016.83.
Obesity and age-related alterations in the gene expression of zinc-transporter proteins in the human brain.
Olesen RH1, Hyde TM2,3,4, Kleinman JE2, Smidt K1, Rungby J1,5, Larsen A1.
The incidence of Alzheimer's disease (AD) is increasing. Major risk factors for AD are advancing age and diabetes. Lately, obesity has been associated with an increased risk of dementia. Obese and diabetic individuals are prone to decreased circulating levels of zinc, reducing the amount of zinc available for crucial intracellular processes. In the brain, zinc co-localizes with glutamate in synaptic vesicles, and modulates NMDA receptor activity. Intracellular zinc is involved in apoptosis and fluctuations in cytoplasmic Zn(2+) affect modulation of intracellular signaling. The ZNT and ZIP proteins participate in intracellular zinc homeostasis. Altered expression of zinc-regulatory proteins has been described in AD patients. Using microarray data from human frontal cortex (BrainCloud), this study investigates expression of the SCLA30A (ZNT) and SCLA39A (ZIP) families of genes in a Caucasian and African-American sample of 145 neurologically and psychiatrically normal individuals. Expression of ZNT3 and ZNT4 were significantly reduced with increasing age, whereas expression of ZIP1, ZIP9 and ZIP13 were significantly increased. Increasing body mass index (BMI) correlated with a significant reduction in ZNT1 expression similar to what is seen in the early stages of AD. Increasing BMI also correlated with reduced expression of ZNT6. In conclusion, we found that the expression of genes that regulate intracellular zinc homeostasis in the human frontal cortex is altered with increasing age and affected by increasing BMI. With the increasing rates of obesity throughout the world, these findings warrant continuous scrutiny of the long-term consequences of obesity on brain function and the d
Effects related to common genetic risk loci distributed throughout the genome are detectable among individuals without dementia. The influence of this genetic risk may begin in early life and make an individual more susceptible to cognitive impairment in late life. Future refinement of polygenic risk scores may help identify individuals at risk for AD dementia.
Neurology. 2016 Jul 6. pii: 10.1212/WNL.0000000000002950. [Epub ahead of print]
Type 2 diabetes mellitus is associated with brain atrophy and hypometabolism in the ADNI cohort.
Li W, Risacher SL, Huang E, Saykin AJ; Alzheimer's Disease Neuroimaging Initiative.
We investigated type 2 diabetes mellitus (T2DM) as a risk factor for brain atrophy and glucose hypometabolism in older adults with or at risk of cognitive impairment.
Participants with the T2DM were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI-1/GO/2 cohorts). Analysis of covariance models were used to compare participants with and without T2DM, controlling for potential confounding factors.
Whole brain volume and whole brain [18F]-fluorodeoxyglucose (FDG) uptake were significantly different as a function of T2DM status, independent of baseline clinical diagnosis. On post hoc analysis, a lower whole brain volume was seen in participants with both mild cognitive impairment (MCI) and T2DM (n = 76) compared with participants who had MCI but not T2DM (n = 747; p = 0.009). Similarly, mean FDG uptake in gray matter and white matter was lower in participants with both MCI and T2DM (n = 72) than in participants with MCI without T2DM (n = 719; p = 0.04). Subsequent regional analysis revealed that the decreased FDG uptake in participants with both MCI and T2DM was mainly manifested in 3 brain regions: frontal lobe, sensory motor cortex, and striatum.
T2DM may accelerate cognition deterioration in patients with MCI by affecting glucose metabolism and brain volume.
It is a free paper, but not an easy one.
Our expression microarray studies showed messenger RNA (mRNA) for solute carrier family 39 (zinc transporter), member 12 (SLC39A12) was higher in dorsolateral prefrontal cortex from subjects with schizophrenia (Sz) in comparison with controls. To better understand the significance of these data we ascertained whether SLC39A12 mRNA was altered in a number of cortical regions (Brodmann's area (BA) 8, 9, 44) from subjects with Sz, in BA 9 from subjects with mood disorders and in rats treated with antipsychotic drugs. In addition, we determined whether inducing the expression of SLC39A12 resulted in an increased cellular zinc uptake. SLC39A12 variant 1 and 2 mRNA was measured using quantitative PCR. Zinc uptake was measured in CHO cells transfected with human SLC39A12 variant 1 and 2. In Sz, compared with controls, SLC39A12 variant 1 and 2 mRNA was higher in all cortical regions studied. The were no differences in levels of mRNA for either variant of SLC39A12 in BA 9 from subjects with mood disorders and levels of mRNA for Slc39a12 was not different in the cortex of rats treated with antipsychotic drugs. Finally, expressing both variants in CHO-K1 cells was associated with an increase in radioactive zinc uptake. As increased levels of murine Slc39a12 mRNA has been shown to correlate with increasing cellular zinc uptake, our data would be consistent with the possibility of a dysregulated zinc homeostasis in the cortex of subjects with schizophrenia due to altered expression of SLC39A12.
Increased cortical expression of the zinc transporter SLC39A12 suggests a breakdown in zinc cellular homeostasis as part of the pathophysiology of schizophrenia
Elizabeth Scarr,1,2,3,7 Madhara Udawela,1,3,7 Mark A Greenough,4 Jaclyn Neo,1,3 Myoung Suk Seo,1 Tammie T Money,1,2,3,5 Aradhana Upadhyay,1,3 Ashley I Bush,3,4 Ian P Everall,1,2,3 Elizabeth A Thomas,6 and Brian Dean1,2,3,*
Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity.
To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease.
Design, Setting, and Participants:
Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites.
Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout.
Main Outcomes and Measures:
Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test.
Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group differenc
Up 10% with vol only 54K ! Looks like in Australia the cheap stocks have already been sold. Interesting to see if that is true also in NY.
Yes, 35% reduction in the atrophy rate in comparison to the placebo but because of the small number of patients the difference in statistical analysis was only a trend, 9% error possible.
Nat Commun. 2016 Jun 21;7:11991. doi: 10.1038/ncomms11991.
Mnemonic convergence in the human hippocampus.
Backus AR1, Bosch SE1, Ekman M1, Grabovetsky AV1, Doeller CF1.
1Radboud University, Donders Institute for Brain, Cognition and Behaviour, Nijmegen 6525 EN, The Netherlands.
The ability to form associations between a multitude of events is the hallmark of episodic memory. Computational models have espoused the importance of the hippocampus as convergence zone, binding different aspects of an episode into a coherent representation, by integrating information from multiple brain regions. However, evidence for this long-held hypothesis is limited, since previous work has largely focused on representational and network properties of the hippocampus in isolation. Here we identify the hippocampus as mnemonic convergence zone, using a combination of multivariate pattern and graph-theoretical network analyses of functional magnetic resonance imaging data from humans performing an associative memory task. We observe overlap of conjunctive coding and hub-like network attributes in the hippocampus. These results provide evidence for mnemonic convergence in the hippocampus, underlying the integration of distributed information into episodic memory representations.
6 months is quite a long time to get the books in order for any audit firm. I just wonder if there could be a dead line when this work is completed. 30th of June could be a perfect dead line.
"In addition, we review the evidence that dormant, non-growing bacteria are a crucial feature of AD, that their growth in vivo is normally limited by a lack of free iron, and that it is this iron dysregulation that is an important factor in their resuscitation. Indeed, bacterial cells can be observed by ultrastructural microscopy in the blood of AD patients. A consequence of this is that the growing cells can shed highly inflammatory components such as lipopolysaccharides (LPS). These too are known to be able to induce (apoptotic and pyroptotic) neuronal cell death. There is also evidence that these systems interact with elements of vitamin D metabolism. This integrative systems approach has strong predictive power, indicating (as has indeed been shown) that both natural and pharmaceutical iron chelators might have useful protective roles in arresting cognitive decline, and that a further assessment of the role of microbes in AD development is more than highly warranted".
"In comparison with the CN group, the AD group had a greater proportion of participants with early AMD (p less than 0.0001, odds ratio 18.67, 95% CI 4.42 - 78.80). A logistic model for early AMD found a significant association with AD diagnosis (p less than 0.0001), after adjusting for confounders (age, smoking, hypertension, high and low density lipoproteins, cataract surgery and APOE ε4 carrier status). The results of this study are consistent with an increased risk of AMD in AD. While the pathophysiology of these diseases are unclear, understanding the shared features between them may provide further knowledge about their pathogenesis and could lead to accelerated development of therapies for both diseases".
These p values indicate that the correlation is very strong even in a this kind of small material. So it looks like AD and AMD are very related diseases.
Curr Alzheimer Res. 2016 Jun 2. [Epub ahead of print]
Alzheimer`s disease and the early signs of age-related macular degeneration.
Frost S, Guymer R, Aung KZ, Macaulay SL, Sohrabi HR, Bourgeat P, Salvado O, Rowe CC, Ames D, Masters CL, Martins RN, Kanagasingam Y, Group AT.
This study investigated signs of age related macular degeneration (AMD) in Alzheimer's disease (AD). These age-related diseases primarily affect different parts of the central nervous system but are substantially similar in terms of abnormal extracellular deposits, metabolic and oxidative stress, neuroinflammation and microvascular abnormalities. While AMD is a retinal disease, AD is reported to affect not only the brain but also the retina, with Aβ deposits, neurodegeneration and vascular changes. Large population based studies have provided conflicting results regarding the comorbidity of AD and AMD. This study investigated signs of AMD in a small but well characterized cohort from the Australian Imaging Biomarkers and Lifestyle study of aging (AIBL). The cohort consisted of 22 AD patients (age 70.2 ± 9.0 yrs, 13 male, 9 female) and 101 cognitively normal (CN) participants (age 71.3 ± 6.0 yrs, 40 male, 61 female). In comparison with the CN group, the AD group had a greater proportion of participants with early AMD (p