Proc Natl Acad Sci U S A. 2015 Sep 8. pii: 201510011 . [Epub ahead of print]
Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer's disease pathogenesis.
Zhu L1, Zhong M2, Elder GA3, Sano M1, Holtzman DM4, Gandy S1, Cardozo C5, Haroutunian V6, Robakis NK7, Cai D8.
The apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer's disease (AD). However, the mechanisms underlying the pathogenic nature of ApoE4 are not well understood. In this study, we have found that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process. We have found that the levels of phosphoinositol biphosphate (PIP2) are reduced in postmortem human brain tissues of ApoE4 carriers, in the brains of ApoE4 knock-in (KI) mice, and in primary neurons expressing ApoE4 alleles compared with those levels in ApoE3 counterparts. These changes are secondary to increased expression of a PIP2-degrading enzyme, the phosphoinositol phosphatase synaptojanin 1 (synj1), in ApoE4 carriers. Genetic reduction of synj1 in ApoE4 KI mouse models restores PIP2 levels and, more important, rescues AD-related cognitive deficits in these mice. Further studies indicate that ApoE4 behaves similar to ApoE null conditions, which fails to degrade synj1 mRNA efficiently, unlike ApoE3 does. These data suggest a loss of function of ApoE4 genotype. Together, our data uncover a previously unidentified mechanism that links ApoE4-induced phospholipid changes to the pathogenic nature of ApoE4 in AD.
Baseline CSF levels of NGRN in patients with AD (median level, 2381 pg/mL [interquartile range, 1651-3416 pg/mL]) were higher than in cognitively normal participants (median level, 1712 pg/mL [interquartile range, 1206-2724 pg/mL]) (P = .04). Baseline NGRN levels were highly correlated with total tau and tau phosphorylated at threonine 181 in all patient groups (all P smaller than .001), but not with Aβ42. Baseline CSF levels of NGRN were also higher in patients with MCI who progressed to AD (median level, 2842 pg/mL [interquartile range, 1882-3950 pg/mL]) compared with those with stable MCI (median level, 1752 pg/mL [interquartile range, 1024-2438 pg/mL]) (P = .004), and they were predictive of progression from MCI to AD (hazard ratio, 1.8 [95% CI, 1.1-2.9]; stratified by tertiles). Linear mixed-model analyses demonstrated that within-person levels of NGRN increased over time in cognitively normal participants (mean [SE] level, 90  pg/mL per year; P smaller than .05) but not in patients with MCI or AD.
Conclusions and Relevance:
Neurogranin is a promising biomarker for AD because levels were elevated in patients with AD compared with cognitively normal participants and predicted progression from MCI to AD. Within-person levels of NGRN increased in cognitively normal participants but not in patients with later stage MCI or AD, which suggests that NGRN may reflect presymptomatic synaptic dysfunction or loss.
JAMA Neurol. 2015 Sep 14:1-7. doi: 10.1001/jamaneurol.2015.1867. [Epub ahead of print]
Neurogranin as a Cerebrospinal Fluid Biomarker for Synaptic Loss in Symptomatic Alzheimer Disease.
Kester MI1, Teunissen CE2, Crimmins DL3, Herries EM3, Ladenson JH3, Scheltens P1, van der Flier WM4, Morris JC5, Holtzman DM5, Fagan AM5.
Neurogranin (NGRN) seems to be a promising novel cerebrospinal fluid (CSF) biomarker for synaptic loss; however, clinical, and especially longitudinal, data are sparse.
To examine the utility of NGRN, with repeated CSF sampling, for diagnosis, prognosis, and monitoring of Alzheimer disease (AD).
Design, Setting, and Participants:
Longitudinal study of consecutive patients who underwent 2 lumbar punctures between the beginning of 1995 and the end of 2010 within the memory clinic-based Amsterdam Dementia Cohort. The study included 163 patients: 37 cognitively normal participants (mean [SE] age, 64  years; 38% female; and mean [SE] Mini-Mental State Examination [MMSE] score, 28 [0.3]), 61 patients with mild cognitive impairment (MCI) (mean [SE] age, 68  years; 38% female; and mean [SE] MMSE score, 27 [0.3]), and 65 patients with AD (mean [SE] age, 65  years; 45% female; and mean [SE] MMSE score, 22 [0.7]). The mean (SE) interval between lumbar punctures was 2.0 (0.1) years, and the mean (SE) duration of cognitive follow-up was 3.8 (0.2) years. Measurements of CSF NGRN levels were obtained in January and February 2014.
Main Outcome and Measure:
Levels of NGRN in CSF samples.
Parkinsonism in Older Adults and Its Association With Adverse Health Outcomes and Neuropathology.
Buchman AS1, Wilson RS2, Shulman JM3, Leurgans SE4, Schneider JA5, Bennett DA4.
Mild parkinsonian signs have been documented in community-dwelling older adults without Parkinson's disease. We estimated the proportion of older adults with parkinsonism and examined its association with adverse health outcomes and indices of brain pathology.
Four parkinsonian signs were assessed with the motor portion of the Unified Parkinson's Disease Rating Scale in 2,962 older adults who agreed to annual evaluation and brain autopsy. We used Cox proportional hazards models to examine the association of parkinsonism (two or more signs) and possible parkinsonism (one sign) with adverse health outcomes and regression models in 1,160 decedents to examine the association of parkinsonism and neuropathology.
At study entry about 25% (N = 776, 26.2%) had parkinsonism and 30% had possible parkinsonism (N = 885, 29.9%). Parkinsonism was strongly related to age. The frequency was 11.8% for people younger than 75 years, 29.1% for those aged 75-84 years, and 43.7% for those aged 85 years or older. Parkinsonism was associated with an increased hazard of death, of mild cognitive impairment, of Alzheimer's disease and disability. Individuals with possible parkinsonism also had an increased risk for adverse health outcomes compared to individuals without parkinsonism. Postmortem indices of macroscopic and microscopic infarcts, arteriolosclerosis, and atherosclerosis were associated with parkinsonism proximate to death.
Parkinsonism is common in older adults and is associated with an increased risk of adverse health outcomes and postmortem indices of brain pathology. Its association with age suggests that it will increase in our aging population.
J Gerontol B Psychol Sci Soc Sci. 2015 Sep 11. pii: gbv043. [Epub ahead of print]
Vascular Health and Genetic Risk Affect Mild Cognitive Impairment Status and 4-Year Stability: Evidence From the Victoria Longitudinal Study.
DeCarlo CA1, MacDonald SW2, Vergote D3, Jhamandas J4, Westaway D5, Dixon RA6.
Mild cognitive impairment (MCI) is a high-risk condition for progression to Alzheimer's disease (AD). Vascular health is a key mechanism underlying age-related cognitive decline and neurodegeneration. AD-related genetic risk factors may be associated with preclinical cognitive status changes. We examine independent and cross-domain interactive effects of vascular and genetic markers for predicting MCI status and stability.
We used cross-sectional and 2-wave longitudinal data from the Victoria Longitudinal Study, including indicators of vascular health (e.g., reported vascular diseases, measured lung capacity and pulse rate) and genetic risk factors-that is, apolipoprotein E (APOE; rs429358 and rs7412; the presence vs absence of ε4) and catechol-O-methyltransferase (COMT; rs4680; met/met vs val/val). We examined associations with objectively classified (a) cognitive status at baseline (not impaired congnitive (NIC) controls vs MCI) and (b) stability or transition of cognitive status across a 4-year interval (stable NIC-NIC vs chronic MCI-MCI or transitional NIC-MCI).
Using logistic regression, indicators of vascular health, both independently and interactively with APOE ε4, were associated with risk of MCI at baseline and/or associated with MCI conversion or MCI stability over the retest interval.
Several vascular health markers of aging predict MCI risk. Interactively, APOE ε4 may intensify the vascular health risk for MCI.
It is also good to remember the paper by Ayton S et al ( 2015) how these iron deposits are formed. It is also a free paper:
J Neurosci. 2015 Feb 25;35(8):3591-7. doi: 10.1523/JNEUROSCI.3439-14.2015.
Parkinson's disease iron deposition caused by nitric oxide-induced loss of β-amyloid precursor protein.
Ayton S1, Lei P1, Hare DJ2, Duce JA3, George JL1, Adlard PA1, McLean C4, Rogers JT5, Cherny RA1, Finkelstein DI1, Bush AI6.
Elevation of both neuronal iron and nitric oxide (NO) in the substantia nigra are associated with Parkinson's disease (PD) pathogenesis. We reported previously that the Alzheimer-associated β-amyloid precursor protein (APP) facilitates neuronal iron export. Here we report markedly decreased APP expression in dopaminergic neurons of human PD nigra and that APP(-/-) mice develop iron-dependent nigral cell loss. Conversely, APP-overexpressing mice are protected in the MPTP PD model. NO suppresses APP translation in mouse MPTP models, explaining how elevated NO causes iron-dependent neurodegeneration in PD.
This free paper below used chelation therapy in PD humans and measured the efficacy also with MRI but not by using contrast as is recommended by the study above. So to be more sensitive you should use this new susceptibility method when measuring the effect on iron.
Antioxid Redox Signal. 2014 Jul 10;21(2):195-210. doi: 10.1089/ars.2013.5593. Epub 2014 Feb 6.
Targeting chelatable iron as a therapeutic modality in Parkinson's disease.
Devos D1, Moreau C, Devedjian JC et al
Mov Disord. 2015 Sep 12. doi: 10.1002/mds.26417. [Epub ahead of print]
Quantitative susceptibility mapping of the midbrain in Parkinson's disease.
Du G1, Liu T2, Lewis MM1,3, Kong L4, Wang Y5, Connor J6, Mailman RB1,3, Huang X1,3,6,7,8.
Parkinson's disease (PD) is marked pathologically by dopamine neuron loss and iron overload in the substantia nigra pars compacta. Midbrain iron content is reported to be increased in PD based on magnetic resonance imaging (MRI) R2* changes. Because quantitative susceptibility mapping is a novel MRI approach to measure iron content, we compared it with R2* for assessing midbrain changes in PD.
Quantitative susceptibility mapping and R2* maps were obtained from 47 PD patients and 47 healthy controls. Midbrain susceptibility and R2* values were analyzed by using both voxel-based and region-of-interest approaches in normalized space, and analyzed along with clinical data, including disease duration, Unified Parkinson's Disease Rating Scale (UPDRS) I, II, and III subscores, and levodopa-equivalent daily dosage. All studies were done while PD patients were "on drug."
Compared with controls, PD patients showed significantly increased susceptibility values in both right (cluster size = 106 mm3 ) and left (164 mm3 ) midbrain, located ventrolateral to the red nucleus that corresponded to the substantia nigra pars compacta. Susceptibility values in this region were correlated significantly with disease duration, UPDRS II, and levodopa-equivalent daily dosage. Conversely, R2* was increased significantly only in a much smaller region (62 mm3 ) of the left lateral substantia nigra pars compacta and was not significantly correlated with clinical parameters.
The use of quantitative susceptibility mapping demonstrated marked nigral changes that correlated with clinical PD status more sensitively than R2*. These data suggest that quantitative susce
Neurology. 2015 Sep 9. pii: 10.1212/WNL.0000000000001991. [Epub ahead of print]
Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease.
Palmqvist S et al
To compare the diagnostic accuracy of CSF biomarkers and amyloid PET for diagnosing early-stage Alzheimer disease (AD).
From the prospective, longitudinal BioFINDER study, we included 122 healthy elderly and 34 patients with mild cognitive impairment who developed AD dementia within 3 years (MCI-AD). β-Amyloid (Aβ) deposition in 9 brain regions was examined with [18F]-flutemetamol PET. CSF was analyzed with INNOTEST and EUROIMMUN ELISAs. The results were replicated in 146 controls and 64 patients with MCI-AD from the Alzheimer's Disease Neuroimaging Initiative study.
The best CSF measures for identifying MCI-AD were Aβ42/total tau (t-tau) and Aβ42/hyperphosphorylated tau (p-tau) (area under the curve [AUC] 0.93-0.94). The best PET measures performed similarly (AUC 0.92-0.93; anterior cingulate, posterior cingulate/precuneus, and global neocortical uptake). CSF Aβ42/t-tau and Aβ42/p-tau performed better than CSF Aβ42 and Aβ42/40 (AUC difference 0.03-0.12, p
Biochem J. 2008 May 15;412(1):141-52. doi: 10.1042/BJ20080103.
Intracellular copper deficiency increases amyloid-beta secretion by diverse mechanisms.
Cater MA1, McInnes KT, Li QX, Volitakis I, La Fontaine S, Mercer JF, Bush AI.
In Alzheimer's disease there is abnormal brain copper distribution, with accumulation of copper in amyloid plaques and a deficiency of copper in neighbouring cells. Excess copper inhibits Abeta (amyloid beta-peptide) production, but the effects of deficiency have not yet been determined. We therefore studied the effects of modulating intracellular copper levels on the processing of APP (amyloid precursor protein) and the production of Abeta. Human fibroblasts genetically disposed to copper accumulation secreted higher levels of sAPP (soluble APP ectodomain)alpha into their medium, whereas fibroblasts genetically manipulated to be profoundly copper deficient secreted predominantly sAPPbeta and produced more amyloidogenic beta-cleaved APP C-termini (C99). The level of Abeta secreted from copper-deficient fibroblasts was however regulated and limited by alpha-secretase cleavage. APP can be processed by both alpha- and beta-secretase, as copper-deficient fibroblasts secreted sAPPbeta exclusively, but produced primarily alpha-cleaved APP C-terminal fragments (C83). Copper deficiency also markedly reduced the steady-state level of APP mRNA whereas the APP protein level remained constant, indicating that copper deficiency may accelerate APP translation. Copper deficiency in human neuroblastoma cells significantly increased the level of Abeta secretion, but did not affect the cleavage of APP. Therefore copper deficiency markedly alters APP metabolism and can elevate Abeta secretion by either influencing APP cleavage or by inhibiting its degradation, with the mechanism dependent on cell type. Overall our results suggest that correcting brain copper imbalance represents a relevant therapeutic target for Alzh
J Neurochem. 2015 Sep 5. doi: 10.1111/jnc.13351. [Epub ahead of print]
Soluble amyloid precursor protein alpha (sAPPα) inhibits tau phosphorylation through modulation of GSK3β signaling pathway.
Deng J1,2, Habib A1, Obregon DF1, Barger SW3, Giunta B4, Wang YJ2, Hou H1, Sawmiller D1, Tan J1.
We recently found that sAPPα decreases Aβ generation by directly associating with β-site amyloid precursor protein (APP) converting enzyme 1 (BACE1), thereby modulating APP processing. Because inhibition of BACE1 decreases GSK3β-mediated Alzheimer's disease (AD)-like tau phosphorylation in AD patient-derived neurons, we determined whether sAPPα also reduces GSK3β-mediated tau phosphorylation. We initially found increased levels of inhibitory phosphorylation of GSK3β (Ser9) in primary neurons from sAPPα over-expressing mice. Further, recombinant human sAPPα evoked the same phenomenon in SH-SY5Y cells. Further, in SH-SY5Y cells overexpressing BACE1, and HeLa cells overexpressing human tau, sAPPα reduced GSK3β activity and tau phosphorylation. Importantly, the reductions in GSK3β activity and tau phosphorylation elicited by sAPPα were prevented by BACE1 but not γ-secretase inhibition. In accord, AD mice overexpressing human sAPPα had less GSK3β activity and tau phosphorylation compared with controls. These results implicate a direct relationship between APP β-processing and GSK3β-mediated tau phosphorylation and further define the central role of sAPPα in APP autoregulation and AD pathogenesis.
Am J Geriatr Psychiatry. 2015 Feb;23(2):141-8. doi: 10.1016/j.jagp.2014.05.001. Epub 2014 May 14.
Depression and synaptic zinc regulation in Alzheimer disease, dementia with lewy bodies, and Parkinson disease dementia.
Whitfield DR1, Vallortigara J1, Alghamdi A2, Hortobágyi T3, Ballard C1, Thomas AJ4, O'Brien JT5, Aarsland D6, Francis PT7.
Depression is a common symptom in dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), and Alzheimer disease (AD), yet its molecular basis remains unclear and current antidepressants do not appear to be effective. Cerebral zinc has been implicated in depression and synaptic dysfunction. We investigated the relationship between synaptic zinc regulation (for which zinc transporter 3 [ZnT3] is responsible) and depression in a large clinicopathologic study.
We examined brains from people with PDD (N = 29), DLB (N = 27), and AD (N = 15) and comparison subjects without depression or dementia (N = 24). Individuals were categorized according to the presence and severity of depression (on a scale of 0-3) based on standardized assessments during life (principally Neuropsychiatric Inventory). Western blotting was used to determine ZnT3 levels in Brodmann area 9 (BA9), and regression analysis was used to determine the relationship between ZnT3 and depression.
Reductions in ZnT3 in BA9 were significantly associated with elevated depression scores in the study cohort (β = -0.351, df = 93, t = -3.318 p = 0.0004). This association remained when only individuals with DLB, PDD, and no dementia or depression were examined (β = -0.347, df = 78, t = -3.271, p = 0.002) or only individuals with AD and no dementia or depression were examined (β = -0.433, df = 37, t = -2.924, p = 0.006).
Although decreased zinc levels have been implicated in the genesis of depression in animal models and in major depressive disorder in humans, this study pro
Metal ions and intrinsically disordered proteins and peptides: from Cu/Zn amyloid-β to general principles.
Faller P1, Hureau C, La Penna G.
The interaction of d-block metal ions (Cu, Zn, Fe, etc.) with intrinsically disordered proteins (IDPs) has gained interest, partly due to their proposed roles in several diseases, mainly neurodegenerative. A prominent member of IDPs is the peptide amyloid-β (Aβ) that aggregates into metal-enriched amyloid plaques, a hallmark of Alzheimer's disease, in which Cu and Zn are bound to Aβ. IDPs are a class of proteins and peptides that lack a unique 3D structure when the protein is isolated. This disordered structure impacts their interaction with metal ions compared with structured metalloproteins. Metalloproteins either have a preorganized metal binding site or fold upon metal binding, resulting in defined 3D structure with a well-defined metal site. In contrast, for Aβ and likely most of the other IDPs, the affinity for Cu(I/II) and Zn(II) is weaker and the interaction is flexible with different coordination sites present. Coordination of Cu(I/II) with Aβ is very dynamic including fast Cu-exchange reactions (milliseconds or less) that are intrapeptidic between different sites as well as interpeptidic. This highly dynamic metal-IDP interaction has a strong impact on reactivity and potential biological role: (i) Due to the low affinity compared with classical metalloproteins, IDPs likely bind metals only at special places or under special conditions. For Aβ, this is likely in the neurons that expel Zn or Cu into the synapse and upon metal dysregulation occurring in Alzheimer's disease. (ii) Amino acid substitutions (mutations) on noncoordinating residues can change drastically the coordination sphere. (iii) Considering the Cu/Zn-Aβ aberrant interaction, therapeutic strategies can be based on removal of Cu/Zn or precluding their binding to the peptide. The latter is very difficult due to the multitu
And now how does PBT434 work:
PBT434 has a moderate binding affinity for iron with a dissociation constant in the same oder of magnitude as alpha-synuclein. This enables PBT434 to compete with alpha-synuclein for iron. PBT434 stabilizes higher oxidation states of iron such that the redox reactions of this metal are inhibited by binding to the drug. Metal binding and chelation properties of PBT434 promote redox silencing of iron, metal homeostasis and intercede in metal induced oxidative modification and aggregatin of toxic alpha-synuclein species.
This was copied from the annual report. Good to read it , page 6.
Mov Disord. 2015 Sep 4. doi: 10.1002/mds.26421. [Epub ahead of print]
Neuropathology of α-synuclein propagation and braak hypothesis.
McCann H1, Cartwright H1, Halliday GM1,2.
Parkinson's disease is a progressive neurodegenerative disorder with multiple factors contributing to increasing severity of pathology in specific brain regions. The Braak hypothesis of Lewy pathology progression in Parkinson's disease proposes a systematic spread of α-synuclein that can be staged, with the later stages correlating with clinical aspects of the disease. The spread of pathology through the different stages suggests progression, a theory that has proven correct from evidence of pathology in healthy neurons grafted into the brains of patients with Parkinson's disease. Progression of pathology occurs on a number of levels, within a cell, between nearby cells, and then over longer distances throughout the brain, and evidence using prion proteins suggests two dissociable mechanisms-intracellular toxicity versus a nontoxic infectious mechanism for propagation. In Parkinson's disease, intracellular changes associated with mitochondria and lysosome dysfunction appear important for α-synuclein propagation, with high stress conditions favoring mitochondrial cell death mechanisms. Functional neurons appear necessary for propagation. Unconventional exocytosis releases α-synuclein under stress conditions, and endocytic uptake occurs in nearby cells. This cell-to-cell transmission of α-synuclein has been recapitulated in both cell culture and animal models, but the timeframe of transmission is considerably shorter than that observed in transplanted neurons. The time course of Lewy pathology formation in patients is consistent with the long time course observed in grafted neurons, and the restricted neuronal loss in Parkinson's disease is potentially important for the propagation of α-synuclein through relatively intact circuits. © 2015 Internationa
Mov Disord. 2015 Sep 4. doi: 10.1002/mds.26364. [Epub ahead of print]
Multivariate prediction of motor diagnosis in Huntington's disease: 12 years of PREDICT-HD.
Long JD1,2, Paulsen JS1,3,4; PREDICT-HD Investigators and Coordinators of the Huntington Study Group.
It is well known in Huntington's disease that cytosine-adenine-guanine expansion and age at study entry are predictive of the timing of motor diagnosis. The goal of this study was to assess whether additional motor, imaging, cognitive, functional, psychiatric, and demographic variables measured at study entry increased the ability to predict the risk of motor diagnosis over 12 years.
One thousand seventy-eight Huntington's disease gene-expanded carriers (64% female) from the Neurobiological Predictors of Huntington's Disease study were followed up for up to 12 y (mean = 5, standard deviation = 3.3) covering 2002 to 2014. No one had a motor diagnosis at study entry, but 225 (21%) carriers prospectively received a motor diagnosis. Analysis was performed with random survival forests, which is a machine learning method for right-censored data.
Adding 34 variables along with cytosine-adenine-guanine and age substantially increased predictive accuracy relative to cytosine-adenine-guanine and age alone. Adding six of the common motor and cognitive variables (total motor score, diagnostic confidence level, Symbol Digit Modalities Test, three Stroop tests) resulted in lower predictive accuracy than the full set, but still had twice the 5-y predictive accuracy than when using cytosine-adenine-guanine and age alone. Additional analysis suggested interactions and nonlinear effects that were characterized in a post hoc Cox regression model.
Measurement of clinical variables can substantially increase the accuracy of predicting motor diagnosis over and above cytosine-adenine-guanine and age (and their interaction). Estima
Yes Kadaicher, the annual report tells clearly that third party specialists have "undertaken extensive safety analyses to characterize the behaviour of PBT2 drug exposure in the dog and human and how this translates to the comparative safety profile in the dog relative to humans". So the dog studies with PBT2 have been done, but most likely years ago.
The report tells also that when testing the toxity of PBT434 dog studies are also used ( page 6 in the report).