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400 | hydrogen sulfide h2s is an endogenous antiinflammatory and neuroprotective agent with antioxidant and antiapoptotic effects in neuronal and glial cells furthermore the levels of sadenosylmethionine an activator of cystathionine βsynthase main h2sproducing enzyme in the brain have been found to be lower in ad brains compared with healthy brains xuan et al wanted to investigate whether h2sreleasing drugs nahs through their antiinflammatory action may inhibit tnfα and thus be beneficial in ad pathology | [15155563 19631409 19540852 8752143 22898621] | this suggests that minocycline may indirectly decrease tnf-α concentration through decreasing microglial activation and increasing il-10. despite tnf-α levels not reaching statistical significance, cognitive benefits were still observed, with minocycline-treated mice performing at par to healthy mice. | [] |
401 | the margin of noninferiority for bai cesd and ies scores was 5 points as used in prior reveal study trials indicative of medium to large effect sizes cohens d 103 064 and 066 respectively this criterion was a more conservative margin than 5 to 10point definitions of clinically meaningful differences used in other studies that are based on the intervals between cutoffs for minimal mild moderate and severe anxiety and depression for igtad scores where prior studies have not identified a meaningful difference we set margins following the strategy used in a related noninferiority analysis three points representing a shift from sometimes to never on a single item and indicative of medium effect sizes cohens d 043 and 048 for distress and positive subscales respectively | [25499536 19605829 19718255 17469892 24449235] | consistent with analyses of prior reveal study trials outcomes at 12 months were considered primary while outcomes at 6 months and 6 weeks were considered secondary data for ad+cad and ad-only disclosure arms were pooled in analyses because interactions between ad-only/ad+cad randomization status and in-person/telephone disclosure randomization status were not observed (p-values for two-way tests of interaction between the two treatment arms and three-way interactions between the treatment arms and time were all greater than 0.05 except for analyses of igt-ad distress scores, as noted earlier). | [25499536 26810768] |
402 | the presence of neuropathological hallmarks ie βamyloid plaques αsynuclein and huntingtin in the retina of these neurodegenerative disorders demonstrates that the retina is specifically affected by neurodegeneration and affords access to potential biomarkers of the disease | [27645291 27551275 28093567 24816946 24785101] | we also underscore the differences in the patterns of optic nerve degeneration described in these disorders which predominantly affect the magnocellular rgcs of the retina in ad and the parvocellular rgcs in pd and hd possibly explained by the predominant mitochondrial dysfunction documented in pd and hd similarities and differences are also discussed in regards to the circadian rhythm imbalance documented in ad and pd. | [ 2314849 26252902 24465663 22436028 24339212 26233693] |
403 | in rikn prnp mice kim et al in our group have observed pathological alterations and some physiological dysfunctions in the olfactory bulb ob recently le pichon et al have proposed that electrophysiological alterations at the dendrodendritic synapse in the ob could underlie the behavior phenotypes in detail the cookie finding phenotype was manifested in three prnp lines zrch i prnp mice ngsk prnp mice npu prnp mice on alternate genetic backgrounds indicating strong evidence of its dependence on prpc rather than other genetic factors prnp mice also displayed altered behavior in the habituationdishabituation task suggesting the phenotype is most likely to be olfactoryspecific
prnp mice exhibited wide spread alterations of oscillatory activity in the ob as well as altered pairedpulse plasticity at the dendrodendritic synapse | [17611634 19098904 1373228 8606772 7999308 17611634 19098904] | taken together, prpc is functionally involved in copper metabolism, signal transduction, neuroprotection, and cell maturation. despite these putative roles mice null for prpc display no consistent phenotype apart from complete resistance to tse infection further searches for prpcinteraction molecules using prnp mice and various types of prnp cell lines under various conditions may elucidate the prpc functions | [1373228 8100741] |
404 | if were found in 270 of the participants which is similar to studies involving older participants and higher than the prevalence typically reported in most previous studies with comparable populations nevertheless some other papers report much higher prevalence rates these discrepancies can be mostly accounted for by the criteria for defining what constitutes an if technical features type and quality of mri sequences and the training of the scan reader
and the characteristics of participants included presence of comorbidities screening selection and ethnicity
for instance in a retrospective study that included 1000 asymptomatic volunteers only 18 of them presented with if in comparison to our study the age range of their population 383 years old was wider including very young participants who are less prone to the present parenchyma atrophy or vascular pathology | [23967214 27337027 17978290 10404909 10404909 16207376 23967214] | in this study, we aimed at describing the prevalence of if from brain mri in healthy participants aged between 45 and 75 of a population-based study, most of them first-degree descendants of patients with ad. the if found were classified on the basis of their mri characteristics alone and were not confirmed by further studies. | [] |
405 | this is not surprising given that csf aβ levels and aβ accumulation as determined by pibpet are validated ad biomarkers | [26635716 17502554 25442939 24012374 23477989] | this becomes particularly pertinent given that there was no overlap between the findings of these two reports. several studies have examined the predictive ability of plasma aβ levels. | [] |
406 | these risks have been described more fully elsewhere as they relate to preclinical ad trials | [23578568 26374677 27220838 21443378 25969699] | thus registries that use fluid or neuroimaging biomarker information such as amyloid positron emission tomography pet and cerebrospinal fluid analysis which require inperson visits for data collection should implement written informed consent the need for written consent is underscored, given that the collection and storage of biomarker information carries ethical and legal risks that must be addressed in these consent documents to ensure autonomous decision making—including the decision not to enroll for some. | [21514248] |
407 | intravascular netosis can be triggered by different stimuli including microbes proinflammatory cytokines activated platelets and antibodyantigen complexes | [23435331 15001782 17384648 23110185 25024378] | our recent results also demonstrate that transgenic ad mouse models treated with a neutrophildepleting antibody show a reduction in both microglial cell density and their activation state suggesting that neutrophils promote the activation of glial cells fueling an inflammatory loop that may promote neuronal injury and memory decline the release of intravascular nets by adherent neutrophils has been observed in several diseases including sepsis atherosclerosis autoimmune pathologies such as autoimmune smallvessel vasculitis experimental deep vein thrombosis transfusionrelated acute lung injury and cancer | [26214837 23435331 19448636 17384648 22980329] |
408 | our findings are consistent with previous reports of an association between pericyte
loss and bbb breakdown in ad and provide further evidence that pericyte loss is related to aβ level and
influenced by apoe genotype at least within the cerebral
cortex there is also a close relationship between pdgfrb content fibrinogen and
blood flow in keeping with in vivo evidence that loss of bbb integrity is related
to pericyte degeneration cerebral hypoperfusion and cognitive impairment uncertainty persists as to the precise timing of the various vascular
abnormalities in ad and the details of the complex causal interrelationships | [25611508 25757756 23126372 27459939 27243267] | in neither cortex nor white matter could loss of pdgfrb be
attributed to a reduced level of pdgf-bb, which was elevated in ad. however, as
discussed below, the differential distribution of fibrillar aβ may have influenced
the availability of this trophic factor. | [] |
409 | mt12 isoforms have been shown to be upregulated in ad 5678 whereas the results for mt3 are less consistent | [ 2780570 9710146 10069577 11470309 18313142] | transition metals such as cu or fe together with zn contribute to oxidative stress as well as to the aggregation and precipitation of amyloidβ peptides in the ad brain a number of studies suggest that the metallothionein (mt) family of proteins may be important for the understanding of ad. | [ 8073293 12689772] |
410 | a range of mechanisms have been proposed for the link between elevated hcy and ad and preclinical studies show that hyperhomocysteinemia induced by genetic manipulation or by bvitamin deficiency causes known hallmarks of ad such as accumulation of amyloidβ peptide 133134135136 and intensified tau protein hyperphosphorylation in the brain | [18243734 11799129 19939226 16516482 17360897] | according to the authors of a recent review low folate and vitamin b12 status contribute to the development of cognitive impairment directly and via elevated hcy levels these mechanisms will be discussed in the following sections. | [27431367] |
411 | fulllength fl app coprecipitated with cmyc antibody was quantified and normalized to the amount of immunoprecipated sorl1 as previously described | [17220890 25382023 21280075 16531402 10993067] | coimmunoprecipitation was performed after cell lysis in 1 chapso buffer using g plus beads with 2 μg mouse monoclonal anticmyc antibody for the immunoprecipitation of sorl1myc immunoblotted with anticterminal app antibody ab365 and anticterminal sorl1 s9200 western blot band intensities were measured with imagej software. | [17220890] |
412 | however the exact agerelated percentages differ between studies with some reporting prevalence rates of 50 or more in people with ds in their 50 s 6 see fig 1 with other genetic and possible environmental factors influencing risk 911fig 1agespecific prevalence of dementia in adults with downs syndrome 9 line with filled diamond data from lai and williams 6 dot with triangle data from visser et al 7 line with filled square data from lai et al 11 line with filled dot data from holland et al | [11983636 2527024 9017086 10430422 9828989] | consequently there has been an increase in the prevalence of age-related morbidities such as dementia. The overall prevalence of dementia in adults with DS is estimated at 1 68 with an increase with age from 89 in individuals up to 49 years to 321 in individuals from to 9 years old | [] |
413 | agespecific prevalence of dementia in adults with downs syndrome 9 line with filled diamond data from lai and williams 6 dot with triangle data from visser et al 7 line with filled square data from lai et al 11 line with filled dot data from holland et al | [11983636 2527024 9017086 10430422 9828989] | The overall prevalence of dementia in adults with DS is estimated at 1 68 with an increase with age from 89 in individuals up to 49 years to 321 in individuals from to 9 years old however the exact agerelated percentages differ between studies with some reporting prevalence rates of 50 or more in people with ds in their 50 s 6 see fig 1 with other genetic and possible environmental factors influencing risk 911fig 1agespecific prevalence of dementia in adults with downs syndrome 9 line with filled diamond data from lai and williams 6 dot with triangle data from visser et al 7 line with filled square data from lai et al 11 line with filled dot data from holland et al | [11983636 2527024 9017086 10430422 9828989] |
414 | subsequently 5 groups independently reported the molecular cloning of the βsecretase enzyme which they variously named bace asp2 and memapsin 2 it is important to note that all the groups agreed on the same polypeptide sequence even though they used different experimental approaches to identify the βsecretase lending strong support for the conclusion that the authentic βsecretase had been cloned | [10531052 10591213 10591214 10656250 10677483] | thus, their molecular identities were vigorously pursued. the properties of aβ generation and secretase activities in cells and tissues led to the development of cell-free and cell-based assays that could be exploited for the identification of the secretases. | [] |
415 | five studies used a transgenic model 16 29 30 34 35 3 studies used a dgalactoseinduced model 3133 2 studies used a cholinergic damage model 37 38 2 studies used an ageadvanced model 11 42 5 studies used an amyloidβ142injected model 12 36 39 41 42 1 study used an aluminium chlorideexposed model 14 and 1 study used a hypercholesterolemia model | [16901557 17935895 22032649 23181273 22032649 19927176] | a total of 10 studies used mice 3 balbc mice 31 32 36 2 kunming mice 33 38 3 pdappv717i transgenic mice 16 29 30 and 2 senescence accelerated prone mice8 34 35 7 studies used spraguedawley rats 11 12 14 37 39 41 42 and 1 study used wistar rats female animals were used in 3 studies 31 32 36 male animals were used in 11 studies 11 12 14 34 35 3742 and both males and females were used in 4 studies | [16901557 17935895 23181273 19927176 22032649 17935895 23181273 19927176
16901557] |
416 | it has been reported that ad pathogenesis and memory impairment can be mitigated by transplanting mesenchymal stem cells into an ad animal model | [22015609 22570192 18550916 19070649 24336078] | these findings indicate that restoring not only damaged neurons but also dysfunctional glial cells may be crucial for the development of an ad therapeutic strategy in line with these observations pluripotent stem cells are a promising regenerative medicine because they can be differentiated to various cell types in the central nervous system | [23112326 21943254 21609820] |
417 | these approaches include transcranial magnetic stimulation tms 10 11 transcranial direct current stimulation tdcs 12 and deep brain stimulation dbs via chronicallyimplanted electrodes | [21246222 23076723 21840288 20687206 24798585] | given the many years of unsuccessful drug intervention studies against ad, investigating new and innovative “non-pharmacologic” interventions against ad are now clearly warranted. neuromodulatory approaches have consequently emerged and are currently being clinically tested against ad. | [] |
418 | there is a marked temporary increase in ttau with normal ptau levels in traumatic brain injury and stroke that correlates with the severity of neuronal damage it is the same for creutzfeldtjakob disease which shows a large increase in ttau reflecting rapid neurodegeneration but normal ptau since there are no neurofibrillary tangles in this condition the csf level of ptau correlates with severity of tau pathology postmortem and high ptau has not been found in disorders other than ad | [11137759 17101890 24566866 16298235 19273758] | biomarkers of βamyloidosis are specific for ad pathology however amyloid pet tracers do bind to aβ deposits in vessel walls and increased tracer binding can be found following acute traumatic brain injury csf aβ42 is decreased ie abnormal in some nonad conditions such as hiv encephalitis and multiple system atrophy typical ad shows an increase in both ttau and ptau and a tight correlation between these biomarkers neither csf ttau nor ptau shows any change in primary tauopathies such as frontotemporal dementia progressive supranuclear palsy or corticobasal degeneration however findings on csf ttau and ptau diverge in conditions with acute brain damage | [12601108 19273758 18339640 24217171 23052602 12539213 8748926 15563479
22925882] |
419 | uchl1 13 and ubiquitin are found in aβ plaques and neurofibrillary tangles in the ad brain supporting evidence for ups dysfunction in ad | [2166150 3033674 3029875 8391280 1706517] | ubiquitin carboxylterminal hydrolase l1 uchl1 also called neuron cytoplasmic protein 95 and pgp 95 is a highly abundant neuronspecific cytoplasmic enzyme it modifies the activity of the ups by acting as a deubiquitinating hydrolase 10 ubiquitin ligase 11 and a monoubiquitin stabilizer | [ 6343558 2964855 2530630 2530630 12408865 12913066] |
420 | several plantderived compounds are known to be protective in models of alzhiemers disease including flavonoids resveratrol green tea polyphenols curcumin and ferulic acid | [21605052 19863373 16153607 26184304 27118174] | The berries of H arbutifolia are eaten fresh and cooked as foods by California Indians and other people the current study examined the chemistry and safety of the plant medicine. | [] |
421 | among the studies analyzed participants were diagnosed with alzheimers disease
according to the diagnostic and statistical manual of mental disorders iv
dsmiv
and by the national institute of neurological and communicative disorders and
stroke and the alzheimers disease and related disorders association
nincdsadrda
only one study investigated for the presence of diffuse brain atrophy on
magnetic resonance imaging mri and decreased blood flow in the parietal lobe and
posterior cingulate gyrus on single emission computed tomography spect | [25504466 23429813 16777648 17132973 21518170] | table 1characteristics and results of studies included in final selection.
gds: geriatric depression scale; npi: neuropsychiatric inventory; hdrs-21:
hamilton rating scale for depression; raid: rating anxiety in dementia;
csdd: the cornell scale for depression in dementia; aes: apathy evaluation
scale; ham-a: hamilton anxiety rating scale; rmbpc: revised memory and
behavior problems checklist. gds: geriatric depression scale; npi: neuropsychiatric inventory; hdrs-21:
hamilton rating scale for depression; raid: rating anxiety in dementia;
csdd: the cornell scale for depression in dementia; aes: apathy evaluation
scale; ham-a: hamilton anxiety rating scale; rmbpc: revised memory and
behavior problems checklist. | [] |
422 | there is some concern that the efficacy of longterm treatment of ad patients with intranasal insulin application could be attenuated by longterm brain insulin receptor desensitisation or decreased efficacy of peripheral mechanisms ie the sink hypothesis for aβ lowering strategies that contribute to insulininduced aβ clearance from the brain | [15750215 22430016 22476197 21330304 21864751] | intranasal insulin treatment for early ad or mild cognitive impairment mci improved memory and attention abilities in four phase 2 clinical trials without significant adverse effects or changes in blood levels of insulin or glucose intranasal insulin administration elicited changes in peripheral glucose metabolism but no significant change in blood insulin levels were detected | [18430999 17942819 18230654 15964100 21911655 17942819 22205300 22162476
25288674 25576060 18442862] |
423 | aβ has been found in the retina in all layers apart from the retinal pigment epithelium | [19271231 23750151 24439169 18691390 20550967] | −absent. app has been found in the ganglion cell layer through the inner nuclear layer in ad animal models | [19271231 23714377 19834067] |
424 | neuroimaging studies have shown that medial temporal lobe and hippocampal atrophy are associated with vad 14 54 and svd 119 167 albeit not to the same extent as in ad | [17962598 21518997 17963999 21613775 19022858] | greater putamen haemosiderin was significantly associated with indices of small vessel ischaemia, including microinfarcts, arteriolosclerosis and perivascular spacing and with lacunes in any brain region but not large vessel disease, or whole brain measures of neurodegenerative pathology. higher levels of putamen haemosiderin were correlated with more microbleeds upon mr imaging, but it is possible that brain iron homoeostasis and small vessel ischaemic change are responsible for these rather than only as a marker for minor episodes of cerebrovascular extravasation. | [] |
425 | many reasons to the failure have been proposed including duration of treatment 127 apoe ε4 allele 128 129 ages 127 disease stages 130 and disease progressing speeds | [25022541 18003940 19448381 25022541 21784351 22687143] | although it supported the use of nsaids for prevention of ad there were no positive results from the randomized control trials rcts moreover in a followup evaluation study of the randomized ad antiinflammatory prevention trial adapt and its followup study adaptfs that treatment for 1 to 3 years with naproxen a nonselective cyclooxygenase cox inhibitor or celecoxib a selective cox2 inhibitor the results show no prevention for the onset of dementia or no attenuation for the cognitive functions in older adults with a family history of ad | [25024454 25227314 25022541] |
426 | nutrition and ppar alphasirt 1 expression related to hepatic fgf21 production has become important to nafld and the metabolic syndrome | [17601491 26451842 24184811 18840786 23663741] | fibroblast growth factor 21 fgf21 is an important activator of sirt 1mediated release of adiponectin fgf21 binds to fgf receptor and beta koltho receptor complex 4748495051 and activates adipose tissue sirt 1 by increases in nad and activation of peroxisome proliferatoractivated receptor gamma coactivator 1alpha pgc1alpha and ampactivated protein kinase ampk | [20616029 18187602 22248288 18762812 24013744 20616029 25932355] |
427 | for example cystatin c cst3 has been suggested to be related to white matter lesions 13 grey matter density 14 and the global neurophysiological phenotype 15 of ad patients and amci individuals and sortilinrelated receptor sorl1 gene variants are associated with hippocampal atrophy and white matter hyperintensities in ad patients | [18511756 20468060 16213753 24938503 21220680] | in a recent study we demonstrated that the opposing trajectories of the influence of the apoe ϵ2 and ϵ4 alleles in the default mode network with age may reflect their antagonistic pleiotropic properties and their association with different ad risk factors other genetic polymorphisms associated with the cholesterol metabolism pathway have also been proposed as risk factors that influence the ad brain. | [25336599] |
428 | mitochondria are the major source of cellular ros and hence stress signaling that induces cellular senescence and apoptosis 118 164 165 166 | [20430626 23102266 16738333 15734681 21982713] | importantly it was found that exercise training also increases brain mitochondrial biogenesis mtdna and pgc1α sirt1 and citrate synthase and this may have important implications not only with regard to fatigue but also with respect to various central nervous system diseases and agerelated dementia that are often characterized by mitochondrial dysfunction therefore, exercise could be considered as a therapeutic option to reduce the negative effects of aging and decrease the risk of ad. | [21817111] |
429 | in order to achieve degradation of aggregated proteins in the autophagylysosome system there must be a successful fusion of the autophagosomes with the lysosomes | [ 2351689 2161853 22966490 1324248 9639028] | the major lysosomal degradative pathway in eukaryotic cells macroautophagy hereafter referred to as autophagy is responsible for degrading longlived or aggregated proteins and is the principal mechanism for turning over cellular material too large to be degraded by the ups autophagy is a highly regulated process that involves the sequestration of cytoplasmic cargo such as aggregated proteins and damaged organelles within doublemembrane vesicles called autophagosomes which are typically labelled by the microtubuleassociated protein 1a1blight chain 3 lc3 | [22966490 20811353 20034776 19653858 22966490 11099404 17909521 20034776] |
430 | the establishment of dna methylation is essential for normal cell development and differentiation 19 and impacts many key cellular processes including gene regulation 20 x chromosome inactivation 21 22 and genomic imprinting | [23925113 21251332 21862626 24186870 17467259] | these changes can arise within cells of an individual and be maintained through mitosis 17 as well as passed from parent to offspring meiotically one of the best-studied epigenetic modifications involves changes in dna methylation at cpg dinucleotides. | [19234478 21933173] |
431 | widespread ad pathology can manifest itself without obvious symptoms and clinically atypical presentations are relatively frequent in addition presence of vascular involvement is very common and has been reported in 80 of over 4500 brains from patients with neuropathologically verified ad one of the core pathophysiologic processes in ad is assumed to be mismetabolism of aβ initiating a series of processes that eventually lead to neuronal degeneration with brain atrophy and cognitive decline as has been outlined in the so called amyloid cascade hypothesis increased basic knowledge about aβrelated issues has resulted in various pharmaceutical attempts to counteract the aβrelated disease process using enzymatic inhibition of the secretases involved in aβ generation and different variants of aβ immune therapy however yet without much success | [21514250 23842566 16472206 24556009 24476230] | alzheimers disease is the most commonly diagnosed disorder causing cognitive dysfunction among adults ad is characterized by deposition of plaques containing aβ aggregates neurofibrillary tangles composed of tau fibrils loss of synapses and degeneration of neurons leading to memory impairment and other cognitive impairments however, it has gradually become clear that the clinical–pathologic correspondence is inconsistent. | [21514250] |
432 | repeated treatment with solanezumab did not show a significant benefit in data obtained from patients with mild or moderate ad dementia but a slowing of cognitive decline was found in approximately 34 of mild ad patients diagnosed as adascog14 ad assessment scale cognitive subscale 606263 supporting the suggestion that amyloidtargeted therapy could be more effective when applied at earlier stages of ad or before visible symptoms appear | [22672770 24450890 26238576 24412277 23411394] | in order to prevent the side effects induced by active immunization, passive immunization was utilized. there were no significant clinical improvements in phase 1 and 2 studies using a single dose of solanezumab an igg1 antiamyloid monoclonal antibody that binds to soluble monomers and lowermolecularweight aβ oligomer species but not to fibrillary aβ species or highermolecularweight aβ oligomer species | [22672770 25045405] |
433 | cerebral small vessel disease csvd is considered as an important pathological process of subcortical structures such as lacunar infarcts white matter lesions and microbleeds csvd is responsible for the pathogenesis of ischemic strokes cerebral hemorrhages and encephalopathy which are associated with advanced age and deteriorated by hypertension and diabetes mellitus csvd mainly contains lacunar infarct or lacunar stroke leukoaraiosis binswangers disease and cerebral microbleeds with the development of imaging examination and its clinical usage it has been well identified that cerebral vascular diseases especially csvd contribute to the occurrence of ad | [ 9368569 22006983 23569023 23887837 20957378] | ad is clinically characterized by cognitive impairment at first and dementia eventually which gradually worsen over a number of years increasing research indicates that ad results from the destruction and death of nerve cells triggered by amyloid plaques and neurofibrillary tangles both of which are thought to contribute to the neurodegenerative death of the neurons in the brain and the subsequent symptoms of ad the main risk factor for ad is advanced age while the incidence of ad increases with the progress of aging substantial clinical research implicates the involvement of vascular risk factors in ad such as hypertension coronary artery disease diabetes and hyperlipidemia these vascular factors increase the risk of ad occurrence | [25387055 25387055 24493463 24626484 23209064 23243502 17110895 25034716
23887837 23209064 23569023] |
434 | increasing imaging results have evidenced that csvd has a close association with cerebral atrophy a prospective followup research conducted by nitkunan et al showed that brain volume is decreased in the patients with csvd with respect to normal aging subjects and this decrease was correlated with cognition decline during 1year prospective followup the leukoaraiosis and disability study further proved that brain atrophy facilitates cognitive decline and brain atrophy is independently related to longitudinal cognitive decline in csvd according to mri measurement the severity of brain atrophy was correlated with the number of lacunar infarcts and the size of subcortical and periventricular white matter lesions while shorter telomere length is associated with brain atrophy and wmh | [23114884 20594616 21148440 22592361 23114884 23933740] | generalized cerebral atrophy will be linked with a range of clinical problems because of the involvement of the whole brain. cerebral atrophy can usually be identified in medical imaging such as computed tomography (ct) and/or mri, which can demonstrate structural changes in the brain. | [] |
435 | alzheimers disease can also be considered a metabolic disease in which brain glucose utilization and energy production are impaired | [ 9720972 11956956 15094078 16340083 15750215] | modulation of gamma secretase activity by nonsteroidal antiinflammatory drug nsaidlike agents has been postulated to reduce brain aβ42 concentrations and to prevent cognitive deficits in animal models of ad however several nsaid enantiomers such as rflurbiprofen have failed to demonstrate clear efficacy in reducing levels of aβ in clinical trials beta-secretase, otherwise known as the beta-site amyloid protein precursor cleaving enzyme (bace 1), is thought to initiate the amyloidogenic pathway by cleaving the amyloid precursor protein. | [] |
436 | agingassociating diseases of different mechanisms such as cardiomyopathy degenerative valvular disease atherosclerosis and osteoarthritis and cataract present mechanical factors interacting with their pathogenesis | [25081406 11925731 24781409 24845389 18221767] | cells are continuously subjected to mechanical forces that influence cell division gene expression cell migration morphogenesis cell adhesion fluid homeostasis ion channel gating and vesicular transport the seminal work of darcy thompson demonstrated that physical forces play a key role in plant and animal morphogenesis | [11274342 21763607] |
437 | the function of antiaβ antibodies is not understood but they have been implied to interfere with aβ toxicity and the oligomerization and fibrillization of aβ | [22805374 21490226 22826245 22355408 12821522] | a vast part of anti-aβ antibodies are believed to be produced in response to aβ in the periphery and central nervous system. It has been proposed that antiAβ antibodies predominantly show affinity toward the toxic aggregated forms of Aβ including oligomers and protofibrils which may be considered nonselfantigens and not to monomers | [] |
438 | in addition the location of the largest decrease in patients compared to controls varied over the studies main differences between groups were found in the anterior and central regions 18 28 29 as well as the posterior regions 21 and in one study both regional increases and decreases were found | [17574912 24726900 9623998 12488788 22902196] | lower functional connectivity in ad has previously been reported in studies using different modalities, but the pattern of this functional connectivity and the methodology varied considerably between studies. in studies with high temporal resolution time series eeg and magnetoencephalography meg functional connectivity in ad was found to be decreased in the higher frequency bands alpha and beta 9 2126 as well as the lower frequency bands theta 22 23 and involving mainly brain regions that are connected by long corticocortical fibers | [18952674 7511505 10727911 16076512 1422803] |
439 | however possible bias and heterogeneity for plasma tau were observed between the different studies with some studies reporting an increase decrease and no change in ad patients | [25054847 24129926 24682919 23383382 24318929] | for plasma aβ measurement, most studies utilised elisa-based methods with sensitivity in the range of 10–70 pg/ml and specificity <0.1%. the funnel plot also indicated that there is minimal bias between the studies used in the analysis | [] |
440 | to gain more insight into cebpd functions in the cns we focused next on the expression of candidate genes previously suggested to be regulated by the transcription factor cebpd in the periphery | [19270711 23028973 18673548 21112127 10594926] | no differences between the c/ebpd(-/-) and c/ebpd(+/+) animals were detectable concerning the expression of neprilysin (membrane metallo-endopeptidase; mme), apolipoprotein e (apoe), low density lipoprotein receptor-related protein 1 (lrp1), cathepsin b (ctsb), endothelin-converting enzyme 1 (ece1), angiotensin i-converting enzyme (ace), insulin-degrading enzyme (ide), and advanced glycosylation end product-specific receptor (ager; formerly termed rage). Hence, the increased Abeta deposition in C/EBPD(-/-) mice was not caused by alterations in expression levels of genes involved in turnover or transport of Abeta (S5 Fig). | [] |
441 | the goodness of usual antiad drugs is just a temporary relief of clinical symptoms and signs of dementia but the efficacy of these cholinesterase inhibitors in ad treatment is not supported by any highquality and longlasting clinical trials9 these medications cannot cure alzheimers dementia or stop the disease progression3132 because ad is a multifactorial disease using multifunctions and multitargeted agents have been considered extensively3334 enormous medical combination therapies have been proposed to cure alzheimers disease35 herbal medicines as a result of multifunction multitarget characteristics have potential of optimum pharmaceuticals and nutraceuticals effects on ad patients10 preclinical and epidemiological studies suggest that herbal drugs might be effective at reversing neurodegenerative pathology and agerelated declines in neurocognitive performance36 herbal drugs may act to protect the brain in a number of ways including by protection of vulnerable neurons promotion of peripheral and cerebral vascular system enhancement of existing neuronal function or by stimulating neuronal regeneration and inhibition of neuroinflammation moreover medicinal herbsderived drugs are natural and hence safer than synthetic drugs and that a complex mixture of herbs can effectively treat complex diseases | [15326237 17018549 22316321 15113710 11295356] | all together these data show that r. damascena extract in medium (600 mg/kg) and high dose (1200 mg/kg) improved long-term memory in a dose-dependent manner. effects of the amyloid-β and rosa damascena extract on long-term memory during the first (b, white color) and second (b, black color) probe trials, respectively, as measured by mean time step-through latency. **p < 0.01; ***p < 0.001 different from the control and sham groups. ##p < 0.01, ###p < 0.001 different from the aβ-injected group (alz + ns), @p < 0.05, @@@p < 0.001 different from the aβ-injected group (alz + 300) | [] |
442 | a mixedeffect beta regression model was selected after testing 10 basic models available in the literature | [19592311 21659625 23211395 12047920 21694449] | disease progression models were established using nonmem (version 7.1.0 with a gnu fortran compiler; icon development solutions, ellicott city, md, usa). data exploration and visualization were performed using r (http://www.r-project.org; version 2.14.0) and xpose package 4.0 (http://xpose.sourceforge.net). | [] |
443 | concentrations of csf tau and ptau are increased in ad and have been shown to positively correlate albeit to differing degrees with tangle load at autopsy and regional brain atrophy as defined by magnetic resonance imaging mri | [19273758 14676043 17012293 21489655 20147537] | csf levels of aβ42 tau and phosphotau181 ptau markers of amyloid neuronal injury and tangles respectively have stood the test of time in exhibiting both diagnostic and prognostic utility individuals diagnosed with very mild or mild ad dementia have low levels of csf aβ42 that inversely correlate with the presence of amyloid as visualized by positron emission tomography pet | [20157306 19822868 12601108 17210801 19268916] |
444 | given that general memories are semanticized due to the loss of episodic detail in ad 12 13 33 34 we were expecting a similar pattern of performances than that obtained for ps that is relatively spared in the early stages of ad and temporally graded | [19497331 12821510 15530208 20153463 15884035] | the aims of the present study were (i) to compare the distribution of specific versus general abms across the lifespan in ad patients compared with healthy elderly controls and (ii) to study the relationship between the specific and general components of abm and regional volumes of the hippocampus and the lateral temporal neocortex. tracking the anatomical substrates of general versus specific memories among two regions of the temporal lobe classically associated with episodic and semantic memory, respectively, we wished to explore whether the abstracted forms of abms are rather associated with the semantic or episodic components of memory. | [] |
445 | it has been proposed that the use of cholesterol and apolipoproteins as biomarkers may facilitate prognostication and guide therapeutic decision making in a broad spectrum of psychiatric illnesses including autistic spectrum disorders major depressive disorder schizophrenia and ad as reviewed by woods et al a reduction in neuronal cholesterol content promotes colocalization of betasecretase 1 and amyloid precursor protein disrupting plasmin generation and contributing to neurotoxic aβ production and associated neurodegeneration however elevated cholesterol levels also promote aβ production and aggregation as well as tau hyperphosphorylation neuritic plaque formation and cerebrovascular ischemia this apparent contradiction highlights the uncertainty regarding the molecular mechanisms implicated in cholesterolmediated ad neuropathology | [22304330 15583033 19199871 9329686 19321181] | the relationship between cholesterol and ad remains incompletely understood. cholesterol plays a key role in neurodevelopment, maintains the structural integrity of neuronal cell membranes, and ensures physiological extra-cellular messenger activity as well as neuronal repair. | [] |
446 | a single mirna capable of downregulating hundreds of target mrnas concurrently fine tunes diverse cellular functions involved in development differentiation proliferation apoptosis and metabolism overall the whole human mirnome regulates greater than 60 of all proteincoding genes importantly aberrant regulation of the mirnome plays a central role in pathological events underlying cancers and neurodegenerative diseases recently we identified 852 experimentally validated target genes for more than 100 mirnas downregulated in ad brains the molecular network analysis of 852 genes revealed that aberrant expression of cell cycle regulators contributes to neurodegeneration in ad | [18668040 18955434 21892151 25027972 21945006] | development of diseasemodifying drugs for ad mainly targeting aβ has been unsuccessful suggesting that both early diagnosis and early treatment are highly important to achieve maximal response to diseasemodifying treatments however an accurate diagnosis of ad is often difficult solely based on neuropsychological examinations because the possibility of numerous dementing diseases such as frontotemporal dementia ftd dementia with lewy bodies dlb vascular dementia hivassociated dementia had and prion diseases should be carefully excluded although decreased aβ42 and increased ptau levels in the cerebrospinal fluid csf serve as a biomarker for the diagnosis of ad the collection of csf is too invasive to apply to routine clinical works therefore establishment of most reliable noninvasive ultrasensitive highthroughput and inexpensive biomarkers that promote the early diagnosis of ad would meet a growing demand from the public micrornas mirnas a class of endogenous small noncoding rnas ncrnas mediate posttranscriptional regulation of proteincoding genes by binding to the 3 untranslated region utr of target mrnas leading to translational inhibition or mrna destabilization or degradation currently 1881 precursor and 2588 mature human mirnas are registered in mirbase release 21 in june 2014 | [21765871 9153154 21514250 24427524 20703300] |
447 | autophagy the molecular machinery for selfdigestion is an essential catabolic process in response to a multitude of physiological and pathological situations it is well known that autophagy is an intracellular degradation system that delivers cytoplasmic components to lysosome and degrades cellular components through autophagylysosomal pathway to alternatively remove unnecessary cellular constituents in the normal physiological function of cell metabolism autophagy upholds the balance between the synthesis degradation and subsequent recycling of cellular products playing an important role in maintaining cellular homeostasis cell survival differentiation and development although numerous studies have revealed the nature and role of autophagy since the 1960s many questions about the actual processes and mechanisms still remain | [15615779 16247502 16247502 19279132 22862962 20811354] | increasing evidence highlights that the activation of mtor is an enhancer of aβ generation and deposition mtor an inhibitor of autophagy decreases the aβ clearance of the autophagylysosome system which accounts for the clearance of abnormal proteins mtor also modulates the metabolism of app by regulating β and γsecretase in addition mtor may interact with several key signaling pathways and regulate aβ generation or aβ clearance including pi3kakt gsk3 ampk and insulinigf1 a variety of research studies have proved that the activation of mtor leads to the failure of aβ removal from the brain since the dysfunction of autophagy triggered by mtor facilitates the process of aβ generation and weakens its clearance | [22344941 19301428 22344941 19210753 20376313 22829447 18023354 19291319
23265840 22367557 19210753 15953364 22829447 23305067] |
448 | antioxidants such as vitamin e could reduce βamyloidinduced neurotoxicity in cultured hippocampal neurons7 and can slow the progression of ad significantly8 similarly ginkgo biloba extract improves cognitive function in ad patients9 walnut extracts have been reported to offer benefits to aβ induced cytotoxicity in pc12 cells10 and pomegranate could improve memory in ad transgenic mice | [ 9987013 9110909 9823823 21706234 17010630] | at present the number of patients suffering from ad is rising continually worldwide and represents one of the biggest challenges for most societies throughout the world1 although the etiology of ad remains unclear increased oxidative stress have been reported to be an important underlying cause of neurodegeneration in ad2 brain structures supporting memory are uniquely sensitive to oxidative stress due to their high demand for oxygen chronic oxidative stress increases with age and ageing is one of the major risk factor for ad Numerous studies have suggested that a diet rich in fruits and vegetables may represent an important alternative therapeutic options by improving agerelated memory decline and cognitive dysfunction observed in AD These beneficial antiageing effects are associated with their high antioxidant capacity | [10071091 9989456 22614926] |
449 | moreover it was seen that altered platelet function such as increased activation 14 or altered membrane fluidity 15 16 as well as an altered app ratio are associated with the development of ad | [ 9561982 3438464 23228953 8912490 9740113] | platelets share some properties with neurons because they store release and take up the neurotransmitter serotonin being a therapeutic target Most importantly platelets store and process also the amyloid precursor protein APP which is cleaved into the toxic βA peptides and accumulates βA in the brain and vessels in AD | [25041722] |
450 | on the other hand whether a gradient of posterioranterior changes or anteriorposterior changes predominates or even a combination of these patterns occurring simultaneously is still under intense debate | [20371138 20368633 19643188 18455835 19100839] | taken together, the majority of tbss-based investigations have attempted to establish a pattern of dti changes that would characterize ad evolution. the sum of evidence regarding a gradient pattern for ad so far remains inconclusive and no firm conclusions can be drawn. | [] |
451 | indeed the phenotypes of beclin 1and vps34deficient mice are more severe e7585 lethal 173 176 than that of other autophagyrelated genes such as atg3 136 atg5 67 and atg16l p1 neonatal lethal | [14657337 21283715 18768753 15525940 18849965] | these mechanisms may be of great importance in ad as decreased pi3p vps34 and beclin 1 levels have all been reported importantly as genetic ablation of beclin 1 or vps34 results in reduced levels of both atg14l and uvrag 53 these changes in addition to compromising autophagy as well may affect endolysosomal trafficking | [20559548 23907271 18497889 18843052 20643123 20643123] |
452 | mci participants at baseline met the petersen criteria or revised petersen criteria furthermore core clinical criteria for mci proposed by the niaaa workgroup were also acceptable these criteria include subjective complaints a decline in memory objectively verified by neuropsychological testing in combination with a history from the patient a decline in other cognitive domains no or minimal impairment of activities of daily living and not meeting the criteria for dementia | [15324362 10190820 15324367 20008648 21514249] | the definition of 11c-pib positivity was that 11c-pib ligand uptake exceeded a certain threshold in the pet imaging protocol and vice versa. the study was a longitudinal cohort study in which amyloid imaging results were obtained at baseline the reference standard clinical outcomes result of mci was identified at followup and the study included at least 10 mci participants | [24782322] |
453 | notably some studies in both subgroups generated their own optimal thresholds prespecified or did not prespecify what constituted a positive or negative test and some reports used visual 11cpibpet interpretation | [20205671 19587325 19475670 23799136 19587325 22441582 19475670] | furthermore the mci subtype was diagnostically unstable in our review large variations and unavailable data of mci subtypes were observed in the included studies grimmer et al 2013 and wolk et al 2009 found no clear association between a particular clinical subtype of mci and 11cpibpet positivity however subjects with multidomain amnestic symptomatology more frequently exhibited a significant clinical decline compared with individuals with isolated memory impairment in grimmer et als study 2013 which is consistent with a previous study none of the included studies analyzed the underlying correlation between 11cpibpet imaging conversion rate and mci subtypes therefore to clarify the correlation between mci subtypes and brain aβ burden further prospective 11cpibpet studies with mci subtypes should be performed | [23102125 23036071 19475670 23036071 23102125] |
454 | a reduction of serotonin 5ht has been reported in several studies across several brain regions as have altered 5ht6 receptor function and a reduction in cell counts in the dorsal raphe nucleus in a recent study a significant reduction in serotonergic tone comprising lower 5hydroxyindoleacetic acid concentrations in the hippocampus and lower 5ht concentrations in the superior temporal gyrus and cerebral cortex correlated with dementia severity it may be that the association observed in previous studies between psychosis in ad and reduced 5ht may be related to regional disease severity in psychotic ad and not an independent risk factor for the emergence of the syndrome | [ 1710105 15707619 18525126 7953058 24685637] | an early postmortem study of neurotransmission in psychotic ad did not identify any abnormalities in markers of dopamine signaling one small postmortem study suggested a selective increase in d3 receptor availability further using 11craclopride pet a modest increase in tracer binding in the striatum was observed in a cohort of delusional patients suggesting some increase in d3 availability yet a recent comprehensive postmortem study of monoaminergic correlates of behavioral symptoms in ad did not observe any relationship between alterations in dopamine or dopamine metabolite concentrations in nine behaviorally and neurochemically relevant brain regions and psychotic symptoms in ad perturbations in serotonergic systems have been reported in postmortem studies of psychotic ad. | [ 1710105 11255451 19204262 24685637] |
455 | furthermore prpc was shown to be related to signaling platforms including several intracellular effectors such as fyn lyn pi3kakt pka erk12 gsk3β and tace among others | [10988071 24810941 20615969 14597699 19457070] | therefore, for development of clinical disease, prpsc has to be close to neuronal prpc in a contiguous compartment. here, it is likely that lipid raft localization of prp isoforms in particular plays a key role. | [] |
456 | a logical compromise solution would be to illuminate the occupied room with a white light source with a high proportion of shortwavelength radiation delivering lower corneal photopic light levels than those previously employed although studies have shown that shortwavelength light or blueenriched light sources can be effective at correcting circadian sleep disorders other studies failed to show differences between lamps of different correlated color temperatures ccts | [ 9110101 18544724 17714459 21276222 18564297] | recent research has shown that the human circadian system is maximally sensitive to shortwavelength blue light with peak wavelength close to 460 nanometers nm this finding opens the door for the potential application of lower more targeted light levels in therapeutic settings using this knowledge two pilot studies showed that evening exposure to 2 hours of shortwavelength light 30 lux at the cornea from lightemitting diodes leds peaking at 470 nm consolidated restactivity rhythms and increased the sleep efficiency of persons with adrd however delivering light to adrd patients via light boxes or light goggles is a challenge and would likely have low compliance rates | [11507175 11487664] |
457 | some emerge rather early braak iiiiv and are sustained some appear early and subside and some are apparent only at a later phase table i
earlyonset changes are most compatible with the notion of causation | [18525125 23962497 24014289 24027266 21946562] | nonetheless there are some fairly consistent changes such as i increases in mir146a in temporal cortex and hippocampus and in an opposite direction decreases in mir132 in several brain regions ii reductions of mir107 in temporal cortex and iii diminished mir181c in frontal cortex and temporal cortex the latter change is interesting since it is mimicked by similar decreases in animal models for ad further aβ42 exerts comparable effects on mir181c in a cellular procedure see further below another interesting point comes from studies that have looked at the timecourse of changes | [20937840 19406203 24014289 21807765 21062284 18234899 21994399 21994399
21720722 20552018] |
458 | thus downregulation in ad of mir124a and 132 which target ptpb will favour aberrant splicing of tau into neurotoxic isoforms third downregulation of mir15a 103107 and 27a3p enhances excess phosphorylation of tau by extracellular regulated kinase erk1 cyclindependent kinase cdk5 and glycogen synthase kinase gskp respectively on the other hand an increase in mir26b would act oppositely to repress gsk3β | [23684085 21807765 20660113 21625387 24027266] | first the synthesis of tau itself would be accelerated by reductions in the levels of mir27a3p and 34a both of which target it directly second the tau precursor can be alternatively spliced by the abovementioned appprocessing enzyme ptpb its actions will modify the ratio of “4r” to slightly-shorter “3r” isoforms, the former being more prominent in ad. | [24212398 24032460] |
459 | disruption in step function has also been implicated in seizures ethanol abuse amphetamamineinduced stereotypies and huntingtons disease although the basis for these changes remain to be determined | [21204826 21464302 19026408 21632937 22523092] | in contrast step levels or activity are lower in several other disorders including stressrelated conditions excessive etoh consumption and cerebral ischemia thus, the current model is that step activity must be within an optimal range and that either high or low levels of step disrupt synaptic plasticity. | [22649233 24012328 24588427 24198371] |
460 | mci is currently regarded as a complex condition that still needs further investigation to better define it and to develop a rigorous understanding about its clinical utility the recent subclassification of mci according to its cognitive features seems to be an effort to set some boundaries regarding the heterogeneity around this concept petersen suggested that mci be subdivided into two variants amnestic mci with clinically significant memory impairment and nonamnestic mci with significant impairment in functions other than memory such as attention executive processing language or visuospatial skills | [18473654 19035823 11735772 22143004 15324362] | also, we will synthesize which eye movement pattern changes might be associated with these deficits in mci/ad patients, and which might need further investigation. researchers have been trying to better understand the changes involved in the process of aging specifically focusing on the cognitive differences between normal and pathological aging mci is generally associated with aging processes and it is thought to be an intermediate state between normal aging and dementia thus increasing the risk of progression to ad however not all aging processes lead to cognitive declines and the pattern of cognitive decline may vary across individuals | [19822781 10190820 11735772 15324362] |
461 | the characteristics of the adni1 subjects have been published extensively briefly the mild ad subjects with csf information 102 subjects with 383 cdrsb observations were between ages of 57 to 89 years mean standard deviation sd 758 years and the lmci subjects with csf biomarker data n199 1219 cdrsb observations were between 55 to 89 years 748 years | [20810324 22990808 21659625 22534009 20042704] | the conditional probability was calculated based on the baseline hazards estimated in the dropout model and the simulated cdr–sb scores at the previous visit. a percentile vpc with confidence intervals was used to assess the extent to which the median prediction and extremes of the 90 prediction interval reflected the median and the fifth and 95th percentiles of the observed data | [19387434] |
462 | in general compared to nonconverters mci to ad converters show greater reductions in naa or naacr in different cerebral locations between baseline and followup 9196 naa or naacr especially those of the hippocampus often correlate with memory test scores 83 92 97 98 and so can be related to memory function and to predict ad with relatively high accuracy | [19427767 19398707 22129910 22390859 18692749 19398707 22390859] | longitudinal mrs investigations of at-risk people (e.g., mci) that involve multiple time-point mrs scans are especially important in understanding disease progression. In the few such studies available, subjects with MCI have been followed for 1-3 years, to characterize metabolite profiles of those who converted to dementia (Table 1). | [] |
463 | sleep deficits are known to impair cognitive function in healthy populations to accelerate cognitive decline and to predict incident mci and dementia | [16126646 21532950 20946702 17287134 19426575] | in addition mood disturbance can contribute not only to impairment of memory but also to sleep disturbance hpa axis dysregulation and autonomic dysfunction and related proinflammatory changes thus helping to promote a vicious cycle of adverse physiologic neuroendocrine and psychosocial changes that foster the development and progression of ad cvd and related chronic conditions sleep disruption also common in cognitively impaired adults likewise has negative effects on health functioning and quality of life and is a major reason for institutionalization | [17658122 17705097 17615391 22415141 19426575 20946702 17287134 18346674] |
464 | the therapeutic potential of cannabinoids 150 in ad becomes apparent in several mechanisms noncompetitive ache inhibition 151 antiaggregation of aβ peptides mediated by ache pas inhibition or by phagocytosis of aβ peptides mediated by cb2 receptors 152 antiglutamatergic effect 153 antioxidant activity 147 antineuroinflammatory properties | [22448595 10191316 17140265 14657172 11831553] | among the substances with the ability to reduce or mitigate neurodegenerative symptoms the group of cannabinoids has to be taken into consideration The connection between the endocannabinoid system and AD has been reported consistently [119, 147-149]. | [18781980 20875047] |
465 | additionally studies using conventional timedomain oct technology lacking eyetracking capabilities found only a subtle rnflt decrease in ad patients | [17543991 21454010 17460292 11595144 20609426] | the rnflt has been examined in several studies using histopathologic techniques, with inconsistent findings. some stated that there is no decrease while others found abnormal rnflt | [3736630 8725900 8498808 7542917] |
466 | the rate of change in the left hippocampus correlates with decline of performance in the boston naming test minimental status examination and the trailmaking test b such analyses help with the definition of special ad subtypes like posterior cortical atrophy or the logopenic variant of ad on the molecular level we find a downregulation of synaptic genes across multiple brain regions and widespread proteomic signs of synaptic stress or decay in the cerebrospinal fluid csf or blood changes in the molecular fine structure of ad brains also arise independently of atrophy as resonance spectroscopic investigations in ad imply | [22940716 22940716 21325651 23273601 23160951 19451528] | highly myelinated neurons are only affected in the final phases of the disease low myelinization increases the overall energy expenditure of neurons in addition subcortical neuron loss occurs in the nucleus basalis of meynert and the locus ceruleus impairing the cholinergic and noradrenergic transmitter systems in the neocortex the parietal lobe along with certain areas of the prefrontal lobe is one of the last areas of the human brain to myelinate and many of its neurons remain poorly myelinated for the entire lifespan which may explain their vulnerability to factors capable of triggering ad the atrophy runs slowly but while in healthy aging only 02 to 041 of the brain volume vanishes per year the rates in ad may be ten times that and in especially vulnerable regions like the hippocampal formation atrophy rates might be even more devastatingly high and surpass 10 per year see also in terms of neuropsychological tests regional atrophy and glucose metabolism correlate well with test results left hippocampal gray matter volume for example significantly correlates with performance in memory tasks and left temporal graymatter volume is related to performance in language tasks | [11193802 7198741 6707659 21130554 22920268 8676724 23554933 22940716] |
467 | functional impairments in ad place the greatest burden on both caregivers and the economy and results from several studies have suggested that neuropsychologic test performance is predictive of activities of daily living performance in patients with ad results from observational studies and clinical trials indicate that deterioration in the ability to carry out activities of daily living can be detected among patients with ad over followup periods comparable with that in the present study | [ 8059882 12614995 15814872 8505464 19929593] | caregiver assessments also indicate that memory and ability to carry out activities of daily living remained stable or improved during therapy with ct. in an assessment of overall memory, 40% of the caregivers reported somewhat better or much better memory after initiation of ct. | [] |
468 | also no correlation was found between the serum aβ42 levels and the aβ42 levels in csf of ad patients and healthy individuals the accumulation of aβ peptides in ad brain or the progression of cognitive deterioration in ad | [11335065 16909004 16372280 10634455 18268197] | reports on potential serumbiomarkers for ad diagnosis have provided contradictory results and it is unclear whether changes in the periphery reflect pathologies within the brain thus studies of aβ42 levels in serum of ad patients showed both reduced and increased values compared to control subjects while other reports indicated no differences between groups | [19698775 15717023 20478847 18534566 10211483 10482274 12873852 8880695] |
469 | consistent with the early disruption of circadian and sleep physiology observed clinically neuropathological evidence in ad clearly implicates ascending brainstem pathways that govern the sleepwake cycle at or near the outset of the disease including cholinergic dopaminergic melatoninergic and neurosteroid systems | [21170538 21145918 22395806 20631712 16416333] | our understanding of ad neurobiology has been transformed by a substantial body of neuroimaging data which demonstrates that the neurodegenerative process has a predictable and regionally specific evolution in the brain the very earliest disease targets in ad remain somewhat contentious but are likely to include entorhinal cortex and brainstem sites including locus coeruleus dorsal raphe nuclei or nucleus tractus solitarius | [ 1759558 21170538 21778116 22219130] |
470 | sorl1 through its codependent interaction with vps26 regulates the intracellular transport and processing of app resulting in reduction of amyloid beta aß peptide production sorl1 knockout mice carrying both pathogenic mutations in the psen1 exon 9 deletion and app swedish k595mn596l exhibited increased production and accumulation of aß sorl1 variants might influence the csf aß42 level in ad patients | [21220680 16174740 22279231 19036982 18541377] | s5 sorl1 also known as sorla and lr11 and app proteins are colocalized in the endosomal and golgi compartments | [16174740] |
471 | s100b is a multifunctional ca2 binding protein that can act as an intracellular regulator or extracellular signal molecule that interacts with a wide variety of proteins including the receptor for advanced glycationend products rage s100b can be neuroprotective at lowphysiological levels or toxic at higher concentrations although not connected to a pd diagnosis increased levels of s100b in the serum of pd patients positively correlated with the progression of disease although controversial this suggests s100b may also serve as a general marker of brain injury or neurodegeneration due to its abundant presence in oligodendrocytes and astrocytes in this context it has been reported that increased levels of s100b result in glycogen synthase kinase 3β gsk3β and hyperphosphorylation of tau our analyses revealed that s100b was significantly and positively correlated with ptau181 | [19110011 12645009 19110011 21303299 15619461 12645009 21303299 18494933] | however, a moderately significant and positive correlation was apparent between aβ42 and apoe carrier status when the pd and nc cohorts were combined. intriguingly, within the nc group only, apoe ɛ4-positive subjects had significantly higher apoe levels and ttr levels. | [] |
472 | our results are consistent with the wellestablished role of the apoe4 allele as a risk factor for sporadic ad p00001 7 | [17596691 19734902 19734903 8350998 17541051] | in the second step, a binomial logistic regression model was used to compare the interactions between apoe*4 and each of the three snps in the entire sample. the statistical analysis was conducted using r software version 2.12.2. | [] |
473 | the aβrebound observed in cells experimental animals and humans is an expected pharmacodynamic feature for all biphasic inhibitors | [16548522 18574238 22323718 15647487 22381714] | in summary the biphasic inhibitors could facilitate potentially pathogenic processes that could explain why clinical trials showed dose dependent cognitive decline with avagacestat and irreversible cognitive decline with semagacestat on the optimistic side, studies of the biphasic inhibitors could give valuable insights in the molecular pathogenesis and lead to novel drug development strategies. | [22381714] |
474 | several studies have suggested that greater cognitive impairment predicts an increased risk of the onset of psychosis in patients with alzheimers disease several neuroimaging studies have implicated the frontal lobe parietal lobe striatal regions and insula in the manifestation of delusions in patients with the disease in a previous study examining structural brain abnormalities significant findings indicated an association between low volumes of regional gray matter in several areas and delusions in patients with alzheimers disease | [16582044 18239195 9813789 20375510 18669506] | however among a wide variety of neuropsychiatric symptoms in patients with alzheimers disease psychotic symptoms such as delusions are particularly associated with increased caregiver burden a decreased quality of life for both the patient and the caregiver and a relatively poor prognosis for the course of the disease a 2year prospective longitudinal study of patients with alzheimers disease reported that the cumulative incidence of psychotic symptoms delusions hallucinations was 369 the examination of possible predictors of the development of psychotic symptoms in patients with alzheimer’s disease is clinically relevant. | [17299264 16401890 16216946 12566599] |
475 | all variances are on the observed 01 scale were estimated using restricted maximum likelihood and were transformed to those on the liability scale as shown previously assuming a disease prevalence lifetime risk of 8 for ed 2 for ad and 01 for ms | [16451790 21376301 21151130 9736873 21833088] | where is the additive genetic variance tagged by the snps, is the error variance, a is the genomic similarity relationship matrix estimated from snp data and i is an identity matrix. the genomic similarity relationship for each pair of individuals is calculated as the sum of the products of snp coefficients between two individuals scaled by the snp heterozygosity | [20562875] |
476 | clusterin also known as apolipoprotein j is a multifunctional lipoprotein involved in amyloidβ aβ fibrillisation and clearance complement inhibition and neuronal apoptosis | [ 7980587 19651157 9200695 9247197 21762182] | biomarkers are therefore urgently needed to correctly identify subjects affected by ad before they have developed dementia and to track disease progression in ad recently several independent genomewide association studies have identified the clu gene encoding clusterin as a genetic locus associated with ad raising hope for clusterin as a potential marker of ad | [19734902 19734903 20460622] |
477 | autopsyproven studies demonstrated a range of prevalence of cerebrovascular lesions in ad from 39 to 68 and that variability mostly depended on differences in the kind of studied vascular lesions macroscopic infarcts microscopic infarcts etc | [11213093 15792814 20173339 17568013 14504965] | this was a naturalistic study conducted in two neurology clinics where patients were referred by their family physicians and, in all cases, a chei was initiated by the attending neurologist. in that context, which seems quite representative of incident ad, one third of the patients (32.5%) qualified for the advc group. | [] |
478 | in addition nmdarenhancing treatment can reduce depressive symptoms 213 214 218 and improve cognitive function in patients with schizophrenia | [15023571 16275807 9892253 15023571 16275807 11806864 15780844] | alternatively, nmdar enhancers may improve the cognitive, mood and psychotic symptom in ad like in schizophrenia and major depression. Previous studies revealed that NMDAR enhancing agent can alleviate psychotic symptoms of patients with schizophrenia [213-217]. | [] |
479 | by adding charged sequences polyethylene glycerol peg 44 nmethylation 45 using denantiomeric residues replacing residues with tyrosine and introducing nterminal acetylation and cterminal amidation 26 27 iaβ5 derivatives with enhanced properties ie higher proteolysis resistance stability activity solubility and bbb permeability could be established | [19250644 12578830 15098004 11967228 10363910] | additionally the charged residue aspartate d was added at the end of the peptide to increase hydrophobicity and bbb permeability despite its significant activity to inhibit aβ fibrillogenesis iaβ5 was unstable and easily degraded by proteases which hampered its therapeutic usage in vivo | [ 9662374 11967228] |
480 | apart from the antiamyloid properties and antitau hyperphosphorylation properties against the two major pathological changes in ad curcumin is also able to regulate the secondary changes that occur during the disease like oxidative stress inflammatory stress and cholesterol regulation which are very beneficial while considering ad therapy | [15974909 19966973 18573304 18573304 11606625 19966973 11755008 15974909
19966973] | curcumin can modulate multiple transcription factors, cytokines, growth factors, kinases and other enzymes. while the intravenously or intraperitoneally administered curcumin is metabolized to tetrahydrocurcumin hexahydrocurcumin dihydroferulic acid and ferulic acid the orally administered curcumin is excreted mainly through feces in unchanged form | [17900536] |
481 | recent studies have identified morphological differences in the sulci of some professional groups including musicians patients with psychiatric and neurological conditions like schizophrenia and bipolar disorder and individuals with cerebral small vessel disease | [19433652 17988891 19270763 18577545 21518996] | indeed cortical folding patterns have been used to predict cytoarchitecture in addition to being a macroscopic probe for hidden architectural organization folding geometry may also provide information on developmental events | [18079129 20489617] |
482 | white matter abnormalities have been widely reported in ad and observed in the 3xtgad mouse brain as well | [14675724 12633151 18926601 18474742 18661556] | in parallel to the reduction of aβ and phospho-tau, apα treatment significantly reduced microglial activation as indicated by reduced expression of ox42. while the reduction in microglia activation by apα is likely a consequence of apα-induced reduction of ad pathology, suppression of microglial activation would relieve the inflammatory burden associated with ad pathology. | [] |
483 | gains tend to be modest and may be best documented as a slight improvement in certain cognitive domains compared with the mmse the skt may be more sensitive to subtle changes because it is a more comprehensive cognitive assessment battery and takes into account processing speed and response accuracy in addition the availability of five parallel versions of the test makes it less prone to learning effects upon retesting which is an important issue in longitudinal studies | [17166312 18430980 19640874 19142405 16255841] | studies involving combined pharmacological and nonpharmacological treatment with multimodal stimulation programs reported slight improvements in mmse scores most studies that have evaluated the effect of nonpharmacological interventions in ad observed stabilization or at most modest improvement of cognitive functions conversely untreated patients may show cognitive decline our results are in agreement with the findings of previous studies, which have suggested that robust changes in cognition are unlikely to occur as a consequence of cognitive training in patients with ad. | [16323385 17297213] |
484 | of reviews supporting the use of memantine in bpsd most relate to patients with moderate to severe 15165051 or moderately severe to severe ad | [19194105 18058838 15852444 17496417 18294023] | the current review demonstrates that the evidence, within their respective licensed indications, is in fact stronger for donepezil. it is of interest to examine the licensed-indication results in the context of previous systematic reviews and meta-analyses. | [] |
485 | researchers have been estimating and interpreting different patient profiles in iiv with respect to reaction times and accuracy ie rightwrong response summary for at least a decade see | [11055261 16820224 20025396 16997285 17484601] | while total scores provide an estimate of overall performance on cognitive measures iiv measures can complement these scores and may improve prediction of global decline functional decline and incident dementia it has been suggested that estimates of iiv provide a quantitative measure of neurobiological integrity in cognitive aging and neurodegenerative disease as greater mean iiv levels have been reported in samples with mild cognitive impairment and mild dementia and has been found to associate with decreased frontal gray matter white matter alterations and altered dopaminergic and acetylcholinergic neurotransmission | [14654726 15832049 18714062 15242692 15910117 11055261 12876148 1710967
16820224 20025396 11765745] |
486 | sorl1 has been associated with lateonset ad through using snps and picalm clu and cr1 have recently been identified by gwas as novel risk factor loci grb2associated binding protein 2gab2 bridging integrator 1 bin1 exocyst component 3like 2 exoc3l2 and methylenetetrahydrofolate dehydrogenase napd dependent 1like mthfd1l have been identified as associated with the development of ad but have been replicated with mixed results other possible ad genes can be found online wwwmolgenuaacbeadmutations
and
wwwalzgeneorg | [20388643 17220890 19734902 19734903 20460622] | however, as already mentioned, some alleles have been identified to increase the risk of developing late-onset ad. apoe ε4 is a wellestablished risk factor for ad and is associated with a fourfold risk of developing the disease since 2007 a number of gwas have been performed confirming that apoe ε4 is the most significant gene associated with lateonset ad other identified genes have only a small effect on the risk of developing ad | [10844923 20388643 20955934 17474819 19734903] |
487 | this is a novel biomarker that may interest several ad researchers as the selective targeting of several neurotrophin receptors has been proposed as a viable mechanism of intervention for neuroprotection with much of the attention being on the p75ntr the common neurotrophin receptor | [19874265 17049785 19710315 19334058 9410912] | as rantes upregulation in ad has been put forward as a mechanism for neuroprotection the concurrent lack of upregulation of blc may point to a protective response that is not properly functioning in early ad worth investigating nt3 neurotrophin 3 nerve growth factor 2 also appears in a meta feature with mip1delta ccl15 chemokine cc motif ligand 15 | [18440671 8114936 9116211] |
488 | building upon previous findings that low csf aβ42 can identify cognitively normal individuals with plaques preclinical ad and that tauaβ42 and ykl40aβ42 ratios can predict risk of developing cognitive impairment this minimal panel of six csf biomarkers ykl40 nrcam chromogranin a carnosinase i tau and aβ42 begins to segregate individuals into six clinicopathological categories normal cognition without amyloid plaques normal cognition with amyloid plaques preclinical ad normal cognition at increased risk to develop dementia converters very mild dementia cdr 05 very mild dementia at increased risk for progression and mild dementia cdr 1 | [16372280 20049742 17210801 17698783 21035623] | currently, however, this panel of six biomarkers appears likely to show much greater promise in its application to csf. indeed by providing proof of concept this study outlines a scheme to categorize the early stages of ad using csf protein biomarkers that reflect established features of the pathophysiological evolution of the disease | [] |
489 | moreover omega3 essential fatty acidrich diets are associated with a trend in reduced risk for mci and with mci conversion to ad whereas dha has been shown to be beneficial in transgenic ad models | [15788759 11724467 19262590 17442823 16040805] | we note that the adam10 cleavage product sappα further induces the conversion of free dha into npd1, thus constituting a positive, neurotrophic feedback loop. dha partially counteracts cognitive decline in the elderly | [19262590] |
490 | early identification of alzheimers disease ad is needed to facilitate timely treatment delivery and to improve quality of life for affected patients and their families cholinergic deficit is present early in the course of ad and is a likely contributor to the earliest clinical manifestations of this illness including declarative memory impairments and disturbances of preattentive information filtering ie impaired auditory sensory gating the latter of these impairments reflects cholinergic deficitrelated abnormal hippocampal physiology disturbances of which are amenable to identification using the functional magnetic resonance imaging fmri auditory sensory gating paradigm | [ 9581218 14747516 15174015 14747516 15174015 7568559 7527772] | functional imaging of hippocampal dysfunction among persons with alzheimer’s disease: a proof-of-concept study | [] |
491 | this measure has been used to study some biological signals such as heart rate time series 42 43 eeg data 23 44 and meg recordings 18 sampen has two input parameters a run length m and a tolerance window r sampen is the negative natural logarithm of the conditional probability that two sequences similar for m points remain similar at the next point | [15886445 12185014 15366100 19130227 10843903] | additionally the algorithm used to compute the sampen is simpler than the apen one despite its advantages over apen, the use of sampen is not widespread. | [10843903] |
492 | glycogen synthase kinase3 is increasingly thought to play a pivotal role in the pathogenesis of alzheimers disease both as a regulator of the accumulation of aβ peptide and through its wellestablished role as a tau kinase | [12761548 17314294 15170327 1336152 11226152] | p<0.01, and p<0.0001 when comparing uas-arcaβ42/uas-gfp;elavgs/+ to uas-arcaβ42/+;elavgs/uas-sggs9e flies on +ru486 sy medium, and uas-arcaβ42/uas-gfp;elavgs/+ +ru to uas-arcaβ42/uas-gfp;elavgs/+ +ru +li respectively. (b) rna levels of uas-arcaβ42/uas-gfp;elavgs/+, uas-arcaβ42/+;elavgs/uas-sggs9e +ru486 sy medium and uas-arcaβ42/uas-gfp;elavgs/+ +ru + lithium flies were measured at day 5. no significant difference was seen in the levels of rna expression, number of independent tests (n) = 3. | [] |
493 | therefore the findings of our study in the iranian population is supported by certain studies in the world and is in contrast with the results of other studies carried out in this subject in other parts of the world | [18585350 20061624 20164592 19655363 20164602] | in another study carried out in spain the difference between this polymorphism with ad was significant in study carried out in the usa 2009 with sample size including 510 cases and 524 controls no significant difference was shown | [20164592] |
494 | however these traditional roles of cox isoform expression are not observed in the brain as cox2 mrna and protein are detectable in neurons in absence of inflammatory stimulus 131415 and cox1 has been reported to contribute to elevations of pge2 in experimental models of neuroinflammation | [ 7608344 8637870 8352945 19825412 15850932] | when considering genetic sequences cox2 has a unique promoter region that allows upregulation of expression by growth factors tumor promoters hormones bacterial endotoxin cytokines anoxia neurotoxins electrical stimulation and proinflammatory stimuli therefore, it has been accepted that cox-1 is constitutively expressed whereas cox-2 is expressed as part of the inflammatory response in most tissues. | [10933512] |
495 | in particular aspirin acetylsalicylic acid or its metabolite salicylic acid has been extensively investigated and has repeatedly conferred protection from the neuronal damage induced by mptp and 6ohda via reduction of ros | [ 9751197 16712818 16318861 12618347 11180504] | animal models generally support the notion that nsaids protect against the dopaminergic neural degeneration that is induced by certain neurotoxins for review see however, the nsaid-associated neuroprotection appears to be dependent on duration, dose, and onset relative to neurotoxin exposure, as well as the specific nsaid utilized. | [17433296] |
496 | some authors revealed changes in the commissural tracts as well | [16614789 16520023 12023417 19043518 18180656] | so far, the vast majority of dti examinations carried out in patients with ad, demonstrated the presence of microstructural changes in white matter, manifested by the decrease in fa value, with inhomogeneous damage of the white matter and of the cerebral cortex. most changes were found in the selected association tracts | [18180656] |
497 | the study group was a relatively small sample 35 patients with ad and 15 controls but the vast majority of dti studies in ad was also carried out within similar or smaller groups of patients | [16614789 16520023 12023417 17905894 18180656] | predilection of changes for the association tracts and preservation of pyramidal tracts and medial cerebellar peduncles, as determined in our study, corresponds to the distribution of cerebral gray matter damage. it possibly proves that the white matter tract damage and wallerian-type degeneration of axons are secondary to neuronal damage in association areas of the cerebral cortex and the limbic system. | [] |
498 | the dynaminlike gtpase drp1 influences mitochondrial density in axons and dendrites and reductions in drp1 levels or increases in drp1 activity by snitrosylation are induced by aβ and detected in ad brains | [16055061 15607982 19605646 19050078 19342591] | the motility of mitochondria is thought to be interrelated with the fissionfusion machinery and an imbalance between mitochondrial fission and fusion induced by aβ42 may result in reduced mitochondria in the axons and dendrites in ad mitochondrial size is increased and mitochondrial numbers are decreased in neurons suggesting that the normally strict regulation of mitochondrial morphology is impaired | [16055061 15607982 19605646 11312286] |
499 | the homozygous arte10 is among those lines displaying a relatively early plaque onset and a high maximal plaque burden | [16906128 11279122 14645205 15261108 17029828] | an in vivo pet study of aβ in arte10 mice using [11c]-labeled pib is reported separately (manook et al, submitted). the onset development and maximal amount of amyloid plaque deposition vary considerably between established mouse lines co expressing app and presenilin mutants | [16567017] |
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