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200 | asc specks in microglia are hallmarks of inflammasome activation and seed new aβ plaque formation | [23254930 29293211 25629724 27091843 27196974] | microglial function in ad is complex having both detrimental 8081 and neuroprotective activities in early ad, microglia in aβ models work to clear amyloid plaques but also release pro-inflammatory cytokines and produce apoptosis-associated speck-like protein containing a card (asc specks). | [23254930 29293211 25213090 25629724 27091843 27196974] |
201 | alzheimer disease pathology is associated with morphologic molecular and functional remodeling of astrocytes a process termed reactive astrogliosis however few astrocyte imaging and fluid biomarkers have been investigated blood levels of glial fibrillary acidic protein gfap a reactive astrogliosis biomarker are higher in individuals with preclinical ad constituting a promising candidate biomarker for this early stage of the disease a recent metaanalysis demonstrated that gfap levels were consistently altered in the cerebrospinal fluid csf of symptomatic patients with ad but studies of blood gfap present relatively high variability | [33589835 20880504 30611668 33431793 33952650] | differences between plasma and cerebrospinal fluid glial fibrillary acidic protein levels across the alzheimer disease continuum currently the most promising blood biomarkers for detecting ad are the phosphorylated tau species ptau and amyloidβ 4240 aβ4240 ratio however it is still desirable to have more sensitive blood biomarkers for preclinical ad | [] |
202 | for instance a few studies found csf ptau was associated with wmh 38 global mean diffusivity in white matter 57 and hypertension 40 two pet studies found pet measures of brain tau were related to vascular health variables | [29572277 30239611 24225352 29023983 29799981] | for example a few studies based on the adni cohort reported significant associations of csf ptau or plasma ptau with wmh 25 37 56 and hypertension in addition, some non-adni studies reported similar findings although without specifically examining relationships in aβ- individuals. | [29387348 26747881 25822631] |
203 | in most studies participants were persons without any cognitive decline or dementia diagnosis at baseline except one of them that included individuals with subjective memory impairment 33 three of them 101116 that included mci persons and three studies that included ad patients at the beginning of the study | [27421618 30698630 30390881 23032941 30390881 23032941 19671904] | mean age of the participants in most studies was over 60 years old except five of them in which younger participants were included according to nationality fourteen studies 1378101317202733353638 included american participants four studies 9153132 included australian participants one study 34 shows results of swedish individuals one study 11 is based on brazilian results other one the participants were german 30 and only one study was performed in france | [29574441 29653991 19671904 25599008 29574441 29653991 29889074 30698630
19204158 19671904 25237654 25681666 27421618 25599008 20847399 16622828
17030648 34153553 29616707 25062901 30390881 33952652 19671905] |
204 | ferulic acid has also been involved in enhancing the cell stress response by regulating heme oxygenasehsp70 95 heme oxygenasebiliverdin reductase hobvr system 9697 superoxide dismutase sod catalase 98 erk ½ and akt 99 and inhibiting caspases | [16634068 16386335 26340979 16038626 17007737] | most importantly it directly alters the kinetics of aβ fibril formation and can directly inhibit plaque formation in vitro however the oral administration of ferulic acid was unable to display any significant effect on aβ oligomers or aβ deposition in vivo which could be due to poor absorption or difficulty in crossing bbb in the body | [16153607 20406252] |
205 | among patients with pd decreased olfactory performance was reported to be associated with lower gray matter volumes in the piriform and orbitofrontal cortices amygdala left putamen right caudate and right thalamus | [24482154 21846992 20007465 28522171 21330398] | patients with impaired olfaction due to nonneurodegenerative causes had decreased gray matter volume in the piriform cortex orbitofrontal cortex nucleus accumbens medial and dorsolateral prefrontal cortex anterior and middle cingulate cortices insular cortex hippocampus parahippocampal gyrus and cerebellum among patients with ad diminished olfactory performance was shown to be associated with atrophy of the primary olfactory cortex parahippocampal and entorhinal cortices left precentral and inferior frontal gyri overall medial temporal lobe and reduced left hippocampal volume | [20231262 25240014 25633674 25934852 12666770 29936148 31474819 31242486] |
206 | second findings in ad patients were mostly in line with previous reports about which regions are involved in olfactory information processing | [31339489 28443000 29301613 28195241 12666770] | the slightly but not statistically significantly worse odor identification performance among patients with ad is also in line with previous findings that higherorder olfactory function impairment is present in both ad and pd but is relatively more pronounced in ad we also found age-related odor identification performance decline among patients with ad, which may indicate both the direct effect of aging, and the effect of more advanced ad pathology in older patients. | [20437286 22414849 29988355] |
207 | a classic ad subgroup was identified by multiple approaches typified by initial atrophy in hippocampus and amygdala followed by mtl atrophy and primarily memory deficits and underlain by apoe ε4 | [30323170 31344486 30514930 30830917 30278855] | all subtypes had an excess of genetic risk for ad and did not differ in disease severity or presence of co‐pathologies. converging evidence from multiple angles—neuropsychological, imaging, blood biomarkers, genetics, and proteomics—points to substantial heterogeneity underlying disease progression. | [] |
208 | the long association fibres for motor control especially in the inferior frontooccipital fasciculus pass through the periventricular white matter and this tract is more susceptible to wmh burden than other fibre tracts wmh are highly variable disease processes with growth and shrinkage especially in ad subjects with a considerable amount of wmh a recent study indicated that controlling blood pressure was associated with a reduction in wmh and preserving white matter integrity in subjects with minor stroke additionally poor glucose management in diabetic patients with ad has been shown to be associated with frontal wmh therefore management of vascular risk factors potentially leads to better brain tissue outcomes and could lead to the maintenance of gait function | [14645885 27432800 27047377 28794252 30258360] | the subcortical occipital region has longitudinal fibres that link frontoorbital areas motor areas and visual conceptualization and deficits in this tract could affect visuospatial processing in gait our study evaluated gait function under conditions that did not require visuospatial processing therefore, gait parameters may be predominantly associated with pvh in the anterior region rather than posterior lesions. | [14645885 21872363 27721745] |
209 | dextromethorphan is a sigma1 receptor agonist which has some moodmodulating properties it is also a low affinity nmda antagonist a serotonin and norepinephrine reuptake inhibitor a histamine h1 receptor agonist and a neuronal nicotinic alpha3 beta4 receptor antagonist quinidine and deuteration appear to prolong dextromethorphans plasma halflife reduce first pass metabolism and facilitate brain penetration deuterated d6dextromethorphanquinidine avp786 is currently being evaluated as a treatment for agitation in people with ad two phase iii trials evaluating efficacy safety and tolerability have been completed nct02442765 february 2020 and nct02442778 august 2020 | [ 8901003 32848775 32052375 27936965 33615952] | some associated cognitive decline and cardiac side effects qtc prolongation however hamper its longterm use results suggest that citalopram needs to be given at least nine weeks to allow enough time for a full response the evidence for its use for this indication nevertheless remains compelling and potentially could be a class effect for all ssris some additional novel and/or repositioned agents are being studied as treatments for agitation in dementia.99 four will be discussed here. | [21328305 31288974] |
210 | moreover mounting evidence from preclinical and clinical studies suggests that oxidative stress is linked with etiopathology of ad 6263 which includes mitochondrial dysfunction 64 increased aβmediated neurotoxicity 65 and synaptic dysfunction and neuronal apoptosis | [14500988 21376020 19245786 10880853 10491580] | oxidant-level-related dysfunctions have been reported in ad patients, which could be attributed to either hyperproduction of oxidants or deficit in antioxidants. Higher levels of MDA are one of the known pointers of oxidative damage in the brains of rats, and MDA levels were quantified in the rat brains as indicated in Figure 6. | [] |
211 | the largest
abc
gene subfamily is abca which consists of a lot of amino acids
abca full transporter is divided into two groups abca1 like abca1471213 and abca5 like abca56810
abca1 and abca2 proteins which play a role in apolipoproteindependent cholesterol efflux sterol homeostasis lipid transport and metabolism share 50 sequence homology | [12456012 19403462 11441126 17266523 18996096] | abc transporters similarly function as a second selective permeability barrier in neurons and glial cells. because of all of these properties of abc transporters they have essential detoxification and neuroprotective roles in the brain
changes in abc carrier expressions or functions lead to β clearance disturbances causing adassociated cerebral amyloid angiopathy caa | [26187753 12415123 15717060 19319544 19061857] |
212 | growing evidence suggests that hbot can induce the neuroplasticity and improve the cognitive function in patients suffering from neurocognitive impairment due to stroke and brain injuries4546 moreover hbot cannot only improve cognitive functions and ameliorate the brain glucose metabolism in ad and amnestic mci amci patients447 but also induce significant senolytic effects including significantly increasing telomere length and clearance of senescent cells in the aging individuals | [25384125 25206655 32548235 30713673 33206062] | given that hypoxia contributes to the pathogenesis of ad, the development of prevention and treatment targeting hypoxia is promising. hbot is a safe, effective, and routinely used medical procedure. | [] |
213 | this hyperphosphorylation of tau is especially caused by the increased activity of kinases namely glycogen synthase kinase3 gsk3 cdk5 and the mapmicrotubule affinityregulating kinase mark which are activated by aβ oligomers | [29561798 28386764 26149638 28464981 21456963] | however under pathological conditions the accumulation of hyperphosphorylated tau in neurons leads to protein misfold and aggregation in intracellular nfts reducing their affinity for microtubules the loss of normal tau protein function leads to a pathological disturbance in the structural and regulatory functions of the cytoskeleton of neuronal cells causing alterations in the morphology neuronal plasticity axonal transport and provoking synaptic dysfunction and neurodegeneration | [30657599 30531004 30980111 31022830 26149638] |
214 | aripiprazole is approved for use in patients with various psychotic disorders including schizophrenia bipolar disorder depression and autism 121314 and it has been reported that some clinical studies showed beneficial effect of aripiprazole for adrelated psychosis such as aggressiveness or anxiousness | [19505266 22447196 21254788 18591574 24389877] | however amyloid remains the most compelling therapeutic target 8 and efforts to find novel therapeutics for ad using new technologies including in silico drug repurposing 9 or fdaapproved drugs are ongoing aripiprazole is a secondgeneration atypical antipsychotic with high affinity for d2 d3 2ht1a and 5ht2a receptors and moderate affinity for d4 5ht2c 5ht7 alpha 1 adrenergic and h1 receptors | [32939050 31116390 20361061] |
215 | 3nitrotyrosine is a product of oxidative damage on proteins generated when a superoxide radical reacts with nitric oxide no to form peroxynitrite which cause nitration of proteins on tyrosine residues 3nitrotyrosine and protein carbonyls these last produced mainly by the action of free radicals on the peptide chain or by oxidation of amino acids are used as biomarkers of oxidative damage in the brain of ad and mci | [30737462 27626216 20084018 27143416 23044265] | it has been hypothesized that tissue injury aging ischemia increased metal levels or energy metabolism deficit can induce ros generation independently from aβ deposition even if ros generation is secondary to other initiating causes it plays an important role in the events that lead to neuron death in ad | [9165306 9165306] |
216 | lastly reactive astrocytes also express chitinase3like protein 1 chi3l1 also known as ykl40 61 62 63 64 and the 18 kda translocator protein tspo although their function remains to be fully elucidated these two proteins are commonly interpreted as evidence of inflammation when measured in csf and detected via pet imaging respectively | [21035623 28599675 29126445 32066474 19077109] | multiple studies report increased immunoreactivity for a wide variety of inflammatory cytokines including the inflammasomeactivating enzyme caspase1 casp1 37 interleukins such as interleukin1 beta il1b 37 38 interleukin6 il6 37 39 40 interleukin18 il18 41 interleukin33 il33 42 and its receptor interleukin1 receptorlike 1 il1rl1 42 as well as tumour necrosis factor tnf 43 chemokines such as cc motif chemokine ligand 2 ccl2 40 cc motif chemokine ligand 4 ccl4 44 cxc motif chemokine ligand 10 cxcl10 45 and stromal cellderived factor 1 cxcl12 46 cell adhesion molecules such as intercellular adhesion molecule 1 icam1 47 eicosanoid metabolism enzymes such as prostaglandin gh synthase 2 ptgs2 also known as cyclooxygenase2 48 cytosolic phospholipase a2 pla2g4a 49 and haematopoietic prostaglandin d synthase hpgds 50 while the microsomal prostaglandin e synthase ptges was reported to be decreased in adra 51 and the immunomodulatory receptor sphingosine 1phosphate receptor 3 s1pr3 52 but not sphingosine 1phosphate receptor 1 s1pr1 in addition some studies have shown increased immunoreactivity for transcription factors known to mediate immune and inflammatory responses such as nuclear factor of activated tcells cytoplasmic 2 nfatc2 54 nuclear factor of activated tcells cytoplasmic 4 nfatc4 54 transcription factor p65 rela also known as nuclear factor nfkappab p65 subunit 55 56 adipocyte enhancerbinding protein 1 aebp1 57 ccaatenhancerbinding protein delta cebpd 58 and glia maturation factor eg gmfb | [27090093 27090093 2529544 27090093 9449432 17658666 24413615 24413615
9665462 10900358 12834106 8337942 11754989 9173912 17549007 27662305
23551178 8905182 23616440 15212823 22035352 23640177] |
217 | to overcome this limitation isobaric peptide labeling methods such as itraq 121 tmt 122 and dileu 123 have been developed to generate isobaric ms1 peaks and enable multiplexed tagging eg 11plex 16plex 18plex and 27plex tmt | [17177251 12713048 25405479 32203386 33900084] | the stable isotope labeling methods have begun with chemical protein labeling such as cysreactive icat 117 aminereactive dimethyl labeling 118 and then metabolic protein labeling like silac in which peptideprotein quantification is attained by ms1 peaks from the pooled samples with differential labels however, the pooling increases the complexity of ms1 spectra, reducing the efficiency of peptide identification. | [10504701 14670044 12415544 17139335] |
218 | one approach
has been immunotherapy with antiamyloid antibodies despite promising preclinical
studies demonstrating central nervous system cns aβ clearance and improvement in
cognitive deficits in transgenic mice several antiamyloid immunotherapies have
failed in clinical trials
possible reasons for this lack of clinical translation include their low bloodbrain
barrier bbb penetrance failure to target the appropriate aβ species or safety
concerns such as amyloidrelated imaging abnormalities aria to address these concerns at
the preclinical level we have recently developed a biomarker platform that allows
longitudinal assessments of the effects of an antiamyloid therapy on imaging and
cerebrospinal fluid csf biomarkers using the app transgenic rat model | [24450890 24450891 27582220 24450890 24450891 26938442 27025652] | preclinical in vivo longitudinal assessment of
kg207-m as a disease-modifying alzheimer’s disease therapeutic amyloidβ aβ aggregates remain an attractive therapeutic target for alzheimers
disease ad based on a multitude of genetic and cellular evidence supporting the
central role of aβ in ad pathophysiology consequently there have been
great efforts to develop therapeutics that target aβ and its clearance | [] |
219 | this separation of local and network mechanisms has been shown to be informative in previous applications to epilepsy | [25393751 27384316 28817568 31632339 27501083] | future work should involve integration of multi-modal neuroimaging data, including functional data (eeg/meg/fmri), structural mri, and pet, to quantify the relationship between spatial patterns of ni and alzheimer’s pathologies, cortical atrophy, vascular dysregulation, metabolic alterations, inflammation, etc. on an individual level. a limitation of the modelling methodology is the use of a static functional network which is independent of cortical excitability. | [] |
220 | prior studies have shown that the concentration of a single protein such as aβ and a tau protein is increased in the csf or blood in ad | [20413866 32310175 33609478 29420472 30857558] | although these methods have been used to predict pathology before clinical symptoms have developed, their invasiveness and cost have limited their use to well funded research settings in academic centers. using our novel assay, we identified ttr, aβ, tau231 and α-syn as constituents of the aggregates seen in adts exposed to sera from patients with ad and mci. | [] |
221 | a high blood cholesterol level is a wellknown risk factor for ad moreover polymorphism in the apolipoprotein e gene apoe is a major risk factor for ad development animal studies have shown that high blood cholesterol disrupts autophagymediated amyloid β clearance cholesterol binds to amyloid β peptides and aids the formation of neurotoxic oligomers statins lower cholesterol levels by inhibiting hmgcoa reductase and improve neurovascular dysfunction by modulating oxidative stress nitrosative stress and inflammation therefore the major benefits of statins in ad might be attributed to these 2 mechanisms | [19715550 31367008 29862881 25000142 24231510] | most degs were downregulated in the statin-treated group. gsea, gene set enrichment analysis; kegg, kyoto encyclopedia of genes and genomes; ad, alzheimer's disease; nes, normalized enrichment score. | [] |
222 | other studies have shown that rta408 increases nrf2 and decreases nfκb | [33017422 28851867 29435098 29925185 31487581] | propofol decreases consciousness and memory and is used as a general anesthesia. rta408 protected against propofolinduced memory impairment assessed with the mwm and increased activation of nrf2 and the inhibition of nfκb p65 nuclear translocation | [33295701] |
223 | this notion has been confirmed by computational studies in which up and down states can be reproduced by models of neural populations with recurrent excitation and slow adaptation eg activitydependent k current or synaptic depression a | [30602773 15537811 19499317 12351744 12612051] | earlier studies showed that slow oscillations can be generated in isolated cortical gyrus a cortical slab and cortical slice suggesting that cortical circuits are sufficient for the generation of slow oscillations subsequent studies have consistently demonstrated that recurrent excitation of layer l 5 pyramidal cells is a source of slow oscillations | [ 8985908 11073868 11017176 19914188 20200108 11017176 23313909] |
224 | to achieve this we performed timetoevent analyses controlling for lifestylerelated markers of obesity diabetes hypertension and inflammation as lifestyle factors affect both dementia progression 33 35 36 and tl dynamics | [32992046 32996171 32979926 18391173 26785477] | this suggests that ltl may predict ad and cognitive decline differently among carriers and non-carriers of apoe ε4. the present study aims to investigate whether baseline ltl alone or in interaction with apoe ε4 predicts the onset of ad in a wellcharacterized populationbased sample of older individuals followed for 25 years | [32992046] |
225 | regular exercise is associated with a delay in onset of ad and our groups recent crosssectional research has demonstrated crf is positively associated with several indices of brain and cognitive health although exercise and crf appear to be beneficial randomized controlled trials have not provided strong evidence that structured exercise can substantially impact the pathophysiological processes of aging and ad eg neurodegeneration an intrinsic limitation to exercise trials is the relatively short durations the typical 6 to 12month intervention may be insufficient to significantly impact the slow progressive pathophysiology of the disease but see also erickson et al | [16418406 28293467 30852709 29113943 21282661] | however, we did not observe significant three‐way interactions; therefore, the genetic specificity of our findings are uncertain. the impact of exercise on brain and cognitive health has received considerable attention in recent years. | [] |
226 | the apolipoprotein e apoe omim 107741 ε4 allele is the most established genetic risk factor for sporadic ad and has been consistently associated with earlier ad symptoms and pathology in the general population | [ 8346443 8446617 20186853 8592548 29672664] | recent estimates indicate a lifetime dementia risk of more than 90 and identify alzheimer dementia as the leading cause of death in this population this elevated risk has led to the conceptualization of ds as a genetically determined form of ad that is similar to autosomal dominant forms this idea is further supported by a recent study that showed that the pattern of ad biomarker changes follows a similar temporal profile in ds as in autosomal dominant forms with a long preclinical phase and pathophysiological processes that are qualitatively comparable to sporadic ad | [30452522 32593336] |
227 | it has been previously described in some studies of diadmc but many studies have relied on surfacebased methods that exclude the cerebellum from analysis | [24049139 20858974 23137948 29397305 24194552] | while cerebellar gm volume in diadmc with dementia was reliably lower than that of asymptomatic diadmc regions typical of sporadic ad were on average more atrophic and together contributed more to the risk score table cerebellar atrophy is generally understudied in ad and diad. | [] |
228 | skeletal muscle undergoes prominent remodeling during aging and exercise powerfully opposes these local deleterious effects activating metabolic and proteostasis pathways to accommodate increased bioenergetic demands | [31642809 12783983 27304505 28011087 31980607] | skeletal muscle has been proposed as a central regulator of organismal metabolism communicating metabolic and proteostasis stress to distant tissues including brain via secretion of circulating myokines in agreement with this multiple epidemiological studies suggest that skeletal muscle aging is a risk factor for the development of ageassociated disease including those of the cns | [26527185 24797482 26527185 27304505 30700801 24742458] |
229 | many accelerated ageing diseases such as xp at cs and ws and neurodegenerative diseases such as ad are closely related to the mutation of ddr proteins and dna damage in both the nucleus and mitochondria | [27732836 27181190 30666569 27686631 25552414] | the accumulation of mtdna damage and the reduction of mitophagy are also hallmarks of premature ageing diseases such as xp and at although organisms have a large number of responses to dna damage not only will dna lesions increase during ageing but the efficiency of ddr will also decrease | [31923475 22144182 24813611 26956196 25456739 29141944 31364066] |
230 | furthermore patients with cushing syndrome an endocrine disorder of hypercortisolism present with wholebody insulin resistance 2324 and are more prone to develop a dementialike phenotype | [20829623 10700481 27515536 27986873 18801622] | additional studies in ad patients have demonstrated an association between insulin levels and cerebral amyloid deposition and importantly hyperinsulinemia doubles the risk of developing ad moreover chronic glucocorticoid exposure is well known to result in wholebody insulin resistance | [15477536 25043908 27861636 27614803] |
231 | in recent studies where hcd or beam type cid were used with a ramp of ms fragmentation energies energyresolved hcd stepped collision energy scehcd informationrich fragments from both the glycan and peptide moiety resulted in peptide identification and glycan sequence as well | [25582509 26729457 26481991 24440233 28874712] | however, cid preferentially cleaves glycopeptides at the glycosidic bonds, which facilitates glycan characterization but leaves the peptide intact yielding only a blind mass. hcd and beam type cid (q-tof) ms/ms have in previous studies demonstrated peptide identification and partial glycan information but less information about glycosylation site. | [] |
232 | reactivation of hsv seems to have a stronger correlation to ad than hsv1 carriage alone furthermore populationbased cohort studies indicate that the genetic background and allele 4 of the apolipoprotein e gene apoe ε4 in particular interact with hsv1 infections to increase the risk of ad
apoe ε4 carriers have an increased risk of cold sores and animal studies have indicated that spread of hsv1 in a host is facilitated by the presence this allele independently of apoe ε4 hsv1 carriage also seems to interact with other genes for ad development and a genetic variant affecting the development of efficient immunity toward hsv1 gm1717 was recently shown to almost double the risk of later ad development together these studies indicate that not so much hsv1 carriage alone but hsv1 together with certain genetic susceptibility factors increases the risk of ad which might explain the relatively modest penetrance of hsv1 carriership itself | [18982063 9014911 14534428 16699018 32709662] | alzheimers disease ad is a common cause of a major neurocognitive disorder that affects millions of people worldwide a growing body of evidence suggests that herpes simplex virus type 1 hsv1 might play a considerable role in the development of ad hsv1 is common worldwide and its prevalence is estimated at 80 in the swedish population longitudinal cohort studies have shown that reactivation of hsv, measured as immunoglobulin (ig) m‐positivity for hsv, increases the risk of developing ad approximately 8 to 10 years after hsv reactivation. | [28491117 26510007] |
233 | positron emission tomography pet studies have demonstrated that the ad patients with apathy had glucose hypometabolism in the acc ofc ventral striatum and medial thalamus 53 54 higher neurofibrillary tangles burden in the acc 55 56 and higher amyloidβ aβ deposition in the bilateral frontal lobe and right acc | [17620493 15705358 16391476 11261510 24133289] | gray matter studies on apathy showed that gray matter atrophy in the bilateral acc and left medial frontal cortex moreover decreased gray matter density in the bilateral acc frontal cortex head of the left caudate nucleus and bilateral putamen 46 and decreased cortical thickness in the left caudal acc left orbitofrontal cortex ofc left superior and ventrolateral frontal region 48 and inferior temporal region were all correlated with the severity of apathy | [17570907 18669506 20872914 23890751] |
234 | more importantly one single csf analysis with fully automated assays can allow simultaneous investigation of all of the atn biomarkers table thus dramatically accelerating diagnostic prognostic and therapeutic decisionmaking | [32573951 30902090 29499171 31914216 31759396] | however, at the current stage, blood‐based biomarkers are still under development, and both analytical validation and standardization efforts as well as much more research is needed to establish their utility in clinical trials and clinical practice. comparing the two more established modalities while pet offers unique insights into the spatial and temporal evolution of ad pathophysiology csf analysis is more costeffective is less resourceintense provides evidence on several pathophysiological processes and is more accessible globally compared to pet brain imaging the number of pet scanners and cyclotrons is limited and existing scanners likely have limited timeslots to accommodate additional patients who need aβ andor tau pet assessments | [31205802] |
235 | downregulated mrnas include those encoding complement
factorh cfh of the innateimmune system 8399 an sh3prolinerich
multidomainscaffolding protein of the postsynaptic density shank3 98 and the triggering receptor expressed in
myeloidmicroglial cells trem2 surface glycoprotein immune receptor | [31588707 22509485 31354434 27378912 32531244] | over the last five years lps andor bflps have been shown i to associate
with the periphery of neuronal nuclei in sporadic alzheimers disease ad
brain 38394 ii to promote the
generation of reactive oxygen species ros the inflammatory transcription factor
nfkb p50p65 complex in human neuronalglial cells in primaryculture 7125783 iii to efficiently enter neurons with the
assistance of aβ42 peptides perhaps as a consequence of aβ42
peptides poreforming capabilities 9596 and iv
to strongly induce the upregulation of the proinflammatory transcription factor
nfkb p50p65 complex and transcription of a selective family of proinflammatory
nfkbsensitive micrornas mirnas that include mirna9 mirna34a mirna125b
mirna146a and mirna155 these mirnas in turn
ultimately bind to the 3’-untranslated region (3’-utr) of multiple
target messenger rnas (mrnas) in brain cells and thereby reduce their expression
post-transcriptionally. | [31588707 27784770 32670176 27725817 31588707 31866832 32792144 27725817
31588707 30568571 31354434] |
236 | to better understand the funding landscape for ad clinical trials we interrogated our database of information from clinicaltrialsgov and our annual reviews published over the past 5 years to determine what agencies and companies were involved in funding current ad clinical trials | [32695874 29067309 29067343 29955663 31334330] | ad drug development represents an urgent unmet need there has been no new drug approval in the united states since 2003 and only one agent has been approved globally in that period an important disincentive to engage in ad drug development is the high cost of development programs a 2014 analysis showed that the outofpocket cost of ad drug development including phases 1 2 and 3 is 413 million when the cost of failures and the cost of capitalization of the funds are included the total cost is 57 billion per drug there are many organizations that support ad drug development including the national institutes of health nih clinical trials funded by philanthropies such as the alzheimers drug discovery foundation addf support for trials from the alzheimers association eg part the cloud initiative and biotechnology and pharmacology companies increasingly trials include publicprivate partnerships ppps involving the nih and biopharmaceutical companies to allow more trials to be conducted while distributing the cost and risk | [25024750 32695874 24673372 24673372 30175227 28899416] |
237 | anticancer drugs for which a publication was available were bexarotene 52 54 masitinib 51 nilotinib 53 and thalidomide | [26822146 29067298 21504563 32468646 28124585] | four phase ii and one phase i studies were identified. for one study, results were also posted on clinicaltrials.gov as mentioned in the previous section. | [] |
238 | the most popular hypothesis to explain the origin of ad proposes that deposition of aβ in senile plaques leads to inflammation and neuron death however attempts to decrease the aβ load or to prevent its formation have had no effect on ad no cure whatsoever exists or seems to be on the horizon these facts together question the validity of this mainstream hypothesis therefore new and bold avenues of research need to be pursued to unravel new pathomechanisms leading to successful prevention andor treatment of ad however integrating the unavoidable aβ cascade hypothesis | [24052108 29562511 31564456 30087609 31297054] | because of the abovementioned relationships, inflammaging is one of the most important links between aging and the age-related neurodegenerative diseases. therefore in this context the production of aβ represents most probably the consequence of the neuroinflammatory process induced by several chronic situations including chronic infection as suggested by the amp nature of aβ | [25376108] |
239 | positive associations were observed between percentage residential green space derived from land use data and spatial working memory and between distance to the nearest natural outdoor environment and visual attentionexecutive processing greater amounts of forest surrounding the residence were associated with greater amygdala integrity whereas amount of neighbourhood urban green space was not associated with mri measures of brain integrity percentage green space and private gardens based on land use data was inversely associated with odds of cognitive impairmentdementia tree canopycover vcf was not associated with attention in children lastly selfreported amount of residential natural environment was not associated with visual attentionexecutive processing | [30187470 28254708 28931835 28082001 28934095 28254708] | the third study found no associations between neighbourhood park area and cognition other measures measures of time spent in green space based on objective gps tracking or selfreport were not associated with cognition | [21515547 27179137 28254708] |
240 | this inclusion criterion may explain why our results show a greater or risk from depression to ad than previous metaanalyses | [32469813 31173329 23637108 22815126 26692556] | furthermore our study includes recent references and it did not analyze data from studies of patient groups with mixed psychiatric histories or all types of dementia even though the metaanalysis of kuring et al analyzed 36 independent studies for all types of dementia they only pooled k 8 studies for ad or 223 | [32469813 32469813] |
241 | damlike cells or mgnd phenotypes have been characterized in the aβproducing 5xfad and apppsδe9 ad mouse models 51171172 the tauproducing p301s ad mouse model 173 mouse models of amyotrophic lateral sclerosis 51174 and mouse models for multiple sclerosis | [28602351 31061494 32008854 28602351 28930663 23850290 28930663] | the majority of these genes are associated with the production of proteins involved in lipid metabolism phagocytosis clearance of apoptotic cell bodies and the immune response interestingly, the mgnd phenotype is consistent across various neurodegenerative mouse models. | [30206328 29775591] |
242 | although one of the strongest risk factors for alzheimers disease both eoad and load is being a carrier of the e4 allele of the apoe gene recent genomewide association studies gwas have shown that variants in more than 50 loci are implicated in load defining load as a polygenic trait genes within alzheimers disease risk loci are enriched in multiple diverse biological pathways such as the immune response cholesterol metabolism amyloid protein processing and app metabolism however the mechanisms involved in the misregulation of gene expression that leads to alzheimers disease have not been elucidated | [ 8346443 32112059 26490334 32112059 21085570 30820047] | alzheimer’s disease can occur sporadically in the population or may be inherited. earlyonset alzheimers disease eoad that accounts for 5 of alzheimers disease cases can be caused by autosomal dominant mutations that may be inherited or occur de novo in the app presenilin 1 psen1 or presenilin 2 psen2 genes however most cases of alzheimers disease are late onset load and occur after the age of 65 years | [1671712 7596406 8817335] |
243 | other studies show that sleep fragmentation with increased n1 and the corresponding decrease in sws appear to be widely associated with sleepiness in osa patients | [ 3383654 15222989 9731004 10351907 11399708] | the results of a study evaluating the relationship between eds and aβ accumulation showed that informantreported apnea witnessed apnea was the only sleeprelated symptom that differed between participants with and without eds it suggests that there is a higher prevalence of osa in individuals with eds. | [29532057] |
244 | indeed there have been clinical trials targeting general cytokine milieus using sargramostim 20 a small molecule rage inhibitor 21 nsaids 22 23 and etanercept 24 in patients with ad or mild cognitive impairment | [28421558 22406537 9065537 27716676 30265513] | therefore, the duration of cytokine-induced microglial response (i.e., transient vs. chronic) is the distinguishing feature of the functional roles of microglia in ad pathogenesis. given the role of chronic neuroinflammation in ad pathogenesis, targeting cytokine milieus to modulate microglial functions is an attractive therapeutic approach for ad. | [] |
245 | it was well known that females showed more intense nps than males | [24887405 28216088 15939839 19581570 11378178] | nps such as anxiety and depression is typical features of ad effect of music therapy on anxiety and depression moderated ad
phenotypes | [30935215 26049034 21889116 19628939] |
246 | the insights from mechanistic studies of biphasic doseresponse can help to achieve reproducible results and sustained progress in future drugdevelopment efforts | [23308095 16548522 16595682 18024430 17556361] | biphasic drugs and fad mutations favor an increase in the production of the longer more hydrophobic aβ catalytic intermediates Presented results indicate that the increase can be attributed to the selective interference with the dynamic conformational changes at the cytosolic end of TM6, TM6a, and TM7 (Figure 7, Figures S1, S4 and S5). | [28978478 18574238 23308095 16548522 22323718 22479317 22505025 18024430] |
247 | inhibition of amyloidogenic or tau fragments aggregation was targeted by dopaminebased hybrid molecules 149 by the reactive catecholaldehyde intermediate of dopamine metabolism dopal 150 multifunctional dopamine d2d3 receptor agonists 151 dopamine appended derivatives of naphthalenediimide ndi 152 and by other rationally designed structural derivatives based on dopamines oxidative transformation | [33523571 33398040 32828429 30285025 29782798] | in ad transgenic mice models eeg modifications in but not restricted to 5xfad mice were associated with alterations in dopaminergic transmission 147 and reduced dopaminergic innervation in the tg2576 hippocampus resulted in reduced synaptic plasticity and excitability of dorsal subiculum pyramidal neurons the lack of causality between brainstem dopamine system failure and ad did not hinder pharmacologists to investigate the possibility of molecular dopamine therapy in ad, with efforts accelerating in the past five years. | [31177214 29778899] |
248 | mutations in human c2cd3 cause skeletal dysplasia caused by defective assembly of the primary cilium a microtubulebased cellular organelle involved in developmental signaling
kif2a encodes the kinesin family member 2a which is required for normal mitotic spindle activity and normal brain development most likely via its atp dependent mtdepolymerase activity like c2cd3 kif2a has also been implicated to affect ciliogenesis relating to its role in the cell cycle kif2arelated cortical development defects have been attributed to decoupling between ciliogenesis and cell cycle a kif2a his321asp missense mutation was identified in a subject with defective cortical development owing to impairment of kif2a microtubule depolymerase activity several members of the kinesin family are overexpressed in the brains of ad patients and kif2a expression is specifically upregulated in axons spinal neurons and oligodendrocytes adjacent to spinal cord injuries finally apc encodes the adenomatosis polyposis coli regulator of wnt signaling pathway as a negative regulator and serves as a major tumor suppressor | [27094867 29077851 29077851 31919497 29060936 31041455] | all three adlinked prkca mutations displayed increased catalytic activity by live imaging versus wildtype prkca and potentiated the ability of aβ to suppress synaptic activity in hippocampal slices it will be interesting to determine whether mutations in prkch have similar aberrant effects on receptor activity the three other genes implicated in the spatial clustering–based analyses included c2cd3, which encodes the c2 domain containing 3 centriole elongation regulator that is expressed at relatively high levels in the brain. | [27165780] |
249 | our findings are in agreement with previous studies that peripheral inflammation triggers a neuroinflammatory response characterized by sustained glial activation with detrimental consequences for learning and memory in neurodegenerative condition thus supporting the view that the gutmicrobial inflammatory response might represent the earliest events of neuroinflammation in ad | [32032696 27776263 24807189 31284126 23531500] | in the present study, we also found that 5xfad mice exhibited age-dependent increased nlrp3 inflammation activation in the gut tissues along with increased expression levels of asc,caspase-1, and gasdermin-d, which are positively correlated with increased production of proinflammatory cytokine il-1β. interestingly, increased peripheral inflammasome activation is positively correlated with activated microglia and astrogliosis in the hippocampus of young and aged 5xfad mice. | [] |
250 | with standard dti axd was higher across multiple regions consistent with prior literature | [30687081 20371138 29922120 23145075 21872362] | for example, lower fa in the cc and fornix is indicative of altered wm integrity (e.g., demyelination) in the ad group; these changes were driven by both higher axd and rd with standard dti, while fw correction showed that these changes in fat may be driven by underlying lower axdt. using fw-dti, lower fw-axdt (ad < hc) were found in wm locations corresponding to lower fat, while the fornix showed simultaneous lower fw-rdt (hc > ad) in a small cluster. | [] |
251 | plasma soluble ssaovap1 is increased in various systemic diseases in diabetes atherosclerosis 107108109110 congestive heart failure 91 and nondiabetic morbidity obesity | [10064104 10892891 12135815 9074703 12800092] | experiments performed in adipocytes evidenced that soluble ssaovap1 could be shed from the membranebound form depending on a matrix metalloproteinase mmp activity in diabetic and obese animals it seems that under pathological conditions soluble ssaovap1 originates from adipocytes endothelial cells and smooth muscle cells but given that various cellular sources can secrete different types of mmps such as neurons cerebral microvascular endothelial cells astrocytes and inflamed neutrophils which kinds of mmps participate in the shedding of soluble ssaovap1 still warrant future investigation | [14968297 15178639] |
252 | most recognized eofadcausative mutations have been found in the genes psen1 psen2 and app 9 the majority of these mutations 63 occur in the gene psen1 10 the zebrafish orthologs of these genes have been identified as psen1 11 psen2 12 appa and appb | [27060961 22472873 10521267 12424519 11862463] | it is easily manipulated genetically and has the capacity to produce large families of siblings which can then be raised together in the same environment to limit the effects of environmental and genetic noise in molecular analyses moreover, zebrafish possess orthologs of the human genes mutated in eofad. | [25071820] |
253 | wholeexome sequencing studies have identified robust ad associations with rare missense variants in trem2 akap9 unc5c znf655 ighg3 casp7 and notch3 and it is expected that more adrelated rare variants will be identified by wholegenome sequencing wgs studies because some rare variants including those in noncoding regions likely contribute to ad risk | [23150934 25172201 25419706 31636380 30924900] | ad is highly heritable h 5879 but common variants explain only onethird of the genetic portion of ad risk highly penetrant rare variants may account for some of the missing heritability | [16461860 16461860 28714976] |
254 | these results are consistent with clinical evidence indicating that diabetes is associated with reduced white matter volume as well as with reductions in hippocampal volume and gray matter volume in addition diabetes is associated with aberrant functional connectivity of the posterior cingulate cortex with the temporal gyrus and frontal gyrus suggesting white matter abnormalities occur in diabetes | [23939539 24647028 23939539 24448784 24658392 24203723] | however, we observed upregulated expression of a subset of genes in app;ob/ob mice, which might illuminate the molecular mechanism underlying the interaction between obesity/diabetes and ad. genes specific to oligodendrocytes and microglial cells were downregulated in both ob/ob and app;ob/ob mice (i.e., mice on the ob/ob background). | [] |
255 | endothelial dysfunction has also been implicated in cerebral vascular diseases however despite a general appreciation of the role of vascular dysfunction in stroke and atherosclerosis the involvement of endothelial dysfunction in the pathophysiology of ad is not fully understood ad patients display reductions in cbf in various regions of brain including the cortex and the hippocampus in conjunction with cognitive dementia whether the contribution of capillarytoarteriole signalingand therefore cbf controlis affected during ad has not been explored | [31248555 9329032 10944232 11129782 31203725] | in 5xfad mice systemic injection of dic16pip2 05 mgkg significantly increased the cbf response to ws 20 min postinjection by enhancing the ba2sensitive component accumulating evidence has established a crucial role for the endothelium and particularly the capillary endothelium in mediating neurovascular coupling and thereby regulating cbf | [24926076 32076269 28319610] |
256 | bche was found in amyloid plaques and neurofibrillary tangles nfts suggesting that the protein may be involved in ads pathogenesis | [22157615 25931333 7979218 8534419 8004445] | nevertheless bche is also found in specific neurons mainly localized in the amygdala hippocampus and thalamus The primary source of BChE in the CNS is nonneuron cells such as astrocytes and microglia which also express nicotinic acetylcholine ACh receptors indicating that BChE might play a regulatory role in the functional status of these cells via its AChhydrolyzing activity | [ 9548556 12811800] |
257 | the group also included parkinsons disease pd subjects n 128 fulfilling the criteria by gelb et al 25 pspn 17 fulfilling the criteria by litvan et al 26 and höglinger et al 27 multiple system atrophy msa n 27 fulfilling the criteria by gilman et al 28 and cbs n 3 fulfilling the criteria by armstrong et al | [ 9923759 8710059 28467028 18725592 23359374] | ad dementia patients (n = 137) fulfilled the diagnostic and statistical manual of mental disorders-5 (dsm-5) criteria for major neurocognitive disorder (dementia) due to ad. the non-ad group (n = 253) included patients with vascular dementia (vad, n = 12), parkinson’s disease dementia (pdd, n = 25), dementia with lewy bodies (dlb, n = 21) and frontotemporal dementia (ftd, n = 5), all fulfilling the respective dsm-5 criteria. | [] |
258 | in the human tau protein htau transgenic model the mice tau gene is replaced by the human gene correlating with nfts development and neurodegeneration | [28025715 33176118 25927677 12859672 23948912] | pathogenic ps1 or ps2 mutations increase the levels of aβ1-42 form in vitro, but do not promote aβ plaques aggregation in vivo in mice. several doubletransgenic 2xtg mouse models have been developed by crossing app and ps1 transgenic mice demonstrating accelerated aβ accumulation leading to the impairment of cognitive functions | [28304309 25927677 27930341] |
259 | many components of pge have a variety of activities in the brain | [28610929 17873848 29375565 19433075 32008007] | in addition ethanol extract of pg has been reported to inhibit acetylcholinesterase ache activity considering the previous studies, pge may exert the neuroprotective effect through the regulation of the imbalance between e/i neurotransmitters in the ad brain, such as activating the excitatory cholinergic and inhibitory gabaergic transmission. | [20521984] |
260 | pla has been used previously to detect both heterotypic 58 as well as homotypic protein interactions which shows the reliability of the pla approach | [17072308 20923550 32025699 25732184 30721406] | the molecular basis of prion and prionlike disorders is the ability of certain proteins to acquire a selftemplating amyloidogenic state in which protein multimerization is a required step for molecular seeding here, we describe tau-pla, a technique that enables the specific histological visualization in situ of the tau–tau interactions, regardless of tau phosphorylation state and conformational changes, with preservation of the cellular and subcellular morphology. | [9759504] |
261 | deep brain stimulation targeting the fornix region fxdbs is currently under investigation for the treatment of alzheimers disease ad a recent paper reported on acute flashbacklike phenomenathe involuntary recall of autobiographical memories described by earlier authors as reminiscences that were experienced by a subset of ad patients during initial postoperative fxdbs programming these were associated with specific stimulation settings and appeared to be unrelated to intrinsic wholebrain or hippocampal volume pioneering 19th and 20th century experiments involving intraoperative direct electrical stimulation of the exposed cortex provided tremendous insight into the causal relationships between cortical areas and reminiscences and these insights still stand however the relationship between these memory phenomena and deep brain structures has not been systematically investigated and it remains unknown which specific structures give rise to the flashbacks reported in the aforementioned fxdbs population | [18232017 20687206 29914028 28445741 31914177 28445741 31914177] | brain structures and networks responsible for stimulation‐induced memory flashbacks during forniceal deep brain stimulation for alzheimer's disease | [] |
262 | previous studies reported in early onset ad that left superior temporal and cuneus 44 lateral temporal 40 45 46 parietal 4648 and occipital regions demonstrate increased aβ | [23507771 16894106 21479849 21709608 21479849 21709608 22265212] | we found high amyloid binding in posterior cingulate/precuneus, lateral temporal, anterior cingulate, and parietal regions in ad. in accordance with prior studies highest amyloid binding was seen in the precuneus 10 4043 and anterior cingulate in typical ad | [17499392 17065593 18263627] |
263 | other rodents including transgenic rats have also been used as animal models of ad although ad pathology does not develop naturally in most rodent brains one exception may be the aged octodon degus a grounddwelling diurnal rodent from the upper mountain regions of chile this rodent shares features of neurodegeneration including production of extracellular aβ deposits and intracellular tau and replicates other characteristics of the ad brain its utility as a translational model for drug development however is at a very early stage and new data suggest that degus raised in captivity do not reproducibly demonstrate the hallmarks of ad reported previously similarly guinea pigs are a developing animal model of ad featuring a humanlike aβ sequence with agedependent diffuse accumulation of amyloid pathology | [19432812 29514054 15748782 27566602 24360504] | critically, there are also substantial differences between mouse and human immune systems. reliance on a singular model an underappreciation of background strain influences and a tendency to anthropomorphize outcomes in behavioralcognitive evaluations may model responses to disease factors that insufficiently translate beyond the specific model utilized this must be addressed to adequately model human disease | [] |
264 | furthermore studies investigating the impact of trem2 signaling on the inflammatory response have produced contradictory results demonstrating either an antiinflammatory or a proinflammatory role for trem2 | [16887962 28100745 25732305 23301011 16951310] | nhd is a rare autosomalrecessive earlyonset dementia characterized by behavioral changes and cognitive decline with or without pathological bone fractures the mechanism by which trem2 influences to neurodegeneration remains obscure. | [23318515 23150934 12080485] |
265 | two studies identified an inverse correlation between retinal vessel density and the fazekas scale a radiographic measure of white matter lesions in the brain often used to assess patients with dementia yoon et al also reported that inferolateral ventricle volume was inversely corrected with scp vessel density and perfusion density furthermore some groups have demonstrated significant associations between retinal vd and neurocognitive testing results including moca and mmse scores though the association between octa findings and clinical ad is not fully understood the fact that ad neuroimaging and neurocognitive tests are associated with octa findings supports the value of octa in the evaluation of ad | [31193094 30507577 31755970 28600299 31118186] | in particular robbins et al recently reported that temporal measurements were the least repeatable among peripapillary octa parameters further research is needed to evaluate the utility of peripapillary octa in ad other studies explored the correlations between octa findings and well-established ad metrics, providing further insight into the biological underpinning of these retinal microvascular abnormalities and their clinical significance in ad. | [] |
266 | our baseline data differ quantitatively from reports by other authors since the bmd obtained in our sample was 0506 0150 gcm2 whereas the data from other authors in patients with ad ranged from 1110 to 2124 gcm2 | [19661621 20164583 9855465 15337610 15759247] | clinical trials aimed at the effects of exercise in older people or postmenopausal women are more frequent although the evidence appears to support the assumption that exercise has positive effects on bone status not all studies provided clear evidence of increased bmd with exercise interventions | [31498937 23775701 31925473 32055889 19196369] |
267 | plasma aβ42 andor aβ40 levels were previously shown to be elevated with age in both crosssectional 23 31 32 and prospective studies | [12873852 17914065 30349853 14610118 17055615] | among the biological variables tested as potential modifiers of plasma biomarker levels (age, sex, apoe
ɛ4 dosage, and mapt h1 haplotype dosage), age, apoe
ɛ4 dosage, and sex showed significant effects. older age had significant associations with elevated plasma levels of aβ42, tau, and tnfα. | [] |
268 | tdo is of particular interest in this regard as it is expressed in the hippocampus and is involved in the regulation of adult neurogenesis in mice neurogenesis within the hippocampus plays a crucial role in memory formation and is affected early in the course of ad hippocampal tdo expression was found to be activated by aβ oligomers and tdo expression was increased in hippocampal regions of ad patients inhibition of tdo prevented neurodegenerationrelated phenotypes in caenorhabditis elegans and drosophila melanogaster models of ad in c elegans this protection was independent of kyn metabolites while in drosophila protection was established by increasing relative levels of ka | [20205802 19323847 27190010 22927396 27114543] | the kyn pathway could be a potential drug target in ad. augmenting cerebral ka production by inhibition of kyn metabolism in the blood thereby increasing kyn transport to the brain prevented synaptic loss and improved memory function in a mouse model of ad in addition kyn pathway enzymes in the brain might be targeted directly | [21640374] |
269 | of interest in this regard is the fact that tdo seems to be integrated in damage response mechanisms in the brain that are regulated by stress signals such as glucocorticoids and prostaglandins which might be activated by aβ finally 680c91 could elevate a global measure of brain extracellular csf serotonin concentration and thereby influence cognitive function | [29241670 27142940 26708701 27190010 7539265] | we, therefore, speculate that tdo might have a role in brain physiology that is independent of its enzymatic function. indeed tdo inhibition reduced aβ toxicity independent of kyn metabolites in c elegans alternatively as tdo expression is highly restricted to subregions in the brain tdo inhibition could impact cellular function without causing measurable changes in metabolite concentrations at a regional level | [22927396] |
270 | this is particularly relevant for the interplay between aβ and the various surrounding cell types which is considered to be crucial in plaque development | [10794847 22398730 2677252 23610434 27196974] | fonseca et al detect lipidrich cellsized depositions surrounding mature plaques using raman microspectroscopy however, as the transferability of findings between mouse models and humans remains unclear, we investigate aβ plaques in human brain tissue here, in order to resemble the disease course and pathology in human brains. | [31657367] |
271 | several groups have applied vibrational imaging to human ad brain tissue before | [26621077 25415602 25600495 23586070 28127051] | however, as the transferability of findings between mouse models and humans remains unclear, we investigate aβ plaques in human brain tissue here, in order to resemble the disease course and pathology in human brains. this is particularly relevant for the interplay between aβ and the various surrounding cell types which is considered to be crucial in plaque development | [10794847 22398730 2677252 23610434 27196974] |
272 | consistently genetic studies have revealed the prominent link of mutations in h3k4 methyltransferases or demethylases to diseases with cognitive impairment including wiedemannsteiner syndrome kmt2a mutations kabuki syndrome kmt2d mutations xlinked claesjensen syndrome kdm5c mutations and autism spectrum disorders kdm5a5b mutations | [25135975 22795537 20711175 15586325 25363768] | methylation at lysines in histone h3 can serve to both activate and repress gene transcription. histone methylation is uniquely suitable to be part of the molecular underpinnings of memory storage because of its tight association with distinct transcriptional states of genes and its active regulation during memory processes | [24045506 23729618] |
273 | only 39 20 of the reviewed studies present class balance that is the number of participants is evenly distributed across the two three or four diagnostic categories | [31427959 28088191 25417086 28436388 29018636] | this section offers insight into another aspect in which lack of consensus and uniformity is obvious. using accurate terminology (i.e., abiding by diagnosis categories) when referring to each of these groups could help establish the relevance of this kind of research to clinical audiences. | [] |
274 | some reported a significant enlargement of the faz in individuals with ad compared to controls 11 12 15 whereas others reported no difference in the faz area | [31408108 28600299 31174670 30507577 31193094] | this finding would also suggest that the use of octa may be more sensitive in detecting changes in ad and mci participants than fundus camera. previous octa studies have quantified the faz area within the scp region automatically using the octa software and reported conflicting results table 4 | [31193094] |
275 | functional pathway analysis showed that adrelated genetic variants were mainly enriched in app metabolism inflammation lipid metabolism tau protein binding endocyticvesicularmediated transport and synaptic function pathways | [29740579 29562532 30820047 28666525 29971646] | a review article by raghavan and tosto summarizes studies of genetogene interactions in ad the concept of functional genomics attempts to link omics data such as genomics, transcriptomics, proteomics, and metabolomics to explain the complex process from genotypes to phenotypes at a comprehensive level. | [28825204] |
276 | the latter causes recruitment of extrasynaptic nmdars and neuronal excitotoxicity resulting in progressive neuronal and memory loss | [21543591 23270879 28209726 27809304 23776240] | however nmda receptors nmdars seem to be particularly important in both animal ad and ms models the alteration of synaptic plasticity in ad models has been linked with oaβinduced increase in glutamate concentration at synapses and its spillover out of the synaptic clefts | [23665072 23295855 21446020 22304707 22894822 23776240] |
277 | the top transcriptional regulators identified by ismara motif enrichment analysis coalesced into the same general categories of diseasecausal endotypes identified by ontology enrichment analysis with consistent activation of transcriptional regulators related to pluripotency including sox2 and sox3 gata2 and gata3 and klf4 cell cycle e2f family members and foxm1 inflammation interferon regulatory factor irf signal transducers and activators of transcription stat and nuclear factor κb nfκb transcriptional regulators and dedifferentiation including tead factors snai2 and prrx2 | [26389663 30517869 23842645 21102550 16979567] | s2c). to characterize the transcriptional regulation of these altered gene programs we performed two complementary transcriptionfactor tf activity analysis approaches motifcentric tf activity analysis by ismara integrated system for motif activity response to characterize the tfs and micrornas mirnas whose motif activity most significantly changes between the psen1 mutant and ndc neurons and tfgene targetcentric activity analysis by dorothea discriminate regulon expression analysis which uses the viper activity inference algorithm with a curated tf target regulon generated from consensus chipseq expression signatures and tf motif studies to predict tf activity based on the directional regulation of target genes by tfs | [24515121 31340985] |
278 | notably the ratio of csf aβ142aβ140 has been found to predict cortical amyloidpet positivity more accurately than csf aβ142 alone 909192 improving the discrimination of ad vs nonad demented patients table 2 | [32123386 28073379 29614646 30352211 19268916] | therefore this biomarker is currently integrated in the diagnostic criteria of ad it is used for subject selection in clinical trials and approved in medical practice as well on the contrary csf aβ140 peptide alone albeit prevailing over the other aβ species in both cns and periphery showed no relevant correlation with ad dementia | [24849862 21514250 29653606 31833025 32123385] |
279 | cerebrospinal fluid levels of ptau mirror changes in the brain tau metabolism and are elevated in all disease stages of ad including the asymptomatic phase when taupet is still normal taupet tracers bind to insoluble paired helical filaments of tau in neurofibrillary tangles and taupet measures become abnormal mainly in symptomatic ad and correlate with brain atrophy and cognitive function together these findings suggest that fluidbased measurements of ptau may be more sensitive than taupet in the earliest stages of ad | [28743782 32426454 31961372 29053874 30626656] | in autosomal-dominant ad, plasma p-tau217 levels started to increase approximately 20 years before the estimated onset of mild cognitive impairment (mci). although both csf p-tau and tau-pet are considered as biomarkers of ad-related tau pathology, new findings suggest that they are not completely interchangeable. | [] |
280 | they develop deficits in spatial reference and object recognition memory correlating with robust neuron loss in the ca1 pyramidal layer in a gene dosedependent manner 65103104 as well as motor deficits 105 and reduced neurogenesis | [23685882 24252153 27138799 31156407 31818124] | a transgenic mouse model (tg4-42) expressing only aβ4-42 under the control of the neuron-specific thy1-promoter has been developed as a tool to assess the in vivo toxicity of this peptide. in good agreement with the abovementioned results in models expressing only specific aβ peptide variants these mice do not develop overt extracellular amyloid pathology but robust intraneuronal aβ accumulation mainly in the hippocampus figure 2 | [23685882] |
281 | as pd can prime macrophages either through microbial factors eg lipopolysaccharide or by activation of other immune and nonimmune cells microglia priming activation and polarization due to pd may be plausible | [28890719 28472719 22696147 28912533 24946875] | the risk of developing pd increases with age; however, pd has a peak rate of occurrence in middle age that may result in priming microglia to a significantly activated state increasing the brain vulnerability to aging and to additional immune challenges or diseases. while microglia in wt mice was impacted by the experimental pd as shown by increased iba1 expression the level of inflammatory cytokines was also impacted suggesting a defective immunological process due to pd that would lead to a disrupted inflammatory response | [30555774] |
282 | several studies have shown that hyperforin activates trpc6 and increases its expression 106133 leading to a decrease in the aβ level and an improvement in cognitive performance in ad models | [22815087 18818211 25039785 16880827 19939230] | When applied intracerebroventricularly to rats immediately after MCAO hyperforin preserves TRPC6 activity reduces infarct volumes promotes functional recovery and increases neurologic scores at 24 h after reperfusion there is a lot of evidence that hyperforin and its derivatives are highly selective towards the trpc6 channel and do not exert similar effects on its closest relative the trpc3 channel | [22815087 17666455 20008516 22832522] |
283 | the action of aβ and app on mitochondria would explain the abnormal amount of free radicals and oxidative stress the impairment of the activity of the enzymes of the intermediate metabolism and the mitochondrial dysfunction observed both in the disease and in the cells intoxicated with the toxic peptide | [28059794 18725189 29029390 23583906 23562762] | autoptic studies on brain tissue of ad patients have confirmed the presence of numerous signs of oxidative stress such as an increase in lipid peroxidation oxidation of proteins and glycides and reduction in antioxidant enzymes furthermore in vitro studies have shown that the neurotoxic properties of aβ can be mediated by ros | [28314935 25944987 24683437 29080524] |
284 | so βamyloid deposition is the reason behind pathological alterations in ad and its clearance when patients are immunized does not stop this disorder | [25231068 23560052 23610434 22993126 18640458] | however the tastpm animal model study pointed out that the concentration of cu in the alzheimers brain does not link to plaques deposition the affinity of cu2 ions for aβ peptides is very high 122123 and it also increases the portion of betasheet and alphahelix in aβ proteins which may be the cause of its aggregation | [26449834 28586203 26178596 17091193] |
285 | thus the available results are generally not comparable since they target different mirna molecules which further increases the complexity of the subject | [30734227 30689565 26527155 32973449 29800558] | another important group of ad biomarkers is the micrornas mirnas which are small noncoding rnas with an average length of 22 nucleotides involved in gene expression at the posttranscriptional level regulation through binding to mrna targets and the subsequent translational repression or degradation of the target by the rnainduced silencing complex although recent studies have been intensively focusing on mirna deregulation associated with ad the lack of standardization in the quantification methods and protocols used is considerably challenging for establishing the discrimination power of mirnas as biomarkers for ad | [31792281 30734227] |
286 | low csf aβ40 levels might also be indicative of frontotemporal dementia ftd 29 30 cerebral amyloid angiopathy caa 31 hiv 32 multiple sclerosis 33 or normal pressure hydrocephalus nph | [21135556 21709372 20028512 30084711 28486988] | this is a useful approach for reducing preanalytical aβ42 biases 2325 and improving the diagnostic performances of csf biomarkers 26 especially in discordant cases this ratio can also be used to account for interindividual amyloid variations in the baseline csf level | [31010420 26034513 17254013] |
287 | previous studies have reported relationship between different neurotransmitters and ad pathology most of them used plasma or csf samples while only a few used noninvasive samples such as urine from murine animal models | [28211810 25751428 23700429 28039808 30316910] | physiologically a reduction of synapsis occurs and neurotransmission is altered in this sense the study of different compounds involved in neurotransmission systems could be useful | [22491782 24410566] |
288 | in contrast to normal ageing excessive accumulation of autophagy vesicles avs autophagosomes and lysosomes has been observed in postmortem brain of ad patients 101102103 raising the question of whether the av accumulation is a result of autophagy dysfunction 102104 or due to excessive autophagy | [16874045 17396135 17118264 17396135 17362839 15528435] | growing evidence shows that soluble aβ42 oligomers are the main toxic species while plaques which mostly contain insoluble fibrils are considered relatively inert secondary contributors to the onset of cellular dysfunction and sometimes even a protective mechanism to limit oligomer toxicity dysfunctional autophagy is implicated in the disruption of cell signalling pathways 98 and increased accumulation of aβ and tau protein aggregates in ad | [26541462 32682953 28923312] |
289 | several risk factors for ad in ds have also been identified including age and the presence of an apoe ε4 however much less is known about the relationship of sex to risk of ad or to rates of progression in adults with ds and the few existing reports have been inconsistent one communitybased study of 100 individuals with ds found that men had an earlier onset and an almost threefold greater risk for ad than women however another similarly powered study found that females had a higher risk for developing ad | [10402500 20946940 8957023 9566384 10430422 9566384 10430422] | these factors may provide potential targets for intervention to delay or prevent onset of ad. major known risk factors for load are age the presence of an apolipoprotein ε4 allele apoe ε4 which has been associated with an increased risk for load and sex where the risk of ad appears to be greater in women compared to men independent of the longer life expectancy for women the literature is inconsistent with respect to the differential effects of sex on ad with several studies finding either no difference between men and women in incidence of ad or a significant effect of age and sex on risk of ad as the incidence of ad is higher in women in the older age range several lines of investigation have shown a protective role for estrogen in load and the loss of estrogen has been identified as an important factor in the increased risk of ad in women after menopause sex may also have an effect on rate of cognitive decline after onset of ad and it appears that women with ad have worse cognitive impairment than men at baseline and may decline faster a recent review on the differential effect of sex on ad highlights knowledge gaps in many aspects of risk factors of progression and biomarkers for ad in the general population and the need for further study | [23296339 20442496 10851365 9008508 11445258 20167003 27870425 27692800
24418360 29189302 29324460 29985474] |
290 | previous studies have demonstrated that microglia instigates tau pathology in diverse ways inducing tau aggregation by proinflammatory cytokine release 404142 and spreading hyperphosphorylated tau oligomers or nft through exosome secretion | [29951498 19289607 20920788 26436904 30227881] | once the balance is weighted on m1 conversion, it cascades into further neuronal deterioration in the presence of tau proteins, not to mention external aβ oligomers. like the pathological conversion of aβ hyperphosphorylated tau oligomer causes microtubule collapse then forms neurofibrillary tangle nft leading to brain atrophy and cognitive decline | [22487856] |
291 | csf pt181 tau has also proven useful in differential diagnosis of dementia 213214215 and to predict cognitive decline in preclinical and prodromal disease stages with specificity for ad | [20157306 29554190 22170879 20157306 22213792 24012374] | from a neuropathological perspective analysis of postmortem brains has shown a certain degree of correlation between the neocortical tau burden and csf ptau tau phosphorylated at threonine 181 pt181 ttau and aβ42 have been extensively validated in the csf as biomarkers of ad and are currently widely used as diagnostic benchmarks in clinical and research studies | [19273758 17012293 24849862 21514249 30488277] |
292 | in ad patients and ad animal models aβ accumulation induces ec dysfunction and reduces the expression of tight junctional protein in brain ecs thus resulting in decreased bbb tightness | [16644119 26143259 23855502 29154819 31047972] | endothelial cells in the brain form the blood–brain barrier (bbb), which tightly regulates solutes exchange between the lumen of blood vessels and the interstitium of the brain parenchyma. bbb breakdown causes accumulation in the brain parenchyma of bloodderived neurotoxic proteins such as fibrinogen thrombin haemoglobin ironcontaining hemosiderin and free iron contributing to neurodegeneration | [20944627 21040844] |
293 | one of the major obstacles for the early diagnosis is related to the complexity of ad etiology and pathogenesis | [30617256 27050320 21304480 27025652 29653606] | Data from The World Health Organization indicate that AD is the fifth cause of death worldwide and predict a dramatic increase in AD incidence in the next years reaching 52 million people affected by 2050 this scenario is worsened by the absence of an effective therapy as well as by the absence of an early diagnosis as it is usually made after symptoms manifestations when neural impairment and brain injury damages are already severe | [30617256 27050320 21304480 27025652] |
294 | opposite to apoeε4 apoeε2 confers a reduced risk of ad 456 although apoeε2 is associated with more severe caa and hemorrhages | [ 8346443 8350998 8446617 26341746 25716356] | the allele frequencies of ε2 ε3 and ε4 are 7 78 and 15 respectively in most caucasian populations showing that apoe3 is the most common isoform in humans and apoe2 is the least common however in patients with ad the frequency of the apoeε4 allele is markedly increased to 4050 | [3283935 8533168] |
295 | however oxidative stress mitochondrial dysfunction and glucose hypometabolism have been well documented in mci and ad brain | [30737462 22037588 10811879 17222480 19142633] | the high metabolic need of the brain cannot be met by glycolytic activity. rather neurons rely on the tricarboxylic acid cycle and oxidative phosphorylation housed in mitochondria to produce atp | [29752396 16285865] |
296 | indeed removal of aβ by the csf lymphatic and glymphatic systems decreases in ad 88 142 possibly with contributing factors including increased stiffening of the arterioles with age 179 and ischaemiainduced changes of other key components such as decreased lymphatic function and aquaporin 4 localisation away from astrocyte endfeet abutting blood vessels | [31104026 27234656 18363936 30046111 31104026 21891870] | a detailed analysis of these proposals has been provided in ad when cbf decreases decreased pulsatility of the middle cerebral artery has been reported and so if this extends to penetrating arterioles less aβ removal by pulsationdriven mechanisms would be expected | [30340614 31908463] |
297 | blood amyloid biomarkers results have been somewhat inconsistent in the literature however plasma aβ4240 ratio measured by mass spectrometry has been shown to provide a sensitive and reliable measure of amyloid status that predicts future progression to positive amyloid pet and correlates with csf aβ42405152 plasma ttau is elevated in persons with ad as well as other brain disorders and plasma ptau has been shown to be a sensitive and specific predictor of elevated brain aβ which suggests it may be useful for screening although more research is needed on the topic | [27534714 29420472 28692710 29487167 29626426] | several studies have shown that plasma nfl correlates with csf nfl and neuroimaging markers as an indicator of neurodegeneration across the ad continuum is higher in people with both mci and ad even after correcting for age and is associated with cognitive decline and neuroimaging biomarkers of ad serum nfl concentration increases 5 to 15 years prior to clinical disease onset in familial ad and may thus be an easily accessible biomarker for onset of neurodegeneration other plasma biomarkers have also shown some promise. | [30055655 28346578 30664784 26870824 30664784] |
298 | given the wealth of research implicating the transentorhinal region selective vulnerability of the alec to agerelated alterations in processing and structural changes associated with agerelated cognitive decline we hypothesized that alec structure specifically ct might provide a suitable biomarker for early ad detection | [ 6474172 1669339 1669710 29518359 28578804] | overall, these results indicate that relative to hippocampal volume, raw alec thickness is a better predictor of ad status and is at least as good a predictor of mci status. future research may consider combining alec ct with other predictors within a machine learning algorithm to better predict ad onset. | [] |
299 | the vt has been employed as an index of tspo binding in multiple studies in alzheimers disease | [25649991 25412766 23775979 25766898 27318133] | thus, it is possible to estimate the density of tspo by calculating the radioligand distribution volume (vt) that takes into account the number of radioligands in the plasma and the presence of metabolites. the vt refers to the relationship between the amount of tspo radioligand in a defined brain area and its concentration in the plasma at steady state. | [] |
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