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100 | similar findings have been reported on another glp1 agonist exendin4 as it has been shown to increase brain insulin synthesis 109 to restore cerebral insulin signalling 110 to attenuate aβ and tau pathology as well as neuroinflammation 111112 and to improve cognition | [34587885 28573460 32737929 31256135 31082410 31082410] | this glp1 agonist has also been shown to reverse memory impairment and synaptic loss in aβ mouse models 106 with similar findings in nonhuman primate models similar findings were observed in ad mouse models in the presence of t2d suggesting multiple mechanisms underlying liraglutides neuroprotective benefits | [25107586 29435980 33467075 34975451] |
101 | there is data indicating direct associations between plasma adipoq levels and the expression of adiponectin receptors in peripheral blood mononuclear cells pbmc | [15897298 21284833 20178558 23510830 25392268] | as mentioned adipoq binds to 3 receptors adipors adiponectin receptor type 1 and type 2 g proteincoupled receptors and tcadherin cadherin family adipor1 is primarily associated with adiponectins metabolic functions while adipor2 is also engaged in the antioxidative and antiinflammatory actions of adipoq | [15897298 16380487 17618856 31377319] |
102 | considering the multifactorial nature of ad a promising therapeutic approach is the development of multitarget drugs having a complex effect on several biological targets responsible for the pathogenesis of this disease | [24533013 28358144 26281952 24493627 24851088] | moreover cu2 and fe2 support the production of reactive oxygen species and increase of oxidative stress thus promoting neurotoxicity therefore selectively reducing brain concentrations of metals with chelating agents is one of the therapeutic approaches proposed for the treatment of ad | [15105262 26343967 21414382 23685572] |
103 | one of the design strategies for multitarget drugs is to use a molecular spacer to link together two pharmacophores that are active against two or more different biological targets and a wellknown anticholinesterase drug molecule is often used as one of the pharmacophores | [26797191 29768996 31735356 30744931 33342413] | therefore selectively reducing brain concentrations of metals with chelating agents is one of the therapeutic approaches proposed for the treatment of ad considering the multifactorial nature of ad a promising therapeutic approach is the development of multitarget drugs having a complex effect on several biological targets responsible for the pathogenesis of this disease | [21414382 23685572 24533013 28358144 26281952 24493627 24851088] |
104 | in humans divergences between
different brain areas have been shown the decrease in bdnf both protein and
mrna has been confirmed in numerous studies but the
putative changes in ngf were not being confirmed although the
cholinergic theory of ad presupposed a decrease in ngf | [ 9387865 10867782 19625522 9387865 10867782 15935057 1742020] | here,
we present what we consider to be some of the most interesting of
these:(a) one possible therapeutic strategy is to compensate the
deficits in neurotrophins (mainly nerve growth factor –ngf- or
brain derived neurotrophic factor - bdnf) caused by the
dysfunction or involution of astroglia. studies on changes in
neurotrophic factors have given rise to controversial results
for years, both in the study of human brains and in the study of
experimental models of ad. | [] |
105 | in humans divergences between
different brain areas have been shown the decrease in bdnf both protein and
mrna has been confirmed in numerous studies but the
putative changes in ngf were not being confirmed although the
cholinergic theory of ad presupposed a decrease in ngf | [ 9387865 10867782 19625522 9387865 10867782 15935057 1742020] | (a) one possible therapeutic strategy is to compensate the
deficits in neurotrophins (mainly nerve growth factor –ngf- or
brain derived neurotrophic factor - bdnf) caused by the
dysfunction or involution of astroglia. studies on changes in
neurotrophic factors have given rise to controversial results
for years, both in the study of human brains and in the study of
experimental models of ad. | [] |
106 | microglia perform preventive actions including the removal of aβ the inhibition of tau hyperphosphorylation and the production of neurotrophic factors which delay the onset of ad symptoms | [27091843 30572908 25630253 33008458 29740062] | aluminum causes damage to nerve cells mitochondria 108 apoptosis and programmed necrosis 109110 aβ deposition 111 abnormal tau protein phosphorylation changes in synaptic plasticity and glial activation microglia activation happens before ad manifests according to in vivo pet imaging studies | [26944603 25971159 28211326 23574527 23219964 26984188] |
107 | numerous neuropathological changes that occur during ad likely contribute to this altered pain experience | [16951408 21257326 23277361 10976641 1300498 16951408 23277361] | this represents substantial numbers because there are 65 million people living with ad in the united states us and over 55 million with dementia globally preliminary neuroimaging studies indicate that major brain regions involved in pain processing continue to demonstrate activation in response to painful stimuli in ad but it remains unknown how this activation contributes to the pain experience in ad | [16951408 28222526] |
108 | both histopathological and ultrastructural shifts were detected in the cerebral microvasculature and in neurons which was supported by results of previous studies | [22792182 23404118 16039562 18305170 19725828] | the tol2 plasmid used to generate this transgenic zebrafish contained a zebrafish promoter, exogenous human cdna, and a cmv promotor and egfp tag. egfp expression was used to examine the time and location of expression of the transgene. the zebrafish telencephalon, which is comparable to the mammalian hippocampus, was morphologically altered in this transgenic model. | [] |
109 | hence genomic studies of the human gitract microbiome indicate that this microbial repository currently represents about 1 thousand times the genetic complexity of all proteincoding sequences found in the entire human genome httpswwwhmpdaccorghmpoverview last accessed on 10 october 2022 | [26338727 17943116 32690973 31415755 27190214] | as a complex microbial repository i this compartment includes a broad spectrum of microbes which represent mostly facultative anaerobes or anaerobic bacteria followed in abundance by archaebacteria fungi protozoa viruses and other microorganisms 123 ii represents the largest source and highest density of microbial species found anywhere in nature 45 and iii comprises about 13 of the human body mass 2 to 6 pounds of microbes in a 200pound adult collectively constituting the largest diffuse organ system in the human body and at least as metabolically active as the liver relatively recent data from us national institutes of health (nih)-funded interdisciplinary human microbiome project (hmp) initially classified over ~200 thousand diverse, non-redundant prokaryotic genomes in the human gi-tract microbiome comprising about ~5 thousand different gi-tract microbial species, which together encode about ~200 million different protein sequences. | [26338727 17943116 32690973 31415755 26338727 17943116 32690973 31415755
27190214] |
110 | interestingly oa structures which represent the outermost and most immunologically exposed component of bacterial lpss are extremely diverse and approximately 200 different serogroups have been identified for escherichia coli alone | [17943116 32690973 31415755 27980292 16953973] | the microbial om is not a phospholipid bilayer but is instead a highly asymmetric capsule containing phospholipids in the inner leaflet and lps molecules in the outer leaflet noncovalently bound and ultimately shed from the om matrix into surrounding biofluids large lps species of approximately 1000 kda per subunit consist of a hydrophobic lipida domain also known as the lps endotoxin attached to a core oligosaccharide coreos and a distal oantigen oa also known as an opolysaccharide httpspubchemncbinlmnihgovcompoundlipopolysaccharide last accessed on 20 september 2022 | [34457996 18194336 12045108 27980292 16953973 34457996 18194336 12045108
27980292 16953973] |
111 | the oxidative stress produced by preoxidants in neurons and neural cell lines can be counteracted by saponins via their antiradical effects | [19447300 19185022 17659841 19138476 18809438] | sources, bioactives and underlying neuroprotective mechanisms of saponins. The antioxidant potentials of saponins are linked with the neuroprotective effects of these compounds (Figure 7). | [] |
112 | a1 astrocytes can enhance local neurodegeneration or conversely they may help
remove unrecoverable neurons in an attempt to repair neuronal circuits | [28099414 31136698 30276955 26232154 32819809] | a1 astrocytes can be identified in vivo by c3d complement upregulation other
suggested markers are h2t23 fkbp5 and ligp1 these neurotoxic astrocytes
can enhance local neurodegeneration or conversely they may help remove
unrecoverable neurons in an attempt to repair neuronal circuits a1 astrocytes
also produce different neurotoxins not well identified until now dserine no and
proinflammatory cytokines tnα and so on these substances produced in
different quantities in the different subtypes of a1 astrocytes induce neuronal
apoptosis and different alterations in oligodendrocytes including
prooligodendrocytes and microglial cells different local physiological
or pathophysiological scenarios can reactivate the neuroinflammatory process that
has started or that is ongoing or on the contrary to initiate an
antiinflammatory response tending to restore normality of the cns although
unfortunately it is the rarest possibility tgfβ and fgfs have been reported to
reduce neuroinflammation caused by activated microglia and astrocytes liddelow et al 2017
further found that tgfβ1 downregulated several genes related to the a1 phenotype | [33803478 34048845 28099414 31136698 30276955 26232154 34048845 34048845
21234816 24616125 30210273] |
113 | the plasticity of glial cells particularly in terms of reactive gliosis
includes modifications to the structure of glial processes changes in cell
motility andmore importantlymodifications in the production of diverse
neuroprotective neurotrophic factors gliotransmitters etc and neurotoxic
substances cytokines chemokines free radicals prostaglandins no or other
neurotoxins the expression of different gfap isoforms in
astrocytes as well as the different reactive forms of these normal
neuroglial cells or subsets of astroglia must also be kept in
mind | [30158892 12909295 11137576 22912745 33589835] | perhaps the most important justifications of the involvement
and the simultaneous or exclusive neurotoxic and/or neurodegenerative effects of
neuroglial cells in ad are indicated below.1) differences in the response of different
neuroglial families or subtypes. 1) differences in the response of different
neuroglial families or subtypes. | [] |
114 | in our study the periodontitisrelated salivary microbiota treatment reduced gut microbial richness and diversity a ubiquitous indicator of diseaseassociated dysbiosis in addition an increased abundance of bacteroidetes was observed in mice gavaged with periodontitisrelated salivary microbiota compared to that in healthy mice in accordance with gut microbiota alterations in patients with ad the phylum bacteroidetes consists of a diverse group of gramnegative commensal bacteria in the intestine and is more predominant than firmicutes in the elderly according to spearmans correlation analysis with adrelated parameters lactobacillus sutterella oscillospira ruminococcus rikenella and helicobacter at the genus level might be crucial for gutbrain bidirectional communication in ad pathogenesis lactobacillus is a probiotic that ameliorates brain inflammation by participating in gastric vagus nerve activity compared with the healthy control the mice in the p group exhibited decreased lactobacillus abundance although not significantly this may be due to the limitation of gavage time | [22411464 29051531 24861948 19508720 21876150] | furthermore, the increased plasma concentrations of tnf-α and il-1β reflected systemic inflammation, which might be attributed to gut-associated lesions. under pathological conditions the oral microbiota can colonize in the gut and disrupt the intestinal gut microbiota since intestinal inflammation and gut microbiota dysbiosis have been considered prominent features in the progression of ad periodontitisrelated salivary microbiota might produce cascade effects on the intestine of pap mice | [31471351 33504065] |
115 | our findings were also consistent with the structural racism and discrimination srd literature and supported the framework of srd patients with adrd | [10936998 25632292 25626224 8450822 35659469] | several sdoh are associated with cognition and adrd diagnosis such as low socioeconomic status low levels of education economically disadvantaged regions with limited physical resources and food security among other factors results of our study suggested that acos aimed at improving access to necessary timely care may help decrease existing disparities resources can be directed toward sdoh to improve the well-being of older adults. | [33756057 34103175] |
116 | in addition rothia haemophilus and alloprevotella are normal in the oral cavity anaerostipes and weissella are common in the intestine with anaerostipes facilitating acetate formation whereas weissella is an emerging genus with potential health benefits capable of inhibiting pathogenic microbial growth through the production of bacteriocins | [22698087 24215821 34870576 33565028 32017095] | it is boldly speculated that the altered microbiota may be associated with a systemic inflammatory response. to further support our speculation we correlated systemic inflammatory markers with microbiota and found that a specific oral and gut microbial composition was associated with inflammatory markers fusobacterium and selenomonas have been reported to be associated with unhealthy microbial characteristics in patients with gingival and periodontal disease whereas fusobacterium may be a major indicator of microbial transformation into inflammatory pathogenic bacteria and a potential biomarker of periodontitis and gingivitis episodes | [34204609 2777378 9495607 9495612] |
117 | the kv21 channels are the main α subunits mediating the delayed rectifier k currents idr in hippocampal and cortical pyramidal neurons where they are present as large highdensity clusters on the pm of somata and proximal dendrites | [10024359 14977411 16988031 22648171 30712450] | mediating k fluxes across the plasma membrane pm k channels are crucial determinants of neuronal excitability Among them voltagegated K channels KV are the largest family of K channels expressed in both the central and peripheral nervous system where they participate in different biological processes including the regulation of action potential conduction neurotransmitter release synaptic plasticity and apoptosis | [] |
118 | activated microglia and astrocytes play an important role in the clearance step of aβ phagocytosis | [31973106 18701698 21757877 28666707 20552234] | therefore, our results support the hypothesis of early plaque formation appearing before the onset of decline in neurogenesis. accumulation of aβ plaques induces inflammatory responses. | [] |
119 | we measured this plasticity through in vivo singleunit recording which although labor intensive and timeconsuming compared to intrinsic optical imaging or visually evoked field potentials 46 is a gold standard in quantifying vc plasticity | [22674275 25164659 8627365 32594561 16195464] | ODP may be a more sensitive readout of abnormalities in circuit functions than pathological or behavioral phenotypes we show that after monocular visual deprivation, 5xfad mice lack odp in vc during the normal critical period. | [] |
120 | recent studies based on neuropsychological tests or brain imaging data identified other mci subtype classification systems in which different subtypes of mci have different conversion rates to ad | [32142126 27239533 31128864 29455029 29323751] | this classification system divides mci into amnestic and nonamnestic mci, each further divided into a group with impairment in a single cognitive domain (single-domain mci) and a group with impairments in multiple cognitive domains (multiple-domain mci). it has been reported that amnestic mci regardless of whether it is single or multipledomain mci comparatively highly converts to dementia mainly ad dementia at a rate of 10 to 15 per year | [19752306] |
121 | affinity measurements of the copper complexes with aβ and tau indicated dissociation constants in the range from nanomolar to attomolar values 110111112 and from micromolar to high picomolar respectively | [20974842 10465554 10936205 18803399 31820933] | a better understanding of their relationship at a molecular level, could be beneficial for elucidating ad pathogenesis. in this regard, determining the affinity of metal ions for tau and aβ proteins is essential to understand the biological relevance of these metal complexes and predict which biomolecule could effectively compete with aβ and/or tau for metal ion complexation. | [] |
122 | although loss of financial capacity is a common consequence of ad 2 parkinsons disease 3 vascular dementia 4 frontotemporal dementia and amnestic mild cognitive impairment 6 only one study has investigated what caregivers of frontotemporal dementia patients believe | [29504530 31115356 32366802 33818175 33136558 33818175] | what biological factors, social determinants, and psychological and behavioral symptoms of patients with mild alzheimer’s disease correlate with caregiver estimations of financial capacity? bringing biases against older women into focus neurocognitive disorders such as alzheimers disease ad are often diagnosed in later stages due to its insidious onset and particularly in greece this can be explained by the fact that the general public is not able to recognize the early symptoms of this disorder attributes the symptoms as part of the normal aging process and shows general ignorance regarding this disease | [] |
123 | all participants provided written informed consent in accordance with the helsinki declaration and approval for the studies was obtained by the local ethics committeestable 4characteristics of the cohorts included in the studyadnijadniaibladdneuromedstudy designlongitudinal multicenter cohortlongitudinal multicenter cohortlongitudinal multicenter cohortlongitudinal multicenter cohortdata collection period2004present201820142006present20042010countryusa and canadajapanaustraliafinland france greece italy poland sweden and united kingdominclusion criteriammse 2026 cdr 051 age 65 nincdsadrda criteria for probable ad gds 6mmse 2026 cdr 051 age 65 nincdsadrda criteria for probable ad gds 6mmse 1826 cdr 05 nincdsadrda for criteria for probable ad icd10mmse 1228 age 60 nincdsadrda for criteria for probable ad and dsmivfollowup intervals312 months612 months18 months12 monthsstructural mri field strength15 t and 3 t15 t15 and 3 t15 tbiomarkers availableyesyesyesnocsf platform cutoffelecsys 880 pgmlaluminex 333 pgmlpet cut offfbb suvr 108av45 suvr 111bav45 suvr 111 pib suvr 148pib suvr 15mmse minimental state examination cdr clinical dementia rating gds geriatric depression scale nincdsadrda national institute of neurological and communicative disorders and strokealzheimers disease and related disorders association icd10 classification of mental and behavioral disorders suvr standardized uptake value ratio av45 florbetapir pib 11cpittsburgh compound b fbb florbetabenathe upenn biomarker batch 9 was used to quantify adni csf positivitybcomposite suvrs for fbp 111 or fbb 108 were defined as positive as described on the adni website httpsadnibitbucketioreferencedocsucberkeleyfbbucberkeley_fbb_methods_041119pdf | [29499171 29753531 29753531 23166389 29753531 27966045 20472326] | this study includes 891 ad dementia patients and 319 cu individuals from four international multicenter cohorts alzheimers disease neuroimaging initiative adni httpadniloniuscedu japanese adni jadni httpshumandbsbiosciencedbcjpenhum0043v1 addneuromed httpsconsortiapediafastercuresorgconsortiaanm and the australian imaging biomarkers and lifestyle study aibl australian adni httpsaiblcsiroau table the ad inclusion criteria of the four cohorts were similar since the research protocols of j-adni, aibl, and addneuromed were designed to be comparable with adni (supplementary material, p. 1–2). | [29753531 19470201] |
124 | obesity as measured by body mass index bmi has been reported to be associated with an increased risk of dementia in middle age and may reduce the risk of dementia in later life one hypothesis to explain the situation is a pattern of the socalled obesity paradox in which excess weight traditionally considered detrimental to health may be beneficial in older adults to reduce the disease risk however although bmi is widely accepted as an indicator of general adiposity in populationbased studies it cannot distinguish between fat and muscle mass which is highly variable at the same bmi level furthermore body composition is more informative than bmi because changes in bmi lag behind changes in body composition with dementia progression | [25866264 25030513 19273752 19273752 12117701 32803916] | total and regional fat‐to‐muscle mass ratio and risks of incident all‐cause dementia, alzheimer's disease, and vascular dementia dementia including alzheimers disease ad and vascular dementia vd is the fifth leading cause of death globally affecting approximately 44 million people worldwide due to the current lack of diseasemodifying therapies dementia prevention has become an urgent public health priority | [] |
125 | alzheimers disease ad the most common cause of dementia is a progressive neurodegenerative disorder that causes deficits in memory thinking decision making and social skills the pathophysiological events of ad begin years before the onset of clinical dementia the national institute on agingalzheimers association niaaa proposed three subsequent stages of ad including the preclinical stage of ad mild cognitive impairment mci and ad dementia the primary hypothesis on the progression of ad pathologies stated that the initial deposition of amyloidβ peptide aβ leads to subsequent tau hyperphosphorylation neuron and synaptic loss and cognitive decline however the continued failure of clinical trials aimed at decreasing aβ plaques implies that there may be alternative causes of disease progression or the neuronal injury of the late mci and ad dementia may be irreversible the long preclinical phase with mild neuronal damage provides a potentially crucial opportunity for exploring the potential pathogenic mechanisms of ad and preventing or delaying the progression of this disease | [21371747 21514250 21514249 21514248 21514248 32568197] | impaired type i interferon signaling activity implicated in the peripheral blood transcriptome of preclinical alzheimer's disease | [] |
126 | positron emission tomography petcomputed tomography ct was performed using pittsburgh compound b for amyloid and flortaucipir for tau and individuals were considered a using a threshold of standardized uptake value ratio suvr 148 centiloid 22 and t using a temporal lobe meta region of interest roi at a threshold of suvr 125 biomarker subgroups were based on the recently proposed research framework for a biological diagnosis of ad and included participants with negative amyloid and tau pet biomarkers at and participants with preclinical ad at | [25443857 18263627 27697430 28138510 29653606] | two participants (7%) in the a+t+ group were diagnosed with mci during at least one of their follow‐up visits (2–4), whereas <1% of a–t– participants were diagnosed with mci. for validation diagnosis followed typical mcsa procedures and was based on consensus among the neuropsychologist study coordinator and examining physician | [18259084] |
127 | mice with complete or partial enos deficiency enos or enos respectively display increased levels of app βsite app cleaving enzyme 1 bace1 and aβ amyloid angiopathy and altered neuronal p25 an aberrant activator of the tau kinase cyclindependent kinase 5 cdk5 in the brain as well as memory deficits | [21127294 23745722 30614363 27601478 26104027] | such agerelated enos deficiency may be an important early event contributing to later neurodegeneration in ad a number of animal studies have explored the link between enos deficiency and ad pathologies. | [24589433 16181125 22842871] |
128 | the oral cholinesterase inhibitor class of drugs is effective for improving the cognitive and global functioning of patients with ad and is the main pharmacological intervention used in the clinical management of ad however the incidence of adverse events aes associated with donepezil eg abdominal pain nausea and vomiting anorexia and diarrhea increases with the administered dose which can lead to difficulty in achieving and maintaining high therapeutic doses in clinical practice these dosedependent adverse symptoms linked to cholinergic hyperstimulation are related to plasma concentration fluctuations a novel therapeutic approach using a transdermal delivery system may be a solution to the abovementioned limitations | [ 9443470 15596605 23462265 28590369 15804207] | a multinational, multicenter, randomized, double-blind, active comparator, phase iii clinical trial to evaluate the efficacy and safety of donepezil transdermal patch in patients with alzheimer’s disease alzheimers disease ad is the most common type of senile dementia affecting 68 of people aged 65 years and nearly 30 of people aged 85 years every 5 years there is a twofold increase in the number of people aged 60 years affected by ad and so ad is expected to affect more than 115 million people worldwide by 2050 donepezil an oral cholinesterase inhibitor is widely used in clinical practice to treat mildtosevere ad symptoms | [] |
129 | the fact that shared risk factors for ad and brain disease such as hypertension 73 74 are also related to motor performance such as gait speed 75 and the fact that there are sex differences in motor performance 76 neuroanatomy 77 neurobiology 78 and agerelated neuropathology warrants studying sex differences | [31381518 21391929 29771288 29287628 30927602] | lastly, the reviewed studies did not look at sex differences in the relationship between motor function and brain measures, but merely adjusted for its effect statistically. it is therefore uncertain if the relationship between motor differences and brain differences in mci and ad differ by sex. | [] |
130 | currently prs seems most applicable to estimate risk in lateonset forms of ad 28 64 and has proven useful to stratify patients for clinical trials to reduce variability 65 66 and for genes that show reduced penetrance eg psen2 prs might influence clinical expression as has been shown for other diseases such as hereditary breast cancer | [34099642 29555425 34621978 31363735 32820175] | although a few families showed higher risk, this currently seems insufficient to justify clinical action — similar to apoe — until disease-modifying therapies or cost-effective preventive measures become available. as a result, although the prs will likely improve when more variants are added to it, we foresee it will not change this view on its clinical utility in familial eoad in the near future. | [] |
131 | alzheimers disease ad is a progressive neurodegenerative disorder manifested by cognitive and memory deterioration in addition to progressive impairments of activities of daily living and behavior and neuropsychiatric symptoms commonly used approved ad treatments are acetylcholinesterase inhibitors donepezil rivastigmine and galantamine and a noncompetitive nmethyldaspartic acid receptor blocker memantine however these do not slow the progression of the disease and only demonstrate modest efficacy to symptomatically improve or stabilize the clinical trajectory for most patients aducanumab an amyloidtargeting monoclonal antibody has been shown to remove amyloid plaques and holds promise for producing modest clinical benefits in early ad but requires monthly infusions and substantial safety monitoring including magnetic resonance imaging mri the modest efficacy and side effects of current treatment options along with a growing elderly population provide an impetus to develop more effective therapeutic agents with a wider range of application | [30704681 30704681 19724715 17466645 30925615 34585212] | effect of masupirdine (suvn‐502) on cognition in patients with moderate alzheimer's disease: a randomized, double‐blind, phase 2, proof‐of‐concept study | [] |
132 | arachidonic acid derivatives and other immune regulators are regulators of the neurogenic outcome and neuroregeneration in zebrafish | [23168169 23138980 27760324 31905199 31719242] | notch signaling is an important determinant of neurogenesis in vertebrate brains 31 and is related to glial cell proliferation arachidonic acid and its derivatives are among the key regulators of the immune system | [26932669 32476207 23863484 34064238] |
133 | in addition to bactericidal effects amps are also antiviral antifungal 33 antitumor 34 and immunomodulatory 22353637 and are involved in autoimmune diseases | [19217824 16257969 30314800 15892627 21178486] | these two modes of action do not allow bacteria to develop resistance unlike what happens to conventional antibiotics amps also inhibit bacterial protein nucleic acid cell wall synthesis and enzymatic activities | [28083516 31438824 11958294 25220491 25113635] |
134 | we present data on the detoxifying effects of gal201 on oligomers formed from aβ142 and on pyroglutamatemodified aβ aβpe3 | [21965666 23747948 12354296 17029395 21903077] | a detailed understanding of the formation of toxic aβ oligomers and their effects is essential to develop urgently required new treatments for ad patients. this manuscript describes pharmacological characteristics of the new drug candidate gal-201 as an aβ aggregation modulator based on data from binding experiments, from a rat pharmacokinetic study and from patch clamp and ltp experiments. | [] |
135 | in the literature it is widowhood of the patient that is reported as a risk factor of nhp as well as the fact of living alone being cared for by an adult offspring caregiver can be considered as a proxy report of living alone or being widowed and as such our finding is consistent with the literature some evidence suggests that spouses regard caregiving as part of their marital duties whereas for adult children such caregiver tasks require an important change in their lifestyle | [18606052 22759566 26658776 20723154 20374966] | we found the status of “offspring caregiver” to be a risk factor of nhp. the literature reports difficulties in life balance among adult offspring caregivers especially with regards to work workfamily life balance in the group of offspring caregivers the incidence of nhp is however similar independently of the patients marital status | [20723154] |
136 | our study also demonstrated that pathogenic genes such as csmd1 rbfox1 ptprd cdh13 and wwox were significantly related to ad | [25024348 32568366 30648269 29771432 34359949] | then, we used the top 10 bonferroni-corrected genes for gene identification. The significant common genes in the three groups are listed in Table 3. | [] |
137 | however the concentrations of these biomarkers in human blood are very low which is motivating the development of ultrasensitive assay technologies | [17499942 19204155 25086887 25300247 26136856] | a trend to evaluate the risk of alzheimers disease ad is the assay of biomarkers in blood the most recognized biomarkers related to ad are amyloid β 140 aβ140 and aβ142 peptides and total tau protein tau | [23470193 23850333 27870940 30922367 29653606 32390633 32784025 33075193] |
138 | several studies exhibited that picomolar concentrations of aβ42 can act as an agonist of α7nachrs 80 81 resulting in increased acetylcholine production in hippocampus 51 activated pi3k 33 and elevated expression of map kinase which eventually led to an increased level of ltp | [15009674 11983690 19749407 8916088 18832563] | aside from the positive correlation reported between low concentrations of aβ and ltp aβ has also been shown to target nicotinic acetylcholine receptors nachrs 76 77 which are known to promote synaptic plasticity neuroprotection learning and memory and regulate transmitter release in several brain regions including hippocampus interestingly, mounting evidence points to the possibility that this interaction too operates under hormesis. | [12436426 19126755 30471405 8878480 9736631] |
139 | a decrease in the volume of these brain regions in patients with depression may be associated with both a decrease in astrocyte density 8485 and neuronal atrophy 8586 and a decrease in the number and functioning of synapses | [26742791 23469922 23469922 15522247 25582786 31801966] | atrophy of these brain regions is considered as a significant predictor of the development of clinical dementia consequently, atrophy of the medial pfc and hippocampus may be associated with pre-existing depression and/or with early stages of dementia development. | [20375138 18258339 26306871] |
140 | depression is also associated with the suppressed expression of astrocytic s100b 114 aquaporin 4 85 as well as connexins 30 and 43 and the transcription factor sox9 regulating the expression of connexins | [20386568 23469922 10392848 21571253 27516431] | along with a decrease in astrocytes density, possibly occurring only in the most severe cases of depression, there are data indicating changes in the functioning of astrocytes in patients with mild depression. in the cortex lc and hippocampus transcriptomic analysis revealed a depressionassociated decrease in the expression of astrocytespecific glutamine synthetase and glutamate transporters which are involved in glutamateglutamine cycle between neurons and astrocytes and play an important role in the functioning of synapses | [ 1881516 20386568 16230605 26519765 19668376] |
141 | neuropsychiatric inventory npi 384649 was used to assess the behavioral symptoms while the wordrecognition task was used to assess recognition memory function | [24678298 31529691 24262299 18525028 24262299 21840288] | for the memory domain the assessment included the wordrecall task 4151 instructionremembering task 4651 rivermead behavioral memory test 38 rey auditory verbal learning test 38 tinetti balance scale 38 tinetti gait scale 38 word list memory test 41 nback 41 wechsler adult intelligence scale 4144 rey complex figure test 42 seoul verbal learning test 42 frontal assessment 43 category verbal fluency test 46 digit cancellation task and wordlist learning task the language was assessed by using the boston naming test 4142 picturenaming task and battery for analysis of aphasic deficits | [31285793 21840288 31529691 21840288 24678298 24678298 24678298 24678298
31285793 31285793 31285793 25346688 31196835 31196835 31555109 31529691
24262299 24262299 31285793 31196835 24678298 24678298] |
142 | as a result it disrupts the differentiation and maturation of precursor nerve cells inhibits the formation of new synapses and reduces the plasticity of neurons | [27725817 29520228 26509334 24711006 27179961] | in ad, however, there is chronic inflammation caused by continuous stimulation with pro-inflammatory agents. this causes the neurodegenerative action of microglia with uncontrolled production of pro-inflammatory cytokines through nf-κb activation and ineffective phagocytosis, preventing effective clearance and promoting β-amyloid production and deposition. | [] |
143 | from our initial list of potential publicly available datasets we selected six datasets based on the data availability the species and the presence of values for a fold change and adjusted pvalue figure 1 table 3 | [31908000 22728825 23430253 26139848 20041192] | the presence of three signalling pathways known to be important for locomotor function in our analysis, strongly suggests a central role for bace1 in the regulation of axon guidance and axonogenesis, beyond that of the cleavage of chl1. we explored the literature for proteomic datasets of proteins differentially expressed (de) in response to changes in bace1, through overexpression, knockout, knockdown, or inhibition. | [] |
144 | conversely epilepsy especially lateonset epilepsy of unknown etiology no cause identified after completing etiological study has been described as a risk factor for the development of ad | [25484360 34117482 33097597 32150220 17182059] | ad dementia and epilepsy frequently coexist, and there are reciprocal relationships between the two diseases. ad is an independent risk factor for epilepsy with an increased risk ranging from 2 to 10 times compared to agematched healthy controls | [33097599 32488295 32116260 28826176 29941211 25484360 26008894 28397967
34117482 29710705 31532186] |
145 | dna damage occurs in response to various endogenous biological activities in cells in which dna doublestrand break dsb is a predominant damage and can lead to cell death if not repaired | [26462757 21055985 19847258 32394945 19847258 22197993] | dna repair failure is a severe phenomenon for neurons since they lack cell division moreover dna damage accumulates in addition to the aging process and failure of dna repair affects transcription and translation resulting in breakdowns for genomic integrity | [26462757 32394945 26462757 15734677 31101070] |
146 | they suggest decreases in excess neuronal activity improved cognitive functions reduced amyloid plaque load in some cases or a rescue from the depletion of neuronal stem cells due to network hyperactivity see for a review | [25878292 22869752 22869752 23889921 23889921 31242408 33741601] | furthermore it appears that asms including lev do elicit such a positive effect on cognition even with chronic treatment in loeu patients without ad especially in patients diagnosed with focal seizures although the amount of randomized casecontrol studies remains too low for further conclusions preclinical results of antiepileptic treatments in ad are promising reviewed by and | [31726425 33314010 33741601 33929683] |
147 | global estimates of pain vary substantially across countries ranging from 10 to 50 country level factors associated with pain include income inequality gini index higher population density gender inequality lower life expectancy and region about 34 of adults in lmics reported chronic pain compared to 30 of adults in hics although there is increasing literature on pain as a potential risk factor for cognitive decline and adrd risk sex and gender differences have not been studied widely and even less so across cultures | [22697274 28586818 34155725 28586818 31694670 30543173] | few studies have assessed whether the relationship between tbi and adrd risk differs by sex and the evidence has been mixed this may be because adverse health and psychosocial factors throughout the lifespan moderate the risk of adrd following tbi for example greater exposure to adverse childhood experiences earlier in life has been observed as a risk factor for both tbi and other poor health behaviors and outcomes that interact throughout life to increase adrd risk many of the overlapping adverse psychosocial risk factors for tbi disproportionally affect women whereas sports and occupations two of the biggest risks for tbi differentially impact men in addition women are at greater risk for poorer healthrelated outcomes including adrd even at equivalent levels of these psychosocial risk factors few studies of tbi and dementia have been conducted in lmics where tbi rates are often higher than hics and few resources for treatment are available for example in pakistan domestic violence against women which sometimes results in head trauma is a significant problem in addition poor safety conditions frequent incidents of terrorism and political violence also contribute to the high rates of tbi in pakistan | [30541865 29801145 30852157 11071494 29381704 29653873 32719017 31806487
25122029 23117388 32031646 32383452 33992149 32031646 30317219 32741501
17615903 22514667 32887574 32425875 32425875] |
148 | several measures have been developed to examine neurocognitive function in populations with high rates of illiteracy andor low levels of formal education including the rowland universal dementia assessment scale neuropsi or the figure memory test although additional tools and normative data to be used in diverse cultural and geographical populations are still needed female advantage on verbal memory tests has critical implications for early detection and intervention because clinical tests of cognitive function in older adults often do not consider sex differences thus the verbal advantage for females could lead to a delayed diagnosis of mci compared to males and subsequently to a more rapid rate of deterioration and diagnosis of dementia for females | [32146910 10439587 34345358 31511111 34719502] | similarly, performance on neuropsychological tests is influenced by an individual's lived experiences and education and learning opportunities. low education levels have been identified as a risk factor for dementia with known gender disparities in access to educational opportunities in both hics and lmics | [31722961] |
149 | indeed the symptoms of the disease typically begin with mild memory difficulties 19 such as episodic memory loss due to the changes in the hippocampal volume 223 and to the disconnection of the hippocampus from the associative neocortical regions | [29653606 28164766 7745409 29147068 21086049] | nevertheless there is still no agreement about which cognitive screening instruments could be more sensitive and specific enough to detect ad in the early phases of disease several neuropsychological tests using long word lists have been usually administered to differentiate the subjective memory complaints which is a common symptom in an aging population 21 with the objective episodic memory impairment which seems to be unique of admci | [30819244 15450043 21594655] |
150 | the minimum clinically important difference mcid in cognitive efficacy was used for clinical significance defined as a mean change of 26 points for the adascog and 14 points for the tmse despite having less evidence regarding mcids for the remaining tests were used cutoffs of 5 points for the adcsadl 1 point for the cdrsb and 8 points for the npi | [33637039 21671540 31417957 20848576 11528012] | the primary endpoint figure in supporting information was the effectiveness of wme treatment versus placebo for enhancing cognitive function and nps as assessed by the neuropsychiatric tests at any visit improvements were measured by examining the mean score change and the proportion of participants who reported beneficial score changes. | [] |
151 | as antiseizure drugs we chose levetiracetam lev and lamotrigine ltg which are most often recommended for ad patients with epilepsy in addition we tested three experimental drugs for mechanistic purpose minocycline min an antiinflammatory antibiotic that has proven anticonvulsive in several seizure models 2 semagacestat sgs a gammasecretase inhibitor that failed to improve memory in a phase 3 clinical trial but proved effective in reducing amyloidβ aβ production in both mouse models and patients and 3 istradephylline ist an adenosine a2a antagonist based on its overexpression in ad patient and appps1 mouse hippocampus and its coupling to nmdamediated overexcitation we chose the doses based on the literature so that they should not cause motor side effects | [28327340 22366182 23883379 19519664 29950682] | the tested drugs and their vehicles and doses are summarized in table they included current ad drugs, donepezil (dpz) as a representative angiotensin‐converting enzyme (ace) inhibitor, and the n‐methyl‐d‐aspartate (nmda) receptor antagonist memantine (mem). | [] |
152 | previous studies have reported that activation of immune mediators is an important regulator of the ad pathology and dysfunction of immunemicroglia molecular network is one pathogenesis of ad 7 as well as of depression 8 trem2 is an immunerelated gene expressed in microglia promoting microglial phagocytosis chemotaxis and survival 9 10 and regulating the transition of microglia from homeostatic to diseaseassociated microglia dam | [31564456 26442697 32531244 30266932 28602351] | Recent evidence suggests that depressive symptoms together with aberrant Aβ accumulation could result in cognitive impairment and the development of dementia and the minimal depressive symptoms mdss a symptom prior to subclinical depressive symptoms were associated with abnormal amyloid pathologies and cognitive impairment | [32980133] |
153 | some studies showed that aβo and tauo impair synaptic plasticity and memory independently 16 17 while others reported that aβo acts upstream of tauo to drive ad pathogenesis | [21421841 28877993 26718979 17478722 18568035] | Low concentrations of AβO and TauO that would not normally perturb synaptic function effectively suppress longterm potentiation LTP and impair memory function when administered together the colocalization of aβo and tauo at the synaptosomes isolated from ad brains has been observed | [18467692] |
154 | lipid metabolism is closely related to the production metabolism and aggregation of aβ an important pathological product of ad abnormal sphingolipid metabolism occurs in the urine plasma brain tissue and cerebrospinal fluid of ad patients | [20303415 18547682 21957010 20953867 22293144] | although countless investments have been made in the war against ad, there is currently no known way to prevent or cure this disease. most of antiad drugs have a single molecular target and are mainly acetylcholinesterase inhibitors which is not an optimal choice for ad patients with multipathogenesis | [33579351] |
155 | in addition we found associations of rs9877502 in gmnc previously associated with ttau levels in this and other datasets 44 63 64 with levels of 696 csf proteins in ad individuals gmnc is involved in neuronal plasticity and regulation of gene expression | [33223526 23562540 28247064 26395491 20383140] | while markers in apbb2 do not show strong evidence for association with ad risk in gwas comparing controls with individuals with addementia the gene represents an interesting functional candidate as apbb2 binds aicd alternative splicing of apbb2 increased the aβ42 aβ40 ratio 87 and overexpression increased aβ140 app and aicd levels and changed gene expression | [30617256 23485396 14527950 23485396 12089154] |
156 | metaanalysis using the random effects model with the dersimonianlaird method of studies reporting relative risks rr a forest plot effect sizes are represented as red squares with 95 confidence intervals | [19634208 19387105 21757907 21490316 18289451] | however chronically insulin receptors at the bbb are downregulated and the amount of insulin that enters the brain decreases this phenomenon is called brain insulin resistance and gives prominence to the key role of gsk3β in ad pathogenesis in particular gsk3β is hyperactive and can phosphorylate tau which aggregates to form neurofibrillary tangles | [22820012 20420491] |
157 | more recently ccs have also been used to determine the role of some neurodegenerative diseaserelated proteins in the regulation of cell excitability ion channel currents bulk exocytosis and the fine kinetics of singlevesicle exocytotic events | [19641596 17108165 16087704 24366265 28259758] | the ccs are integrated into the sympathoadrenal axis which helps to maintain the body homoeostasis during both routine life and acute stress conditions these cells are widely used to explore neurotransmitter release and synaptic transmission and are considered to be the amplifying arm of the sympathetic nervous system the sudden and fast exocytotic release of their catecholaminesstored in noradrenergic and adrenergic cellsplays a fundamental role in the fightorflight response to stress | [22249377 22249377] |
158 | autophagic receptors such as nbr1 and p62 directly bind to atg8 homologs on autophagosomes for the degradation of protein aggregates | [21189453 16286508 18524774 19250911 17580304] | the receptor sqstm1-p62 (p62), the neighbor of brca1 gene 1 (nbr1), and the large junction protein alfy are important in aggrephagy. a deficiency of alfy or p62 is associated with neurodegeneration | [12598614 18346206] |
159 | the involvement of sdcs in the pathogenesis of ad has also been confirmed in several human studies the colocalization of sdcs with amyloid plaques has already been observed along with the correlation between ad pathology and sdc gene expression pattern | [34671250 2140065 2974240 1488123 30016411] | according to our studies, overexpression of sdcs, especially the neuronal sdc3, creates favorable conditions for the cellular accumulation and subsequent aggregation of misfolded proteins. seeding and spreading of pathological protein aggregates on the other hand has paramount importance in inducing neurodegeneration | [21624403 21045796] |
160 | another key mediator uncovered in our gsems is pa a factor positively affecting brain health neuroimaging studies on humans show brain atrophy with age that is mitigated in older adults who exercise exercise promotes neurogenesis in aged mice by stimulating mitochondrial regeneration and expression of vascular endothelial growth factor vegfa a growth factor supporting neuron proliferation brainderived neurotrophic factor bdnf a key mediator in brain connectivity and plasticity both supports growth and differentiation of new neurons and protects existing ones exercise in mice increases brain bdnf levels ubiquitously including with cognitionrelated regions although bdnf plays a critical role in ad controversial findings from human and animal studies question its precise role | [18094706 12586857 25002036 12086747 12086747 32052374] | noteworthy is the mediating effect of nutritional biomarkers, particularly among men, and that of diet quality among women. in fact several antioxidant vitamins including vitamins a and e as well as carotenoids and folate were previously found to directly impact brain function a recent trial vitacog carried out among patients with mild cognitive impairment indicated that brain gray matter regions vulnerable to ad eg medial temporal lobe benefited from highdose b vitamin supplementation by slowing 2year brain atrophy rates an effect detected only among hyperhomocysteinemic individuals the trial also suggested that b vitamin supplementation can stabilize executive function and reduce decline in global cognition and episodic and semantic memory moreover among carotenoids lutein or lutein zeaxanthin may have beneficial cognitive effects in older men and women as indicated by a recent randomized controlled trial more generally a recent study examining multiple nutritional biomarkers including plasma n3 fatty acids 25hydroxyvitamin d and homocysteine found that participants presenting without nutritional risk factors exhibited cognitive enhancement 003 standard units suy whereas each nutritional risk index nri point increase associated with an incremental acceleration cognitive decline nri1 reduced n3 fatty acids β 004 suy p 03 nri2 reduced 25hydroxyvitamin d β 008 suy p 0001 and nri3 elevated homocysteine β 011 suy p 0008 a recent study examining gender and race differences in the association between diet quality and cognition using more recent waves of nhanes 20112014 found that a 1 unit increase in the mediterranean diet score medi was associated with a 0039 95 ci 0016 to 0062 higher global cognitive zscore with the effect being stronger among nhw and in men conversely we found that diet quality is a stronger mediating factor in women than in men for racial disparities in dementia particularly for the nhb versus nhw contrast | [28130638 23690582 23321337 21780182 18510807 23690582 21780182 18510807
31921969 33614896] |
161 | the participants classification was accomplished according to a neuropsychological evaluation ad cooperative study adl scale for mild cognitive impairment adcsadlmci 24 clinical dementia rating cdr 25 functionality assessment questionnaire faq 26 minimental state examination mmse 27 repeatable battery for the assessment of neuropsychological statusdelayed memory rbansdm 28 and csf biomarkers ßamyloid42 total tau ttau and phosphorylated tau ptau following the recommendations of the national institute on agingalzheimers association niaaa | [ 9236950 7104545 7069156 9845158 21514249] | the latter group consisted of patients diagnosed with ftd or dlb. it should be noted that the study protocol was approved (approve number: 2019/0105) by the ethics committee (ceic) and all the participants gave their prior consent. | [] |
162 | in 2018 a national institute on agingalzheimers association niaaa working group developed a research framework to biologically define alzheimers disease ad similarly to previous clinicobiological criteria the research framework recommends dichotomization of ad biomarkers that is the use of normalabnormal status based on a single threshold to define biomarker profiles for amyloid tau and neurodegeneration proposing the atn system although this practical approach has enabled systematic characterization of ads preclinical phase and facilitated recruitment for clinical trials of diseasemodifying therapies the niaaa research framework acknowledges that dichotomization is context dependent and that continuousvariable modeling might be more appropriate for many studies in fact it also suggests that a threerange approach might also be a useful strategy in ad research | [29653606 21514248 24849862 29653606 21514248 24849862 23229078 30958413
29653606] | a three‐range approach enhances the prognostic utility of csf biomarkers in alzheimer's disease | [] |
163 | while treatments such as trazodone 21 40 60 risperidone 53 70 and suvorexant showed some promise in improving clinical and caregiver symptoms further data from larger prospective trials are required | [24495406 30689583 15157345 26279176 31944580] | as a result there remains uncertainty about the balance of benefits and risks associated with common sleep treatments when used in ad few studies evaluating the use of sleep medications in ad patients were identified and were generally small. | [29067350] |
164 | while no significant adverse events were reported in the studies included in this review antipsychotics can cause residual sedation confusion and falls and have metabolic and cardiovascular side effects | [26834500 24846773 12670415 7579786 19187704] | the use of antipsychotics in the treatment of sleep and other behavioral disturbances in ad has been extensively discussed while they may be useful in the treatment of sleep disturbances and to alleviate neuropsychiatric symptoms they are not without risks | [26834500 24846773 18346674 12670415 11602004 26279176] |
165 | over the last 10 years advances in technology have led to innovative solutions for the diagnosis 1617181920 management 21 and treatment of pwad | [28574362 27855415 29512255 27148050 28798682] | This screening finally yielded 8 articles for evaluation (Figure 1). two independent reviewers (d.m.c. and g.c.) extracted data of interest, and disagreements were discussed until a consensus was reached. | [] |
166 | enrolled individuals were outpatients in two cases 1618 in other cases they were recruited from memory clinics 17 alzheimers day centers 2022 or social senior centers | [28574362 29512255 27855415 27148050 28798682] | two studies 1618 based the ad diagnosis on the national institute on agingalzheimers association niaaa criteria 24 and three studies 171923 based it on the national institute of neurological and communicative disorders and stroke and the alzheimers disease related disorders association nincdsadrda criteria 25 with the supplement of the diagnostic and statistical manual of mental disorders fourth edition dsmiv 26 criteria in one case heterogeneity among participants was also found. | [28574362 29512255 21514250 27855415 28798682 6610841] |
167 | regarding animal models in spite of a convincingly demonstrated crosstalk between i gut microbiota perturbation and peripheral immunomodulation impact of microbiota on peripheral inflammation immunity and impact of microbiota on neuroinflammation ii peripheral inflammation and neuroinflammation 7 26 27 34 and iii neuroinflammation and neuronal activity the impact on synaptic activity of modulating microbiota has not been explored so far particularly when considering the presymptomatic changes in ad | [33582183 32340575 33381913 26048578 29735654] | targeting the gut microbiota and restoring its balance could represent a promising therapeutic strategy in ad. several approaches can be considered such as prebiotics food components typically nondigestible fiber compounds with the capacity of inducing growth or activity of beneficial microorganisms probiotics live microorganisms which confer a health benefit on the host when administered in adequate amounts or fmt which consists in transferring a solution of fecal matter from a healthy donor to restore the gut microbiota of a patient suffering from a microbiotarelated diseases | [33246175 32791113] |
168 | the finger population characteristics 24 trial protocol details 25 main relevant findings 26 and neuroimaging substudy have been previously published in detail | [25211775 23332672 25771249 29263220 31164160] | samples are sorted by apoe genotype apoe3/apoe3 (e3/e3) and e4/e4. student t-test was used to analyze the differences between groups. *p < 0.05; **p < 0.01; ****p < 0.0001 | [] |
169 | our bioinformatics strategy is based entirely on publicly available genomic datasets including genotype data gwas results and functional genomic datasets such as annotation of enhancer elements encode chromatin state position probability matrices for tf motifs encode homer factorbook hocomoco gene expression gtex portal and cardiogenetics and chipseq data | [22955616 29126249 20513432 22955990 23175603] | b, single tissue eqtls for various tissues including brain. eqtl, expression quantitative trait loci; gwas, genome‐wide association study; load, late‐onset alzheimer's disease; snp, single nucleotide polymorphism; tf, transcription factor in this article, we developed a new bioinformatics analysis pipeline to characterize and prioritize snps in enhancers located in load gwas regions based on their predicted effect to alter tf binding sites. | [] |
170 | while newer mechanisms and potential targets for diseasemodifying treatments are being explored there remains an urgent need for novel symptomatic drugs that can reinstate damaged or dysfunctional neurotransmission to provide sustained and clinically meaningful benefits for patients regardless of the outcome of the disease modification strategies | [30450030 31062825 31367008 32339611 29441009] | over the last two decades, many of the drug discovery strategies for alzheimer's disease (ad) have focused on disease‐modifying treatments targeting amyloid beta (aβ) pathology. despite extensive research and large numbers of clinical trials these as well as other targeted approaches have generally failed to show clinical benefit in the future it seems probable that multiple therapeutic approaches will be necessary to successfully treat ad | [30610216] |
171 | knowledge from the fields of oncology and genetic testing may offer a good starting point | [28317644 30507575 32393330 24179789 23578568] | nonetheless others did not consider biomarker information medically meaningful a dozen papers addressed the need for guidance regarding who to test what findings signify whether to disclose and how | [30154216 28891443 22550984 32393330] |
172 | for example cholinergic receptors may be adversely affected by beta amyloid peptides 15 but cholinergic neurotransmission also influences amyloid processing 16 17 and may protect neurons from amyloid toxicity | [17039298 7605915 1411529 26979166 33571523] | further support for the role of the cholinergic system in cognition comes from observations that cholinergic antagonists worsen attention and memory whereas procholinergic treatments provide modest symptomatic improvement in patients with ad dementia relationships between cholinergic system dysfunction and other ad pathologies are complex and bidirectional. | [29850777 22232050] |
173 | there are additional complex links between cholinergic system dysfunction and tau processing 2123 neuroinflammation 18 24 cortical volume loss 25 26 and apolipoprotein e ε4mediated neuronal alterations in the medial temporal cortex | [26979166 33921376 27312991 27811848 27707979] | for example cholinergic receptors may be adversely affected by beta amyloid peptides 15 but cholinergic neurotransmission also influences amyloid processing 16 17 and may protect neurons from amyloid toxicity tau pathology is prominent in the basal forebrain early in the ad process 4 and may initiate distant cortical degeneration | [17039298 7605915 1411529 26979166 33571523 23852922 32203580] |
174 | a total of 27 studies qualified with 26 of these studies being included in the ad blood gsh metaanalysis 3661 and 7 of these studies being included in the mci analysis | [18780972 18297609 18073509 31356205 26690564] | The search returned 299 unique records (Fig. 2). of the records screened, 40 studies were excluded as they were non-clinical studies (including reviews, editorials, and or conference abstracts); 70 studies were excluded because these studies involved non-human subjects; 81 studies were excluded as they were not conducted in ad or mci patients; 23 studies were excluded as they were post-mortem studies; 9 studies were excluded as they did not include a healthy control group; 47 studies were excluded as they did not measure gsh in whole blood, plasma, or serum; and 2 were excluded as full results could not be obtained. | [] |
175 | in studies examining blood gsh in ad 7 studies used the hachiniski ischaemic score his 4 to differentiate those with ad from those with potential vascular causes 41 46 and 5 of those studies further used neuroimaging to support diagnosis table 2 | [15202788 18073509 30443289 12094909 30611996 30443289 12094909 30611996] | ad patients were identified primarily using the diagnostic and statistical manual of mental disorders dsm 63 andor the national institute of neurological and communicative diseases and strokealzheimers disease and related disorders association the national institute on agingalzheimers association diagnostic guidelines 65 the dementia rating scale2 66 international classification of diseases 10th revision 67 and the consortium to establish a registry for alzheimers disease 68 neuropsychological battery were used in 5 gsh studies respectively | [ 6610841 21514250 18631955 29560372 17069783 26295825 25316430] |
176 | neuroinflammation is a key mechanism contributing to ad pathology previously it has been shown that appps1 mice express higher levels of proinflammatory cytokines and inflammasome we therefore investigated nob effects on cytokine gene expression and inflammasome formation using cortex samples figure | [25792098 34067173 27511018 25756590 33257576] | metascape analysis of these circadian deps revealed several enriched pathways including protein membrane localization and autophagy pathways in wtcntl receptor tyrosine kinase signaling in appps1cntl and behavior and mrna metabolic process in appps1nob figure c overall these results indicate nob restored protein landscape in app/ps1 mice in a circadian time‐dependent manner. | [] |
177 | the two most commonly used preclinical behavioral approaches in the evaluation of antipsychotics are the quantification of locomotive behavior hyperkinesis being an analogue of behavioral disorganization in psychosis and sensorimotor gating integrity with prepulse inhibition ppi of acoustic startle deficits of which have been reported in psychotic conditions currently approved typical and atypical d2receptorblocking medications used in the treatment of psychosis have been extensively studied in mice and consistently inhibit locomotive velocity rescue ppi deficits driven by psychotomimetic compounds and even increase sensorimotor gating integrity in otherwise untreated wildtype mice though there is evidence that pimavanserin which does not antagonize dopamine receptors can rescue ppi deficits and increase locomotion driven by psychotomimetics its ability to impact these behaviors has not been previously reported in transgenic models of ad | [31278012 19900963 19900963 17097724 21921840 22750845] | there is evidence that pimavanserin a medication approved for the treatment of parkinsons disease pd psychosis may be effective in treating psychosis in ad and other dementias pimavanserin is novel among antipsychotics as it does not antagonize dopamine receptors as all other available antipsychotics do rather it acts as an inverse agonist primarily at neuronal 5ht2a and to a lesser extent 5ht2c receptors with no appreciable activity at other targets including dopamine receptors this unique binding profile avoids the extrapyramidal side effects such as dystonia tremor and akathisia associated with dopamine blocking antipsychotics although the phenomenology of psychosis is a strictly human construct, a common strategy in the development of novel antipsychotic medications involves screening candidate compounds in preclinical models using behavioral outcomes established in human psychosis that can be observed in animal models. | [24682754 29452684 30298184 24682754 27503570] |
178 | these markers showed high diagnostic accuracy for established ad 4249 and identified ad before onset of dementia at the mci stage evidenced in single center 150 and largescale multicenter studies | [31884486 31526625 29558986 31201098 29287745] | the framework of ad diagnosis and research has changed dramatically through the development and application of biomarkers. core ad biomarkers include 1 cerebrospinal fluid csf low levels of aβ42 or the aβ4240 ratio and brain amyloid deposition evidenced by pet imaging 2 increased total tau ttau and phosphorylated tau ptau representing cortical neuronal loss and cortical tangle formation respectively and 3 hippocampal atrophy shown on mri | [27931796] |
179 | in this regard compelling evidence including geneticimaging studies suggests that genetic variants of the dlg1 gene are functionally linked to abnormal cognitive patterns in scz patients | [22225629 28990294 30319465 32692143 33133161] | conversely, no changes were observed in the expression levels of the protein encoded by the dlg1 gene, sap97, in both brain regions. taken together these results are puzzling since it has been demonstrated a pivotal role of this synaptic element in regulating the trafficking of the glutamate ampa receptors whose expression and function have been reported to be altered in scz | [32513544] |
180 | this test battery includes 10 different computerized tasks and eeg on a wide range of cns domains and is also sensitive to cholinergic effects all eligible patients entered the challenge phase consisting of two study days during which the effects of galantamine or placebo were measured according to a predefined time schedule with a 1 week washout period in between | [19648218 20142308 21306419 18187530 28217868] | before entering the study, all patients were screened for eligibility, including evaluation of diagnosis, use of medication, presence of contraindications for the use of galantamine, electrocardiogram (ecg) and laboratory investigations. also, a training session for the pharmacodynamic measurements performed with the neurocart® cns test battery was planned. | [] |
181 | interestingly tg2 also interacts with various other proteins strongly associated with the pathophysiology of ad such as apolipoprotein e heparan sulphate proteoglycans heat shock proteins gelsolin various mitochondrial proteins and proteins of the ubiquitin system | [26088696 23122413 16385579 29382685 26702927] | in addition tg2 and its crosslinking activity are present in sps and caa in post mortem tissue of ad cases and in glial cells associated with these lesions apart from tg2 association with ad brain lesions it is known to directly interact and posttranslationally modify soluble aβ monomers inducing neurotoxic protein multimers | [18673368 9797004 8103081 7922559 21300794 18055545 31923381 18397883] |
182 | recently researchers have identified elastin degradation as a potential contributor to aging oxidative stress and ad pathology | [10216959 1466664 19560218 22099332 29992983] | several reports demonstrate that oxidative stressinduced increases in metal ion redox potential also stimulate the upregulation of tau kinases amyloidbeta aβ is also implicated as a contributor to the cascade of molecular events that result in tau hyperphosphorylation and the inhibition of tau binding to microtubules by promoting glycogen synthase kinase 3 gsk3 activation | [22528780 12358761 9890432 24954411 10617124 17662457 28269780 7718249
19782073 19246243 15867159 9809590 18258852] |
183 | numerous studies have reported that ghrelin agonists improve diverse adrelated neuropathological features similar to asm inhibition | [33381011 31434007 33103129 31413143 22005105] | the effects on mitigation of hippocampal neurogenesis could also result from ceramide reduction by asm activity inhibition, and these combined effects of kari 201 contributed to an overall effective improvement of hippocampal memory impairment of ad mice (si appendix, fig. s23b | [] |
184 | for example after tbi ischemia and in neurodegenerative disease astrocytes enter a hypertrophic state characteristic of astrogliosis 31 117 and this process can contribute to impairments in gliovascular connections bbb permeability and cerebral blood circulation | [33589835 20012068 25828533 15846805 26671410] | this observation suggests that high concentrations of human aβ present in the tg mouse brain confers susceptibility for chronic dysfunction of perivascular astrocytes in the context of btbi exposure. astrocyte dysfunction has been reported in multiple models of cns insult. | [] |
185 | fibronectin is the adhesive protein that connects cells with collagen fibres in the ecm binds to cellsurface integrin regulating cytoskeleton reorganization and facilitates cell migration | [20944663 15250583 12732238 28092265 20690820] | this protein can bind to fibrinogen fibronectin laminin type v collagen and integrins alphavbeta1 hsamir1323p and hsamir2123p inversely related to cd44 which was previously found upregulated in severe alzheimers disease 46 hsamir30e5p and integrin beta1 itgb1 a receptor for collagen is another interaction and it was suggested to undergo plasticity through interactions with ecm proteins modulating ion channels intracellular ca2 and protein kinases signalling and reorganization of cytoskeletal filaments ecm and integrin aberrations are likely to contribute to imbalanced synaptic function in epilepsy alzheimers disease mental deficiency schizophrenia and other brain conditions hsamir13p hsamir4253p and hsamir12373p are all downregulated and all show the upregulated fibronectin fn1 as potential target | [22233753] |
186 | in this group of families we also found variants in app psen1 and psen2 usually associated with familial earlyonset forms of ad and mapt grn and c9orf72 usually associated with frontotemporal dementia ftd the most frequent variants were found were psen1 pa79v 046 of the families and the c9orf72 expansion 048 of the families | [26433351 29486463 22312439 29091718 29688227] | however, a number of other loci, labeled on the manhattan plot below, were nominally significant. many of these loci supported several large metaanalyses that included other cohorts | [24162737 30820047 30617256] |
187 | homoor heterodimers exhibit potent enzyme inhibition efficacy as assessed using computational and preclinical studies | [12369973 18517184 26325402 31132435 33930191] | cheis such as donepezil can inhibit ache activity via transitory binding to the pas andor the catalytic site of the enzyme potential control of ache activity via dual inhibitory binding site occupancy has led to the generation of hybrid ligands separated by suitable linkers or spacers. | [23478436 32096991] |
188 | recent evidence points towards autophagy as a key player in postischemic hippocampal neurodegeneration | [27472881 29363901 29128811 31707369 17035724] | according to the first option, the aforementioned lysosomal degradation of the cytoplasm’s own structures provides the neuron with substrates for energy production and protein synthesis. the second option is blamed on autophagyprogrammed neuronal cell death | [27472881 29363901 29128811 31707369] |
189 | clinical diagnosis for probable ad dlb and ftld was made according to international guidelines | [21325651 28592453 6610841 21514250 21810890] | our data strongly support a critical role for sorl1 in ad and related diseases and highlight sorl1 as a potential therapeutic target for drug development. This retrospective study was carried out on DNA from a total of n = 697 patients (n = 282 AD, n = 114 DLB, n = 301 FTLD) and n = 251 subjects with normal cognitive function (CTRL) (Table 1). | [] |
190 | plasma aβ42aβ40 was measured using a mass spectrometrybased assay araclon biotech phosphorylated tau ptau217 cerebrospinal fluid csf and plasma was measured on a meso scale discovery platform using an assay developed by eli lilly plasma neurofilament light was analyzed using a simoabased assay csf aβ4240 and neurofilament light were measured using the elecsys platform roche main analyses were performed using plasma biomarkers with findings using csfbased biomarkers reported in etables 3 to 5 in the | [27567833 32123385 32246036 31009028 33336877] | ethical approval was given by the regional ethical committee in lund, sweden. approval for pet imaging was obtained from the swedish medicines and products agency and the local radiation safety committee at skåne university hospital in sweden. | [] |
191 | each modification may be associated with activation of the target gene as in lysine acetylation 141142143144 and in other cases with repression and inactivation of a gene | [18628954 26136662 26159193 30559478 18234899] | the diversity of ptm-hs includes methylation, acetylation, o-glcnac modification, adp-ribosylation, the phosphorylation of serine and tyrosine residues, ubiquitination and the binding of molecules of the small ubiquitin-like modifier class (sumo) system via sumoylation. the methylation of lysine serine or arginine by the enzymatic action of histone methyltransferases hmt and demethylases hdmt and their acetylation by acetyltransferases hat and deacetylases hdac are among the beststudied epigenetic events with modifications controlled by fluctuations in the total histone levels and the enzymatic activities of several functionally distinct histones figure 2 | [25484284] |
192 | several tau pet tracers label nfts including 18fflortaucipir 2 18fgtp1 3 18fro948 4 18fmk240 5 and 18fpi220 | [26505746 31254035 30635637 29880509 31712323] | baseline [18f]gtp1 tau pet imaging is associated with subsequent cognitive decline in alzheimer’s disease neurofibrillary tangles nfts comprised of hyperphosphorylated tau protein are one of the defining neuropathological characteristics of alzheimers disease ad | [] |
193 | although astrocyte reactivity has so far been considered mainly a process aimed at resolving tissue damage the functional consequences on astrocytes are still controversial and studies have pointed out that the impact on surrounding cells might be beneficial or detrimental | [31429127 28099414 34616039 27027288 25014177] | concerning gfap, it is a key constituent of intermediate filaments in astrocytes and the most widely used marker of astrocyte reactivity. gfap immunoreactivity characterizes astrocytes in many cns disorders including ad 4789 however it does not necessarily characterize all reactive astrocytes and its upregulation varies depending on the pathology | [22553043 24269023 33908669 20185032 31429127] |
194 | of these seven articles five showed very good quality and low risk of bias supplementary materials table s6 | [28201726 22541366 23179169 26680338 16323253] | out of eight ma 1017182122242628 only five 18192225 detected publication bias using funnel plots 36 and another one also applied kendalls tau correlation coefficient seven articles concluded that the achei donepezil galantamine rivastigmine and tacrine have little or poor riskbenefit ratio in improving cognitive status and overall patient outcome by clinical interview supplementary materials table s5 | [27582220 28201726 17154660 18686744 16081444 10713577 16323253 28201726
22541366 18686744 26680338 12517232 9310563 12517232 28201726 22541366
12391943 23179169 16081444 26680338 16323253] |
195 | there are however several studies reporting lack of alterations in the aforementioned regions | [11255451 2908095 2975188 10908891 2252449] | the third main finding of this study pertains to the different vulnerability of the two main dopaminergic pathways in ad. previous in vivo and postmortem studies focused mainly on the nigrostriatal dopaminergic pathway reporting alterations in the sn 26 and in its major subcortical targets ie putamen 8 11 15 16 23 41 and caudate nucleus | [ 6204013 8742039 2870131 10908891 6155966 6200784 8742039 2870131
10908891 6155966] |
196 | as transcription regulates the abundance of metabolites metabolites also transfer the information back to the transcription network directly or indirectly interacting with a transcription factor | [21685093 31578326 24658329 27498839 20461071] | to further infer causal relationships among a large collection of dissimilar variables at different omics layers we can conduct bayesian probabilistic causal network bn analysis as we and others have previously done in ad and other complex traits moreover the static state bn analysis can be expanded to model dynamic and timedependent regulation changes in a longitudinal or timeseries dataset for example a dynamic bn dbn framework had been used to model the dynamic causal network of blood gene expression in response to food intake over multiple time points where intratimeslice bn structure from a large dataset generated at static states was combined with intertimeslice structure inferred from the time series data the datadriven causal networks will provide a systemswide context for understanding the mechanisms of known regulators and discovering novel key causal regulators among mrna protein and metabolite levels | [17432931 18552845 30283032 19270708 23622250 33238137 32770063 22806142
18822406 20168994] |
197 | recent studies used initialization or feature extraction by cnnbased tl architectures such as resnet deep resnet caffenet alexnet densenets vgg16 and inception with or without finetuning followed by an extended network architecture | [31853655 32275915 30598877 32210685 31132373] | however, the training process consumes considerable time, and the size of neuroimaging datasets is restricted, which may lead to overfitting. as we have seen in the previous discussion of dl architectures, tl is less time-consuming and shows better performance in comparison to training from scratch. | [] |
198 | several studies used different combinations of biomarkers to improve the accuracy of ad detection 9293pet images were used in | [28721928 30028955 29502031 29454006 32210685] | it is mainly beneficial for the early detection of ad as it can demonstrate the distinctive patterns of ad earlier them mri for mci subjects another type of pet is amyloidpet which is used to assess brain amyloid deposition one of the main neuropathological milestones of ad with an elevated sensitivity and specificity in patients with established alzheimers disease who underwent an autopsy within one year of pet imaging | [33098804 33098804] |
199 | dietary dha intake can modify the dha status of peripheral tissues such as blood and adipose tissue 79808182 dietary dha correlates with hippocampal volume in vivo 83 and neurological deficits of dha deficiency resolve with supplementation | [18435934 12612178 12499320 17574755 2139096] | similarly greater erythrocyte dha content corresponds with reduced risk of cognitive decline more recently a metaanalysis has shown that altered blood fatty acid composition is evident in individuals with mci and ad versus controls with individuals with ad showing the greatest number of altered fatty acids and degree of change of these fatty acids including dha | [12663275 32194194] |
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