Arterial Stiffening and Cerebrovascular Resistance in Cognitive Decline and Alzheimer’s Disease

2020 ◽  
pp. 274-301
Author(s):  
Belinda Yew ◽  
Anna Blanken ◽  
Daniel A. Nation
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Vascular Dysfunction ◽  
Vascular Cognitive Impairment ◽  
Arterial Stiffening ◽  
Small Vessels ◽  
Cerebrovascular Resistance ◽  
The Impact

The impact of vascular factors on cognitive decline and Alzheimer’s disease (AD) has been increasingly recognized. AD and vascular cognitive impairment exhibit significant overlap, individuals with vascular risk factors experience elevated risk for AD, and vascular mechanisms have been implicated in the genetic and pathological processes underlying development of AD. Arterial stiffening and cerebrovascular resistance have been identified as potential junctions through which vascular dysfunction promotes AD pathogenesis and cognitive decline. This chapter outlines the pathophysiology of arterial stiffening and cerebrovascular resistance, beginning in the aorta and small vessels of the brain, respectively. As these processes proliferate, cerebral circulation is disrupted, compromising capacity to meet neuronal metabolic needs and culminating in cognitive declines. An overview is provided of in vivo markers for arterial stiffening and cerebrovascular resistance, including methods employing pulse wave velocity, transcranial Doppler ultrasonography, and arterial spin labeling magnetic resonance imaging. Relevant research developments and their implications for conceptualization of vascular contributions to cognitive decline are discussed.

scholarly journals Neuroticism alters the transcriptome of the frontal cortex to contribute to the cognitive decline and onset of Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Céline H. De Jager ◽  
Charles C. White ◽  
David A. Bennett ◽  
Yiyi Ma
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Brain Regions ◽  
Personality Characteristics ◽  
Tau Pathology ◽  
Postmortem Human Brain ◽  
Brain Transcriptome ◽  
Neo Five Factor Inventory ◽  
The Impact

AbstractAccumulating evidence has suggested that the molecular transcriptional mechanism contributes to Alzheimer’s disease (AD) and its endophenotypes of cognitive decline and neuropathological traits, β-amyloid (Aβ) and phosphorylated tangles (TAU). However, it is unknown what is the impact of the AD risk factors, personality characteristics assessed by the NEO Five-Factor Inventory, on the human brain’s transcriptome. Using postmortem human brain samples from 466 subjects, we found that neuroticism has a significant overall impact on the brain transcriptome (omnibus P = 0.005) but not the other four personality characteristics. Focused on those cognitive decline related gene co-expressed modules, neuroticism has nominally significant associations (P < 0.05) with four neuronal modules, which are more related to PHFtau than Aβ across all eight brain regions. Furthermore, the effect of neuroticism on cognitive decline and AD might be mediated through the expression of module 7 and TAU pathology (P = 0.008). To conclude, neuroticism has a broad impact on the transcriptome of human brains, and its effect on cognitive decline and AD may be mediated through gene transcription programs related to TAU pathology.

scholarly journals P-tau and neurodegeneration mediate the effect of β-amyloid on cognition in non-demented elders

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Ling-Zhi Ma ◽  
Hao Hu ◽  
Zuo-Teng Wang ◽  
Ya-Nan Ou ◽  
Qiang Dong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Mediating Effect ◽  
Total Effect ◽  
Independent Effect ◽  
Carrier Status ◽  
Mediation Effects ◽  
Β Amyloid ◽  
The Impact

Abstract Background There are many pathological changes in the brains of Alzheimer’s disease (AD) patients. For many years, the mainstream view on the pathogenesis of AD believes that β-amyloid (Aβ) usually acts independently in addition to triggering functions. However, the evidence now accumulating indicates another case that these pathological types have synergies. The objective of this study was to investigate whether effects of Aβ pathology on cognition were mediated by AD pathologies, including tau-related pathology (p-tau), neurodegeneration (t-tau, MRI measurements), axonal injury (NFL), synaptic dysfunction (neurogranin), and neuroinflammation (sTREM2, YKL-40). Methods Three hundred seventy normal controls (CN) and 623 MCI patients from the ADNI (Alzheimer’s Disease Neuroimaging Initiative) database were recruited in this research. Linear mixed-effects models were used to evaluate the associations of baseline Aβ with cognitive decline and biomarkers of several pathophysiological pathways. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects of AD pathologies on cognition. Results Tau-related pathology, neurodegeneration, neuroinflammation are correlated with the concentration of Aβ, even in CN participants. The results show that age, gender, and APOE ε4 carrier status have a moderating influence on some of these relationships. There is a stronger association of Aβ with biomarkers and cognitive changes in the elderly and females. In CN group, Aβ pathology is directly related to poor cognition and has no mediating effect (p < 0.05). In mild cognitive impairment, tau-related pathology (26.15% of total effect) and neurodegeneration (14.8% to 47.0% of total effect) mediate the impact of Aβ on cognition. Conclusions In conclusion, early Aβ accumulation has an independent effect on cognitive decline in CN and a tau, neurodegeneration-dependent effect in the subsequent cognitive decline in MCI patients.

Cognitive Decline and the Changing Self in Relationship

2015 ◽  
pp. 61-75
Author(s):  
Darby Morhardt ◽  
Marcia Spira
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Family Member ◽  
Family Members ◽  
Well Being ◽  
Family Roles ◽  
The Family ◽  
Person With Dementia ◽  
The Impact

When a member of a family is diagnosed with Alzheimer's disease, the impact of the disease reverberates throughout the relationships within the family. This paper explores the challenges and strengths within one family as members manage and cope with Alzheimer's disease. The person with dementia and his family members are individually interviewed and each person explores the consequences of the disease on personal well-being as well as the relationships within the family. The family demonstrates how dementia in one family member demands flexibility in family roles as they navigate life through the challenges of living with dementia.

Hemodynamics in Alzheimer’s Disease and Vascular Cognitive Impairment and Dementia

2020 ◽  
pp. 302-330
Author(s):  
Francis Cambronero ◽  
Angela L. Jefferson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Cerebrovascular Disease ◽  
Vascular System ◽  
Clinical Symptoms ◽  
Vascular Dysfunction ◽  
Critical Role ◽  
Vascular Cognitive Impairment ◽  
Aging Adults

Hemodynamic impairment is a prominent feature in aging, vascular cognitive impairment and dementia, and Alzheimer’s disease, including patterned changes in cerebral blood flow (CBF) that can be detected prior to concomitant pathologies. These CBF abnormalities drive vascular dysfunction through a variety of biological pathways and ultimately contribute to cerebrovascular disease associated with cognitive impairment. Importantly, the co-existence of cerebrovascular disease and Alzheimer’s disease is exceedingly common and worsens the progression of clinical symptoms, likely through accelerating neurotoxic protein deposition and the loss of cerebrovascular integrity. Emerging evidence further suggests that the brain may be more susceptible to subclinical cardiovascular dysfunction in aging adults, particularly since the accumulation of cardiovascular risk factors over the lifespan creates a more vulnerable vascular system. Although age-associated CBF dysregulation has varied and complex origins, it undoubtedly serves a critical role in the early progression of neurodegenerative disease and may help explain the considerable overlap between the most common clinical dementias.

scholarly journals Anti-Inflammatory Activity of A Polyphenolic Extract from Arabidopsis thaliana in In Vitro and In Vivo Models of Alzheimer’s Disease

2019 ◽  
Vol 20 (3) ◽  
pp. 708 ◽  
Author(s):  
Roberto Mattioli ◽  
Antonio Francioso ◽  
Maria d’Erme ◽  
Maurizio Trovato ◽  
Patrizia Mancini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Arabidopsis Thaliana ◽  
Heme Oxygenase 1 ◽  
Neuroprotective Effects ◽  
In Vivo Models ◽  
Polyphenolic Extract ◽  
Anti Inflammatory ◽  
The Impact

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the primary form of dementia in the elderly. One of the main features of AD is the increase in amyloid-beta (Aβ) peptide production and aggregation, leading to oxidative stress, neuroinflammation and neurodegeneration. Polyphenols are well known for their antioxidant, anti-inflammatory and neuroprotective effects and have been proposed as possible therapeutic agents against AD. Here, we investigated the effects of a polyphenolic extract of Arabidopsis thaliana (a plant belonging to the Brassicaceae family) on inflammatory response induced by Aβ. BV2 murine microglia cells treated with both Aβ25–35 peptide and extract showed a lower pro-inflammatory (IL-6, IL-1β, TNF-α) and a higher anti-inflammatory (IL-4, IL-10, IL-13) cytokine production compared to cells treated with Aβ only. The activation of the Nrf2-antioxidant response element signaling pathway in treated cells resulted in the upregulation of heme oxygenase-1 mRNA and in an increase of NAD(P)H:quinone oxidoreductase 1 activity. To establish whether the extract is also effective against Aβ-induced neurotoxicity in vivo, we evaluated its effect on the impaired climbing ability of AD Drosophila flies expressing human Aβ1–42. Arabidopsis extract significantly restored the locomotor activity of these flies, thus confirming its neuroprotective effects also in vivo. These results point to a protective effect of the Arabidopsis extract in AD, and prompt its use as a model in studying the impact of complex mixtures derived from plant-based food on neurodegenerative diseases.

The Impact of Amyloid-β or Tau on Cognitive Change in the Presence of Severe Cerebrovascular Disease

2020 ◽  
Vol 78 (2) ◽  
pp. 573-585
Author(s):  
Hyemin Jang ◽  
Hee Jin Kim ◽  
Yeong Sim Choe ◽  
Soo-Jong Kim ◽  
Seongbeom Park ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Interaction Effect ◽  
Significant Interaction ◽  
Amyloid Β ◽  
Cognitive Change ◽  
Significant Interaction Effect ◽  
The Impact

Background: As Alzheimer’s disease (AD) and cerebral small vessel disease (CSVD) commonly coexist, the interaction between two has been of the considerable interest. Objective: We determined whether the association of Aβ and tau with cognitive decline differs by the presence of significant CSVD. Methods: We included 60 subcortical vascular cognitive impairment (SVCI) from Samsung Medical Center and 82 Alzheimer’s disease-related cognitive impairment (ADCI) from ADNI, who underwent Aβ (florbetaben or florbetapir) and tau (flortaucipir, FTP) PET imaging. They were retrospectively assessed for 5.0±3.9 and 5.6±1.9 years with Clinical Dementia Rating-sum of boxes (CDR-SB)/Mini-Mental State Examination (MMSE). Mixed effects models were used to investigate the interaction between Aβ/tau and group on CDR-SB/MMSE changes. Results: The frequency of Aβ positivity (45% versus 54.9%, p = 0.556) and mean global FTP SUVR (1.17±0.21 versus 1.16±0.17, p = 0.702) were not different between the two groups. We found a significant interaction effect of Aβ positivity and SVCI group on CDR-SB increase/MMSE decrease (p = 0.013/p < 0.001), and a significant interaction effect of global FTP uptake and SVCI group on CDR-SB increase/MMSE decrease (p < 0.001 and p = 0.030). Finally, the interaction effects of regional tau and group were prominent in the Braak III/IV (p = 0.001) and V/VI (p = 0.003) not in Braak I/II region (p = 0.398). Conclusion: The association between Aβ/tau and cognitive decline is stronger in SVCI than in ADCI. Therefore, our findings suggested that Aβ positivity or tau burden (particularly in the Braak III/IV or V/VI regions) and CSVD might synergistically affect cognitive decline.

scholarly journals Targeting MicroRNA-485-3p Blocks Alzheimer’s Disease Progression

2021 ◽  
Vol 22 (23) ◽  
pp. 13136
Author(s):  
Han Seok Koh ◽  
SangJoon Lee ◽  
Hyo Jin Lee ◽  
Jae-Woong Min ◽  
Takeshi Iwatsubo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Treatment Strategies ◽  
Tau Pathology ◽  
Memory Decline ◽  
Tnf Α ◽  
The Brain

Alzheimer’s disease (AD) is a form of dementia characterized by progressive memory decline and cognitive dysfunction. With only one FDA-approved therapy, effective treatment strategies for AD are urgently needed. In this study, we found that microRNA-485-3p (miR-485-3p) was overexpressed in the brain tissues, cerebrospinal fluid, and plasma of patients with AD, and its antisense oligonucleotide (ASO) reduced Aβ plaque accumulation, tau pathology development, neuroinflammation, and cognitive decline in a transgenic mouse model of AD. Mechanistically, miR-485-3p ASO enhanced Aβ clearance via CD36-mediated phagocytosis of Aβ in vitro and in vivo. Furthermore, miR-485-3p ASO administration reduced apoptosis, thereby effectively decreasing truncated tau levels. Moreover, miR-485-3p ASO treatment reduced secretion of proinflammatory cytokines, including IL-1β and TNF-α, and eventually relieved cognitive impairment. Collectively, our findings suggest that miR-485-3p is a useful biomarker of the inflammatory pathophysiology of AD and that miR-485-3p ASO represents a potential therapeutic candidate for managing AD pathology and cognitive decline.

scholarly journals Neuropathological correlates and genetic architecture of microglial activation in elderly human brain

2018 ◽  
Author(s):  
Daniel Felsky ◽  
Tina Roostaei ◽  
Kwangsik Nho ◽  
Shannon L. Risacher ◽  
Elizabeth M. Bradshaw ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Cognitive Decline ◽  
Genetic Architecture ◽  
Microglial Activation ◽  
Brain Health ◽  
Positron Emission ◽  
Genome Wide

AbstractMicroglia, the resident immune cells of the brain, have important roles in brain health. However, little is known about the regulation and consequences of microglial activation in the aging human brain. We assessed the effect of microglial activation in the aging human brain by calculating the proportion of activated microglia (PAM), based on morphologically defined stages of activation in four regions sampled postmortem from up to 225 elderly individuals. We found that cortical and not subcortical PAM measures were strongly associated with β-amyloid, tau-related neuropathology, and rates of cognitive decline. Effect sizes for PAM measures are substantial, comparable to that of APOE ɛ4, the strongest genetic risk factor for Alzheimer’s disease. Mediation modeling suggests that PAM accelerates accumulation of tau pathology leading to cognitive decline, supporting an upstream role for microglial activation in Alzheimer’s disease. Genome-wide analyses identified a common variant (rs2997325) influencing cortical PAM that also affected in vivo microglial activation measured by positron emission tomography using [11C]-PBR28 in an independent cohort. Finally, we identify overlaps of PAM’s genetic architecture with those of Alzheimer’s disease, educational attainment, and several other traits.

scholarly journals Cholesterol Alters Mitophagy by Impairing Optineurin Recruitment and Lysosomal Clearance in Alzheimer’s Disease

2020 ◽  
Author(s):  
Vicente Roca-Agujetas ◽  
Elisabet Barbero-Camps ◽  
Cristina de Dios ◽  
Petar Podlesniy ◽  
Albert Morales ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholesterol Homeostasis ◽  
Critical Event ◽  
Primary Neurons ◽  
Cholesterol Levels ◽  
Swedish Mutation ◽  
Intracellular Cholesterol ◽  
The Impact

Abstract Background: Emerging evidence indicates that impaired mitophagy-mediated clearance of defective mitochondria is a critical event in Alzheimer’s disease (AD) pathogenesis. Amyloid-beta (A) metabolism and the microtubule-associated protein tau have been reported to regulate key components of the mitophagy machinery. However, the mechanisms that lead to mitophagy dysfunction in AD are not fully deciphered. We have previously shown that intraneuronal cholesterol accumulation can disrupt the autophagy flux, resulting in low A clearance. In this study, we examine the impact of neuronal cholesterol changes on mitochondrial removal by autophagy.Methods: Regulation of PINK1-parkin-mediated mitophagy was investigated in conditions of acute (in vitro) and chronic (in vivo) high cholesterol loading using cholesterol-enriched SH-SY5Y cells, cultured primary neurons from transgenic mice overexpressing active SREBF2 (sterol regulatory element binding factor 2), and mice of increasing age that express the amyloid precursor protein with the familial Alzheimer Swedish mutation (Mo/HuAPP695swe) and mutant presenilin 1 (PS1-dE9) together with active SREBF2.Results: In cholesterol-enriched SH-SY5Y cells and cultured primary neurons, high intracellular cholesterol levels stimulated mitochondrial PINK1 accumulation and mitophagosomes formation triggered by A while impairing lysosomal-mediated clearance. Antioxidant recovery of cholesterol-induced mitochondrial glutathione (GSH) depletion prevented mitophagosomes formation indicating mitochondrial ROS involvement. Interestingly, when brain cholesterol accumulated chronically in aged APP-PSEN1-SREBF2 mice the mitophagy flux was affected at the early steps of the pathway, with defective recruitment of the key autophagy receptor optineurin (OPTN). Sustained cholesterol-induced alterations in APP-PSEN1-SREBF2 mice promoted an age-dependent accumulation of OPTN into HDAC6-positive aggresomes, which disappeared after in vivo treatment with GSH ethyl ester (GSHee). The analyses in post-mortem brain tissues from individuals with AD confirmed these findings, showing OPTN in aggresome-like structures that correlated with high mitochondrial cholesterol levels in late AD stages. Conclusions: Our data demonstrate that accumulation of intracellular cholesterol reduces the clearance of defective mitochondria and suggest recovery of the cholesterol homeostasis and the mitochondrial scavenging of ROS as potential therapeutic targets for AD.

scholarly journals In vivo Braak‐staging using 18 F‐Flortaucipir‐tau‐PET as a predictive marker for future cognitive decline in Alzheimer’s disease

2021 ◽  
Vol 17 (S1) ◽  
Author(s):  
Davina Biel ◽  
Matthias Brendel ◽  
Anna Rubinski ◽  
Katharina Buerger ◽  
Daniel Janowitz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Predictive Marker ◽  
Braak Staging ◽  
Tau Pet
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