In vivo and neuropathology data support locus coeruleus integrity as indicator of Alzheimer’s disease pathology and cognitive decline

2021 ◽  
Vol 13 (612) ◽  
Author(s):  
Heidi I. L. Jacobs ◽  
John A. Becker ◽  
Kenneth Kwong ◽  
Nina Engels-Domínguez ◽  
Prokopis C. Prokopiou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Locus Coeruleus ◽  
Data Support

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 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

scholarly journals Lower MR-indexed locus coeruleus integrity in autosomal-dominant Alzheimer’s disease is related to cortical tau burden and memory deficits

2020 ◽  
Author(s):  
Martin J. Dahl ◽  
Mara Mather ◽  
Markus Werkle-Bergner ◽  
Briana L. Kennedy ◽  
Yuchuan Qiao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
High Resolution ◽  
Locus Coeruleus ◽  
Autosomal Dominant ◽  
Brain Regions ◽  
Cognitive Testing ◽  
Autosomal Dominant Alzheimer’S Disease

AbstractAbnormally phosphorylated tau, an indicator of Alzheimer’s disease, begins to accumulate in the first decades of life in the locus coeruleus (LC), the primary source of cortical norepinephrine. Ensuing dysfunction in noradrenergic neuromodulation is hypothesized to contribute to Alzheimer’s progression. However, research into the role of the LC has been impeded by a lack of effective ways of assessing it in vivo. Advances in high-resolution brainstem magnetic resonance imaging (MRI) hold potential to investigate the association of locus coeruleus integrity and Alzheimer’s-related neuropathological markers in vivo.Leveraging a meta-analytical approach, we first synthesized LC localizations and dimensions across previously published studies to improve the reliability and validity of MR-based locus coeruleus detection. Next, we applied this refined volume of interest to determine whether MR-indexed LC integrity can serve as a marker for noradrenergic degeneration in early-onset Alzheimer’s disease. Eighteen participants (34.7±10.1 years; 9♀) with or known to be at-risk for mutations in genes associated with autosomal-dominant Alzheimer’s disease (ADAD) were investigated. Genotyping confirmed mutations in seven participants (PSEN1, n = 6; APP, n = 1), of which four were symptomatic. Participants underwent 3T-MRI, flortaucipir positron emission tomography (PET), and cognitive testing. LC MRI intensity, a non-invasive proxy for neuronal density, was semi-automatically extracted from high-resolution brainstem scans across the rostrocaudal extent of the nucleus.Relative to healthy controls, symptomatic participants showed lower LC intensity. This effect was pronounced in rostral segments of the nucleus that project to the mediotemporal lobe and other memory-relevant areas. Among carriers of ADAD-causing mutations, closer proximity to the mutation-specific median age of dementia diagnosis was associated with lower LC intensity. Leveraging a multivariate statistical approach, we revealed a pattern of LC-related tau pathology in occipito-temporo-parietal brain regions. Finally, higher locus intensity was closely linked to memory performance across a variety of neuropsychological tests.Our finding of diminished MR-indexed LC integrity in autosomal-dominant Alzheimer’s disease suggest a role of the noradrenergic system in this neurodegenerative disease.

scholarly journals The locus coeruleus: In‐vivo characterization with advanced MRI methods and associations with memory in older adults at risk for Alzheimer’s disease

2020 ◽  
Vol 16 (S4) ◽  
Author(s):  
Seraphina K. Solders ◽  
Alexandra L. Clark ◽  
Alexandra J. Weigand ◽  
Scott F. Sorg ◽  
Vitaly Galinsky ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
At Risk ◽  
Locus Coeruleus ◽  
In Vivo Characterization ◽  
With Memory

scholarly journals Associations of AT(N) biomarkers with neuropsychiatric symptoms in preclinical Alzheimer’s disease and cognitively unimpaired individuals

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Kok Pin Ng ◽  
Hui Chiew ◽  
Pedro Rosa-Neto ◽  
Nagaendran Kandiah ◽  
Zahinoor Ismail ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Longitudinal Studies ◽  
Neuropsychiatric Symptoms ◽  
Amyloid Β ◽  
Cross Sectional ◽  
Preclinical Ad ◽  
Cross Sectional Studies

AbstractThe development of in vivo biomarkers of Alzheimer’s disease (AD) has advanced the diagnosis of AD from a clinical syndrome to a biological construct. The preclinical stage of AD continuum is defined by the identification of AD biomarkers crossing the pathological threshold in cognitively unimpaired individuals. While neuropsychiatric symptoms (NPS) are non-cognitive symptoms that are increasingly recognized as early manifestations of AD, the associations of NPS with AD pathophysiology in preclinical AD remain unclear. Here, we review the associations between NPS and AD biomarkers amyloid-β (Aβ), tau and neurodegeneration in preclinical AD and cognitively-unimpaired individuals in 19 eligible English-language publications (8 cross-sectional studies, 10 longitudinal, 1 both cross-sectional and longitudinal). The cross-sectional studies have consistently shown that NPS, particularly depressive and anxiety symptoms, are associated with higher Aβ. The longitudinal studies have suggested that greater NPS are associated with higher Aβ and cognitive decline in cognitively unimpaired subjects over time. However, most of the studies have either cross-sectionally or longitudinally shown no association between NPS and tau pathology. For the association of NPS and neurodegeneration, two studies have shown that the cerebrospinal fluid total-tau is linked to longitudinal increase in NPS and that the NPS may predict longitudinal metabolic decline in preclinical AD, respectively. However, evidence for the association between atrophy and NPS in preclinical AD is less consistent. Therefore, future longitudinal studies with well-designed methodologies and NPS measurements are required not only to determine the relationship among AT(N) biomarkers, NPS and cognitive decline, but also to elucidate the contribution of comorbid pathology to preclinical AD.

scholarly journals In vivo assessment of the noradrenergic nucleus locus coeruleus in Alzheimer’s disease and other types of dementia

2020 ◽  
Vol 16 (S5) ◽  
Author(s):  
Filippo Sean Giorgi ◽  
Alessandro Galgani ◽  
Francesco Lombardo ◽  
Giovanni Palermo ◽  
Hlavata Hana ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Locus Coeruleus ◽  
In Vivo Assessment

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.

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