scholarly journals Objective subtle cognitive difficulties predict future amyloid accumulation and neurodegeneration

Neurology ◽  
2019 ◽  
Vol 94 (4) ◽  
pp. e397-e406 ◽  
Author(s):  
Kelsey R. Thomas ◽  
Katherine J. Bangen ◽  
Alexandra J. Weigand ◽  
Emily C. Edmonds ◽  
Christina G. Wong ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Neuropsychological Testing ◽  
Selective Vulnerability ◽  
Hippocampal Volume ◽  
Rate Of Change ◽  
Hippocampal Atrophy ◽  
Amyloid Pet ◽  
Cortical Thinning ◽  
Cognitive Difficulties ◽  
Amyloid Accumulation

ObjectiveTo determine the temporal sequence of objectively defined subtle cognitive difficulties (Obj-SCD) in relation to amyloidosis and neurodegeneration, the current study examined the trajectories of amyloid PET and medial temporal neurodegeneration in participants with Obj-SCD relative to cognitively normal (CN) and mild cognitive impairment (MCI) groups.MethodA total of 747 Alzheimer's Disease Neuroimaging Initiative participants (305 CN, 153 Obj-SCD, 289 MCI) underwent neuropsychological testing and serial amyloid PET and structural MRI examinations. Linear mixed effects models examined 4-year rate of change in cortical 18F-florbetapir PET, entorhinal cortex thickness, and hippocampal volume in those classified as Obj-SCD and MCI relative to CN.ResultAmyloid accumulation was faster in the Obj-SCD group than in the CN group; the MCI and CN groups did not significantly differ from each other. The Obj-SCD and MCI groups both demonstrated faster entorhinal cortical thinning relative to the CN group; only the MCI group exhibited faster hippocampal atrophy than CN participants.ConclusionRelative to CN participants, Obj-SCD was associated with faster amyloid accumulation and selective vulnerability of entorhinal cortical thinning, whereas MCI was associated with faster entorhinal and hippocampal atrophy. Findings suggest that Obj-SCD, operationally defined using sensitive neuropsychological measures, can be identified prior to or during the preclinical stage of amyloid deposition. Further, consistent with the Braak neurofibrillary staging scheme, Obj-SCD status may track with early entorhinal pathologic changes, whereas MCI may track with more widespread medial temporal change. Thus, Obj-SCD may be a sensitive and noninvasive predictor of encroaching amyloidosis and neurodegeneration, prior to frank cognitive impairment associated with MCI.

Hippocampal Volume and Amyloid PET Status Three Years After Ischemic Stroke: A Pilot Study

2021 ◽  
Vol 80 (2) ◽  
pp. 527-532
Author(s):  
Amy Brodtmann ◽  
Mohamed Salah Khlif ◽  
Laura J. Bird ◽  
Toby Cumming ◽  
Emilio Werden
Keyword(s):  
Ischemic Stroke ◽  
Cognitive Impairment ◽  
Pilot Study ◽  
Neurodegenerative Disorders ◽  
Hippocampal Volume ◽  
Hippocampal Atrophy ◽  
Stroke Survivors ◽  
Amyloid Pet ◽  
Recall Memory ◽  
Cardinal Feature

Hippocampal atrophy is seen in many neurodegenerative disorders and may be a cardinal feature of vascular neurodegeneration. We examined hippocampal volume (HV) in a group of ischemic stroke survivors with amyloid 18F-NAV4694 PET imaging three years after stroke. We compared HV between the amyloid-positive (n = 4) and amyloid-negative (n = 29) groups, and associations with co-morbidities using Charlson Comorbidity Indices and multi-way ANOVA. Amyloid status was not associated with verbal or visual delayed free recall memory indices or cognitive impairment. We found no association between amyloid status and HV in this group of ischemic stroke survivors.

The role of high-mobility group box protein 1 in chronic cerebral hypoperfusion-induced vascular cognitive impairment animals

2019 ◽  
Author(s):  
Amelia Nur Vidyanti ◽  
Jia-Yu Hsieh ◽  
Kun-Ju Lin ◽  
Yao-Ching Fang ◽  
Ismail Setyopranoto ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Decline ◽  
High Mobility ◽  
Vascular Cognitive Impairment ◽  
High Mobility Group ◽  
Cerebral Hypoperfusion ◽  
Hippocampal Atrophy ◽  
Amyloid Pet ◽  
Knock Out

Abstract Background: The molecular mechanisms of vascular cognitive impairment (VCI) are diverse and still in puzzle. VCI could be attributed to chronic cerebral hypoperfusion (CCH). CCH may cause a cascade of reactions involved in ischemia and neuro-inflammation which plays important roles in the pathophysiology of VCI. High-mobility group box protein 1 (HMGB1) is a non-histone protein that serves as a damage-associated molecular signal leading to cascades of inflammation. Increased level of HMGB1 has been established in the acute phase of CCH. However, the role of HMGB1 at the chronic phase of CCH remains elucidated. Methods: We performed modified bilateral common carotid artery occlusion (BCCAO) in C57BL/6 mice to induce CCH. We examined the cerebral blood flow (CBF) reduction by laser doppler flowmetry, the protein expression of HMGB1 and its pro-inflammatory cytokines (TNF-a, IL-1b, and IL-6) by western blotting and immunohistochemistry. The brain pathology was assessed by 7T-animal MRI and amyloid-b accumulation was assessed by amyloid-PET scanning. We further evaluated the effect of HMGB1 suppression by injecting CRISPR/Cas9 knock-out plasmid intra-hippocampus bilaterally. Results: There were reduction of CBF up to 50% which persisted three months after CCH. The modified-BCCAO animals developed significant cognitive decline. The 7T-MRI image showed hippocampal atrophy, although the amyloid-PET showed no significant amyloid-beta accumulation. Increased protein levels of HMGB1, TNF-a and IL-1b were found three months after BCCAO. HMGB1 suppression by CRISPR/Cas9 knock-out plasmid restored the CBF, IL-1B, TNF-alpha, IL-6, and attenuated hippocampal atrophy and cognitive decline. Conclusion: HMGB1 plays a pivotal role in the pathophysiology of the animal model of CCH and it might be a candidate as therapeutic targets of VCI.

Hippocampal atrophy correlates with the severity of cognitive decline

2006 ◽  
Vol 19 (4) ◽  
pp. 767-777 ◽  
Author(s):  
Burcu Balam Yavuz ◽  
Servet Ariogul ◽  
Mustafa Cankurtaran ◽  
Kader Karli Oguz ◽  
Meltem Halil ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Cognitive Impairment ◽  
Early Diagnosis ◽  
Cognitive Decline ◽  
Multivariate Regression Analysis ◽  
Hippocampal Volume ◽  
Cognitive Status ◽  
Hippocampal Atrophy ◽  
Covariate Effects ◽  
Left Hippocampus

Background: The aim of this study is to compare the results of magnetic resonance (MR) imaging, particularly the decline in hippocampal volume, of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) with healthy age-matched controls, to examine the reliability of hippocampal volumetry in the early diagnosis of AD and the correlation of the severity of hippocampal atrophy with the severity of cognitive decline.Methods: Twenty-six AD, 22 MCI and 15 normal cognitive status (NCS) patients were scanned with a 3 Tesla MR scanner. Hippocampus volumes were detected manually by Osiris 4.18.Results: Multivariate regression analysis, which was performed to adjust the covariate effects of education, age, gender, hypertension and diabetes mellitus, showed that hippocampal atrophy was correlated with AD and MCI for right hippocampus; AD, MCI and age for left hippocampus independent of other parameters. A second regression analysis revealed that MMSE was correlated with hippocampal volume.Conclusions: Hippocampal volumetry can be used in early diagnosis of cognitive impairment, as well as grading cognitive decline.

scholarly journals Sirt1 Protects Against Hippocampal Atrophy and its Induced Cognitive Impairment in Middle-aged Mice

2021 ◽  
Author(s):  
Zuhao Sun ◽  
Shuang Zhao ◽  
Xinjun Suo ◽  
Yan Dou
Keyword(s):  
Cognitive Impairment ◽  
Molecular Mechanisms ◽  
Hippocampal Volume ◽  
Sirtuin 1 ◽  
Spatial Learning And Memory ◽  
Hippocampal Atrophy ◽  
Middle Aged ◽  
Adeno Associated Virus ◽  
Aged Mice ◽  
Magnetic Resonance Imaging Mri

Abstract Background: Sirtuin 1 (Sirt1) is a recognized longevity gene and has been shown to be associated with aging and its related diseases. Hippocampal volume is considered to be the most sensitive brain imaging phenotype for cognition, but the effect of Sirt1 on hippocampal morphology during aging has not been reported. Results: Herein, we investigated the effect of conditional Sirt1 knockdown on hippocampal volume in middle-aged mice, as well as its cognitive function and the underlying molecular mechanisms. Brain structural magnetic resonance imaging (MRI) showed that adeno-associated virus (AAV) mediated hippocampal Sirt1 knockdown caused hippocampal atrophy in 8-month-old mice. Open field test (OFT) and Morris Water Maze (MWM) test revealed that hippocampal Sirt1 knockdown significantly weakened spatial learning and memory of mice without effect on anxiety and exploratory behavior. Western blotting analysis showed that p-tau levels were significantly increased while PSD95 levels were obviously reduced, indicating that hippocampal Sirt1 knockdown could activate tau pathology and synaptic damage.Conclusions: This work revealed that Sirt1 is an important protective gene against hippocampal atrophy and its induced cognitive impairment during aging, providing potential therapeutic targets for the prevention and intervention of aging-related neuropsychic diseases.

scholarly journals Altered Volume and Structural Connectivity of the Hippocampus in Alzheimer’s Disease and Amnestic Mild Cognitive Impairment

2021 ◽  
Vol 13 ◽  
Author(s):  
Feng Feng ◽  
Weijie Huang ◽  
Qingqing Meng ◽  
Weijun Hao ◽  
Hongxiang Yao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Diffusion Tensor ◽  
Structural Connectivity ◽  
Hippocampal Volume ◽  
Brain Regions ◽  
Amnestic Mild Cognitive Impairment ◽  
Hippocampal Atrophy

Background: Hippocampal atrophy is a characteristic of Alzheimer’s disease (AD). However, alterations in structural connectivity (number of connecting fibers) between the hippocampus and whole brain regions due to hippocampal atrophy remain largely unknown in AD and its prodromal stage, amnestic mild cognitive impairment (aMCI).Methods: We collected high-resolution structural MRI (sMRI) and diffusion tensor imaging (DTI) data from 36 AD patients, 30 aMCI patients, and 41 normal control (NC) subjects. First, the volume and structural connectivity of the bilateral hippocampi were compared among the three groups. Second, correlations between volume and structural connectivity in the ipsilateral hippocampus were further analyzed. Finally, classification ability by hippocampal volume, its structural connectivity, and their combination were evaluated.Results: Although the volume and structural connectivity of the bilateral hippocampi were decreased in patients with AD and aMCI, only hippocampal volume correlated with neuropsychological test scores. However, positive correlations between hippocampal volume and ipsilateral structural connectivity were displayed in patients with AD and aMCI. Furthermore, classification accuracy (ACC) was higher in AD vs. aMCI and aMCI vs. NC by the combination of hippocampal volume and structural connectivity than by a single parameter. The highest values of the area under the receiver operating characteristic (ROC) curve (AUC) in every two groups were all obtained by combining hippocampal volume and structural connectivity.Conclusions: Our results showed that the combination of hippocampal volume and structural connectivity (number of connecting fibers) is a new perspective for the discrimination of AD and aMCI.

scholarly journals Obstructive Sleep Apnea is Associated with Longitudinal Increases in Amyloid Burden in Elderly Mild Cognitive Impairment Individuals

2019 ◽  
Vol 15 (4) ◽  
pp. 71-77 ◽  
Author(s):  
Megan Hogan ◽  
Amanda Shim ◽  
Ogie Queen Umasabor-Bubu ◽  
Mukhtar Fahad ◽  
Omonigho Michael Bubu
Keyword(s):  
Obstructive Sleep Apnea ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Sleep Apnea ◽  
Rate Of Change ◽  
Amyloid Pet ◽  
Amyloid Burden ◽  
Obstructive Sleep ◽  
History Of ◽  
Over Time

Cross sectional analysis has shown an association between Obstructive Sleep Apnea (OSA) severity and Aβ burden using amyloid-PET among Mild Cognitive Impairment (MCI) patients. However, whether OSA accelerates longitudinal increases in amyloid beta (Aβ) burden in MCI patients is presently unclear. Study participants included a total of 798 subjects with a diagnosis of MCI and were a subset of the ADNI cohort (adni.loni.usc.edu). OSA was self-reported and participants were labeled either as OSA+ or OSA−. Aβ burden was determined by florbetapir SUVRs. To test whether OSA is associated with the rate of change in Aβ data longitudinally, multilevel mixed effects linear regression was used to fit the models with randomly varying intercepts and slopes allowing dependence on OSA status. The final model was adjusted for age, sex, body mass index, education, CPAP use status, history of respiratory disease, hypertension, diabetes, and history of cardiovascular disease. A significant variation in the change (slope) in Aβ volumes over time was seen (p<.0001). The covariance between the baseline Aβ level and Aβ volume change over time indicated that OSA subjects experienced greater mean change differences in brain Aβ volumes over time (p < .0001). The rate of change in Aβ deposition also varied significantly across OSA groups over the follow-up period. Obstructive Sleep Apnea possibly facilitates longitudinal increases in amyloid burden in elderly Mild Cognitive Impairment individuals. Further research examining mechanisms underlying effects of OSA on the longitudinal increases in Aβ burden is needed.

scholarly journals Obstructive sleep apnea and longitudinal Alzheimer’s disease biomarker changes

SLEEP ◽  
2019 ◽  
Vol 42 (6) ◽  
Author(s):  
Omonigho M Bubu ◽  
Elizabeth Pirraglia ◽  
Andreia G Andrade ◽  
Ram A Sharma ◽  
Sandra Gimenez-Badia ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Obstructive Sleep Apnea ◽  
Cognitive Impairment ◽  
Sleep Apnea ◽  
Rate Of Change ◽  
Csf Biomarkers ◽  
Amyloid Pet ◽  
Obstructive Sleep ◽  
T Tau

Abstract Study Objectives To determine the effect of self-reported clinical diagnosis of obstructive sleep apnea (OSA) on longitudinal changes in brain amyloid PET and CSF biomarkers (Aβ42, T-tau, and P-tau) in cognitively normal (NL), mild cognitive impairment (MCI), and Alzheimer’s disease (AD) elderly. Methods Longitudinal study with mean follow-up time of 2.52 ± 0.51 years. Data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Participants included 516 NL, 798 MCI, and 325 AD elderly. Main outcomes were annual rate of change in brain amyloid burden (i.e. longitudinal increases in florbetapir PET uptake or decreases in CSF Aβ42 levels); and tau protein aggregation (i.e. longitudinal increases in CSF total tau [T-tau] and phosphorylated tau [P-tau]). Adjusted multilevel mixed effects linear regression models with randomly varying intercepts and slopes was used to test whether the rate of biomarker change differed between participants with and without OSA. Results In NL and MCI groups, OSA+ subjects experienced faster annual increase in florbetapir uptake (B = .06, 95% CI = .02, .11 and B = .08, 95% CI = .05, .12, respectively) and decrease in CSF Aβ42 levels (B = −2.71, 95% CI = −3.11, −2.35 and B = −2.62, 95% CI = −3.23, −2.03, respectively); as well as increases in CSF T-tau (B = 3.68, 95% CI = 3.31, 4.07 and B = 2.21, 95% CI = 1.58, 2.86, respectively) and P-tau (B = 1.221, 95% CI = 1.02, 1.42 and B = 1.74, 95% CI = 1.22, 2.27, respectively); compared with OSA− participants. No significant variations in the biomarker changes over time were seen in the AD group. Conclusions In both NL and MCI, elderly, clinical interventions aimed to treat OSA are needed to test if OSA treatment may affect the progression of cognitive impairment due to AD.

Hippocampal Volume Loss, Brain Amyloid Accumulation, and APOE Status in Cognitively Intact Elderly Subjects

2019 ◽  
Vol 19 (3-4) ◽  
pp. 139-147 ◽  
Author(s):  
Sven Haller ◽  
Marie-Louise Montandon ◽  
Cristelle Rodriguez ◽  
Valentina Garibotto ◽  
François R. Herrmann ◽  
...  
Keyword(s):  
Hippocampal Volume ◽  
Elderly Subjects ◽  
Neuropsychological Performance ◽  
Amyloid Pet ◽  
Volume Loss ◽  
Apoe Ε4 ◽  
Amyloid Accumulation ◽  
Ε4 Allele ◽  
The Impact

Background: Hippocampal volume loss (HVL), PET-documented brain amyloid accumulation, and APOE-ε4 status are predictive biomarkers of the transition from mild cognitive impairment to Alzheimer disease (AD). In asymptomatic cases, the role of these biomarkers remains ambiguous. In contrast to the idea that HVL occurs in late phases of neurodegeneration, recent contributions indicate that it might occur before abnormal amyloid PET occurrence in elderly subjects and that its severity could be only marginally related to APOE variants. Using a longitudinal design, we examined the determinants of HVL in our sample, i.e., brain amyloid burden and the presence of APOE-ε4, and made a longitudinal assessment of cognitive functions. Methods: We performed a 4.5-year longitudinal study on 81 elderly community dwellers (all right-handed;, 48 (59.3%) women; mean age 73.7 ± 3.7 years) including MRI at baseline and follow-up, PET amyloid during follow-up, neuropsychological assessment at 18 and 54 months, and APOE genotyping. All cases were assessed using a continuous cognitive score (CCS) that took into account the global evolution of neuropsychological performance. Linear regression models were used to identify predictors of HVL. Results: There was a negative association between the CCS and HVL bilaterally. In multivariate models adjusting for demographic variables, the presence of APOE-ε4 was related to increased HVL bilaterally. A trend of significance was observed with respect to the impact of amyloid positivity on HVL in the left hemisphere. No significant interaction was found between amyloid positivity and the APOE-ε4 allele. Conclusion: The progressive decrement of neuropsychological performance is associated with HVL long before the emergence of clinically overt symptoms. In this cohort of healthy individuals, the presence of the APOE-ε4 allele was shown to be an independent predictor of worst hippocampal integrity in asymptomatic cases independently of amyloid positivity.

scholarly journals Falls Associate with Neurodegenerative Changes in ATN Framework of Alzheimer’s Disease

2020 ◽  
Vol 77 (2) ◽  
pp. 745-752
Author(s):  
Audrey Keleman ◽  
Julie K. Wisch ◽  
Rebecca M. Bollinger ◽  
Elizabeth A. Grant ◽  
Tammie L. Benzinger ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Connectivity ◽  
Hippocampal Volume ◽  
Cross Sectional Study ◽  
Amyloid Pet ◽  
Resting State Functional Connectivity ◽  
Cross Sectional ◽  
Preclinical Ad ◽  
Amyloid Accumulation

Background: Behavioral markers for Alzheimer’s disease (AD) are not included within the widely used amyloid-tau-neurodegeneration framework. Objective: To determine when falls occur among cognitively normal (CN) individuals with and without preclinical AD. Methods: This cross-sectional study recorded falls among CN participants (n = 83) over a 1-year period. Tailored calendar journals recorded falls. Biomarkers including amyloid positron emission tomography (PET) and structural and functional magnetic resonance imaging were acquired within 2 years of fall evaluations. CN participants were dichotomized by amyloid PET (using standard cutoffs). Differences in amyloid accumulation, global resting state functional connectivity (rs-fc) intra-network signature, and hippocampal volume were compared between individuals who did and did not fall using Wilcoxon rank sum tests. Among preclinical AD participants (amyloid-positive), the partial correlation between amyloid accumulation and global rs-fc intra-network signature was compared for those who did and did not fall. Results: Participants who fell had smaller hippocampal volumes (p = 0.04). Among preclinical AD participants, those who fell had a negative correlation between amyloid uptake and global rs-fc intra-network signature (R = –0.75, p = 0.012). A trend level positive correlation was observed between amyloid uptake and global rs-fc intra-network signature (R = 0.70, p = 0.081) for preclinical AD participants who did not fall. Conclusion: Falls in CN older adults correlate with neurodegeneration biomarkers. Participants without falls had lower amyloid deposition and preserved global rs-fc intra-network signature. Falls most strongly correlated with presence of amyloid and loss of brain connectivity and occurred in later stages of preclinical AD.

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