Discordant Alzheimer's neurodegenerative biomarkers and their clinical outcomes in older adults without dementia

Abstract Background: In 2018 ATN framework, Alzheimer's neurodegenerative biomarkers comprised cerebrospinal fluid (CSF) total tau, 18 F-fluorodeoxyglucose-positron emission tomography, and brain atrophy. Although these biomarkers could be used interchangeably, some cases had discordant neurodegenerative biomarkers. Our aim was to assess the clinical outcomes of having discordant Alzheimer's neurodegenerative biomarkers. Methods: A total of 721 non-demented individuals from the Alzheimer's Disease Neuroimaging Initiative database were included and then further categorized into concordant negative, discordant, and concordant positive groups. Demographic distributions of the groups were compared. Longitudinal changes in clinical outcomes and risk of conversion were assessed using linear mixed-effects models and multivariate Cox proportional hazard models, respectively. Results: Discordant group was intermediate to concordant-negative and concordant-positive groups in terms of APOE ε4 positivity, CSF amyloid-beta and phosphorylated tau. Compared with concordant-negative group, discordant group deteriorated faster in cognitive scores (Mini-Mental State Examination, the Clinical Dementia Rating Scale-Sum of Boxes, and the Functional Activities Questionnaire) and demonstrated greater rates of atrophy in brain structures (hippocampus, entorhinal cortex and whole brain), and concordant-positive group performed worse over time than discordant group. Moreover, the risk of cognitive progression increased from concordant-negative to discordant to concordant-positive. The longitudinal results were validated in A+T+, cognitively normal and mild cognitive impairment individuals, and were also validated by applying different cut-offs for neurodegenerative biomarkers. Conclusions: Discordant neurodegenerative status denotes a stage of cognitive function which is intermediate between concordant-negative and concordant-positive. Identification of discordant cases would provide insights into intervention and new therapy approaches, particularly in A+T+ individuals. Moreover, this work may be a complement to the ATN scheme.

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Discordant Alzheimer's neurodegenerative biomarkers and their clinical outcomes in older adults without dementia

10.21203/rs.3.rs-18282/v1 ◽

2020 ◽

Author(s):

Yu Guo ◽

Hong-Qi Li ◽

Lin Tan ◽

Shi-Dong Chen ◽

Yu-Xiang Yang ◽

...

Keyword(s):

Clinical Outcomes ◽

Rating Scale ◽

Brain Structures ◽

Clinical Dementia Rating ◽

Functional Activities ◽

Cox Proportional Hazard ◽

Positron Emission ◽

Discordant Group ◽

Cox Proportional Hazard Models ◽

Positive Groups

Abstract Background In 2018 ATN framework, Alzheimer's neurodegenerative biomarkers comprised cerebrospinal fluid (CSF) total tau, 18 F-fluorodeoxyglucose-positron emission tomography, and brain atrophy. Although these biomarkers could be used interchangeably, some cases had discordant neurodegenerative biomarkers. Our aim was to assess the clinical outcomes of having discordant Alzheimer's neurodegenerative biomarkers. Methods A total of 721 non-demented individuals from the Alzheimer's Disease Neuroimaging Initiative database were included and then further categorized into concordant negative, discordant, and concordant positive groups. Demographic distributions of the groups were compared. Longitudinal changes in clinical outcomes and risk of conversion were assessed using linear mixed-effects models and multivariate Cox proportional hazard models, respectively. Results Discordant group was intermediate to concordant-negative and concordant-positive groups in terms of APOE ε4 positivity, CSF amyloid-beta and phosphorylated tau. Compared with concordant-negative group, discordant group deteriorated faster in cognitive scores (Mini-Mental State Examination, the Clinical Dementia Rating Scale-Sum of Boxes, and the Functional Activities Questionnaire) and demonstrated greater rates of atrophy in brain structures (hippocampus, entorhinal cortex and whole brain), and concordant-positive group performed worse over time than discordant group. Moreover, the risk of cognitive progression increased from concordant-negative to discordant to concordant-positive. The longitudinal results were validated in A+T+, cognitively normal and mild cognitive impairment individuals, and were also validated by applying different cut-offs for neurodegenerative biomarkers. Conclusions Discordant neurodegenerative status denotes a stage of cognitive function which is intermediate between concordant-negative and concordant-positive. Identification of discordant cases would provide insights into intervention and new therapy approaches, particularly in A+T+ individuals. Moreover, this work may be a complement to the ATN scheme.

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Efficacy and Limitations of rCBF-SPECT in the Diagnosis of Alzheimer’s Disease With Amyloid-PET

American Journal of Alzheimer s Disease & Other Dementias® ◽

10.1177/1533317519841192 ◽

2019 ◽

Vol 34 (5) ◽

pp. 314-321

Author(s):

Miwako Takahashi ◽

Tomoko Tada ◽

Tomomi Nakamura ◽

Keitaro Koyama ◽

Toshimitsu Momose

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rating Scale ◽

Single Photon ◽

Photon Emission ◽

Emission Computed Tomography ◽

Amyloid Pet ◽

Clinical Dementia Rating ◽

Positron Emission ◽

Rcbf Spect

This study aimed to assess efficacy and limitations of regional cerebral blood flow imaging using single-photon emission computed tomography (rCBF-SPECT) in the diagnosis of Alzheimer’s disease (AD) with amyloid-positron emission tomography (amyloid-PET). Thirteen patients, who underwent both rCBF-SPECT and amyloid-PET after clinical diagnosis of AD or mild cognitive impairment, were retrospectively identified. The rCBF-SPECTs were classified into 4 grades, from typical AD pattern to no AD pattern of hypoperfusion; amyloid-beta (Aβ) positivity was assessed by amyloid-PET. Four patients were categorized into a typical AD pattern on rCBF-SPECT, and all were Aβ+. The other 9 patients did not exhibit a typical AD pattern; however, 4 were Aβ+. The Mini-Mental State Examination score and Clinical Dementia Rating scale were not significantly different between Aβ+ and Aβ– patients. A typical AD pattern on rCBF-SPECT can reflect Aβ+; however, if not, rCBF-SPECT has a limitation to predict amyloid pathology.

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Variation in noninvasive ventilation use in amyotrophic lateral sclerosis

Neurology ◽

10.1212/wnl.0000000000007776 ◽

2019 ◽

Vol 93 (3) ◽

pp. e306-e316 ◽

Cited By ~ 3

Author(s):

Nimish J. Thakore ◽

Brittany R. Lapin ◽

Erik P. Pioro ◽

Loutfi S. Aboussouan

Keyword(s):

Clinical Trials ◽

Amyotrophic Lateral Sclerosis ◽

Noninvasive Ventilation ◽

Rating Scale ◽

Factors Affecting ◽

Cox Proportional Hazard ◽

Bulbar Onset ◽

Cox Proportional Hazard Models ◽

R Factors ◽

Lateral Sclerosis

ObjectiveWe sought to examine prevalence and predictors of noninvasive ventilation (NIV) in a composite cohort of patients with amyotrophic lateral sclerosis (ALS) followed in a clinical trials setting (Pooled Resource Open-Access ALS Clinical Trials database).MethodsNIV initiation and status were ascertained from response to question 12 of the revised ALS Functional Rating Scale (ALSFRS-R). Factors affecting NIV use in patients with forced vital capacity (FVC) ≤50% of predicted were examined. Predictors of NIV were evaluated by Cox proportional hazard models and generalized linear mixed models.ResultsAmong 1,784 patients with 8,417 simultaneous ALSFRS-R and FVC% measures, NIV was used by 604 (33.9%). Of 918 encounters when FVC% ≤50%, NIV was reported in 482 (52.5%). Independent predictors of NIV initiation were lower FVC% (hazard ratio [HR] 1.27, 95% confidence interval [CI] 1.17–1.37 for 10% drop), dyspnea (HR 2.62, 95% CI 1.87–3.69), orthopnea (HR 4.09, 95% CI 3.02–5.55), lower bulbar and gross motor subscores of ALSFRS-R (HRs 1.09 [95% CI 1.03–1.14] and 1.13 [95% CI 1.07–1.20], respectively, per point), and male sex (HR 1.73, 95% CI 1.31–2.28). Adjusted for other variables, bulbar onset did not significantly influence time to NIV (HR 0.72, 95% CI 0.47–1.08). Considerable unexplained variability in NIV use was found.ConclusionNIV use was lower than expected in this ALS cohort that was likely to be optimally managed. Absence of respiratory symptoms and female sex may be barriers to NIV use. Prospective exploration of factors affecting adoption of NIV may help bridge this gap and improve care in ALS.

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Effect of the Interaction Between Hypertension and Cerebral White Matter Changes on the Progression of Alzheimer Disease

Current Alzheimer Research ◽

10.2174/1567205015666181002141013 ◽

2018 ◽

Vol 15 (14) ◽

pp. 1354-1360 ◽

Cited By ~ 4

Author(s):

Ping-Song Chou ◽

Yi-Hui Kao ◽

Meng-Ni Wu ◽

Mei-Chuan Chou ◽

Chun-Hung Chen ◽

...

Keyword(s):

White Matter ◽

Alzheimer Disease ◽

Rating Scale ◽

Vital Role ◽

Independent Effect ◽

Cerebral White Matter ◽

Clinical Dementia Rating ◽

White Matter Changes ◽

Age Related ◽

The Mean

Background: Cerebrovascular pathologies and hypertension could play a vital role in Alzheimer disease (AD) progression. However, whether cerebrovascular pathologies and hypertension accelerate the AD progression through an independent or interaction effect is unknown. Objective: To investigate the effect of the interactions of cerebrovascular pathologies and hypertension on AD progression. Method: A retrospective longitudinal study was conducted to compare AD courses in patients with different severities of cerebral White Matter Changes (WMCs) in relation to hypertension. Annual comprehensive psychometrics were performed. WMCs were rated using a rating scale for Age-related WMCs (ARWMC). Results: In total, 278 patients with sporadic AD were enrolled in this study. The mean age of the patients was 76.6 ± 7.4 years, and 166 patients had hypertension. Among AD patients with hypertension, those with deterioration in clinical dementia rating-sum of box (CDR-SB) and CDR had significantly severe baseline ARWMC scales in total (CDR-SB: 5.8 vs. 3.6, adjusted P = 0.04; CDR: 6.4 vs. 4.4, adjusted P = 0.04) and frontal area (CDR-SB: 2.4 vs. 1.2, adjusted P = 0.01; CDR: 2.4 vs. 1.7, adjusted P < 0.01) compared with those with no deterioration in psychometrics after adjustment for confounders. By contrast, among AD patients without hypertension, no significant differences in ARWMC scales were observed between patients with and without deterioration. Conclusion: The effect of cerebrovascular pathologies on AD progression between those with and without hypertension might differ. An interaction but not independent effect of hypertension and WMCs on the progression of AD is possible.

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Periodontal Antibodies and All-Cause and Cardiovascular Disease Mortality

Journal of Dental Research ◽

10.1177/0022034519884012 ◽

2019 ◽

Vol 99 (1) ◽

pp. 51-59 ◽

Cited By ~ 1

Author(s):

J. Qi ◽

Z. Zihang ◽

J. Zhang ◽

Y.M. Park ◽

D. Shrestha ◽

...

Keyword(s):

Cardiovascular Disease ◽

Igg Antibody ◽

Actinomyces Naeslundii ◽

Health And Nutrition ◽

Cox Proportional Hazard ◽

Disease Mortality ◽

All Cause Mortality ◽

Yellow Orange ◽

Cox Proportional Hazard Models ◽

Cvd Mortality

Periodontitis is positively linked to cardiovascular disease (CVD), diabetes, cancer, and increased mortality. Empirically derived clusters of IgG antibodies against 19 selected periodontal microorganisms have been associated with hyperglycemia. We further investigated associations between these serum IgG antibody clusters and all-cause and CVD mortality in a representative US population. Participants free of CVD and cancer and aged ≥40 y at baseline ( N = 6,491) from the Third National Health and Nutrition Examination Survey (1988 to 1994) were followed up until December 31, 2011. Antibodies were categorized into 4 clusters: red-green, orange-red, yellow-orange, and orange-blue. Over a 23-y follow-up, 2,702 deaths occurred, including 810 CVD-related deaths. In fully adjusted Cox proportional hazard models, the red-green cluster was positively associated with all-cause mortality (tertile 3 vs. tertile 1: hazard ratio [HR] = 1.43, 95% CI = 1.08 to 1.90, P = 0.015). The yellow-orange cluster was inversely associated with all-cause mortality (tertile 3 vs. tertile 1: HR = 0.78, 95% CI = 0.63 to 0.97, P = 0.028) and CVD mortality (tertile 2 vs. tertile 1: HR = 0.57, 95% CI = 0.42 to 0.77, P = 0.005). The orange-blue cluster (composed of antibodies against Eubacterium nodatum and Actinomyces naeslundii) was inversely associated with all-cause mortality (tertile 3 vs. tertile 1: HR = 0.65, 95% CI = 0.55 to 0.78, P < 0.0001) and CVD mortality (tertile 3 vs. tertile 1: HR = 0.65, 95% CI = 0.47 to 0.88, P = 0.007). These antibodies could predict prognosis or be potential intervention targets to prevent systemic effects of periodontal disease if further studies establish a causal relationship.

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Lumbar Disc Herniation and Preoperative Modic Changes: A Prospective Analysis of the Clinical Outcomes After Microdiscectomy

Global Spine Journal ◽

10.1177/2192568220976089 ◽

2021 ◽

pp. 219256822097608

Author(s):

Dinesh Kumarasamy ◽

Shanmuganathan Rajasekaran ◽

Sri Vijay Anand K. S ◽

Dilip Chand Raja Soundararajan ◽

Ajoy Prasad Shetty T ◽

...

Keyword(s):

Patient Satisfaction ◽

Back Pain ◽

Clinical Outcomes ◽

Lumbar Disc Herniation ◽

Disc Herniation ◽

Rating Scale ◽

Lumbar Disc ◽

Modic Changes ◽

P Value ◽

Functional Scores

Study design: Prospective comparative cohort study. Objectives: The study aims to elucidate the relationship between Modic endplate changes and clinical outcomes after a lumbar microdiscectomy. Methods: Consecutive patients undergoing microdiscectomy for lumbar disc herniation (LDH) were prospectively studied. Pre-operative clinical and radiological parameters were recorded. The pain was assessed by Numeric pain rating scale (NPRS), and functional assessment by Oswestry Disability Index (ODI). Minimal clinically important difference (MCID) in outcome was calculated for both the groups. Complications related to surgery were studied. Follow-up was done at 6 weeks, 3 months, 6 months and 1 year. Mac Nab criteria were used to assess patient satisfaction at 1 year. Results: Out of 309 patients, 86 had Modic changes, and 223 had no Modic changes. Both groups had similar back pain (p-value: 0.07) and functional scores (p-value: 0.85) pre-operatively. Postoperatively patients with Modic changes had poorer back pain and ODI scores in the third month, sixth month and 1 year (p-value: 0.001). However, MCID between the groups were not significant (p-value: 0.18 for back pain and 0.58 for ODI scores). Mac Nab criteria at 1 year were worse in Modic patients (p-value: 0.001). No difference was noted among Modic types in the pre-operative and postoperative pain and functional outcomes. Four patients in Modic group (4.7%) and one patient in the non-Modic group (0.5%) developed postoperative discitis (p-value: 0.009). Conclusions: Preoperative Modic changes in lumbar disc herniation is associated with less favorable back pain, functional scores and patient satisfaction in patients undergoing microdiscectomy.

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Azathioprine immunosuppression and disease modification in Parkinson’s disease (AZA-PD): a randomised double-blind placebo-controlled phase II trial protocol

BMJ Open ◽

10.1136/bmjopen-2020-040527 ◽

2020 ◽

Vol 10 (11) ◽

pp. e040527

Author(s):

Julia C Greenland ◽

Emma Cutting ◽

Sonakshi Kadyan ◽

Simon Bond ◽

Anita Chhabra ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Immune System ◽

Phase Ii ◽

Rating Scale ◽

Positron Emission Tomography Imaging ◽

Clinical Markers ◽

Double Blind ◽

Positron Emission ◽

Immunosuppressant Medication

IntroductionThe immune system is implicated in the aetiology and progression of Parkinson’s disease (PD). Inflammation and immune activation occur both in the brain and in the periphery, and a proinflammatory cytokine profile is associated with more rapid clinical progression. Furthermore, the risk of developing PD is related to genetic variation in immune-related genes and reduced by the use of immunosuppressant medication. We are therefore conducting a ‘proof of concept’ trial of azathioprine, an immunosuppressant medication, to investigate whether suppressing the peripheral immune system has a disease-modifying effect in PD.Methods and analysisAZA-PD is a phase II randomised placebo-controlled double-blind trial in early PD. Sixty participants, with clinical markers indicating an elevated risk of disease progression and no inflammatory or immune comorbidity, will be treated (azathioprine:placebo, 1:1) for 12 months, with a further 6-month follow-up. The primary outcome is the change in the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale gait/axial score in the OFF state over the 12-month treatment period. Exploratory outcomes include additional measures of motor and cognitive function, non-motor symptoms and quality of life. In addition, peripheral and central immune markers will be investigated through analysis of blood, cerebrospinal fluid and PK-11195 positron emission tomography imaging.Ethics and disseminationThe study was approved by the London-Westminster research ethics committee (reference 19/LO/1705) and has been accepted by the Medicines and Healthcare products Regulatory Agency (MHRA) for a clinical trials authorisation (reference CTA 12854/0248/001–0001). In addition, approval has been granted from the Administration of Radioactive Substances Advisory Committee. The results of this trial will be disseminated through publication in scientific journals and presentation at national and international conferences, and a lay summary will be available on our website.Trial registration numbersISRCTN14616801 and EudraCT- 2018-003089-14.

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Height in Adolescence as a Risk Factor for Glioma Subtypes: a Nationwide Retrospective Cohort Study of 2.2 Million Subjects

Neuro-Oncology ◽

10.1093/neuonc/noab049 ◽

2021 ◽

Author(s):

Roi Tschernichovsky ◽

Lior H Katz ◽

Estela Derazne ◽

Matan Ben-Zion Berliner ◽

Maya Simchoni ◽

...

Keyword(s):

Risk Factor ◽

Statistical Significance ◽

Positive Association ◽

High Grade Glioma ◽

Low Grade ◽

Cox Proportional Hazard ◽

Cox Proportional Hazard Models ◽

Glioma Risk ◽

Incident Cases

Abstract Background Gliomas manifest in a variety of histological phenotypes with varying aggressiveness. The etiology of glioma remains largely unknown. Taller stature in adulthood has been linked with glioma risk. The aim of this study was to discern whether this association can be detected in adolescence. Methods The cohort included 2,223,168 adolescents between the ages of 16-19. Anthropometric measurements were collected at baseline. Incident cases of glioma were extracted from the Israel National Cancer Registry over a follow-up period spanning 47,635,745 person-years. Cox proportional hazard models were used to estimate the hazard ratio for glioma and glioma subtypes according to height, body mass index (BMI) and sex. Results 1,195 patients were diagnosed with glioma during the study period. Mean(SD) age at diagnosis was 38.1 (11.7) years. Taller adolescent height (per 10cm increase) was positively associated with the risk for glioma of any type (HR 1.15; p=0.002). The association was retained in subgroup analyses for low-grade glioma (HR 1.17; p=0.031), high-grade glioma (HR 1.15; p=0.025), oligodendroglioma (HR 1.31; p=0.015), astrocytoma (HR 1.12; p=0.049), and a category of presumed IDH-mutated glioma (HR 1.17; p=0.013). There was a trend towards a positive association between height and glioblastoma, however this had borderline statistical significance (HR: 1.15; p=0.07). After stratification of the cohort by sex, height remained a risk factor for men, but not for women. Conclusions The previously - established association between taller stature in adulthood and glioma risk can be traced back to adolescence. The magnitude of association differs by glioma subtype.

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A Biomarker-based Biological Age in UK Biobank: Composition and Prediction of Mortality and Hospital Admissions

The Journals of Gerontology Series A ◽

10.1093/gerona/glab069 ◽

2021 ◽

Author(s):

Mei Sum Chan ◽

Matthew Arnold ◽

Alison Offer ◽

Imen Hammami ◽

Marion Mafham ◽

...

Keyword(s):

Principal Components ◽

Hospital Admissions ◽

Later Life ◽

Chronological Age ◽

Uk Biobank ◽

Hand Grip ◽

Cox Proportional Hazard ◽

Prediction Of Mortality ◽

Age Related ◽

Cox Proportional Hazard Models

Abstract Background Chronological age is the strongest risk factor for most chronic diseases. Developing a biomarker-based age and understanding its most important contributing biomarkers may shed light on the effects of age on later-life health and inform opportunities for disease prevention. Methods A subpopulation of 141 254 individuals healthy at baseline were studied, from among 480 019 UK Biobank participants aged 40–70 recruited in 2006–2010, and followed up for 6–12 years via linked death and secondary care records. Principal components of 72 biomarkers measured at baseline were characterized and used to construct sex-specific composite biomarker ages using the Klemera Doubal method, which derived a weighted sum of biomarker principal components based on their linear associations with chronological age. Biomarker importance in the biomarker ages was assessed by the proportion of the variation in the biomarker ages that each explained. The proportions of the overall biomarker and chronological age effects on mortality and age-related hospital admissions explained by the biomarker ages were compared using likelihoods in Cox proportional hazard models. Results Reduced lung function, kidney function, reaction time, insulin-like growth factor 1, hand grip strength, and higher blood pressure were key contributors to the derived biomarker age in both men and women. The biomarker ages accounted for >65% and >84% of the apparent effect of age on mortality and hospital admissions for the healthy and whole populations, respectively, and significantly improved prediction of mortality (p < .001) and hospital admissions (p < 1 × 10−10) over chronological age alone. Conclusions This study suggests that a broader, multisystem approach to research and prevention of diseases of aging warrants consideration.

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LAMB1 Is Related to the T Stage and Indicates Poor Prognosis in Gastric Cancer

Technology in Cancer Research & Treatment ◽

10.1177/15330338211004944 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110049

Author(s):

Tao Ran ◽

ZhiJi Chen ◽

LiWen Zhao ◽

Wei Ran ◽

JinYu Fan ◽

...

Keyword(s):

Gastric Cancer ◽

Poor Prognosis ◽

Hazard Models ◽

Proportional Hazard ◽

Kegg Analysis ◽

Proportional Hazard Models ◽

Cox Proportional Hazard ◽

Kaplan Meier ◽

Cox Proportional Hazard Models ◽

Gastric Cancer Patients

Background and Objective: Gastric cancer (GC) is a common tumor malignancy with high incidence and poor prognosis. Laminin is an indispensable component of basement membrane and extracellular matrix, which is responsible for bridging the internal and external environment of cells and transmitting signals. This study mainly explored the association of the LAMB1 expression with clinicopathological characteristics and prognosis in gastric cancer. Methods: The expression data and clinical information of gastric cancer patients were downloaded from The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG). And we analyzed the relationship between LAMB1 expression and clinical characteristics through R. CIBERSORTx was used to calculate the absolute score of immune cells in gastric tumor tissues. Then COX proportional hazard models and Kaplan-Meier curves were performed to evaluate the role of LAMB1 and its influence on prognosis in gastric cancer patients. Finally, GO and KEGG analysis were applied for LAMB1-related genes in gastric cancer, and PPI network was constructed in Cytoscape software. Results: In the TCGA cohort, patients with gastric cancer frequently generated LAMB1 gene copy number variation, but had little effect on mRNA expression. Both in the TCGA and ACRG cohorts, the mRNA expression of LAMB1 in gastric cancer tissues was higher than it in normal tissues. All patients were divided into high expression group and low expression group according to the median expression level of LAMB1. The elevated expression group obviously had more advanced cases and higher infiltration levels of M2 macrophages. COX proportional hazard models and Kaplan-Meier curves revealed that patients with enhanced expression of LAMB1 have a worse prognosis. GO/KEGG analysis showed that LAMB1-related genes were enriched in PI3K-Akt signaling pathway, focal adhesion, ECM-receptor interaction, etc. Conclusions: The high expression of LAMB1 in gastric cancer is related to the poor prognosis of patients, and it may be related to microenvironmental changes in tumors.

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