Brain β-Amyloid and Atrophy in Individuals at Increased Risk of Cognitive Decline

Abstract Objective: We have often observed dementia symptoms or severe neurocognitive decline in the long-term course of schizophrenia. While there are epidemiological reports that patients with schizophrenia are at an increased risk of developing dementia, there are also neuropathological reports that the prevalence of Alzheimer’s disease (AD) in schizophrenia is similar to that in normal controls. It is difficult to distinguish, based solely on the clinical symptoms, whether the remarkable dementia symptoms and cognitive decline seen in elderly schizophrenia are due to the course of the disease itself or a concomitant neurocognitive disease. Neuropathological observation is needed for discrimination. Methods: We conducted a neuropathological search on three cases of schizophrenia that developed cognitive decline or dementia symptoms after a long illness course of schizophrenia. The clinical symptoms of total disease course were confirmed retrospectively in the medical record. We have evaluated neuropathological diagnosis based on not only Hematoxylin–Eosin and Klüver–Barrera staining specimens but also immunohistochemical stained specimens including tau, β-amyloid, pTDP-43 and α-synuclein protein throughout clinicopathological conference with multiple neuropathologists and psychiatrists. Results: The three cases showed no significant pathological findings or preclinical degenerative findings, and poor findings consistent with symptoms of dementia were noted. Conclusion: Although the biological background of dementia symptoms in elderly schizophrenic patients is still unclear, regarding the brain capacity/cognitive reserve ability, preclinical neurodegeneration changes in combination with certain brain vulnerabilities due to schizophrenia itself are thought to induce dementia syndrome and severe cognitive decline.

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APOE ε2ε4 genotype, incident AD and MCI, cognitive decline, and AD pathology in older adults

Neurology ◽

10.1212/wnl.0000000000005677 ◽

2018 ◽

Vol 90 (24) ◽

pp. e2127-e2134 ◽

Cited By ~ 13

Author(s):

Shahram Oveisgharan ◽

Aron S. Buchman ◽

Lei Yu ◽

Jose Farfel ◽

Vladimir Hachinski ◽

...

Keyword(s):

Older Adults ◽

Cognitive Impairment ◽

Cognitive Decline ◽

Reference Group ◽

Cox Proportional Hazards ◽

European Ancestry ◽

Linear Regression Models ◽

Mixed Effect ◽

Increased Risk ◽

Β Amyloid

ObjectiveTo examine the association of the APOE ε2ε4 genotype with incident Alzheimer disease (AD), mild cognitive impairment (MCI), cognitive decline, and AD pathology in older adults.MethodsWe used data from 2,151 older adults of European ancestry who were free of dementia at baseline and underwent structured annual clinical evaluation in a longitudinal study for incident AD and MCI, and cognitive decline. Postmortem examination in decedents documented pathologic AD and quantified β-amyloid and neurofibrillary tangles. Participants were stratified into 4 groups based on APOE genotyping: ε2ε4, ε4 (ε4ε4, ε4ε3), ε2 (ε2ε2, ε2ε3), with ε3ε3 carriers serving as the reference group. We used Cox proportional hazards models to examine the association of APOE genotype with incident AD and MCI. Linear mixed-effect models were used to examine the association with cognitive decline. Logistic and linear regression models were used to examine AD pathology. All the models controlled for age, sex, and education.ResultsOf the 2,151 participants included in this study, ε2ε4 accounted for 2.1%, ε3/4 and 4/4 21.8%, ε2/3 and 2/2 14.0%, and ε3ε3 62.1%. We did not observe a difference in the risk of AD for ε2ε4 compared to ε3ε3. In cases without cognitive impairment at baseline, ε2ε4 carriers had an increased risk of incident MCI (hazard ratio 2.13, 95% confidence interval 1.34–3.39, p = 0.002) and a faster rate of cognitive decline (estimate −0.047, SE 0.018, p = 0.008) compared to ε3ε3 carriers. In decedents (n = 1,100), ε2ε4 showed a 3-fold increased odds of pathologic AD and a higher β-amyloid load than ε3ε3.ConclusionAPOE ε2ε4 genotype in older adults is associated with risk of MCI, cognitive decline, and a greater burden of AD pathology, especially β-amyloid.

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Continuous and Cyclic Progesterone Differentially Interact with Estradiol in the Regulation of Alzheimer-Like Pathology in Female 3×Transgenic-Alzheimer’s Disease Mice

Endocrinology ◽

10.1210/en.2009-1487 ◽

2010 ◽

Vol 151 (6) ◽

pp. 2713-2722 ◽

Cited By ~ 57

Author(s):

Jenna C. Carroll ◽

Emily R. Rosario ◽

Angela Villamagna ◽

Christian J. Pike

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Postmenopausal Women ◽

Transgenic Mouse Model ◽

Dependent Behavior ◽

Potential Efficacy ◽

Increased Risk ◽

Neural Interactions ◽

Β Amyloid ◽

Insight Into

Depletion of estrogens and progesterone at menopause has been linked to an increased risk for the development of Alzheimer’s disease (AD) in women. A currently controversial literature indicates that although treatment of postmenopausal women with hormone therapy (HT) may reduce the risk of AD, several parameters of HT may limit its potential efficacy and perhaps, even exacerbate AD risk. One such parameter is continuous vs. cyclic delivery of the progestogen component of HT. Recent experimental evidence suggests that continuous progesterone can attenuate neural actions of estradiol (E2). In the present study, we compared the effects of continuous and cyclic progesterone treatment in the presence and absence of E2 in ovariectomized 3×Tg-AD mice, a transgenic mouse model of AD. We found that ovariectomy-induced hormone depletion increases AD-like pathology in female 3×Tg-AD mice, including accumulation of β-amyloid, tau hyperphosphorylation, and impaired hippocampal-dependent behavior. E2 treatment alone prevents the increases in pathology. Continuous progesterone did not affect β-amyloid levels when delivered alone but blocked the Aβ-lowering action of E2. In contrast, cyclic progesterone significantly reduced β-amyloid levels by itself and enhanced rather than inhibited the E2 effects. These results provide new insight into the neural interactions between E2 and progesterone that may prove valuable in optimizing HT regimens in postmenopausal women.

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Brain Glucose Metabolism in Health, Obesity, and Cognitive Decline—Does Insulin Have Anything to Do with It? A Narrative Review

Journal of Clinical Medicine ◽

10.3390/jcm10071532 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1532

Author(s):

Eleni Rebelos ◽

Juha O. Rinne ◽

Pirjo Nuutila ◽

Laura L. Ekblad

Keyword(s):

Insulin Resistance ◽

Glucose Metabolism ◽

Cognitive Decline ◽

Fdg Pet ◽

Metabolic Disorders ◽

Brain Glucose ◽

Brain Glucose Metabolism ◽

Systemic Insulin Resistance ◽

Increased Risk ◽

18F Fdg

Imaging brain glucose metabolism with fluorine-labelled fluorodeoxyglucose ([18F]-FDG) positron emission tomography (PET) has long been utilized to aid the diagnosis of memory disorders, in particular in differentiating Alzheimer’s disease (AD) from other neurological conditions causing cognitive decline. The interest for studying brain glucose metabolism in the context of metabolic disorders has arisen more recently. Obesity and type 2 diabetes—two diseases characterized by systemic insulin resistance—are associated with an increased risk for AD. Along with the well-defined patterns of fasting [18F]-FDG-PET changes that occur in AD, recent evidence has shown alterations in fasting and insulin-stimulated brain glucose metabolism also in obesity and systemic insulin resistance. Thus, it is important to clarify whether changes in brain glucose metabolism are just an epiphenomenon of the pathophysiology of the metabolic and neurologic disorders, or a crucial determinant of their pathophysiologic cascade. In this review, we discuss the current knowledge regarding alterations in brain glucose metabolism, studied with [18F]-FDG-PET from metabolic disorders to AD, with a special focus on how manipulation of insulin levels affects brain glucose metabolism in health and in systemic insulin resistance. A better understanding of alterations in brain glucose metabolism in health, obesity, and neurodegeneration, and the relationships between insulin resistance and central nervous system glucose metabolism may be an important step for the battle against metabolic and cognitive disorders.

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Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology

Science Advances ◽

10.1126/sciadv.abe4601 ◽

2021 ◽

Vol 7 (21) ◽

pp. eabe4601

Author(s):

Sandro Da Mesquita ◽

Jasmin Herz ◽

Morgan Wall ◽

Taitea Dykstra ◽

Kalil Alves de Lima ◽

...

Keyword(s):

T Cells ◽

Cognitive Decline ◽

Brain Aging ◽

Therapeutic Potential ◽

T Cell Response ◽

Age Related ◽

Lymphatic Vasculature ◽

Amyloid Aβ ◽

Β Amyloid ◽

Old Mice

Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)–dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer’s disease–like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aβ deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases.

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The ACHIEVE Trial: Lessons Learned From Nesting a Randomized Controlled Trial Within an Observational Cohort Study

Innovation in Aging ◽

10.1093/geroni/igaa057.2950 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 811-811

Author(s):

Jennifer Deal ◽

Nicholas Reed ◽

David Couper ◽

Kathleen Hayden ◽

Thomas Mosley ◽

...

Keyword(s):

Older Adults ◽

Randomized Controlled Trial ◽

Observational Study ◽

Cognitive Decline ◽

Controlled Trial ◽

Lessons Learned ◽

Community Dwelling ◽

Randomized Controlled ◽

Study Staff ◽

Increased Risk

Abstract Hearing impairment in older adults is linked to accelerated cognitive decline and a 94% increased risk of incident dementia in population-based observational studies. Whether hearing treatment can delay cognitive decline is unknown but could have substantial clinical and public health impact. The NIH-funded ACHIEVE randomized controlled trial of 977 older adults aged 70-84 years with untreated mild-to-moderate hearing loss, is testing the efficacy of hearing treatment versus health education on cognitive decline over 3 years in community-dwelling older adults (Clinicaltrials.gov Identifier: NCT03243422.) This presentation will describe lessons learned from ACHIEVE’s unique study design. ACHIEVE is nested within a large, well-characterized multicenter observational study, the Atherosclerosis Risk in Communities Study. Such nesting within an observational study maximizes both operational and scientific efficiency. With trial results expected in 2022, this presentation will focus on the benefits gained in design and recruitment/retention, including dedicated study staff, well-established protocols, and established study staff-participant relationships. Part of a symposium sponsored by Sensory Health Interest Group.

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Subjective cognitive decline: The first clinical manifestation of Alzheimer's disease?

Dementia & Neuropsychologia ◽

10.1590/s1980-5764-2016dn1003002 ◽

2016 ◽

Vol 10 (3) ◽

pp. 170-177 ◽

Cited By ~ 22

Author(s):

Adalberto Studart Neto ◽

Ricardo Nitrini

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Decline ◽

Clinical Manifestation ◽

Neurodegenerative Disorder ◽

Subjective Cognitive Decline ◽

Subjective Memory ◽

Increased Risk

ABSTRACT Background: Mild cognitive impairment is considered as the first clinical manifestation of Alzheimer's disease (AD), when the individual exhibits below performance on standardized neuropsychological tests. However, some subjects before having a lower performance on cognitive assessments already have a subjective memory complaint. Objective: A review about subjective cognitive decline, the association with AD biomarkers and risk of conversion to dementia. Methods: We performed a comprehensive non-systematic review on PubMed. The keywords used in the search were terms related to subjective cognitive decline. Results: Subjective cognitive decline is characterized by self-experience of deterioration in cognitive performance not detected objectively through formal neuropsychological testing. However, various terms and definitions have been used in the literature and the lack of a widely accepted concept hampers comparison of studies. Epidemiological data have shown that individuals with subjective cognitive decline are at increased risk of progression to AD dementia. In addition, there is evidence that this group has a higher prevalence of positive biomarkers for amyloidosis and neurodegeneration. However, Alzheimer's disease is not the only cause of subjective cognitive decline and various other conditions can be associated with subjective memory complaints, such as psychiatric disorders or normal aging. The features suggestive of a neurodegenerative disorder are: onset of decline within the last five years, age at onset above 60 years, associated concerns about decline and confirmation by an informant. Conclusion: These findings support the idea that subjective cognitive complaints may be an early clinical marker that precedes mild cognitive impairment due to Alzheimer's disease.

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Association of naturally occurring antibodies to β-amyloid with cognitive decline and cerebral amyloidosis in Alzheimer’s disease

Science Advances ◽

10.1126/sciadv.abb0457 ◽

2021 ◽

Vol 7 (1) ◽

pp. eabb0457

Author(s):

Yu-Hui Liu ◽

Jun Wang ◽

Qiao-Xin Li ◽

Christopher J. Fowler ◽

Fan Zeng ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Plasma Levels ◽

Imaging Biomarkers ◽

Amino Terminus ◽

Cross Sectional ◽

Naturally Occurring ◽

Β Amyloid ◽

Naturally Occurring Antibodies

The pathological relevance of naturally occurring antibodies to β-amyloid (NAbs-Aβ) in Alzheimer’s disease (AD) remains unclear. We aimed to investigate their levels and associations with Aβ burden and cognitive decline in AD in a cross-sectional cohort from China and a longitudinal cohort from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. NAbs-Aβ levels in plasma and cerebrospinal fluid (CSF) were tested according to their epitopes. Levels of NAbs targeting the amino terminus of Aβ increased, and those targeting the mid-domain of Aβ decreased in both CSF and plasma in AD patients. Higher plasma levels of NAbs targeting the amino terminus of Aβ and lower plasma levels of NAbs targeting the mid-domain of Aβ were associated with higher brain amyloidosis at baseline and faster cognitive decline during follow-up. Our findings suggest a dynamic response of the adaptive immune system in the progression of AD and are relevant to current passive immunotherapeutic strategies.

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Likelihood of Participation in Home-Based Cognitive Assessment: The Role of Subjective Cognitive Decline and Age

Innovation in Aging ◽

10.1093/geroni/igaa057.940 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 293-294

Author(s):

Moriah Splonskowski ◽

Holly Cooke ◽

Claudia Jacova

Keyword(s):

Older Adults ◽

Cognitive Decline ◽

Old Age ◽

Cognitive Assessment ◽

Community Dwelling ◽

Subjective Cognitive Decline ◽

Cognitive State ◽

Home Based ◽

Increased Risk

Abstract Home-based cognitive assessment (HBCA) services are emerging as a convenient alternative to in-clinic cognitive assessment and may aid in mitigating barriers to detecting cognitive impairment (CI). It is unknown which older adults would be likely to participate in HBCA. Here we investigated the role of age and Subjective Cognitive Decline (SCD). SCD has demonstrated an increased risk for progression to CI/dementia. A nation-wide community-dwelling sample of 494 adults age 50+ were recruited via Amazon Mechanical Turk to complete an online survey assessing perceptions around HBCA and SCD. Our sample was 91.9% White and 66.8% female. It consisted of 174 respondents aged 50-60, 265 aged 61- 70, and 55 aged 71-79. Age groups were comparable with respect to their acceptance of cognitive assessment (Range 4-20, higher score=higher acceptance, 7.9±3.3, 8.15±3.2, 8.05±3.43) and SCD-Q total (43.1±5.8, 43.2±5.7, 43.3±5.7). Correlation analysis revealed a relationship between SCD-QSCD total and perceived likelihood of participation in HBCA for those ages 61-70 (r(263) = .222 p = .000), but not for ages 50-60 or 71-79 (r(172) = .102 p = .152; r(53) = -.102 p = .458). Our findings suggest that SCD influences the likelihood of participation in HBCA for older adults’ transitioning to old age (61-70). Findings show that for adults transitioning into old age (61-70), perceived cognitive state influences their likelihood of participation in HBCA. Importantly, concerns about CI/dementia may generate more favorable perceptions of HBCA for this group.

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Abstract 033: Cardio-Cerebro-Vascular Diseases: Prevention in Metabolic Syndrome Patients

Circulation Research ◽

10.1161/res.113.suppl_1.a033 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Günter Siegel ◽

Eugeny Ermilov

Keyword(s):

Metabolic Syndrome ◽

Second Messengers ◽

Vascular Diseases ◽

Sulfate Proteoglycan ◽

Egb 761 ◽

Increased Risk ◽

Β Amyloid ◽

Hs Crp ◽

Brain Microvessel ◽

Biomarkers Of Oxidative Stress

Background: ALP and GGT are indispensable constituents of brain microvessel endothelial cells, expressed and induced by IL-6. High values are entangled in affecting blood-brain barrier functionality. Since SOD bound to brain basement membrane and matrix heparan sulfate proteoglycan, is implicated in β-amyloid efflux, we examined in a pilot study of 11 patients with metabolic syndrome (MS) whether these biomarkers can be beneficially influenced through an antioxidant phytochemical approach with Ginkgo biloba (EGb 761, 2 × 120 mg/d). Also, MS is associated with an increased risk of developing diabetes and cardio-cerebro-vascular diseases (CCVD) (Figure). Methods: Photometric methods, ELISAs, EIAs and laser ellipsometry were applied. Results: A 2-month medication led to brain/liver biomarker changes: ALP -14.8% (p < 0.004), GGT -11.3% (p < 0.010). Antioxidative biomarker changes: SOD +17.7% (p < 0.009), GPx +11.6% (p <0.001), oxLDL/LDL -21.0% (p < 0.002), 8- iso -PGF 2α -39.8% (p < 0.003), MPO -29.6% (p < 0.014). Antiinflammatory biomarker changes: IL-6 -12.9% (p < 0.041), Lp(a) -26.3% (< 0.001), hs-CRP -39.3% (< 0.005), WBC -6.3% (< 0.023), MMP-9 -32.9% (< 0.042). Vasodilator biomarker changes: cAMP +43.5% (< 0.001), cGMP +32.9% (< 0.001), nanoplaque formation -14.3% (p < 0.008), nanoplaque size -23.4% (p < 0.0004). Conclusion: Since under ginkgo ALP and GGT were downregulated and SOD upregulated, and plasma biomarkers of oxidative stress, plaque stability and progression, inflammation, vasodilatory second messengers and lipid composition beneficially altered, this phytochemical may be estimated as complementary drug with potentially preventive character for CCVD.

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