AFFECTIVE NEUROPSYCHIATRIC SYMPTOMS MAY BE EARLY SIGNS OF ALZHEIMER'S DISEASE IN NON-DEMENTED OLDER ADULTS

Abstract The current study sought to investigate the association between affective neuropsychiatric symptoms (aNPS: depression, anxiety, apathy, irritability), Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers profiles, and the risk of progression to dementia in non-demented older adults. Participants consisted of 763 individuals with normal cognition (CN) (mean age = 73.73 ± 6.68) and 617 with mild cognitive impairment (MCI) (mean age = 73.19 ± 7.40) at baseline, who were enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Latent class analyses (LCA) identified three subgroups of older adults within CN and MCI, respectively, showing distinct patterns of the neuropsychiatric inventory (NPI) domains. Results indicated that the subgroup with higher probabilities of aNPS had elevated risk of progression to dementia (HR = 3.18, 95% CI [1.70, 5.94] in CN, HR = 1.79, 95% CI [1.01, 3.16] in MCI), adjusting for age, sex, and Apolipoprotein E e4 (APOE4) carrier status. Subgroups did not differ in their profiles of AD CSF biomarkers. Findings suggest that aNPS might be symptoms of secondary disease processes in the brain, lowering the threshold for AD pathophysiology to manifest clinically in CN and MCI. The current study highlights the importance of assessment and interventions for emotional and behavioral symptoms in non-demented older adults.

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Affective Neuropsychiatric Symptoms as Early Signs of Dementia Risk in Older Adults

Journal of Alzheimer s Disease ◽

10.3233/jad-200190 ◽

2020 ◽

Vol 77 (3) ◽

pp. 1195-1207

Author(s):

Jung Yun Jang ◽

Jean K. Ho ◽

Anna E. Blanken ◽

Shubir Dutt ◽

Daniel A. Nation ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Latent Class ◽

Neuropsychiatric Symptoms ◽

Community Dwelling ◽

Dementia Risk ◽

Increased Risk ◽

Risk Of Progression

Background: Affective neuropsychiatric symptoms (aNPS: depression, anxiety, apathy, irritability) have been linked to increased dementia risk. However, less is known whether this association is independent of Alzheimer’s disease (AD) pathophysiology. Objective: To investigate the contribution of early aNPS to dementia risk in cognitively normal (CN) older adults and mild cognitive impairment (MCI) patients, with and without AD biomarker abnormality. Methods: Participants included 763 community-dwelling, stroke-free older adults identified as CN and 617 with MCI at baseline, drawn from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Baseline assessments included a neuropsychological battery, the Neuropsychiatric Inventory (NPI), and apolipoprotein E ɛ4 (ApoE4) genotyping. A participant subset completed cerebrospinal fluid (CSF) AD biomarker assessment. Time to progression to dementia was measured based on months at follow-up when an individual was diagnosed with dementia, over the follow-up period of 48 months. Results: Latent class analysis identified 3 subgroups of older adults in CN and MCI, indicated by the baseline profiles of neuropsychiatric symptoms (NPS). Subgroups with higher aNPS were at increased risk of progression to dementia in both CN (HR = 3.65, 95% CI [1.80, 7.40]) and MCI (HR = 1.52, 95% CI [1.16, 2.00]; HR = 1.86 [1.05, 3.30]) groups, adjusting for age, sex, global cognition, and ApoE4, compared with their counterparts with minimal NPS. There was no difference between higher aNPS and minimal NPS subgroups in their CSF AD biomarker profiles. Conclusion: Findings suggest that aNPS may represent a neurobiological vulnerability that uniquely contribute to the dementia risk, independent of AD biomarker profiles.

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Diagnosing Alzheimer’s Disease from Circulating Blood Leukocytes Using a Fluorescent Amyloid Probe

Journal of Alzheimer s Disease ◽

10.3233/jad-215402 ◽

2021 ◽

pp. 1-14

Author(s):

Stefanie A.G. Black ◽

Anastasiia A. Stepanchuk ◽

George W. Templeton ◽

Yda Hernandez ◽

Tomoko Ota ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Misfolding ◽

Mononuclear Cells ◽

Immune Cell ◽

Amyloid Β ◽

Csf Biomarkers ◽

Blood Leukocytes ◽

Peripheral Blood Mononuclear ◽

The Brain

Background: Toxic amyloid-β (Aβ) peptides aggregate into higher molecular weight assemblies and accumulate not only in the extracellular space, but also in the walls of blood vessels in the brain, increasing their permeability, and promoting immune cell migration and activation. Given the prominent role of the immune system, phagocytic blood cells may contact pathological brain materials. Objective: To develop a novel method for early Alzheimer’s disease (AD) detection, we used blood leukocytes, that could act as “sentinels” after trafficking through the brain microvasculature, to detect pathological amyloid by labelling with a conformationally-sensitive fluorescent amyloid probe and imaging with confocal spectral microscopy. Methods: Formalin-fixed peripheral blood mononuclear cells (PBMCs) from cognitively healthy control (HC) subjects, mild cognitive impairment (MCI) and AD patients were stained with the fluorescent amyloid probe K114, and imaged. Results were validated against cerebrospinal fluid (CSF) biomarkers and clinical diagnosis. Results: K114-labeled leukocytes exhibited distinctive fluorescent spectral signatures in MCI/AD subjects. Comparing subjects with single CSF biomarker-positive AD/MCI to negative controls, our technique yielded modest AUCs, which improved to the 0.90 range when only MCI subjects were included in order to measure performance in an early disease state. Combining CSF Aβ 42 and t-Tau metrics further improved the AUC to 0.93. Conclusion: Our method holds promise for sensitive detection of AD-related protein misfolding in circulating leukocytes, particularly in the early stages of disease.

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Delirium, dementia, and other cognitive disorders

Psychiatry ◽

10.1093/oso/9780198754008.003.0034 ◽

2019 ◽

Author(s):

Rebecca McKnight ◽

Jonathan Price ◽

John Geddes

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Psychiatric Disorders ◽

Brain Function ◽

Healthcare Services ◽

Common Condition ◽

Organic Brain Disease ◽

The Brain

Organic psychiatric disorders result from brain dysfunction caused by organic pathology inside or outside the brain. Dementia is the most common condition, with Alzheimer’s disease alone affecting 1 per cent of the population at 60 years, rising to 40 per cent over 80 years. Many of the rarer organic psychiatric disorders tend to affect a wider age range, but present in similar ways. Given the changing demographics of most developed countries, disorders producing cognitive impairment in older adults are becoming increasingly important for provision of healthcare services and in daily clinical practice. This chapter will cover the more common causes of cognitive impairment, and there is additional information in Chapters 18 and 20 on psychiatry of older adults in psychiatry and medicine. There are three common clinical presentations of organic psychiatric disorders: … 1 Delirium— an acute generalized impairment of brain function, in which the most important feature is impairment of consciousness. The disturbance of brain function is generalized, and the primary cause is often outside the brain; for example, sepsis due to a urinary tract infection. 2 Dementia— chronic generalized impairment, in which the main clinical feature is global intellectual impairment. There are also changes in mood and behaviour. The brain dysfunction is generalized, and the primary cause is within the brain; for example, a degenerative condition such as Alzheimer’s disease. 3 Specific syndromes— which include disorders with a predominant impairment of isolated areas; for example, memory (amnesic syndrome), thought, mood, or personality change. These include neurological disorders that frequently result in organic psychological complications; for example, epilepsy…. Table 26.1 lists the main categories of psychiatric disorder associated with organic brain disease. The following sections describe these syndromes and the psychiatric consequences of a number of neurological conditions. Organic causes of other core psychiatric conditions (e.g. anxiety and psychosis) are covered in the relevant specific chapters. Delirium is characterized by an acute impairment of consciousness producing a generalized cognitive impairment. The word delirium is derived from the Latin, ‘lira’, which means to wander from the furrow. Delirium is a common condition, affecting up to 30 per cent of patients in general medical or surgical wards, with the primary cause often being a systemic illness. The term ‘acute confusional state’ is a synonym for delirium.

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Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease

Science Advances ◽

10.1126/sciadv.aaz9360 ◽

2020 ◽

Vol 6 (43) ◽

pp. eaaz9360 ◽

Cited By ~ 1

Author(s):

Lenora Higginbotham ◽

Lingyan Ping ◽

Eric B. Dammer ◽

Duc M. Duong ◽

Maotian Zhou ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Wide Spectrum ◽

Csf Biomarkers ◽

Protein Biomarkers ◽

Cerebrospinal Fluid Biomarkers ◽

Brain Proteome ◽

The Brain ◽

Underlying Pathophysiology

Alzheimer’s disease (AD) lacks protein biomarkers reflective of its diverse underlying pathophysiology, hindering diagnostic and therapeutic advancements. Here, we used integrative proteomics to identify cerebrospinal fluid (CSF) biomarkers representing a wide spectrum of AD pathophysiology. Multiplex mass spectrometry identified ~3500 and ~12,000 proteins in AD CSF and brain, respectively. Network analysis of the brain proteome resolved 44 biologically diverse modules, 15 of which overlapped with the CSF proteome. CSF AD markers in these overlapping modules were collapsed into five protein panels representing distinct pathophysiological processes. Synaptic and metabolic panels were decreased in AD brain but increased in CSF, while glial-enriched myelination and immunity panels were increased in brain and CSF. The consistency and disease specificity of panel changes were confirmed in >500 additional CSF samples. These panels also identified biological subpopulations within asymptomatic AD. Overall, these results are a promising step toward a network-based biomarker tool for AD clinical applications.

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The Effect of Traumatic Brain Injury History with Loss of Consciousness on Rate of Cognitive Decline Among Older Adults with Normal Cognition and Alzheimer’s Disease Dementia

Journal of Alzheimer s Disease ◽

10.3233/jad-160585 ◽

2017 ◽

Vol 59 (1) ◽

pp. 251-263 ◽

Cited By ~ 9

Author(s):

Yorghos Tripodis ◽

Michael L. Alosco ◽

Nikolaos Zirogiannis ◽

Brandon E. Gavett ◽

Christine Chaisson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Cognitive Decline ◽

Loss Of Consciousness ◽

Normal Cognition ◽

Alzheimer’S Disease Dementia

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Polygenic hazard scores in preclinical Alzheimer’s disease

10.1101/156331 ◽

2017 ◽

Author(s):

Chin Hong Tan ◽

Leo P. Sugrue ◽

Iris J. Broce ◽

Elizabeth Tong ◽

Jacinth J. X. Tan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Clinical Importance ◽

Incidence Rates ◽

Elevated Risk ◽

Carrier Status ◽

Older Individuals ◽

Preclinical Alzheimer’S Disease ◽

Asymptomatic Individuals

ABSTRACTIdentifying asymptomatic older individuals at elevated risk for developing Alzheimer’s disease (AD) is of clinical importance. Among 1,081 asymptomatic older adults, a recently validated polygenic hazard score (PHS) significantly predicted time to AD dementia and steeper longitudinal cognitive decline, even after controlling for APOE ε4 carrier status. Older individuals in the highest PHS percentiles showed the highest AD incidence rates. PHS predicted longitudinal clinical decline among older individuals with moderate to high CERAD (amyloid) and Braak (tau) scores at autopsy, even among APOE ε4 non-carriers. Beyond APOE, PHS may help identify asymptomatic individuals at highest risk for developing Alzheimer’s neurodegeneration.

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Biomarkers for Alzheimer’s Disease Early Diagnosis

Journal of Personalized Medicine ◽

10.3390/jpm10030114 ◽

2020 ◽

Vol 10 (3) ◽

pp. 114 ◽

Cited By ~ 2

Author(s):

Eva Ausó ◽

Violeta Gómez-Vicente ◽

Gema Esquiva

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuronal Loss ◽

Diagnostic Tools ◽

Csf Biomarkers ◽

Diagnosis And Prognosis ◽

Positron Emission ◽

The Central Nervous System ◽

Magnetic Resonance Imaging Mri ◽

The Brain

Alzheimer’s disease (AD) is the most common cause of dementia, affecting the central nervous system (CNS) through the accumulation of intraneuronal neurofibrillary tau tangles (NFTs) and β-amyloid plaques. By the time AD is clinically diagnosed, neuronal loss has already occurred in many brain and retinal regions. Therefore, the availability of early and reliable diagnosis markers of the disease would allow its detection and taking preventive measures to avoid neuronal loss. Current diagnostic tools in the brain, such as magnetic resonance imaging (MRI), positron emission tomography (PET) imaging, and cerebrospinal fluid (CSF) biomarkers (Aβ and tau) detection are invasive and expensive. Brain-secreted extracellular vesicles (BEVs) isolated from peripheral blood have emerged as novel strategies in the study of AD, with enormous potential as a diagnostic evaluation of therapeutics and treatment tools. In addition; similar mechanisms of neurodegeneration have been demonstrated in the brain and the eyes of AD patients. Since the eyes are more accessible than the brain, several eye tests that detect cellular and vascular changes in the retina have also been proposed as potential screening biomarkers. The aim of this study is to summarize and discuss several potential markers in the brain, eye, blood, and other accessible biofluids like saliva and urine, and correlate them with earlier diagnosis and prognosis to identify individuals with mild symptoms prior to dementia.

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Protective Factors Modulate the Risk of Beta Amyloid in Alzheimer’s Disease

Behavioural Neurology ◽

10.1155/2020/7029642 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Bin Zhou ◽

Kenichiro Tanabe ◽

Shinsuke Kojima ◽

Satoshi Teramukai ◽

Masanori Fukushima ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuropsychological Tests ◽

Cox Regression ◽

Clinical Trial Design ◽

Beta Amyloid ◽

Carrier Status ◽

Protective Function ◽

Magnetic Resonance Imaging Mri ◽

Normal Cognition

Aim. To identify the factors protecting Abeta-positive subjects with normal cognition (NC) or mild cognitive impairment (MCI) from conversion to Alzheimer’s disease (AD). Methods. Subjects with MCI in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, with baseline data for neuropsychological tests, brain beta amyloid (Abeta), magnetic resonance imaging (MRI), APOE genotyping, and 18F-FDG-PET (FDG), were included for analysis. Results. Elevated brain amyloid was associated with a higher risk of conversion from MCI to AD (41.5%) relative to Abeta levels of <1.231 (5.5%) but was not associated with conversion from NC to AD (0.0 vs. 1.4%). In the multivariate Cox regression analyses, elevated Abeta increased the risk of AD, while higher whole-brain cerebral glucose metabolism (CGM) assessed by FDG decreased the risk of AD in subjects with the same amount of Abeta. Even in the patients with heavily elevated brain amyloid, those with FDG > 5.946 had a lower risk of AD. ApoE4 carrier status did not influence the protective effect. Conclusion. Higher average CGM based on FDG modified the progression to AD, indicating a protective function. The results suggest that the inclusion of this CGM measured by FDG would enrich clinical trial design and that increasing CGM along with the use of anti-Abeta agents might be a potential prevention strategy for AD.

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In Vivo Microdialysis in Mice Captures Changes in Alzheimer’s Disease Cerebrospinal Fluid Biomarkers Consistent with Developing Pathology

Journal of Alzheimer s Disease ◽

10.3233/jad-210715 ◽

2021 ◽

pp. 1-14

Author(s):

Christiana Bjorkli ◽

Claire Louet ◽

Trude Helen Flo ◽

Mary Hemler ◽

Axel Sandvig ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Mouse Model ◽

Amyloid Β ◽

Csf Biomarkers ◽

Intracerebral Microdialysis ◽

Preclinical Models ◽

The Brain

Background: Preclinical models of Alzheimer’s disease (AD) can provide valuable insights into the onset and progression of the disease, such as changes in concentrations of amyloid-β (Aβ) and tau in cerebrospinal fluid (CSF). However, such models are currently underutilized due to limited advancement in techniques that allow for longitudinal CSF monitoring. Objective: An elegant way to understand the biochemical environment in the diseased brain is intracerebral microdialysis, a method that has until now been limited to short-term observations, or snapshots, of the brain microenvironment. Here we draw upon patient-based findings to characterize CSF biomarkers in a commonly used preclinical mouse model for AD. Methods: Our modified push-pull microdialysis method was first validated ex vivo with human CSF samples, and then in vivo in an AD mouse model, permitting assessment of dynamic changes of CSF Aβ and tau and allowing for better translational understanding of CSF biomarkers. Results: We demonstrate that CSF biomarker changes in preclinical models capture what is observed in the brain; with a decrease in CSF Aβ observed when plaques are deposited, and an increase in CSF tau once tau pathology is present in the brain parenchyma. We found that a high molecular weight cut-off membrane allowed for simultaneous sampling of Aβ and tau, comparable to CSF collection by lumbar puncture in patients. Conclusion: Our approach can further advance AD and other neurodegenerative research by following evolving neuropathology along the disease cascade via consecutive sampling from the same animal and can additionally be used to administer pharmaceutical compounds and assess their efficacy (Bjorkli, unpublished data).

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