Combining Select Neuropsychological Assessment with Blood-Based Biomarkers to Detect Mild Alzheimer's Disease: A Molecular Neuropsychology Approach

Edwards, Melissa; Balldin, Valerie Hobson; Hall, James; O’Bryant, Sid

doi:10.3233/jad-140852

Cited by 12 publications

(9 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Systemic infection in AD was also associated with a reduction in several pro-inflammatory cytokines, mainly associated with the adaptive immune system. The few studies that have examined their role in AD have found: (i) elevated serum IL7 in early to mild AD [ 20 ]; (ii) elevated IL12p40 levels in the cerebrospinal fluid (CSF) of Alzheimer’s patients [ 68 ]; (iii) administration of IL12p40 subunit blocker enhanced microglial phagocytosis and reduced inflammation in Aβ transgenic mice [ 68 ]; (iv) raised IL15 levels in the CSF and serum of Alzheimer’s patients correlated with severity of cognitive dysfunction [ 6 , 58 ]; (v) increased peripheral IL16 in AD [ 19 ]; and overexpression of IL17A decreased soluble Aβ levels without exacerbating neuroinflammation in a mouse model of Aβ accumulation [ 73 ].…”

Section: Discussionmentioning

confidence: 99%

Systemic infection modifies the neuroinflammatory response in late stage Alzheimer’s disease

Rakić

Hung

Smith

et al. 2018

acta neuropathol commun

View full text Add to dashboard Cite

Clinical studies indicate that systemic infections accelerate cognitive decline in Alzheimer’s disease. Animal models suggest that this may be due to enhanced pro-inflammatory changes in the brain. We have performed a post-mortem human study to determine whether systemic infection modifies the neuropathology and in particular, neuroinflammation, in the late-stage of the disease.Sections of cerebral cortex and underlying white matter from controls and Alzheimer's patients who died with or without a terminal systemic infection were immunolabelled and quantified for: (i) Αβ and phosphorylated-tau; (ii) the inflammation-related proteins Iba1, CD68, HLA-DR, FcγRs (CD64, CD32a, CD32b, CD16), CHIL3L1, IL4R and CCR2; and (iii) T-cell marker CD3. In Alzheimer's disease, the synaptic proteins synaptophysin and PSD-95 were quantified by ELISA, and the inflammatory proteins and mRNAs by MesoScale Discovery Multiplex Assays and qPCR, respectively.Systemic infection in Alzheimer's disease was associated with decreased CD16 (p = 0.027, grey matter) and CD68 (p = 0.015, white matter); increased CD64 (p = 0.017, white matter) as well as increased protein expression of IL6 (p = 0.047) and decreased IL5 (p = 0.007), IL7 (p = 0.002), IL12/IL23p40 (p = 0.001), IL15 (p = 0.008), IL16 (p < 0.001) and IL17A (p < 0.001). Increased expression of anti-inflammatory genes CHI3L1 (p = 0.012) and IL4R (p = 0.004) were detected in this group. T-cell recruitment to the brain was reduced when systemic infection was present. However, exposure to systemic infection did not modify the pathology. In Alzheimer's disease, CD68 (p = 0.026), CD64 (p = 0.002), CHI3L1 (p = 0.016), IL4R (p = 0.005) and CCR2 (p = 0.010) were increased independently of systemic infection.Our findings suggest that systemic infections modify neuroinflammatory processes in Alzheimer's disease. However, rather than promoting pro-inflammatory changes, as observed in experimental models, they seem to promote an anti-inflammatory, potentially immunosuppressive, environment in the human brain.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0592-3) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Systemic infection modifies the neuroinflammatory response in late stage Alzheimer’s disease

Rakić

Hung

Smith

et al. 2018

acta neuropathol commun

View full text Add to dashboard Cite

show abstract

“…Through this work, researchers have sought to provide utility for identifying blood-based biomarkers associated with neuropsychological functioning to establish biomarker profiles of disease states [7] . This effort termed Molecular Neuropsychology has identified biomarker profiles of neurocognitive functioning and begun combining select blood biomarkers with select cognitive assessments with the goal of establishing a point-of-care device for primary care settings that can be used to identify those with early AD [7] , [8] . This work has stemmed from the growing need for a rapid screening measure for those early in the disease process.…”

Section: Introductionmentioning

confidence: 99%

“…In our recent work, we demonstrated that combining two of the top five biomarkers (TNF-α and IL-7) with one neuropsychological measure (Clock 4-point), yielded excellent accuracy in detecting early AD [8] . Even for very early AD cases, this approach was able to provide an overall accuracy of 91% with a sensitivity of 97% and specificity of 72% [8] . This work has shown that combining neuropsychological screening measures with a limited number of biomarkers can increase the ability to identify those who are at a higher risk for the development of AD.…”

Section: Introductionmentioning

confidence: 99%

Molecular markers of neuropsychological functioning and Alzheimer's disease

Edwards

Balldin

Hall

et al. 2015

Alz & Dem Diag Ass & Dis Mo

Self Cite

View full text Add to dashboard Cite

BackgroundThe current project sought to examine molecular markers of neuropsychological functioning among elders with and without Alzheimer's disease (AD) and determine the predictive ability of combined molecular markers and select neuropsychological tests in detecting disease presence.MethodsData were analyzed from 300 participants (n = 150, AD and n = 150, controls) enrolled in the Texas Alzheimer's Research and Care Consortium. Linear regression models were created to examine the link between the top five molecular markers from our AD blood profile and neuropsychological test scores. Logistical regressions were used to predict AD presence using serum biomarkers in combination with select neuropsychological measures.ResultsUsing the neuropsychological test with the least amount of variance overlap with the molecular markers, the combined neuropsychological test and molecular markers was highly accurate in detecting AD presence.ConclusionThis work provides the foundation for the generation of a point-of-care device that can be used to screen for AD.

show abstract

“…The longitudinal dynamics and predictive performance of this multimodal approach is not definitely established and should be examined according to our expectation, in terms of sensitivity and/or specificity, and their condition, i.e. in combination or isolated (166, 167). Moreover, opinions of regulatory agencies and industry stakeholders in AD biomarker discovery area are constantly in discussion and development (168–170).…”

Section: Directions For Ad Biomarker Researchmentioning

confidence: 99%

Precision Medicine - The Golden Gate for Detection, Treatment and Prevention of Alzheimer’s Disease

Hampel¹,

O’Bryant

Castrillo

et al. 2016

J Prev Alz Dis

View full text Add to dashboard Cite

During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer’s disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy. This approach will likely be based on the success found from more advanced research fields, such as oncology. Precision medicine will require integration and transfertilization across fragmented specialities of medicine and direct reintegration of Neuroscience, Neurology and Psychiatry into a continuum of medical sciences away from the silo approach. Precision medicine is biomarker-guided medicine on systems-levels that takes into account methodological advancements and discoveries of the comprehensive pathophysiological profiles of complex multi-factorial neurodegenerative diseases, such as late-onset sporadic AD. This will allow identifying and characterizing the disease processes at the asymptomatic preclinical stage, where pathophysiological and topographical abnormalities precede overt clinical symptoms by many years to decades. In this respect, the uncharted territory of the AD preclinical stage has become a major research challenge as the field postulates that early biomarker guided customized interventions may offer the best chance of therapeutic success. Clarification and practical operationalization is needed for comprehensive dissection and classification of interacting and converging disease mechanisms, description of genomic and epigenetic drivers, natural history trajectories through space and time, surrogate biomarkers and indicators of risk and progression, as well as considerations about the regulatory, ethical, political and societal consequences of early detection at asymptomatic stages. In this scenario, the integrated roles of genome sequencing, investigations of comprehensive fluid-based biomarkers and multimodal neuroimaging will be of key importance for the identification of distinct molecular mechanisms and signaling pathways in subsets of asymptomatic people at greatest risk for progression to clinical milestones due to those specific pathways. The precision medicine strategy facilitates a paradigm shift in Neuroscience and AD research and development away from the classical “one-size-fits-all” approach in drug discovery towards biomarker guided “molecularly” tailored therapy for truly effective treatment and prevention options. After the long and winding decade of failed therapy trials progress towards the holistic systems-based strategy of precision medicine may finally turn into the new age of scientific and medical success curbing the global AD epidemic.

show abstract

Combining Select Neuropsychological Assessment with Blood-Based Biomarkers to Detect Mild Alzheimer's Disease: A Molecular Neuropsychology Approach

Cited by 12 publications

References 24 publications

Systemic infection modifies the neuroinflammatory response in late stage Alzheimer’s disease

Systemic infection modifies the neuroinflammatory response in late stage Alzheimer’s disease

Molecular markers of neuropsychological functioning and Alzheimer's disease

Precision Medicine - The Golden Gate for Detection, Treatment and Prevention of Alzheimer’s Disease

Contact Info

Product

Resources

About