A Precision Medicine Initiative for Alzheimer's disease: the road ahead to biomarker-guided integrative disease modeling.

After intense scientific exploration and more than a decade of failed trials, Alzheimer's disease (AD) remains a fatal global epidemic. A traditional research and drug development paradigm continues to target heterogeneous late-stage clinically phenotyped patients with single 'magic bullet' drugs. Here, we propose that it is time for a paradigm shift towards the implementation of precision medicine (PM) for enhanced risk screening, detection, treatment, and prevention of AD. The overarching structure of how PM for AD can be achieved will be provided through the convergence of breakthrough technological advances, including big data science, systems biology, genomic sequencing, blood-based biomarkers, integrated disease modeling and P4 medicine. It is hypothesized that deconstructing AD into multiple genetic and biological subsets existing within this heterogeneous target population will provide an effective PM strategy for treating individual patients with the specific agent(s) that are likely to work best based on the specific individual biological make-up. The Alzheimer's Precision Medicine Initiative (APMI) is an international collaboration of leading interdisciplinary clinicians and scientists devoted towards the implementation of PM in Neurology, Psychiatry and Neuroscience. It is hypothesized that successful realization of PM in AD and other neurodegenerative diseases will result in breakthrough therapies, such as in oncology, with optimized safety profiles, better responder rates and treatment responses, particularly through biomarker-guided early preclinical disease-stage clinical trials.

Vitamin C Supplementation, APOE4 Genotype and Cognitive Functioning in a Rural-Dwelling Cohort.

OBJECTIVE: Apolipoprotein E4 (APOE4) genotype has been implicated as a moderating factor in cognitive function studies. Although prior studies have suggested that vitamin C is associated with better cognitive function in elders, link between the two has been mixed. Limited data exist as to whether the APOE4 genotype influences these associations. Therefore, this study sought to determine whether the association between vitamin C and cognition in a rural community dwelling cohort differs by the APOE4 genotype. DESIGN AND PARTICIPANTS: Data were analyzed on 582 participants (n=183 men; n=399 women) from a rural community-based cohort. Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status and The Executive Interview. APOE genotyping was ascertained by standard methods. The relation between vitamin C supplementation and cognition were analyzed first with ANOVA and then ANCOVA with age, gender, education as covariates. Analyses were initially run in the full sample and then split by APOE4 presence (yes/no). RESULTS: Overall, Vitamin C supplementation was associated with significantly better immediate memory (p=0.04), visuospatial skills (p=0.002), language (p=0.01), and global cognitive functioning (p=0.006). Among APOE4 non-carriers, vitamin C supplementation was positively associated with immediate memory (F[1,392] =6.7, p=0.01), visuospatial skills (F[1,391]=10.6, p=0.001), language (F[1,392]=13.0, p<0.001), attention (F[1,386]=7.9, p=0.005, and global cognition (F[1,382]=11.0, p=0.001. However, there was no significant link between vitamin C supplementation and cognition among APOE4 carriers. CONCLUSION: Vitamin C supplementation was found to be positively associated with cognition among this rural-dwelling community-based sample; however, the associations appeared to differ by APOE4 status. These data may suggest that targeted genotype-specific cognitive enhancement studies are needed to clarify the potential benefits of vitamin C supplementation.

PRECISION MEDICINE - The Golden Gate for Detection, Treatment and Prevention of Alzheimer's Disease.

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.

The Road Ahead to Cure Alzheimer's Disease: Development of Biological Markers and Neuroimaging Methods for Prevention Trials Across all Stages and Target Populations.

Alzheimer's disease (AD) is a slowly progressing non-linear dynamic brain disease in which pathophysiological abnormalities, detectable in vivo by biological markers, precede overt clinical symptoms by many years to decades. Use of these biomarkers for the detection of early and preclinical AD has become of central importance following publication of two international expert working group's revised criteria for the diagnosis of AD dementia, mild cognitive impairment (MCI) due to AD, prodromal AD and preclinical AD. As a consequence of matured research evidence six AD biomarkers are sufficiently validated and partly qualified to be incorporated into operationalized clinical diagnostic criteria and use in primary and secondary prevention trials. These biomarkers fall into two molecular categories: biomarkers of amyloid-beta (Aß) deposition and plaque formation as well as of tau-protein related hyperphosphorylation and neurodegeneration. Three of the six gold-standard ("core feasible) biomarkers are neuroimaging measures and three are cerebrospinal fluid (CSF) analytes. CSF Aß1-42 (Aß1-42), also expressed as Aß1-42 : Aß1-40 ratio, T-tau, and P-tau Thr181 & Thr231 proteins have proven diagnostic accuracy and risk enhancement in prodromal MCI and AD dementia. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up. Magnetic resonance imaging (MRI) at increasing field strength and resolution allows detecting the evolution of distinct types of structural and functional abnormality pattern throughout early to late AD stages. Anatomical or volumetric MRI is the most widely used technique and provides local and global measures of atrophy. The revised diagnostic criteria for "prodromal AD" and "mild cognitive impairment due to AD" include hippocampal atrophy (as the fourth validated biomarker), which is considered an indicator of regional neuronal injury. Advanced image analysis techniques generate automatic and reproducible measures both in regions of interest, such as the hippocampus and in an exploratory fashion, observer and hypothesis-indedendent, throughout the entire brain. Evolving modalities such as diffusion-tensor imaging (DTI) and advanced tractography as well as resting-state functional MRI provide useful additionally useful measures indicating the degree of fiber tract and neural network disintegration (structural, effective and functional connectivity) that may substantially contribute to early detection and the mapping of progression. These modalities require further standardization and validation. The use of molecular in vivo amyloid imaging agents (the fifth validated biomarker), such as the Pittsburgh Compound-B and markers of neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) (as the sixth validated biomarker) support the detection of early AD pathological processes and associated neurodegeneration. How to use, interpret, and disclose biomarker results drives the need for optimized standardization. Multimodal AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping fashion. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. AD biomarkers can be combined to increase accuracy or risk. A list of genetic risk factors is increasingly included in secondary prevention trials to stratify and select individuals at genetic risk of AD. Although most of these biomarker candidates are not yet qualified and approved by regulatory authorities for their intended use in drug trials, they are nonetheless applied in ongoing clinical studies for the following functions: (i) inclusion/exclusion criteria, (ii) patient stratification, (iii) evaluation of treatment effect, (iv) drug target engagement, and (v) safety. Moreover, novel promising hypothesis-driven, as well as exploratory biochemical, genetic, electrophysiological, and neuroimaging markers for use in clinical trials are being developed. The current state-of-the-art and future perspectives on both biological and neuroimaging derived biomarker discovery and development as well as the intended application in prevention trials is outlined in the present publication.

The Link between Cognitive Measures and ADLs and IADL Functioning in Mild Alzheimer's: What Has Gender Got to Do with It?

Objectives. To investigate the link between neurocognitive measures and various aspects of daily living (ADL and IADL) in women and men with mild Alzheimer's disease (AD). Methods. Participants were 202 AD patients (91 male, 111 female) with CDR global scores of ≤1. ADLs and IADLs ratings were obtained from caregivers. Cognitive domains were assessed with neuropsychological testing. Results. Memory and executive functioning were related to IADL scores. Executive functioning was linked to total ADL. Comparisons stratified on gender found attention predicted total ADL score in both men and women. Attention predicted bathing and eating ability in women only. Language predicted IADL functions in men (food preparation) and women (driving). Conclusions. Associations between ADLs/IADLs and memory, learning, executive functioning, and language suggest that even in patients with mild AD, basic ADLs require complex cognitive processes. Gender differences in the domains of learning and memory area were found.

Performance on a measure of category fluency in cognitively impaired elderly.

Measures of verbal fluency are widely used in the assessment of cognitive functioning of the elderly. However, limited research has evaluated patterns (across specific timed intervals) of performance on tasks of language fluency in different forms of dementia. The current study investigated semantic fluency in 488 elderly individuals (249 with Alzheimer's dementia, 97 Vascular dementia, 97 Mild Cognitive Impairment and 45 cognitively intact) across 15-second intervals in an animal naming task using retrospective chart review. Normal controls produced significantly more exemplars and AD patients produced fewer animal names than the other groups. After the first 15- second time interval, the demented groups produced significantly fewer exemplars than the non-demented. At the end of 30 seconds it was possible to differentiate normal aging from MCI who no longer differed from the VaD group. Overall, it appears that the greatest and most clinically meaningful differences between the diagnostic groups were detected in the first three 15-second intervals. The present findings support the use of time intervals and total scores on tasks of verbal fluency in clinical settings and for research purposes.

Coin rotation task (CRT): a new test of motor dexterity.

Coin-rotation task (CRT), a measure of rapid, coordinated finger movements, was devised as a convenient, easily administered bedside test of motor dexterity; however, very little psychometric data exist regarding this task. The current project was undertaken to (a) provide preliminary normative data, (b) examine the convergent and discriminant validity of the task when compared with other standardized motor measures, and (c) examine the diagnostic accuracy of the CRT. The sample of 86 male participants included 60 controls and 26 patients with unilateral lesions of the left (n = 13) and right (n = 13) hemispheres. The CRT was not significantly correlated with age or education; non-adjusted left- and right-hand normative data are provided. The CRT demonstrated good convergent and divergent validity when compared with other standardized motor measures. The CRT was successful in differentiating control and brain damaged groups with mild motor impairment, and demonstrated an overall classification rate of 84.9%. Levels of sensitivity and specificity of the CRT were comparable with or better than other standardized tests of manual dexterity. The CRT offers a valid, quick, and convenient bedside measure of subtle motor impairment.

CXC chemokine receptors expression during chronic relapsing experimental autoimmune encephalomyelitis.

Chemokines are small proinflammatory cytokines that possess the ability to stimulate migration of inflammatory cells towards the tissue site of inflammation. Previous reports showed that several chemokines may be involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of autoimmune central nervous system (CNS) inflammation. Inflammatory cells respond to chemotactic chemokine gradient through the chemokine receptors (ChRs). The goal of this study was to analyze expression of ChRs belonging to CXC subfamily during different stages of chronic relapsing EAE. We found significantly increased expression of CXCR2 and CXCR4 in the spinal cord during the first and second disease attacks. The kinetics of this expression in CNS and blood suggests that CXCR2 is expressed by leukocytes migrating from the blood, but CXCR4 is expressed mainly by CNS parenchymal cells. Those results support the interpretation that chemokine-chemokine receptor interactions may play an important role in the development of CNS autoimmune inflammation.

Treatment with BBB022A or rolipram stabilizes the blood-brain barrier in experimental autoimmune encephalomyelitis: an additional mechanism for the therapeutic effect of type IV phosphodiesterase inhibitors.

We examined the treatment effects of two structurally distinct phosphodiesterase type IV (PDE IV) inhibitors, BBB022 and rolipram, in murine and rat models of experimental autoimmune encephalomyelitis (EAE). Based on our data, we propose a mechanism of action which may supplement immunomodulatory effects of PDE IV inhibitors. In particular, PDE inhibitors promote elevation of intracellular cAMP levels, increasing the electrical resistance of endothelial monolayers by stabilizing intercellular junctional complexes. Such an effect on central nervous system (CNS) vascular endothelium has the potential to reduce disease severity in EAE, because both inflammatory cells and humoral factors readily cross a disrupted blood-brain barrier (BBB). In this report, we demonstrate the capacity of BBB022 and rolipram to decrease clinical severity of EAE. further, PDE IV inhibitors significantly reduced BBB permeability in the spinal cords of mice with EAE. These results provide evidence that PDE IV-inhibitors may exert therapeutic effects in EAE by modifying cerebrovascular endothelial permeability, reducing tissue edema as well as entry of inflammatory cells and factors.

Older widows and independent lifestyles.

Societies differ over the importance of individualistic/independent behaviors. In the United States, such behaviors are highly valued. Thus, subtle pressures exist on older widowed Americans to develop and maintain independent lifestyles. Respondents (N = 300) were older widows, age 60+, who were individually interviewed in their own homes. Various measures of self-sufficiency were derived from a list of fifteen life-maintenance tasks. The ability of widows to accomplish traditionally female tasks is significantly related to health, education, age, and work history, whereas their ability to accomplish traditionally male tasks is significantly related to income, living alone, and work history. Results did not support the hypotheses in that neither high levels of overall self-sufficiency or male-task sufficiency are related to widows' psychological well-being or life satisfaction.

Recent widows' kin support and orientations to self-sufficiency.

This paper examines two issues: the role of the adult child network in task support to widows, and whether widows' attitudes toward independence result in lower levels of task support. Data on recently widowed women suggest that many are quite self-sufficient; however, in those areas where support is needed, they largely rely on children. Widows' past experiences and attitudes toward independence influence the amount of overall help they receive, whereas income, number of children, and perceived willingness of children to help affect the proportion of help that comes from children.

Financial experience and well-being among mature widowed women.

Widowhood for women may be complicated by a lack of financial experience or knowledge, further diminishing well-being. Analyzed were data from 300 widowed women aged 60 and older regarding financial experience prior to widowhood, planning undertaken before death of spouse, and their effects on well-being in early widowhood. Shown by the findings was that preparation was associated with somewhat better well-being among widows, but financial experience prior to widowhood had no effect.

Adolescent discipline: Different family members' perception.

Adolescence is perhaps the most difficult period of child rearing for parents. This study attempted to identify disciplinary techniques used by parents as perceived by mothers, fathers, and their adolescent children. Results indicated several significant areas of intrafamilial disagreement in regard to disciplinary techniques utilized, although all subjects tended to agree that some form of verbal reasoning was the primary disciplinary technique utilized with these adolescents.