Faculty Bibliography

BACKGROUND:Little is known with respect to behavioral markers of subjective cognitive decline (SCD), a condition initially described in association with Global Deterioration Scale (GDS) stage 2. OBJECTIVE:Two-year interval behavioral markers were investigated herein. METHODS:Subjects from a published 7-year outcome study of GDS stage 2 subjects were selected. This study had demonstrated a hazard ratio of 4.5 for progression of GDS stage 2, in comparison with GDS stage 1 (no subjective or objective cognitive decline) subjects, after controlling for demographic and temporal variables. Because GDS 2 subjects have previously demonstrated impairment in comparison with healthy persons free of complaints, we herein suggest the terminology "SCD(I)" for these persons. 98 SCD(I) persons, 63 women and 35 men, mean baseline age, 67.12±8.75 years, with a mean educational background of 15.55±2.60 years, and mean baseline MMSE scores of 28.9±1.24 were followed for 2.13±0.30 years. RESULTS:Observed annual decline on the GDS was 6.701% per annum, very close to a 1986 published estimate. At follow up, the MMSE, and 7 of 8 psychometric tests did not decline significantly. Of 21 Hamilton Depression Scale items, 2 improved and the remainder were unchanged. Anxieties declined from multiple perspectives. The Brief Cognitive Rating Scale (BCRS) declined significantly (p < 0.001), with component declines in Remote memory (p < 0.01), and Functioning/self-care (p = 0.01). CONCLUSION/CONCLUSIONS:SCD(I) persons decline at an annual rate of approximately 6.7% /year from several recent studies. The BCRS assessments and the Digit Symbol Substitution Test can be sensitive measures for future studies of progression mitigation.

There are growing genetic, transcriptomic and proteomic data pointing to the complexity of Alzheimer's disease (AD) pathogenesis. Unbiased "omics" approaches are essential for the future development of effective AD research, which will need to be combined and personalized, given that multiple distinct pathways can drive AD pathology. It is essential to gain a better understanding of the AD pathogenesis subtype variety and to develop several distinct therapeutic approaches tailored to address this diversity, as well as the common presence of mixed pathologies. These nonmutually exclusive therapeutic approaches include the targeting of multiple toxic oligomeric species concurrently, targeting the apolipoprotein E/amyloid β interaction and the modulation of innate immunity, as well as more "out of the box" ideas such as targeting infectious agents that may play a role in AD.

Traumatic brain injury (TBI) is a risk factor for a group of neurodegenerative diseases termed tauopathies, which includes Alzheimer's disease and chronic traumatic encephalopathy (CTE). Although TBI is stratified by impact severity as either mild (m), moderate or severe, mTBI is the most common and the most difficult to diagnose. Tauopathies are pathologically related by the accumulation of hyperphosphorylated tau (P-tau) and increased total tau (T-tau). Here we describe: (i) a novel human tau-expressing transgenic mouse model, TghTau/PS1, to study repetitive mild closed head injury (rmCHI), (ii) quantitative comparison of T-tau and P-tau from brain and plasma in TghTau/PS1 mice over a 12 month period following rmCHI (and sham), (iii) the usefulness of P-tau as an early- and late-stage blood-based biochemical biomarker for rmCHI, (iii) the influence of kinase-targeted therapeutic intervention on rmCHI-associated cognitive deficits using a combination of lithium chloride (LiCl) and R-roscovitine (ros), and (iv) correlation of behavioral and cognitive changes with concentrations of the brain and blood-based T-tau and P-tau. Compared to sham-treated mice, behavior changes and cognitive deficits of rmCHI-treated TghTau/PS1 mice correlated with increases in both cortex and plasma T-tau and P-tau levels over 12 months. In addition, T-tau, but more predominantly P-tau, levels were significantly reduced in the cortex and plasma by LiCl + ros approaching the biomarker levels in sham and drug-treated sham mice (the drugs had only modest effects on the T-tau and P-tau levels in sham mice) throughout the 12 month study period. Furthermore, although we also observed a reversal of the abnormal behavior and cognitive deficits in the drug-treated rmCHI mice (compared to the untreated rmCHI mice) throughout the time course, these drug-treated effects were most pronounced up until 10 and 12 months where the abnormal behavior and cognition deficits began to gradually increase. These studies describe: (a) a translational relevant animal model for TBI-linked tauopathies, and (b) utilization of T-tau and P-tau as rmCHI biomarkers in plasma to monitor novel therapeutic strategies and treatment regimens for these neurodegenerative diseases.

Different strategies for treatment and prevention of Alzheimer's disease (AD) are currently under investigation, including passive immunization with anti-amyloid β (anti-Aβ) monoclonal antibodies (mAbs). Here, we investigate the therapeutic potential of a novel type of Aβ-targeting agent based on an affibody molecule with fundamentally different properties to mAbs. We generated a therapeutic candidate, denoted Z_SYM73-albumin-binding domain (ABD; 16.8 kDa), by genetic linkage of the dimeric Z_SYM73 affibody for sequestering of monomeric Aβ-peptides and an ABD for extension of its in vivo half-life. Amyloid precursor protein (APP)/PS1 transgenic AD mice were administered with Z_SYM73-ABD, followed by behavioral examination and immunohistochemistry. Results demonstrated rescued cognitive functions and significantly lower amyloid burden in the treated animals compared to controls. No toxicological symptoms or immunology-related side-effects were observed. To our knowledge, this is the first reported in vivo investigation of a systemically delivered scaffold protein against monomeric Aβ, demonstrating a therapeutic potential for prevention of AD.

INTRODUCTION/BACKGROUND:In autism spectrum disorder, lack of coherence and of complex information processing, and narrowly focused interests and repetitive behaviors are considered a sign of long-range underconnectivity and short-range overconnectivity. The goal of this morphometric study of five anatomically and functionally different segments of the corpus callosum (CC) was to establish patterns of differences between long-range interhemispheric connections in nine neurotypical and nine autistic subjects. RESULTS:Electron microscopy revealed a significant reduction in average axon diameter and axon cross-sectional area in autistic subjects, and reduction in CC segment-specific diversification of connections of functionally different cortical regions. The study shows an increase in the percentage of small diameter axons (< 0.651 μm) and a decrease in the percentage of axons with large diameter (> 1.051 μm). The total number of small-diameter axons is reduced in segment I and III by 43% on average. The number of medium- and large-diameter axons is reduced in all five CC segments by an average of 49 and 72%, respectively. CONCLUSIONS:The detected pattern of pathology suggests a failure of mechanisms controlling guidance of axons during development leading to axonal deficit, and failure of mechanisms controlling axon structure. A reduction in axon diameter may affect the velocity and volume of signal transmission, and distort functional specialization of CC segments. Significant deficits in axon number and reduction in axon size in all five CC segments appear to be substantial components of brain connectome integrity distortion which may contribute to the autism phenotype.

Structural and functional elements of biological systems are highly conserved across vertebrates. Many neurological and psychiatric conditions affect both humans and animals. A cross-species approach to the study of brain and behaviour can advance our understanding of human disorders via the identification of unrecognized natural models of spontaneous disorders, thus revealing novel factors that increase vulnerability or resilience, and via the assessment of potential therapies. Moreover, diagnostic and therapeutic advances in human neurology and psychiatry can often be adapted for veterinary patients. However, clinical and research collaborations between physicians and veterinarians remain limited, leaving this wealth of comparative information largely untapped. Here, we review pain, cognitive decline syndromes, epilepsy, anxiety and compulsions, autoimmune and infectious encephalitides and mismatch disorders across a range of animal species, looking for novel insights with translational potential. This comparative perspective can help generate novel hypotheses, expand and improve clinical trials and identify natural animal models of disease resistance and vulnerability.

Background: We have previously demonstrated the feasibility of eliciting a unique antibody response independent of the primary and tertiary structure of proteins/peptides and specifically recognizing generic secondary beta-sheet structure dominant on misfolded proteins of oligomeric form; a hallmark of toxic prion-like "infectious" pathology in neurodegenerative diseases and specifically in the dual Abeta and tau Alzheimer's disease (AD) (Goni et al 2013 J. Neuroinflammation). As a putative antigen we have used a small peptide with a non-self primary structure, only beta-sheet secondary structure and no tertiary structure do to its size. The highly polymerized peptide (pBri) preserved a stable 90% beta-sheet secondary structure without any other outstanding epitope that could be recognized by an immune system. Young animals of AD models APP/PS1, 3xTg and SwDI as well as wild type animals, all developed polyclonal antibodies IgM and IgG that recognized oligomers of Abeta and tau and significantly ameliorated pathology. CD-1 animals were used to produced monoclonal antibodies (mAbs) that proved unequivocally the recognition was not to a sequence dependent epitope but to a generic beta-sheet secondary structure of pathologic oligomers but not fibrils or native proteins (Goni et al 2017 Scientific reports). The mAbs were characterized as specific anti-beta-sheet secondary structure monoclonal antibodies (AbetaComAbs). Either the stable IgM or the engineered IgG AbetaComAbs could reverse pathology and produce cognitive rescue in 3xTg animals (Goni et al 2018, Alz Res Therapy; Herline et al 2018 Alz Res Therapy).
Objective(s): To demonstrate that small engineered peptides with similar beta-sheet dominant structure but different primary sequences would elicit similar anti-beta-sheet responses and ameliorate pathology on 3xTg animals. To demonstrate that old 3xTg animals with already flourished pathology would develop the same type of anti-beta-sheet polyclonal IgM and IgG response and compared to AbetaComAbs infused animals produced comparable cognitive rescue and reduced oligomeric pathology. Finally, to demonstrate the specific reaction to the secondary structure but not the primary/tertiary structure does not produce antibody dependent cerebral microhemorrhages in an old SwDI CAA model of AD.
Method(s): Groups of 8 to 12 male and female 16 months old 3xTg AD and SwDI animals were inoculated i.p. weekly for 9 weeks with either 100 mug of the stable IgMk GW-23B7 or the derived TWF9 IgG2ak AbetaComAbs in 100 muL of sterile saline or with 100 muL of vehicle alone. Other groups of young 3xTg were inoculated with several tailored made mutations of the original pBri; whereas groups of 17 months old 3xTg were inoculated with the highly polymerized original pBri. The pBri immunizations and the AbetaComAbs were repeated in aged 16 month old SwDI animals prone to develop cerebral amyloid angiopathy due to the nature of the model, exacerbated by eventual reaction to Abeta amyloid epitopes existing in vessels of the brain. All animals were subjected to radial arm maze, locomotor tests or Barnes maze after the treatment and before sacrifice. Histochemical and biochemical analysis were performed on brains from treated and control animals.
Result(s): No adverse reactions were demonstrated during any one of the different treatments. Old animals inoculated with the pBri produced a fare anti-beta-sheet response; however, lower than in young animals. There was a significant cognitive rescue compared to controls and a significant reduction of both Abeta and tau oligomers. The mutated peptides were not as efficient to elicit anti-beta-sheet polyclonal response but still produce a significant amelioration on cognitive decline close to the results obtained by the original pBri. All SwDI animals either pBri immunized or AbetaComAbs infused -stable IgMk or IgG2aK- did not show any signs of vascular complication. In all cases the main biochemical improvement was the significant decrease on the number of oligomers of both Abeta and tau as assessed by specific blots of solubilized brain extractions, ELISAs and MSD measurements. Immunohistochemically the extracellular Abeta in plaques was significantly decreased whereas the intracellular PHF-tau remained fairly the same.
Conclusion(s): The development of a specific antibody response -polyclonal or monoclonal- to strictly the secondary structure of a protein or peptide frozen in a stable beta-sheet state is successfully achieved by the immunization with a highly polymerized, beta-sheet only, immunogen with no other visible epitope. That specific response is completely independent of the primary structure of pathological conformers; thus, it interferes only with oligomeric pathologic conformers that show the dominant beta-sheet secondary structure. Either treatment can produce , in various degrees, amelioration of AD pathology or evident cognitive rescue depending on the time of start of treatment. The mechanism is likely related to reductions of the levels of soluble oligomeric forms of Abeta and Tau; the species most closely linked to cognitive deficits in AD patients and the prionlike propagation. These results are extremely encouraging for the further testing of potential combinations of immunizations and AbetaComAbs in clinical trials with disease modifying potential and minimal risk of autoimmune complications