Memory impairment in amnesia and dementia: implications for the use of animal models

Cases of amnesia, in which there is a stable memory impairment with sparing of other cognitive functions, have taught us a great deal about the neuroanatomic basis of memory storage and retrieval; animal models of amnesia have provided even more precise information about the brain mechanisms responsible for specific aspects of memory functioning. Amnestic syndromes are rare, however, and constitute only a tiny fraction of the clinical cases in which memory is impaired. Dementia, particularly that due to Alzheimer's disease, is much more common but differs from the amnestic syndromes in three important ways: (1) a variety of of cognitive functions including language and praxis are affected, (2) the condition is usually progressive with gradual loss of several neuronal populations, and (3) the etiology of dementia is not well understood at present but clinical data suggest some role for genetic, viral, vascular and toxic environmental factors. It is argued that animal models should give greater attention to these important features of the common clinical dementias.     

Rasch models of aphasic performance on syntactic comprehension tests

Responses of 42 people with aphasia to 11 sentence types in enactment and sentence-picture matching tasks were characterized using Rasch models that varied in the inclusion of the factors of task, sentence type, and patient group. The best fitting models required the factors of task and patient group but not sentence type. The results provide evidence that aphasic syntactic comprehension is best accounted for by models that include different estimates of patient ability in different tasks and different difficulty of all sentences in different groups of patients, but that do not include different estimates of patient ability for different types of sentences.     

Rasch models of aphasic performance on syntactic comprehension tests

Responses of 42 people with aphasia to 11 sentence types in enactment and sentence–picture matching tasks were characterized using Rasch models that varied in the inclusion of the factors of task, sentence type, and patient group. The best fitting models required the factors of task and patient group but not sentence type. The results provide evidence that aphasic syntactic comprehension is best accounted for by models that include different estimates of patient ability in different tasks and different difficulty of all sentences in different groups of patients, but that do not include different estimates of patient ability for different types of sentences.     

Effects of hypothyroidism on the respiratory system and control of breathing: Human studies and animal models

Hypothyroidism, subclinical hypothyroidism and euthyroid sick syndrome, are prevalent disorders that affect all body systems including the respiratory system and control of breathing. The purpose of this review article is to discuss the regulation of thyroid hormone production and their function at the cellular level; the many causes of hypothyroidism; the effects of hypothyroidism on the respiratory system and on control of ventilation in hypothyroid patients; the variety of ways animal models of hypothyroidism are induced; and how in animal models hypothyroidism affects the respiratory system and control of breathing including neurotransmitters that influence breathing. Finally, this review will present controversies that exist in the field and thus encourage new research directions. Because of the high prevalence of hypothyroidism and subclinical forms of hypothyroidism and their influence on ventilation and the respiratory system, understanding underlying molecular mechanisms is necessary to ascertain how and sometimes why not thyroid replacement may normalize function.     

Assessing the performance of different outcomes for tumor growth studies with animal models

The consistency of reporting results for patient‐derived xenograft (PDX) studies is an area of concern. The PDX method commonly starts by implanting a derivative of a human tumor into a mouse, then comparing the tumor growth under different treatment conditions. Currently, a wide array of statistical methods (e.g., t‐test, regression, chi‐squared test) are used to analyze these data, which ultimately depend on the outcome chosen (e.g., tumor volume, relative growth, categorical growth). In this simulation study, we provide empirical evidence for the outcome selection process by comparing the performance of both commonly used outcomes and novel variations of common outcomes used in PDX studies. Data were simulated to mimic tumor growth under multiple scenarios, then each outcome of interest was evaluated for 10 000 iterations. Comparisons between different outcomes were made with respect to average bias, variance, type‐1 error, and power. A total of 18 continuous, categorical, and time‐to‐event outcomes were evaluated, with ultimately 2 outcomes outperforming the others: final tumor volume and change in tumor volume from baseline. Notably, the novel variations of the tumor growth inhibition index (TGII)—a commonly used outcome in PDX studies—was found to perform poorly in several scenarios with inflated type‐1 error rates and a relatively large bias. Finally, all outcomes of interest were applied to a real‐world dataset.     

Autoimmune mechanisms in patients and animal models

Autoimmune diseases in patients and animal models are reviewed from the standpoint of immunoregulatory defects which predispose to autoimmunity. New information is provided about autoantibodies which indicates, on the basis of idiotypic cross-reactivity, that they may be closer to normal antibodies than previously thought. The importance of estrogens as a predisposing factor and androgens as a protective factor is discussed in relation to modulation of immune response by sex hormones. Similarities between autoimmune diseases and Acquired Immunodeficiency Syndrome (AIDS) are presented and new therapeutic approaches are discussed.     

Screening tests for animal TSE: present and future

In 1999, three rapid tests (Prionics, Bio-Rad, Enfer) have been validated by the European Commission for the post-mortem diagnosis of BSE in cattle. They are now used on a large scale over the entire Europe. In absence of antibodies specifically recognizing the native conformation PrPres, its selective determination is based on the biochemical properties of this abnormal form (PK resistance, aggregation in presence of detergents). In addition, all these tests include a denaturation step so that PrP can be detected by appropriate antibodies. When applied on "risk populations" or on "healthy animals" entering into the human food chain, these rapid tests have provided a better estimation of the epizootic and allowed an efficient removal of animals bearing a risk for human consumption. Since 2002, they have also been used for the post-mortem diagnosis of scrapie in sheep and goat. Five new tests have been recently evaluated (ID-Lelystad; Perkin-elmer, Prionics Check LIA, UCSF, Imperial college) but it is too early to know which place they will take in the field. Current tests allow a preclinical diagnosis of TSE, especially in sheep and goats for which a very early detection is possible in peripheral lymphoid tissues. However, to date, no test on living animal has been validated. Taking into account the important number of research teams now involved on this topic one may expect spectacular progress in the forthcoming years.     

Update on animal models for HIV research

Animal models for HIV research have been indispensible in fulfilling Koch's postulate and in exploring issues of viral infectivity and pathogenesis, sequence divergence, route(s) of acquisition, tissue distribution and tropism, immunogenicity and protection capacity of vaccine candidates, escape from adaptive immunity, and more. Did they fail to predict the efficacy of T‐cell vaccines in humans? This article summarizes progress and status of models to inform and complement clinical work.     

Human and animal models of V(D)J recombination deficiency

V(D)J recombination not only comprises the molecular mechanism that insures diversity of the immune system but also constitutes a critical checkpoint in the developmental program of B and T lymphocytes. The analysis of human patients with severe combined immune deficiency (SCID) has enabled (and will enable in the future) the discovery of important factors involved in this reaction. The finding that the V(D)J recombinase apparatus includes components of the general DNA repair machinery of the cells has provided some new and interesting insights into the role of V(D)J recombination deficiency in the development of lymphoid malignancies, a hypothesis that has been tackled and proven in several animal models.     

MMPI/MMPI-2: comparisons of amnesic patients.

The amnesic population provides a unique opportunity to examine the reliability of clinical tests because amnesics do not consciously recollect initial testing sessions. In this study, amnesic subjects were studied to examine the reliability between the Minnesota Multiphasic Personality Inventory (MMPI) and the MMPI-2. Findings indicated that there were no statistical differences between versions of the MMPI and further revealed that many of the scales were significantly correlated. Amnesic patients produced elevated scores on subscales two (depression) and eight (schizophrenia), not unlike various other groups of neurologically impaired individuals. This indicates that MMPI and MMPI-2 scores in these patient populations may reflect the medical and psychosocial effects of brain damage rather than premorbid personality dysfunction. A close evaluation of amnesics' performance, in conjunction with the critical items they endorsed, offers insight into the personality traits of the amnesic patient population. The relative stability of performance across personality tests administered over several weeks is relevant to the formation and stability of the amnesic's concept of self.     

Apomorphine susceptibility and animal models for psychopathology: genes and environment

Many years ago we found a bimodal distribution of a number of different behaviors in our regular outbred Wistar stock. This was observed in the response to novelty, the response in a resident-intruder test as well as in the stereotypy response to the dopamine agonist apomorphine. On the basis of that, we decided to selectively breed these animals, which resulted in the the APO-SUS and APO-UNSUS lines. The APO-SUS rats show a strong, stereotyped gnawing response, whereas APO-UNSUS show only a weak gnawing response. Follow-up studies have shown that the phenotypical expression of these rats depend on genetic and early and late environmental factors. Because these rats were not selected on the basis of a specific behavioral trait, but rather on the basis of a difference in susceptibility for a specific neurotransmitter, it is not surprising that these animals show major differences in the neurochemical state of the central nervous system. In fact, in many respects they represent mirror images of each other. Moreover, these animals show clear differences in their endocrine and immunological systems. APO-SUS rats can be characterized as having a hyper-reactive hypothalamus-pituitary-adrenal axis, and a dominance of the T_H2 system. Apart from discussing the main differences between APO-SUS and APO-UNSUS rats, the review specifically focuses on the former as a potential model for schizophrenia. We have been able to show that APO-SUS rats indeed share a large number of behavioral, neurochemical, endocrinological, and immunological similarities with patients suffering from schizophrenia. Because schizophrenia is also likely to result from an interaction between genetic and early stressful life events, the APO-SUS rat might represent a promising animal model for studying this severe mental disorder.     

The antialgesic drugs: Human therapeutic correlates of their potency in laboratory animal models of hyperalgesia

This survey discusses the correlation between the oral potency of antialgesic drugs in several pharmacology laboratories and their human oral dose in clinical practice. We also present a brief overview of a few biological assays that have been successfully used to direct the synthesis of newer antialgesic drugs. The laboratory assay that our analysis showed to be most predictive of the clinical analgesic dose is based upon the response of rats to flexion of an arthritic joint. Laboratory ED₅₀ values from the ACh-induced abdominal constriction assay in mice are nearly as predictive while the predictive power of the yeast-induced hyperalgesia assay in rats is somewhat less. Probably because of the small number of experiments, the correlation between the efficacy of these agents in a canine model of synovitis and their clinical doses only reached borderline statistical significance (p=0.0651). Regression equations are presented that permit calculations of single clinical analgesic doses from efficacy data in individual tests. Calculation of stepwise multiple regression showed that the clinical dose could be best predicted when efficacy data obtained in the joint flexion assay in rats and the ACh-induced constriction assay in mice are both taken into account. We have concluded that the effective doses are highly predictive of clinical efficacy because these animal assays have been designed to reflect the action of drugs upon prostanoid-induced hyperalgesia.     

Characteristics of animal models for COVID-19

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) is the causative agent of coronavirus disease 2019(COVID-19), the most consequential pandemic of this century, threatening human health and public safety. SARS-CoV-2 has been continuously evolving through mutation of its genome and variants of concern have emerged. The World Health Organization R&D Blueprint plan convened a range of expert groups to develop animal models for COVID-19, a core requirement for the prevention and contro...     

Movement performance and body size: the relationship for different groups of tests

It has been shown that inconsistently applied normalization for body size could be an important methodological problem in testing physical performance in areas such as sports, physical education, ergonomy, or physical medicine and rehabilitation. The aim of this study was to evaluate a part of the recently proposed classification of physical performance tests (Jaric 2003) based on the role of body size in the tested performance. Presuming a normalization method P_n=P/S^b based on an allometric relationship between the tested performance P and a selected index of body size S (P_n performance normalized for body size; b allometric parameter), we specifically hypothesized that: (1) the tests of exertion of external force (e.g., lifting weight, pushing, pulling), (2) tests of rapid movements (jumping, sprinting, kicking) and (3) tests of supporting body weight (chin-ups, squats) would reveal the values of the allometric parameters b=0.67, b=0 and b=–0.33 when body size is expressed as body mass, or b=2, b=0 and b=–1 when body size is expressed as body height, respectively. Male physical education students (n=77) were tested on 18 standard physical performance tests belonging to the aforementioned three groups. The obtained values of the allometric parameters proved to be closely in line with the hypothesized ones. While the finding regarding the tests of exertion of external force (i.e., the tested force should be divided by m^0.67 in order to normalize the force for body size) have been already demonstrated by some authors, the findings related to the tests of rapid movements and, particularly, tests of supporting body weight are novel. Although the normalization methods discussed need further evaluation, a more accurate and consistently applied assessment of the body size-independent indices of the evaluated groups of standard tests could improve the methodology of physical performance testing in general.     

Relevance of animal models for clinical treatment

The use of animal models has become an integral part of the evaluation of drugs for antimicrobial chemotherapy. Animal models can be used to define the penetration of antimicrobial agents at foci of infections, the time course of in vivo antimicrobial therapy, dose-response relationships, and the influence of therapy on the pathophysiologic consequences of infection. Animal models have been useful in the delineation of many of the basic principles currently used in clinical practice and in the selection of new agents and new therapeutic approaches for clinical trials in humans. In spite of the many positive aspects of animal models, several problems, such as altered pharmacokinetics in animals, can preclude direct application of results to clinical practice. Studies in animal models cannot replace the need for human clinical trials.     

Spinal fusion surgery: animal models for tissue-engineered bone constructs

Animal models have been used extensively to investigate the biology of fracture healing and spinal fusion. The goal of each spinal fusion model is to try and reproduce the correct sequence of events during osseous healing in humans. Animal models allow us the capability of dialing in fusion rates and fusion parameters depending upon the study conditions. These models have become invaluable in assessing the clinical potential of emerging technologies such as recombinant growth factors and gene therapy.     

Ectopic lymphoid follicles in progressive multiple sclerosis: From patients to animal models

Ectopic lymphoid follicles (ELFs), resembling germinal centre‐like structures, emerge in a variety of infectious and autoimmune and neoplastic diseases. ELFs can be found in the meninges of around 40% of the investigated progressive multiple sclerosis (MS) post‐mortem brain tissues and are associated with the severity of cortical degeneration and clinical disease progression. Of predominant importance for progressive neuronal damage during the progressive MS phase appears to be meningeal inflammation, comprising diffuse meningeal infiltrates, B‐cell aggregates and compartmentalized ELFs. However, the absence of a uniform definition of ELFs impedes reproducible and comparable neuropathological research in this field. In this review article, we will first highlight historical aspects and milestones around the discovery of ELFs in the meninges of progressive MS patients. In the next step, we discuss how animal models may contribute to an understanding of the mechanisms underlying ELF formation. Finally, we summarize challenges in investigating ELFs and propose potential directions for future research.