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Successful vs. Unsuccessful Aging in the Rhesus Monkey
Published in David R. Riddle, Brain Aging, 2007
Mark B. Moss, Tara L. Moore, Stephen P. Schettler, Ronald Killiany, Douglas Rosene
Several possibilities have been advanced to account for mild or marked age-related cognitive decline, ranging from widespread cortical neuronal loss and neurotransmitter depletion, to amyloid deposition and to the development of neuritic plaques. While likely contributing to cognitive dysfunction, we believe that these factors are unlikely primary candidates to account for age-related cognitive decline. With few exceptions, neurons in the cerebral cortex do not undergo marked loss [95] and the presence and the extent of neuritic plaques or amyloid burden are quite variable and are not correlated with cognitive decline [96]. Rather, we have accumulated evidence over the past several years that lead us to the view that alteration and loss of white matter may be the principal neurobiological change that underlies age-related cognitive decline [3]. In electron microscopic (EM) studies of the effects of aging in the cerebral cortex [97, 98], corpus callosum [98], and optic nerve [99] of monkeys, myelin sheaths have been found to show marked age-related changes, including the accumulation of dense cytoplasm and the formation of fluid-filled balloons. In addition, the formation of sheaths with redundant myelin and thick sheaths occur with continued formation of myelin with age [100]. Of particular interest, the frequency of these alterations in myelin with age correlates significantly with the cognitive decline exhibited by monkeys. In support of this, using diffusion tensor magnetic resonance imaging (DT-MRI), we have recently reported significant age-related loss of fractional anisotropy (FA) in forebrain white matter of the frontal lobe. Reduced FA is regarded as a marker of white matter abnormalities and, like the EM measures, correlates with cognitive decline [101]. Further, unpublished data from our group on conduction across the corpus callosum indicates that, with age, there is a significant alteration in the profile of conduction parameters. This result could be explained if the myelin dystrophy observed in the corpus callosum [98] disrupts conduction in a fraction of the nerve fibers and suggests that alterations in myelin integrity and consequent disruption of conduction may alter the signal strength and hence the information transfer that is critical for neuronal circuits to operate properly. Finally, using designed-based stereology and MRI in separate studies, our group has demonstrated nerve fiber loss with age from the optic nerves [99], a 40% loss of nerve fibers in the anterior commissure of aged rhesus monkeys, and a significant loss of white matter volume on with MRI, with an accompanying increase in ventricular size (Wisco, Killiany, and Rosene, unpublished observations). These observations lend further support to the notion that there is likely to be a global loss of myelinated nerve fibers with age. Extensive multidisciplinary investigations into the precise mechanisms of these age-related changes in white matter and their relationship to cognitive decline are the focus of our current studies with the continued use of our nonhuman primate model of normal aging.
Neuroinflammation, immune response and α-synuclein pathology: how animal models are helping us to connect dots
Published in Expert Opinion on Drug Discovery, 2023
Tiziano Balzano, Noelia Esteban-García, Javier Blesa
Considering the high failure rate from preclinical to clinical studies, the choice of the correct model is probably the first crucial step along the path leading to discovery of new targets, which could build a robust bridge between preclinical studies and more reliable therapeutic candidates. In this direction, we consider anti-inflammatory and immunologic/immunosuppressant agents as promising candidates to reduce disease progression especially at very early stages; however, most of these drugs failed to show efficacy in the first phases of clinical trials [116]. These dramatic results may be related to the fact that 50–70% of the nigrostriatal dopaminergic neurons and axons may be lost before motor symptoms arise, making PD a difficult disease to stop. For this reason, one of the major challenges in PD will be the development of noninvasive tools to identify individuals exhibiting neuroinflammation and brain immune response, not only to predict the disease progression but also to improve the success rate when using anti-inflammatory and immunomodulatory agents. Along these lines, the use of noninvasive breath volatile organic compound mass-spectrometry and free-water measurement in diffusion-tensor magnetic resonance imaging (DT-MRI) have been suggested as promising technologies to accomplish this goal [23]. The implementation of these new technologies for the early detection of neuroinflammatory and brain immune changes in PD patients, together with the development of new models for the discovery of new molecular targets and more reliable therapeutic candidates, probably represent the only way to reduce the enormous gap in comparison with dopaminergic drugs, which have dominated the therapeutic market for sixty years now.
What is the role of placebo in neurotherapeutics?
Published in Expert Review of Neurotherapeutics, 2022
Elisa Frisaldi, Aziz Shaibani, Marco Trucco, Edoardo Milano, Fabrizio Benedetti
A natural situation in which hidden therapies are delivered is represented by impaired cognition. Cognitively impaired patients do not have expectations about therapeutic benefits, so that the psychological (placebo) component of a treatment is likely to be absent. On the basis of these considerations, Benedetti et al. [74] studied Alzheimer patients at the initial stage of the disease and after one year, in order to see whether the placebo component of the therapy was affected by the disease. The placebo component of an analgesic therapy was found to be correlated with both cognitive status and functional connectivity among different brain regions, according to the rule ‘the more impaired the prefrontal connectivity, the smaller the placebo response’ [74]. To support this view, there are a number of studies which indicate that placebo responses are reduced when prefrontal functioning is impaired. First, the individual placebo analgesic effect is correlated with white matter integrity indexed by fractional anisotropy, as assessed through diffusion tensor magnetic resonance imaging; stronger placebo analgesic responses are associated with increased mean fractional anisotropy values within white matter tracts connecting the PAG with the rACC and the DLPFC [75]. Second, inactivation of the frontal cortex with repetitive transcranial magnetic stimulation completely blocks the analgesic placebo response [76]. Third, the opioid antagonist naloxone blocks placebo analgesia, along with a reduction in the activation of the DLPFC, suggesting that a prefrontal opioidergic mechanism is crucial in the placebo analgesic response [32]. Therefore, both magnetic and pharmacological inactivation of the prefrontal lobes have the same effects as those observed in prefrontal degeneration in Alzheimer’s disease and reduced integrity of prefrontal white matter.