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Pharmacological Management of Parkinson’s Disease
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Newman Osafo, Samuel Obeng, David D. Obiri, Oduro K. Yeboah, Leslie B. Essel
A body of proof from neuropathological findings implicated degeneration of neurons in PD as not being limited to the basal ganglia and dopamine containing neurons. Per the Braak staging system (Braak et al., 2003), inclusion bodies that contain α-synuclein occur in caudal brainstem nuclei (stage 1) with the involvement of the substantia nigra (stage 3). During stage 2, serotonin containing neurons that are located in the raphe nucleus become affected, so do the locus coeruleus derived noradrenaline producing projection neurons. At advanced phases of PD progression, there are extension of the neurodegeneration to cholinergic neurons in the neocortex and pedunculopontine tegmental nucleus. The mutiliplicity of affected neurotransmitter systems leads to the development of several symptoms. It is imperative for clinicians and their patients to note that, these symptoms may only be responsive to adjunctive nondopamine therapies (Hung and Schwarzschild, 2014). This chapter discusses a detailed pathogenesis of PD and the possible CNS mediators that contribute to the development of the neurodegenerative disorder. Again, the chapter particularizes on PD pharmacotherapy and the pharmacodynamics and pharmacokinetic profiles of these agents employed in managing the disorder, as well as its signs.
Pathology, aetiology and pathogenesis
Published in Jeremy Playfer, John Hindle, Andrew Lees, Parkinson's Disease in the Older Patient, 2018
The Braak staging has been used to classify the progression of pathological changes in PD as it progresses from the brainstem in an ascending course, ultimately reaching the cortex.15 In Stage 1, changes are confined to the dorsal motor nucleus and olfactory bulb. This is responsible for the loss of olfactory function commonly seen in pre-clinical PD and suggested as a means of defining an at-risk population.16 Braak Stage 2 involves Lewy body formation and neuronal loss in the pons and medulla. By Stages 3 and 4 the pathology has advanced to the stage where clinical symptoms emerge in response to nigro-striatal cell loss and clinical diagnosis becomes possible. By Stages 5 and 6 neocortical areas are affected and this is associated with the late development of cognitive problems including dementia.17
Neuropathology and pathogenesis of dementia with Lewy bodies
Published in John O'Brien, Ian McKeith, David Ames, Edmond Chiu, Dementia with Lewy Bodies and Parkinson's Disease Dementia, 2005
LBD can be classified based upon the distribution of LBs (Kosaka et al, 1984). Diffuse Lewy body disease (DLBD) is the pathological diagnosis for cases with LBs widely distributed in the neocortex, while transitional LBD is the term used to describe cases with LBs limited to the limbic lobe. When LBs are minimal in cortical areas, but present in brainstem and forebrain nuclei, the term brainstem-type LBD is used. This staging has been expanded upon by Braak et al (2003), who have added refinements to the brainstem- predominant stage. Table 11.1 summarizes the distribution of LBs in the Kosaka and Braak staging schemes.
Cortical hyperexcitability and plasticity in Alzheimer’s disease: developments in understanding and management
Published in Expert Review of Neurotherapeutics, 2022
Mehdi A. J van den Bos, Parvathi Menon, Steve Vucic
At a macroscopic level, cortical atrophy often begins within the entorhinal cortex, spreading to the limbic and para-limbic regions extending to involve neo-cortical associative areas[16]. The structural changes are typically evident in later stages of AD[17]. Functional changes seem to develop much earlier in the disease process, perhaps reflecting changes in cortical function and network connectivity. Whilst pathological involvement in Braak staging appears late in the motor cortex [18], studies of early AD patients with functional MRI has noted increased co-activation of bilateral motor and visual areas along with the primary cortex for a visually cued simple motor task[19] whilst TMS studies have noted demonstrated a wealth of functional changes within the motor cortex in prodromal and early AD stages. Interestingly recent work[20] using PET using a novel biomarker has noted a widespread reduction of synaptic density including in pericentral regions even in early AD – how this may reflect the functional changes seen with TMS has yet to be directly examined.
Mixed neuropathology in frontotemporal lobar degeneration
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2020
Catherine Pennington, Luca Marini, Elizabeth Coulthard, Seth Love
The UK Brain Bank Network has harmonized diagnostic protocols, based on the assessment of 13 core formalin-fixed paraffin-embedded blocks (frontal BA46, cingulate BA32/24, superior temporal BA41/42, amygdala, anterior hippocampus, posterior hippocampus, striatum, thalamus, posterior parietal lobule BA39, primary visual cortex BA17, cerebellar cortex, midbrain, pons, medulla, spinal cord-cervical, thoracic, and lumbar). Each block is stained with hematoxylin and eosin and stained with luxol fast blue/cresyl violet. Immunohistochemistry for Aβ, α-synuclein, phosphorylated TDP-43, etc. is assessed using same antibody clones in each bank. Standard criteria are applied for staging of disease: NIA-AA criteria for Alzheimer’s disease (13) including Braak tangle stages (14,15) and Thal amyloid phases (16) and Braak staging of Lewy body diseases (17).
Small RNA fingerprinting of Alzheimer’s disease frontal cortex extracellular vesicles and their comparison with peripheral extracellular vesicles
Published in Journal of Extracellular Vesicles, 2020
Lesley Cheng, Laura J. Vella, Kevin J. Barnham, Catriona McLean, Colin L. Masters, Andrew F. Hill
Staging of Alzheimer’s disease (AD) related pathology and lesions, in particular amyloid-β (Aβ) plaques and neurofibrillary tangles, occurs in a predictable sequence across interconnected regions of the brain, known as Braak staging. These neuropathological changes occur at early stages before the onset of dementia which is difficult to diagnose, thus highlighting a need to identify biomarkers that can inform early changes in the brain. Neurofibrillary tangles appear at Braak stage I and II within the transentorhinal region and entorhinal region during the pre-clinical stage of AD, stage III and IV in the temporo-occipital cortex and temporal cortex on the appearance of symptoms followed by stage V and VI in the occipital cortex and neocortex [1]. Generally, transcriptional deregulation can be detected earlier than the presence of pathological hallmarks and may be considered as the first indication of phenotypic changes in the brain [2–4]. miRNA is highly present in the brain compared to other tissues [5] and early studies identified brain-enriched miRNA [6] including those associated with AD detected as early as Braak stage III [7,8]. To further enhance sensitivity and detection at pre-clinical stage, miRNA can be isolated from enriched preparations of extracellular vesicles (EVs) from the brain to study the molecular events in the development of AD. Furthermore, the deregulation of miRNA expression can also spread via “horizontal” RNA transfer through EVs to act in conjunction with proteins leading to changes in mRNA and consequently destruction of biological functions within neuron and glia cells of the brain.