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Biochemical Markers for Alzheimer Disease as Reflection of the Neuropathology in Cerebrospinal Fluid:
Published in Robert E. Becker, Ezio Giacobini, Alzheimer Disease, 2020
C. Bancher, H.M. Wisniewski, P.D. Mehta, K.S. Kim, I. Grundke-Iqbal, K. Iqbal
False positive results may be due to increased presence of cross-reactive elements in the brain tissue. Nothing is known on the solubility properties of these structures, but for theoretical purposes the existence of soluble derivatives in the CSF has to be considered. Especially corpora amylacea can be numerous in the aging brain and are preferentially found near the pial and ventricular surfaces. Theoretically, increased numbers of Lewy bodies could also lead to a false positive test since these lesions contain ubiquitin (Kuzuhara et al. 1988) and react with the PHF mAbs (Galloway et al. 1988; Bancher et al. 1989a). Diffuse Lewy body disease, characterized by the widespread occurrence of Lewy bodies in the cerebral cortex, has recently been shown to be a significant substrate of dementia in old age (Byrne et al. 1989; Dickson et al. 1989) and represents an important differential diagnosis to AD. However, as seen by immunocytochemistry with antibodies to ubiquitin or PHF, the total amount of reactivity in the tissue of these cases is only a small fraction of what one observes in the AD brain. This difference makes it unlikely that high numbers of Lewy bodies will be reflected by elevated levels of 5-25 immunoreactivity in the CSF.
The Neuropathology of Alzheimer’s Disease
Published in Zaven S. Khachaturian, Teresa S. Radebaugh, Alzheimer’s Disease, 2019
Suzanne S. Mirra, William R. Markesbery
Until recently, degeneration of the substantia nigra, a dopaminergic nucleus in the midbrain along with the microscopic finding of Lewy bodies, round concentric cytoplasmic inclusions in pigmented neurons in this region and other subcortical sites, was widely regarded as the morphologic correlate of idiopathic Parkinson’s disease (Figure 7). Patients with this disorder classically present with extrapyramidal signs including bradykinesia (slow movement), rigidity, and tremor. Over the past few years, however, there has been increased recognition that patients with cognitive impairment resembling AD as well as certain additional clinical features including fluctuation in cognition and hallucinations may show similar neuropathology. The classification of this entity in which the presence of cortical Lewy bodies is emphasized (they have also been reported in idiopathic Parkinson’s disease) is controversial as exemplified by the numerous appellations applied to it, e.g., diffuse Lewy body disease, Lewy body variant of AD, AD plus Parkinson’s disease, and senile dementia of the Lewy body type. The crux of the debate revolves around whether this form of Lewy body disease is indeed a variant of AD or whether it represents a distinctive clinical and neuropathological entity. It seems reasonable to consider the Lewy body diseases as a clinical-pathological spectrum, ranging from idiopathic Parkinson’s disease, the movement disorder, at one end to a primary dementia with similar pathology, i.e., diffuse Lewy body disease (with or without coexistent AD) at the other end.
Development of palliative medicine in the United Kingdom and Ireland
Published in Eduardo Bruera, Irene Higginson, Charles F von Gunten, Tatsuya Morita, Textbook of Palliative Medicine and Supportive Care, 2015
Younger patients do better than older patients with an expected prognosis of 20-30 years when motor manifestations can be controlled by drugs and neurosurgical procedures such as deep brain stimulation. In particular, older patients may, 5-10 years following diagnosis, begin to experience more difficulties with problems that are not only related to druginduced on-off periods but also to neuropsychiatric problems. Hallucinations and cognitive decline often herald the onset of diffuse Lewy body disease or dementia with Lewy bodies [26]. Depression is more common in older patients and complicates at least 20% of such cases, rising with increasing age of onset.
Dyspnea in Parkinson’s disease: an approach to diagnosis and management
Published in Expert Review of Neurotherapeutics, 2020
Srimathy Vijayan, Bhajan Singh, Soumya Ghosh, Rick Stell, Frank L. Mastaglia
There is a paucity of research in this field and a number of important questions still remain to be resolved regarding the pathophysiology and natural history of dyspnea in PD. Further carefully planned studies are required to investigate more fully the epidemiology of dyspnea in PD and its relationship to the progressive course of the disease and motor symptoms. In addition, further longitudinal studies of large patient cohorts at different stages of the disease will be essential to better characterize the natural history of dyspnea, and determine whether it may indeed be an early or prodromal symptom as has been proposed. Such studies will need to be complemented by physiological studies of central respiratory drive and brainstem and carotid body chemoreceptor responses at different stages of the disease, as well as neuropathological studies of brainstem respiratory centers to confirm that they are affected by the disease process, as has been demonstrated in other α-synucleinopathies such as Diffuse Lewy Body disease and Multiple System Atrophy [12,76–79]. If impaired central ventilatory control is indeed shown to occur in early PD, and to predate the onset of motor symptoms, this would then provide another potential prodromal biomarker, like REM sleep behavior disorder and olfactory dysfunction, which could be used to identify high-risk individuals for inclusion in early intervention clinical trials of novel disease-modifying neuroprotective therapies.
Pimavanserin: novel pharmacotherapy for Parkinson’s disease psychosis
Published in Expert Opinion on Drug Discovery, 2018
Zeyad T. Sahli, Frank I. Tarazi
Parkinson’s disease (PD) is a common neurological disorder defined primarily by motor symptoms, including limb tremor at rest tremor, loss of spontaneous movements, facial expression and eye blinking (akinesia and bradykinesia), muscle rigidity, postural instability, reduced volume and clarity of speech, and less legible handwriting [1–3]. Patients are typically diagnosed based on their medical history and extensive neurological, psychiatric, and physical examinations. Bradykinesia, in combination with rest tremor, rigidity, or both should be present for the diagnosis of PD. At least two of the four core motor symptoms of PD (tremor, rigidity, akinesia, and postural instability) should be present to confirm diagnosis [4]. Brain imaging scans, including magnetic resonance imaging, positron emission tomography (PET), single emission computed tomography, ultrasonography, and radiotracer-based imaging, can be utilized to confirm diagnosis and to rule out related disorders including progressive supranuclear palsy, drug-induced parkinsonism, vascular parkinsonism, motor neuron disease, diffuse Lewy body disease, and multiple system atrophy [5,6].
The diagnosis of progressive supranuclear palsy: current opinions and challenges
Published in Expert Review of Neurotherapeutics, 2018
The NINDS-SPSP and NNIPPS criteria recognize only PSP-RS phenotype which is highly predictive of PSP pathology. However, other clinical syndromes resulting from PSP received less attention. In an autopsy series of 103 patients, 54% had classic PSP-RS [6], whereas in another series of 100 patients, only 24% had classic PSP-RS [7]. Other phenotypes include progressive apraxia of speech (AOS) [8,9], predominantly frontal/cognitive dysfunction [10], asymmetric Parkinsonism resembling corticobasal syndrome [11] or progressive non-fluent aphasia [7,12,13]. PSP-RS phenotype fulfilling the NINDS-SPSP criteria may only develop late in the disease course or not at all. Misdiagnosis as corticobasal degeneration (CBD), Parkinson’s disease (PD), or diffuse Lewy body disease is common [14]. As such, four main functional domains or ‘predominance-types’ of PSP have been suggested and neuropathologically confirmed [15]. These include ocular motor dysfunction, akinesia, postural instability and cognitive dysfunction, and constitute the core clinical features of the recent Movement Disorders Society PSP Study Group (MDS-PSP) diagnostic criteria published in 2017 [16]. The criteria stratify symptoms by level of certainty under each core clinical feature, provides supportive clinical/imaging clues, and identifies several phenotypes of PSP neuropathology [16]. Although we now recognize phenotypic variability within PSP, these phenotypes overlap considerably with other neurodegenerative disorders. Early prediction of PSP neuropathology remains a challenge. Disease-specific markers are urgently needed for accurate patient identification and targeted trials of disease-modifying drugs. In this review, we discuss clinical phenotypes of PSP, the most recent diagnostic criteria, emerging disease biomarkers and progress in treatment strategies.