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Introduction to dementia
Published in Joanne Brooke, Dementia in Prison, 2020
Dementia with Lewy bodies (DLB) is sometimes known by other names, such as Lewy body dementia, Lewy body variant of Alzheimer’s disease, diffuse Lewy body disease and cortical Lewy body disease. Lewy bodies are named after Dr Friedrich Heinrich Lewy, a German-born neurologist. In 1912, two years out of medical school and in his first year as director of the Neuropsychiatric Laboratory at the University of Breslau (now Wroclaw, Poland) Medical School, he discovered ‘spherical neuronal inclusions’ in the brain of a deceased Parkinson’s patient (Sweeney et al., 1997). Lewy bodies are microscopic protein deposits in the brain associated with the death of brain cells. However, it is not known whether the Lewy bodies are the cause or effect of degeneration of brain cells, but they are thought to be the result of the misfolding of the protein alpha-synuclein (Gomperts et al., 2008).
The nervous system and the eye
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
James A.R. Nicoll, William Stewart, Fiona Roberts
In Parkinson's disease there is selective and progressive destruction of the pigmented neurons in the substantia nigra, accompanied by the deposition of granules of neuromelanin pigment. Residual pigmented neurons contain large intracytoplasmic inclusions known as Lewy bodies (Figure 12.40). In advanced cases, depigmentation of the substantia nigra is readily apparent macroscopically (Figure 12.40A). The neurons of the substantia nigra project to the corpus striatum (globus pallidus and putamen) where they release the neurotransmitter dopamine. Treatment with a dopamine precursor (L-dopa) may relieve the symptoms of the disease but does not slow the progress of the underlying neuronal degeneration. Most cases of Parkinson's disease occur sporadically but, rarely, it is inherited as an autosomal dominant trait with mutations in the PARK1 gene on chromosome 4 encoding α-synuclein, a component of Lewy bodies, among many other mutations that have been identified. There is a poorly understood overlap with dementia with Lewy bodies.
Dementia
Published in Jane Higgs, Gill Wakley, Ruth Chambers, Clare Gerada, Demonstrating your Clinical Competence in Depression, Dementia, Alcoholism, Palliative Care and Osteoporosis, 2018
Jane Higgs, Gill Wakley, Ruth Chambers, Clare Gerada
The North of England evidence-based guidelines development project and the Scottish Intercollegiate Guidelines Network (SIGN) give similar recommendations for pharmacological treatments.16,17 Neuroleptic drugs are the mainstay of pharmacological treatment for Alzheimer’s disease but they do have side-effects such as parkinsonism, drowsiness, tardive dyskinesia, falls accelerating cognitive decline, and severe neuroleptic sensitivity reactions. Patients with dementia from Lewy bodies are more sensitive to the side-effects of neuroleptic medication and should not be prescribed these medications, so an accurate diagnosis is imperative.16 Behavioural problems (e.g. aggression or restlessness) change with the course of the dementia, therefore medication should be reviewed regularly to see if it is still needed.18
Early-start vs delayed-start donepezil against cognitive decline in Parkinson disease: a randomized clinical trial
Published in Expert Opinion on Pharmacotherapy, 2021
Hideyuki Sawada, Tomoko Oeda, Masayuki Kohsaka, Satoshi Tomita, Atsushi Umemura, Kwiyoung Park, Kenji Yamamoto, Kosuke Kiyohara
Patient eligibility criteria for phase 1 were the following: 20–80 years of age (inclusive) at the time of signing the consent, diagnosed as PD according to steps 1 and 2 of the United Kingdom Brain Bank Parkinson’s disease criteria, with modified Hoehn-Yahr (mH-Y) stage from 2.5 to 4 (‘ON’ period if patients suffered from motor fluctuations), and MMSE scores of 24 or more [19]. For 8 weeks before study enrollment, patients must have had no hallucinations or delusions according to the Parkinson Psychosis Questionnaire (PPQ), because the original purpose of EDAP was to investigate the prophylactic effect of donepezil against psychosis in PD. Exclusion criteria for phase 1 were the following: 1) taken donepezil, 2) taken central anticholinergic drugs within 4 weeks prior to week 0, 3) taken Yokukansan within 4 weeks, 4) taken antipsychotics within 12 weeks, 5) patients who fulfilled the criteria of probable dementia with Lewy bodies, 6) diagnosed with schizophrenia, 7) history of stereotactic surgery, 8) allergic to piperidine derivatives, 9) severe hepatic or renal dysfunction, 10) sick sinus syndrome or intra-atrial or AV nodal block, 11) patients with present or previous serious gastrointestinal ulcer, bronchial asthma or obstructive pulmonary diseases, 12) bradycardia (heart rate of 45 bpm or less), 13) QTc time longer than 460 ms, 14) pregnant or feeding a baby, 15) having participated in other clinical trials within 12 weeks, 16) diagnosed with malignancy, or 17) judged as not suitable by the investigators.
An update on the therapeutic potential of calpain inhibitors: a patent review
Published in Expert Opinion on Therapeutic Patents, 2020
Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders characterized by the accumulation of α-synuclein (α-syn). Calpain has been implicated in truncation of the c-terminus of α-syn and is considered a potential therapeutic target for these diseases hence Hassan et al. [61] studied Gabadur as potential treatment for PD and DLB. They showed that intraperitoneal administration of Gabadur (30 mg/kg, twice daily/30 days) is effective in PD and DLB. The compound reduced α-syn related pathology and improved activity performance of α-syn transgenic mice. While the results are encouraging, additional preclinical studies that capture the time course and dose-dependent inhibition of calpain in the brain as well as the pharmacokinetic and pharmacodynamic profiles of the compound are needed to support Gabadur as a promising drug candidate for development as treatment for neurodegenerative disorders.
Therapeutic approaches to cholinergic deficiency in Lewy body diseases
Published in Expert Review of Neurotherapeutics, 2020
Matthew J. Barrett, Leslie J. Cloud, Harsh Shah, Kathryn L. Holloway
Lewy body diseases are neurodegenerative diseases characterized by the presence of intraneuronal Lewy bodies and Lewy neurites. The primary constituent of Lewy bodies is α-synuclein, and thus, Lewy body diseases are also considered α-synucleinopathies along with multiple system atrophy (MSA). The primary Lewy body diseases are Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), and dementia with Lewy bodies (DLB). In PD, an intermediate stage of mild cognitive impairment (PD-MCI) was defined to indicate those who have ‘cognitive decline that is not normal for age but with essentially normal functional activities’ [1]. There are efforts underway to define a diagnostic category for individuals with MCI who do not meet clinical criteria for PD and who are predicted to progress to DLB based on their cognitive profile and the presence of one or more core clinical criteria or indicative biomarkers of DLB [2]. Lastly, evidence has emerged that idiopathic REM sleep behavior disorder (RBD) represents a Lewy body disease in most cases, as most individuals with RBD ultimately develop PD or DLB. The exception to this is the small proportion who are later diagnosed with MSA [3]. It is important to recognize that RBD may be secondary to medications or other sleep disorders. RBD may result from antidepressant or antipsychotic use [4], but at least in the case of antidepressants, emergence of RBD may reflect a susceptibility to developing a Lewy body disease [5].