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Neuropsychiatric features 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
Liana G Apostolova, Jeffrey L Cummings
DLB patients frequently display rapid eye movement (REM) sleep behavior disorder (RBD), characterized by loss of physiological skeletal muscle atonia during REM cycles and dream enactment. RBD predates dementia by an average of 9 years. It precedes the extrapyramidal features and VH in 50% and the fluctuations in 80% (Ferman, 1999, 2002). Several a-synucleinopathies, including PD and multiple system atrophy (MSA) as well as DLB, feature RBD. a-synuclein inclusions were present in all 10 neurodegenerative cases with RBD - pathologically confirmed as 9 DLB and 1 MSA. The positive predictive value for DLB in a demented patient with parkinsonism and RBD is 92% (Boeve et al, 1998, 2001). Hence RBD may be included in the revised diagnostic criteria for DLB (Ferman et al, 2002; Boeve et al, 2003a).
Targeting protein clearance pathways in GBA1-associated Parkinson disease
Published in Expert Opinion on Therapeutic Targets, 2022
Chase Chen, Ellen Hertz, Yu Chen, Ellen Sidransky
Small molecule chaperones aimed to assist in GCase protein folding are also in development. These can effectively penetrate the BBB, and, competitively or non-competitively, stabilize GCase to promote trafficking from the endoplasmic reticulum (ER) to the lysosome. Inhibitory chaperones (e.g. iminosugars) are well-studied but are hampered by their intrinsic dose-dependent inhibition of enzymatic activity [14]. Ambroxol (ABX), a common cough expectorate, binds to the active site of GCase at neutral pH facilitating cellular translocation, but less at the lysosomal acidic condition. Preclinical studies show increased levels and activity of GCase upon Ambroxol treatment, as well as activation of macroautophagy in neurons with GBA1-mutations [17]. An open-label, non-randomized and non-controlled trial in 17 patients with PD, with and without GBA1-mutations, demonstrated detection of ABX in CSF and enhanced GCase and total α-synuclein levels [18], but the clinical effect was difficult to interpret. More extensive studies with ABX are ongoing to evaluate motor and cognitive symptoms in patients with synucleinopathies. Other non-inhibitory GCase modulators have been shown to restore GCase activity in cellular and animal models of GBA1-PD and GD [19]. One allosteric modulator of GCase, LTI-29, was shown to cross the BBB and was well tolerated in healthy volunteers, but efficacy in patients is still undetermined [20].
α-synuclein as an emerging pathophysiological biomarker of Alzheimer’s disease
Published in Expert Review of Molecular Diagnostics, 2022
Maria Francesca Beatino, Ciro De Luca, Nicole Campese, Elisabetta Belli, Rebecca Piccarducci, Linda Giampietri, Claudia Martini, Giulio Perugi, Gabriele Siciliano, Roberto Ceravolo, Andrea Vergallo, Harald Hampel, Filippo Baldacci
In an effort to assess the potential role of α-syn in the diagnostic workup of synucleinopathies, several conventional detection techniques (e.g. ELISA, multiplex immunoassays) have been applied so far, but with unsatisfactory sensitivity and specificity [66]. The lack of homogeneity in inter-laboratory analytical protocols, a substantial inability of detection antibodies in distinguishing α-syn oligomeric from fibrillary forms and the selective affinity for certain α-syn species rather than others may have led to these inconsistent outcomes. Due to their ability to identify and selectively amplify different α-syn conformational strains, ultrasensitive seed amplification techniques may play a pivotal role in the dissection of NDDs, independent of their non-specific clinical manifestations. In recent years, most of the research concerning RT-QuIC and PMCA has focused on CSF, while only limited data are available in other matrices.
Dementia with Lewy bodies: emerging drug targets and therapeutics
Published in Expert Opinion on Investigational Drugs, 2021
Evans D. Pope, Laura Cordes, Jiong Shi, Zoltan Mari, Boris Decourt, Marwan Noel Sabbagh
Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist used for the management of type 2 diabetes mellitus, has shown neuroprotective benefits in APP/PS1 mice, a transgenic mouse model of AD [13]. Seven-month-old APP/PS1 mice administered liraglutide showed improved performance object recognition and maze navigation tasks, while mice in the normal control group showed no improvements, suggesting that liraglutide is effective only when given to subjects with these genetic risk factors. APP/PS1 mice also showed higher degrees of neural plasticity, but these effects were seen in mice in the at-risk group. Duarte et al. recently (2020) studied the benefits of peripheral liraglutide treatment in AD female mice by administering 0.2 mg/kg, once daily for 28 days [14]. The following parameters affected in AD were evaluated: Aβ and p-tau, motor and cognitive function, glucose metabolism, inflammation and oxidative/nitrosative stress. Ultimately, liraglutide only reduced cortical Aβ1-42 levels in the mice. Further research appears necessary to discern the role of genetics in the etiology of synucleinopathies.