Cholinergic system associated DOPA-refractory motor and cognitive symptoms-a need for novel therapeutic approaches:Accumulating evidence points to significant motor and non-motor morbidities associated with hypocholin...Cholinergic system associated DOPA-refractory motor and cognitive symptoms-a need for novel therapeutic approaches:Accumulating evidence points to significant motor and non-motor morbidities associated with hypocholinergic deficits in central and peripheral neural systems in Parkinson’s disease(PD)(Bohnen et al.,2018,2022).This so-called“malignant”hypocholinergic disease phenotype is associated with DOPA-refractory dementia and mobility disturbances,such as falls and freezing of gait,and augur novel therapeutic approaches targeting cholinergic systems in PD.Cholinergic pharmacotherapy in PD has been an interest for a long time.However,the development of cholinergic augmentation pharmacotherapy has been hampered by limited clinical efficacy,the presumption that changes in cholinergic activity are homogeneous in the central nervous system(CNS)and peripheral nervous system,tolerance or safety of cholinesterase inhibitor drugs,low CNS penetrance,high rate of peripheral autonomic side-effects and clinical contra-indications.The development of nicotinic or muscarinic receptor modulating drugs appears more promising but is still in the development stage.Given the current unmet need for managing DOPA-refractory cognitive and mobility impairments associated with hypocholinergic neural systems,there is a need for novel and complementary therapeutic and more personalized approaches.展开更多
Background With bipolar disorder(BD)having a lifetime prevalence of 4.4%and a significant portion of patients being chronically burdened by symptoms,there has been an increased focus on uncovering new targets for inte...Background With bipolar disorder(BD)having a lifetime prevalence of 4.4%and a significant portion of patients being chronically burdened by symptoms,there has been an increased focus on uncovering new targets for intervention in BD.One area that has shown early promise is the mitochondrial hypothesis.However,at the time of publication no studies have utilized positron emission tomography(PET)imaging to assess mitochondrial function in the setting of BD.Case Presentation Our participant is a 58 year-old male with a past medical history notable for alcohol use disorder and BD(unspecified type)who underwent PET imaging with the mitochondrial complex I PET ligand^(18)F-BCPP-EF.The resulting images demonstrated significant overlap between areas of dysfunction identified with the^(18)F-BCPP-EF PET ligand and prior functional magnetic resonance imaging(MRI)techniques in the setting of BD.That overlap was seen in both affective and cognitive circuits,with mitochondrial dysfunction in the fronto-limbic,ventral affective,and dorsal cognitive circuits showing particularly significant differences.Conclusions Despite mounting evidence implicating mitochondria in BD,this study represents the first PET imaging study to investigate this mechanistic connection.There were key limitations in the form of comorbid alcohol use disorder,limited statistical power inherent to a case study,no sex matched controls,and the absence of a comprehensive psychiatric history.However,even with these limitations in mind,the significant overlap between dysfunction previously demonstrated on functional MRI and this imaging provides compelling preliminary evidence that strengthens the mechanistic link between mitochondrial dysfunction and BD.展开更多
基金supported by the National Institute of Health,No.P50 NS123067The Farmer Family Foundation+2 种基金supported by the NIHR Newcastle Biomedical Research Centre(BRC)The NIHR BRC is a partnership between Newcastle Hospitals NHS Foundation Trust and Newcastle Universityfunded by the National Institute for Health and Care Research(NIHR)。
文摘Cholinergic system associated DOPA-refractory motor and cognitive symptoms-a need for novel therapeutic approaches:Accumulating evidence points to significant motor and non-motor morbidities associated with hypocholinergic deficits in central and peripheral neural systems in Parkinson’s disease(PD)(Bohnen et al.,2018,2022).This so-called“malignant”hypocholinergic disease phenotype is associated with DOPA-refractory dementia and mobility disturbances,such as falls and freezing of gait,and augur novel therapeutic approaches targeting cholinergic systems in PD.Cholinergic pharmacotherapy in PD has been an interest for a long time.However,the development of cholinergic augmentation pharmacotherapy has been hampered by limited clinical efficacy,the presumption that changes in cholinergic activity are homogeneous in the central nervous system(CNS)and peripheral nervous system,tolerance or safety of cholinesterase inhibitor drugs,low CNS penetrance,high rate of peripheral autonomic side-effects and clinical contra-indications.The development of nicotinic or muscarinic receptor modulating drugs appears more promising but is still in the development stage.Given the current unmet need for managing DOPA-refractory cognitive and mobility impairments associated with hypocholinergic neural systems,there is a need for novel and complementary therapeutic and more personalized approaches.
基金supported by the Eisenberg Depression Center Impact Accelerator Grant.
文摘Background With bipolar disorder(BD)having a lifetime prevalence of 4.4%and a significant portion of patients being chronically burdened by symptoms,there has been an increased focus on uncovering new targets for intervention in BD.One area that has shown early promise is the mitochondrial hypothesis.However,at the time of publication no studies have utilized positron emission tomography(PET)imaging to assess mitochondrial function in the setting of BD.Case Presentation Our participant is a 58 year-old male with a past medical history notable for alcohol use disorder and BD(unspecified type)who underwent PET imaging with the mitochondrial complex I PET ligand^(18)F-BCPP-EF.The resulting images demonstrated significant overlap between areas of dysfunction identified with the^(18)F-BCPP-EF PET ligand and prior functional magnetic resonance imaging(MRI)techniques in the setting of BD.That overlap was seen in both affective and cognitive circuits,with mitochondrial dysfunction in the fronto-limbic,ventral affective,and dorsal cognitive circuits showing particularly significant differences.Conclusions Despite mounting evidence implicating mitochondria in BD,this study represents the first PET imaging study to investigate this mechanistic connection.There were key limitations in the form of comorbid alcohol use disorder,limited statistical power inherent to a case study,no sex matched controls,and the absence of a comprehensive psychiatric history.However,even with these limitations in mind,the significant overlap between dysfunction previously demonstrated on functional MRI and this imaging provides compelling preliminary evidence that strengthens the mechanistic link between mitochondrial dysfunction and BD.
