Dopamine overdose hypothesis: Evidence and clinical implications

About a half a century has passed since dopamine was identified as a neurotransmitter, and it has been several decades since it was established that people with Parkinson's disease receive motor symptom relief from oral levodopa. Despite the evidence that levodopa can reduce motor symptoms, there has been a developing body of literature that dopaminergic therapy can improve cognitive functions in some patients but make them worse in others. Over the past two decades, several laboratories have shown that dopaminergic medications can impair the action of intact neural structures and impair the behaviors associated with these structures. In this review, we consider the evidence that has accumulated in the areas of reversal learning, motor sequence learning, and other cognitive tasks. The purported inverted‐U shaped relationship between dopamine levels and performance is complex and includes many contributory factors. The regional striatal topography of nigrostriatal denervation is a critical factor, as supported by multimodal neuroimaging studies. A patient's individual genotype will determine the relative baseline position on this inverted‐U curve. Dopaminergic pharmacotherapy and individual gene polymorphisms can affect the mesolimbic and prefrontal cortical dopaminergic functions in a comparable, inverted‐U dose‐response relationship. Depending on these factors, a patient can respond positively or negatively to levodopa when performing reversal learning and motor sequence learning tasks. These tasks may continue to be relevant as our society moves to increased technological demands of a digital world that requires newly learned motor sequences and adaptive behaviors to manage daily life activities. © 2013 International Parkinson and Movement Disorder SocietyPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102168/1/mds25687.pd

Atrophy of the cholinergic basal forebrain can detect presynaptic cholinergic loss in Parkinson's Disease

Objectives: Structural imaging of the cholinergic basal forebrain may provide a biomarker for cholinergic system integrity that can be used in motor and non-motor outcome studies in Parkinson's disease. However, no prior studies have validated these structural metrics with cholinergic nerve terminal in vivo imaging in Parkinson's disease. Here, we correlate cholinergic basal forebrain morphometry with the topography of vesicular acetylcholine transporter in a large Parkinson's sample. Methods: [18F]-Fluoroethoxybenzovesamicol vesicular acetylcholine transporter positron emission tomography was carried out in 101 non-demented people with Parkinson's (76.24% male, mean age 67.6 ± 7.72 years, disease duration 5.7 ± 4.4 years). Subregional cholinergic basal forebrain volumes were measured using magnetic resonance imaging morphometry. Relationships were assessed via volume-of-interest based correlation analysis. Results: Subregional volumes of the cholinergic basal forebrain predicted cholinergic nerve terminal loss, with most robust correlations occurring between the posterior cholinergic basal forebrain and temporofrontal, insula, cingulum, and hippocampal regions, and with modest correlations in parieto-occipital regions. Hippocampal correlations were not limited to the cholinergic basal forebrain subregion Ch1-2. Correlations were also observed in the striatum, thalamus, and brainstem. Interpretation: Cholinergic basal forebrain morphometry is a robust predictor of regional cerebral vesicular acetylcholine transporter bindings, especially in the anterior brain. The relative lack of correlation between parieto-occipital binding and basal forebrain volumes may reflect the presence of more diffuse synaptopathy in the posterior cortex due to etiologies that extend well beyond the cholinergic system. ANN NEUROL 2023;93:991–998

Case Report Motor Speech Apraxia in a 70-Year-Old Man with Left Dorsolateral Frontal Arachnoid Cyst: A [ 18 F]FDG PET-CT Study

Motor speech apraxia is a speech disorder of impaired syllable sequencing which, when seen with advancing age, is suggestive of a neurodegenerative process affecting cortical structures in the left frontal lobe. Arachnoid cysts can be associated with neurologic symptoms due to compression of underlying brain structures though indications for surgical intervention are unclear. We present the case of a 70-year-old man who presented with a two-year history of speech changes along with decreased initiation and talkativeness, shorter utterances, and dysnomia. [ 18 F]Fluorodeoxyglucose (FDG) Positron Emission and Computed Tomography (PET-CT) and magnetic resonance imaging (MRI) showed very focal left frontal cortical hypometabolism immediately adjacent to an arachnoid cyst but no specific evidence of a neurodegenerative process

Cholinergic Denervation Patterns Across Cognitive Domains in Parkinson's Disease

BackgroundThe cholinergic system plays a key role in cognitive impairment in Parkinson’s disease (PD). Previous acetylcholinesterase positron emission tomography imaging studies found memory, attention, and executive function correlates of global cortical cholinergic losses. Vesicular acetylcholine transporter positron emission tomography allows for more accurate topographic assessment of not only cortical but also subcortical cholinergic changes.ObjectiveThe objectiveof this study was to investigate the topographic relationship between cognitive functioning and regional cholinergic innervation in patients with PD.MethodsA total of 86 nondemented patients with PD (mean ± SD age 67.8 ± 7.6 years, motor disease duration 5.8 ± 4.6 years), and 12 healthy control participants (age 67.8 ± 7.8 years) underwent cholinergic [18F]Fluoroethoxybenzovesamicol positron emission tomography imaging. Patients with PD underwent neuropsychological assessment. The z scores for each cognitive domain were determined using an age‐matched, gender‐matched, and educational level–matched control group. Correlations between domain‐specific cognitive functioning and cholinergic innervation were examined, controlling for motor impairments and levodopa equivalent dose. Additional correlational analyses were performed using a mask limited to PD versus normal aging binding differences to assess for disease‐specific versus normal aging effects.ResultsVoxel‐based whole‐brain analysis demonstrated partial overlapping topography across cognitive domains, with most robust correlations in the domains of memory, attention, and executive functioning (P < 0.01, corrected for multiple comparisons). The shared pattern included the cingulate cortex, insula/operculum, and (visual) thalamus.ConclusionOur results confirm and expand on previous observations of cholinergic system involvement in cognitive functioning in PD. The topographic overlap across domains may reflect a partially shared cholinergic functionality underlying cognitive functioning, representing a combination of disease‐specific and aging effects. © 2020 International Parkinson and Movement Disorder SocietyPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167040/1/mds28360_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167040/2/mds28360.pd

Thalamic cholinergic innervation is spared in Alzheimer disease compared to parkinsonian disorders

There are two major sources of cholinergic projections in the brain. The nucleus basalis of Meynert provides the principal cholinergic input of the cortical mantle and the pedunculopontine nucleus-laterodorsal tegmental complex (PPN-LDTC; hereafter referred to as PPN) provides the major cholinergic input to the thalamus. Cortical cholinergic denervation has previously been shown to be part of Alzheimer and parkinsonian dementia but there is less information about subcortical thalamic cholinergic denervation. We investigated thalamic cholinergic afferent integrity by measuring PPN-Thalamic (PPN-Thal) acetylcholinesterase (AChE) activity via PET imaging in Alzheimer (AD), Parkinson disease without dementia (PD), Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB)

Color discrimination errors associate with axial motor impairments in Parkinson’s Disease

BackgroundVisual function deficits are more common in imbalance‐predominant compared to tremor‐predominant PD, suggesting a pathophysiological role of impaired visual functions in axial motor impairments.ObjectiveTo investigate the relationship between changes in color discrimination and motor impairments in PD while accounting for cognitive or other confounder factors.MethodsPD subjects (n = 49, age 66.7 ± 8.3 years; Hoehn & Yahr stage 2.6 ± 0.6) completed color discrimination assessment using the Farnsworth‐Munsell 100 Hue Color Vision Test, neuropsychological, motor assessments, and [11C]dihydrotetrabenazine vesicular monoamine transporter type 2 PET imaging. MDS‐UPDRS sub‐scores for cardinal motor features were computed. Timed Up & Go mobility and walking tests were assessed in 48 subjects.ResultsBivariate correlation coefficients between color discrimination and motor variables were significant only for the Timed Up & Go test (RS = 0.44, P = 0.0018) and the MDS‐UPDRS axial motor scores (RS = 0.38, P = 0.0068). Multiple regression confounder analysis using the Timed Up & Go as outcome parameter showed a significant total model (F(5,43) = 7.3, P < 0.0001) with significant regressor effects for color discrimination (standardized β = 0.32, t = 2.6, P = 0.012), global cognitive Z‐score (β = −0.33, t = −2.5, P = 0.018), duration of disease (β = 0.26, t = 1.8, P = 0.038), but not for age or striatal dopaminergic binding. The color discrimination test was also a significant independent regressor in the MDS‐UPDRS axial motor model (standardized β = 0.29, t = 2.4, P = 0.022; total model t(5,43) = 6.4, P = 0.0002).ConclusionsColor discrimination errors associate with axial motor features in PD independent of cognitive deficits, nigrostriatal dopaminergic denervation, and other confounder variables. These findings may reflect shared pathophysiology between color discrimination visual impairments and axial motor burden in PD.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141397/1/mdc312527.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141397/2/mdc312527_am.pd

Targeting the pedunculopontine nucleus in Parkinson’s disease: Time to go back to the drawing board

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147041/1/mds27540.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147041/2/mds27540_am.pd

Cholinergic system changes of falls and freezing of gait in Parkinson’s disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149240/1/ana25430_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149240/2/ana25430.pd

Regional vesicular acetylcholine transporter distribution in human brain: A [18F]fluoroethoxybenzovesamicol positron emission tomography study

Prior efforts to image cholinergic projections in human brain in vivo had significant technical limitations. We used the vesicular acetylcholine transporter (VAChT) ligand [18F]fluoroethoxybenzovesamicol ([18F]FEOBV) and positron emission tomography to determine the regional distribution of VAChT binding sites in normal human brain. We studied 29 subjects (mean age 47 [range 20–81] years; 18 men; 11 women). [18F]FEOBV binding was highest in striatum, intermediate in the amygdala, hippocampal formation, thalamus, rostral brainstem, some cerebellar regions, and lower in other regions. Neocortical [18F]FEOBV binding was inhomogeneous with relatively high binding in insula, BA24, BA25, BA27, BA28, BA34, BA35, pericentral cortex, and lowest in BA17–19. Thalamic [18F]FEOBV binding was inhomogeneous with greatest binding in the lateral geniculate nuclei and relatively high binding in medial and posterior thalamus. Cerebellar cortical [18F]FEOBV binding was high in vermis and flocculus, and lower in the lateral cortices. Brainstem [18F]FEOBV binding was most prominent at the mesopontine junction, likely associated with the pedunculopontine–laterodorsal tegmental complex. Significant [18F]FEOBV binding was present throughout the brainstem. Some regions, including the striatum, primary sensorimotor cortex, and anterior cingulate cortex exhibited age‐related decreases in [18F]FEOBV binding. These results are consistent with prior studies of cholinergic projections in other species and prior postmortem human studies. There is a distinctive pattern of human neocortical VChAT expression. The patterns of thalamic and cerebellar cortical cholinergic terminal distribution are likely unique to humans. Normal aging is associated with regionally specific reductions in [18F]FEOBV binding in some cortical regions and the striatum.Using [18F]FEOBV PET, we describe the distribution of cholinergic terminals in human brain. The distribution of cholinergic terminals is similar to that found in other mammals with some distinctive features in cortex, thalamus, and cerebellum. There are regionally specific age‐related changes in cholinergic terminal density.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146604/1/cne24541.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146604/2/cne24541_am.pd

Cholinergic system changes in Parkinson's disease: emerging therapeutic approaches

In patients with Parkinson's disease, heterogeneous cholinergic system changes can occur in different brain regions. These changes correlate with a range of clinical features, both motor and non-motor, that are refractory to dopaminergic therapy, and can be conceptualised within a systems-level framework in which nodal deficits can produce circuit dysfunctions. The topographies of cholinergic changes overlap with neural circuitries involved in sleep and cognitive, motor, visuo-auditory perceptual, and autonomic functions. Cholinergic deficits within cognition network hubs predict cognitive deficits better than do total brain cholinergic changes. Postural instability and gait difficulties are associated with cholinergic system changes in thalamic, caudate, limbic, neocortical, and cerebellar nodes. Cholinergic system deficits can involve also peripheral organs. Hypercholinergic activity of mesopontine cholinergic neurons in people with isolated rapid eye movement (REM) sleep behaviour disorder, as well as in the hippocampi of cognitively normal patients with Parkinson's disease, suggests early compensation during the prodromal and early stages of Parkinson's disease. Novel pharmacological and neurostimulation approaches could target the cholinergic system to treat motor and non-motor features of Parkinson's disease