Prevalence of Late-Stage Parkinson's Disease in the US Healthcare System: Insights from TriNetX.

BACKGROUND: Patients in late-stage Parkinson's disease (PDLS) are caregiver-dependent, have low quality of life, and higher healthcare costs. OBJECTIVE: To estimate the prevalence of PDLS patients in the current US healthcare system. METHODS: We downloaded the 2010-2022 data from the TriNetX Diamond claims network that consists of 92 US healthcare sites. PD was identified using standard diagnosis codes, and PDLS was identified by the usage of wheelchair dependence, personal care assistance, and/or presence of diagnoses of dementia. Age of PDLS identification and survival information were obtained and stratified by demographic and the disability subgroups. RESULTS: We identified 1,031,377 PD patients in the TriNetX database. Of these, 18.8% fitted our definition of PDLS (n = 194,297), and 10.2% met two or more late-stage criteria. Among all PDLS, the mean age of PDLS identification was 78.1 (±7.7) years, and 49% were already reported as deceased. PDLS patients were predominantly male (58.5%) with similar distribution across PDLS subgroups. The majority did not have race (71%) or ethnicity (69%) information, but for the available information >90% (n = 53,162) were White, 8.2% (n = 5121) Hispanic/Latino, 7.8% (n = 4557) Black, and <0.01% (n = 408) Asian. Of the PDLS cohort, 71.6% identified with dementia, 12.9% had personal care assistance, and 4.8% were wheelchair-bound. CONCLUSIONS: Late-stage patients are a significant part of the PD landscape in the current US healthcare system, and largely missed by traditional motor-based disability staging. It is imperative to include this population as a clinical, social, and research priority. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Dopamine D1 Agonist Versus Methylphenidate in Modulating Prefrontal Cortical Working Memory.

Methylphenidate is used widely to treat symptoms of attention-deficit/hyperactivity disorder (ADHD), but like other stimulants has significant side effects. This study used a rodent model (spontaneously hypertensive rat) of spatial working memory (sWM) to compare the effects of methylphenidate with the novel dopamine D1-like receptor agonist 2-methyldihydrexidine. Acute oral administration of methylphenidate (1.5 mg/kg) caused sWM improvement in half of the tested rats, but impairment in the others. Both improvement or impairment were eliminated by administration of the D1 antagonist SCH39266 directly into the prefrontal cortex (PFC). Conversely, 2-methyldihydrexidine showed greater sWM improvement compared with methylphenidate without significant impairment in any subject. Its effects correlated negatively with vehicle-treated baseline performance (i.e., rats with lower baseline performance improved more than rats with higher baseline performance). These behavioral effects were associated with neural activities in the PFC. Single neuron firing rate was changed, leading to the alteration in neuronal preference to correct or error behavioral responses. Overall, 2-methyldihydrexidine was superior to methylphenidate in decreasing the neuronal preference, prospectively, in the animals whose behavior was improved. In contrast, methylphenidate, but not 2-methyldihydrexidine, significantly decreased neuronal preference, retrospectively, in those animals who had impaired performance. These results suggest that a D1 agonist may be more effective than methylphenidate in regulating sWM-related behavior through neural modulation of the PFC, and thus may be superior to methylphenidate or other stimulants as ADHD pharmacotherapy. SIGNIFICANCE STATEMENT: Methylphenidate is effective in ADHD by its indirect agonist stimulation of dopamine and/or adrenergic receptors, but the precise effects on specific targets are unclear. This study compared methylphenidate to a dopamine D1 receptor-selective agonist by investigating effects on working memory occurring via neural modulation in the prefrontal cortex. The data suggest that pharmacological treatment selectively targeting the dopamine D1 may offer a superior approach to ADHD pharmacotherapy.

Dynamics of Nigral Iron Accumulation in Parkinson's Disease: From Diagnosis to Late Stage.

BACKGROUND: Higher nigral iron has been reported in Parkinson's disease (PD). OBJECTIVE: The aim is to understand the dynamics of nigral iron accumulation in PD and its association with drug treatment. METHODS: Susceptibility magnetic resonance imaging data were obtained from 79 controls and 18 drug-naive (PDDN ) and 87 drug-treated (PDDT ) PD patients. Regional brain iron in basal ganglia and cerebellar structures was estimated using quantitative susceptibility mapping. Nigral iron was compared between PDDN and PDDT subgroups defined by disease duration (early [PDE, <2 years], middle [PDM, 2-6 years], and later [PDL, >6 years]). Associations with both disease duration and types of antiparkinson drugs were explored using regression analysis. RESULTS: Compared to controls, PDDN had lower iron in the substantia nigra (P = 0.018), caudate nucleus (P = 0.038), and globus pallidus (P = 0.01) but not in the putamen or red nucleus. In contrast, PDDT had higher iron in the nigra (P < 0.001) but not in other regions, compared to either controls or PDDN . Iron in the nigra increased with disease duration (PDE > PDDN [P = 0.001], PDM > PDE [P = 0.045]) except for PDM versus PDL (P = 0.226). Levodopa usage was associated with higher (P = 0.013) nigral iron, whereas lower nigral iron was correlated with selegiline usage (P = 0.030). CONCLUSION: Nigral iron is lower before the start of dopaminergic medication and then increases throughout the disease until it plateaus at late stages, suggesting increased iron may not be an etiological factor. Interestingly, PD medications may have differential associations with iron accumulation that need further investigation. © 2022 International Parkinson and Movement Disorder Society.

D1 dopamine receptors intrinsic activity and functional selectivity affect working memory in prefrontal cortex.

Dopamine D1 agonists enhance cognition, but the role of different signaling pathways (e.g., cAMP or ß-arrestin) is unclear. The current study compared 2-methyldihydrexidine and CY208,243, drugs with different degrees of both D1 intrinsic activity and functional selectivity. 2-Methyldihydrexidine is a full agonist at adenylate cyclase and a super-agonist at ß-arrestin recruitment, whereas CY208,243 has relatively high intrinsic activity at adenylate cyclase, but much lower at ß-arrestin recruitment. Both drugs decreased, albeit in dissimilar ways, the firing rate of neurons in prefrontal cortex sensitive to outcome-related aspects of a working memory task. 2-Methyldihydrexidine was superior to CY208,243 in prospectively enhancing similarity and retrospectively distinguishing differences between correct and error outcomes based on firing rates, enhancing the micro-network measured by oscillations of spikes and local field potentials, and improving behavioral performance. This study is the first to examine how ligand signaling bias affects both behavioral and neurophysiological endpoints in the intact animal. The data show that maximal enhancement of cognition via D1 activation occurred with a pattern of signaling that involved full unbiased intrinsic activity, or agonists with high ß-arrestin activity.

Decoupling of Global Brain Activity and Cerebrospinal Fluid Flow in Parkinson's Disease Cognitive Decline.

BACKGROUND: Deposition and spreading of misfolded proteins (α-synuclein and tau) have been linked to Parkinson's disease cognitive dysfunction. The glymphatic system may play an important role in the clearance of these toxic proteins via cerebrospinal fluid (CSF) flow through perivascular and interstitial spaces. Recent studies discovered that sleep-dependent global brain activity is coupled to CSF flow, which may reflect glymphatic function. OBJECTIVE: The objective of this current study was to determine if the decoupling of brain activity-CSF flow is linked to Parkinson's disease cognitive dysfunction. METHODS: Functional and structural MRI data, clinical motor (Unified Parkinson's Disease Rating Scale), and cognitive (Montreal Cognitive Assessment [MoCA]) scores were collected from 60 Parkinson's disease and 58 control subjects. Parkinson's disease patients were subgrouped into those with mild cognitive impairment (MoCA < 26), n = 31, and those without mild cognitive impairment (MoCA ≥ 26), n = 29. The coupling strength between the resting-state global blood-oxygen-level-dependent signal and associated CSF flow was quantified, compared among groups, and associated with clinical and structural measurements. RESULTS: Global blood-oxygen-level-dependent signal-CSF coupling decreased significantly (P < 0.006) in Parkinson's disease patients showing mild cognitive impairment, compared with those without mild cognitive impairment and controls. Reduced global blood-oxygen-level-dependent signal-CSF coupling was associated with decreased MoCA scores present in Parkinson's disease patients (P = 0.005) but not in controls (P = 0.65). Weaker global blood-oxygen-level-dependent signal-CSF coupling in Parkinson's disease patients also was associated with a thinner right entorhinal cortex (Spearman's correlation, -0.36; P = 0.012), an early structural change often seen in Alzheimer's disease. CONCLUSIONS: The decoupling between global brain activity and associated CSF flow is related to Parkinson's disease cognitive impairment. © 2021 International Parkinson and Movement Disorder Society.

Parkinson's Disease-Related Motor and Nonmotor Symptoms in the Lancaster Amish.

INTRODUCTION: Previous research has suggested that the Amish may experience a relatively high prevalence of Parkinson's disease (PD) and/or parkinsonian motor signs. METHODS: In a large sample from the Amish community in Lancaster County, Pennsylvania, age ≥18 years, we assessed the prevalence of self-reported PD diagnosis. For those without self-reported PD diagnosis, we assessed the frequency of PD-related motor symptoms using a 9-item questionnaire that was designed by the PD Epidemiology Research Group. Lastly, we queried study participants for the presence of 2 nonmotor symptoms that have been commonly linked to PD: bowel movement frequency and daytime sleepiness. RESULTS: Among 2,025 subjects who answered the PD questionnaire, 430 were older than 60 years. Of 430 participants ≥60 years, 5 (1.2%) reported a PD diagnosis. Of those without a PD diagnosis, 10.5% reported ≥1 and 1.2% ≥ 4 motor symptoms for the 9-item PD screening questionnaire. Of the 3,789 subjects who answered the question about bowel movement frequency, 0.7% reported ≤3 bowel movements per week. Among 1,710 subjects who answered the question about daytime sleepiness, 8.1% of the participants reported "always" sleepy during the day. DISCUSSION: These data neither support a markedly higher PD prevalence in the older Lancaster Amish nor do they show dramatically higher motor and/or selected nonmotor symptoms than the general population. Future studies that employ more rigorous procedures for case identification and PD-specific preclinical symptoms/tests are needed to determine the potential differences and similarities among different Amish populations and between Amish and non-Amish populations.

Cancer and the Dopamine D2 Receptor: A Pharmacological Perspective.

The dopamine D2 receptor (D2R) family is upregulated in many cancers and tied to stemness. Reduced cancer risk has been correlated with disorders such as schizophrenia and Parkinson's disease, in which dopaminergic drugs are used. D2R antagonists are reported to have anticancer efficacy in cell culture and animal models where they have reduced tumor growth, induced autophagy, affected lipid metabolism, and caused apoptosis, among other effects. This has led to several hypotheses, the most prevalent being that D2R ligands may be a novel approach to cancer chemotherapy. This hypothesis is appealing because of the large number of approved and experimental drugs of this class that could be repurposed. We review the current state of the literature and the evidence for and against this hypothesis. When the existing literature is evaluated from a pharmacological context, one of the striking findings is that the concentrations needed for cytotoxic effects of D2R antagonists are orders of magnitude higher than their affinity for this receptor. Although additional definitive studies will provide further clarity, our hypothesis is that targeting D2-like dopamine receptors may only yield useful ligands for cancer chemotherapy in rare cases.

Brain cholesterol metabolism and Parkinson's disease.

BACKGROUND: Circulating cholesterol levels have been linked to PD, but not directly to brain physiology. OBJECTIVE: To assess whether brain cholesterol metabolism is related to PD. METHODS: Sixty PD patients and 64 controls were recruited from an academic movement disorder clinic (2009-2012). Thirty-five PD patients and 33 controls returned approximately 36 months later. Fasting plasma (S)24-OH-cholesterol (brain-derived cholesterol metabolite) and 27-OH-cholesterol (peripheral cholesterol metabolite) were quantified. Odds ratios for PD were derived from logistic regression models, adjusting for potential confounders. Relationships between the oxysterols and clinical measurements were explored using Spearman correlation coefficients. RESULTS: Mean age of PD subjects was 63.8 ± 8.3 years and disease duration was 5.0 ± 5.4 years. Plasma (S)24-OH-cholesterol levels were inversely associated with the odds of having PD, with an odds ratio of 0.92 (95% confidence interval: 0.87-0.97) for each 1-ng/mL increase (P = 0.004). Compared to the lowest tertile, the odds ratio was 0.34 (0.12-0.98) for the second tertile (P = 0.045) and 0.08 (0.02-0.31) for the highest tertile (P < 0.001). Higher (S)24-OH-cholesterol levels also were correlated with better sense of smell (r = 0.35; P = 0.01). No significant associations were found between clinical measures and 27-OH-cholesterol, a peripheral cholesterol metabolite. Furthermore, (S)24-OH-cholesterol levels were stable over time, whereas 27-OH-cholesterol decreased with time in both cases and controls. CONCLUSIONS: Results indicate that plasma (S)24-OH-cholesterol (possibly reflecting brain cholesterol metabolism) is inversely linked to PD, is relatively stable over time, and may serve as a new biomarker for PD. Further investigation is necessary to determine the mechanistic and clinical implications. © 2019 International Parkinson and Movement Disorder Society.

Characterization of the Neurochemical and Behavioral Effects of Solriamfetol (JZP-110), a Selective Dopamine and Norepinephrine Reuptake Inhibitor.

Excessive sleepiness (ES) is associated with several sleep disorders, including narcolepsy and obstructive sleep apnea (OSA). A role for monoaminergic systems in treating these conditions is highlighted by the clinical use of US Food and Drug Administration-approved drugs that act on these systems, such as dextroamphetamine, methylphenidate, modafinil, and armodafinil. Solriamfetol (JZP-110) is a wake-promoting agent that is currently being evaluated to treat ES in patients with narcolepsy or OSA. Clinical and preclinical data suggest that the wake-promoting effects of solriamfetol differ from medications such as modafinil and amphetamine. The goal of the current studies was to characterize the mechanism of action of solriamfetol at monoamine transporters using in vitro and in vivo assays. Results indicate that solriamfetol has dual reuptake inhibition activity at dopamine (DA; IC50 = 2.9 µM) and norepinephrine (NE; IC50 = 4.4 µM) transporters, and this activity is associated in vivo with increased extracellular concentration of DA and NE as measured by microdialysis. Solriamfetol has negligible functional activity at the serotonin transporter (IC50 > 100 µM). Moreover, the wake-promoting effects of solriamfetol are probably owing to activity at DA and NE transporters rather than other neurotransmitter systems, such as histamine or orexin. The dual activity of solriamfetol at DA and NE transporters and the lack of significant monoamine-releasing properties of solriamfetol might explain the differences in the in vivo effects of solriamfetol compared with modafinil or amphetamine. Taken together, these data suggest that solriamfetol may offer an important advancement in the treatment of ES in patients with narcolepsy or OSA.

Projection of the prevalence of Parkinson's disease in the coming decades: Revisited.

OBJECTIVE: Previous studies have estimated future PD prevalence based on population aging. This study revisits that projection by accounting for the potential impact of declining rates of smoking. METHODS: The age- and gender-stratified smoking prevalence in the United States from 2000 to 2040 were obtained from the U.S. Census Bureau and the U.S. Surgeon General's Smoking Report. PD prevalence was estimated based on population aging with and without an account of the impact of declining smoking rates. Relative risks of 0.56 and 0.78 were applied for current and former smokers, respectively. RESULTS: Accounting for aging alone, ∼700,000 PD cases are predicted by 2040. After accounting for the declining smoking prevalence, ∼770,000 cases, an increase of ∼10% over the estimate without smoking, is predicted. CONCLUSIONS: If the epidemiological association of smoking and PD is causal, projecting future cases without considering smoking may underestimate disease burden, underscoring the urgency of adequate resource allocation. © 2017 International Parkinson and Movement Disorder Society.

Distinct progression pattern of susceptibility MRI in the substantia nigra of Parkinson's patients.

BACKGROUND: Susceptibility MRI may capture Parkinson's disease-related pathology. This study delineated longitudinal changes in different substantia nigra regions. METHODS: Seventy-two PD patients and 62 controls were studied at both baseline and after 18 months with MRI. R2* and quantitative susceptibility mapping values from the substantia nigra pars compacta and substantia nigra pars reticulata were calculated. Mixed-effects models compared controls with PD or PD subgroups having different disease durations: early (<1 year), middle (<5 years, middle-stage PD), and late (>5 years, late-stage PD). Pearson's correlation assessed associations between imaging and clinical measures. RESULTS: At baseline, R2* and quantitative susceptibility mapping were higher in both the substantia nigra pars compacta and substantia nigra pars reticulata in all PD patients (group effect, P ≤ 0.003). Longitudinally, the substantia nigra pars compacta R2* showed a faster increase in PD compared with controls (time × group, P = 0.002), whereas quantitative susceptibility mapping did not (P = 0.668). The substantia nigra pars reticulata R2* and quantitative susceptibility mapping did not differ between PD and controls (time × group, P ≥ 0.084), although both decreased longitudinally (time effect, P ≤ 0.004). Baseline substantia nigra pars compacta R2* was higher in all PD subgroups (group, P ≤ 0.006), but showed a significantly faster increase only in later-stage PD (time × group, P < 0.0001) that correlated with changes in nonmotor symptoms (r = 0.746, P = 0.002). Baseline substantia nigra pars reticulata quantitative susceptibility mapping was higher in middle-stage PD and later-stage PD (group, P ≤ 0.002), but showed a longitudinal decrease (time × group, P = 0.004) only in later-stage PD that correlated with changes in motor signs (r = 0.837, P < 0.001). CONCLUSION: Susceptibility MRI revealed distinct patterns of PD progression in the substantia nigra pars compacta and substantia nigra pars reticulata. The different patterns are particularly clear in later-stage patients. These findings may resolve past controversies and have implications in the pathophysiological processes during PD progression. © 2018 International Parkinson and Movement Disorder Society.

Susceptibility MRI captures nigral pathology in patients with parkinsonian syndromes.

BACKGROUND: Parkinsonisms are neurodegenerative disorders characterized pathologically by α-synuclein-positive (e.g., PD, diffuse Lewy body disease, and MSA) and/or tau-positive (e.g., PSP, cortical basal degeneration) pathology. Using R2* and quantitative susceptibility mapping, susceptibility changes have been reported in the midbrain of living parkinsonian patients, although the exact underlying pathology of these alterations is unknown. OBJECTIVE: The current study investigated the pathological correlates of these susceptibility MRI measures. METHODS: In vivo MRIs (T1- and T2-weighted, and T2*) and pathology were obtained from 14 subjects enrolled in an NINDS PD Biomarker Program (PDBP). We assessed R2* and quantitative susceptibility mapping values in the SN, semiquantitative α-synuclein, tau, and iron values, as well as neuronal and glial counts. Data were analyzed using age-adjusted Spearman correlations. RESULTS: R2* was associated significantly with nigral α-synuclein (r = 0.746; P = 0.003). Quantitative susceptibility mapping correlated significantly with Perls' (r = 0.758; P = 0.003), but not with other pathological measurements. Neither measurement correlated with tau or glial cell counts (r ≤ 0.11; P ≥ 0.129). CONCLUSIONS: Susceptibility MRI measurements capture nigral pathologies associated with parkinsonian syndromes. Whereas quantitative susceptibility mapping is more sensitive to iron, R2* may reflect pathological aspects of the disorders beyond iron such as α-synuclein. They may be invaluable tools in diagnosing differential parkinsonian syndromes, and tracking in living patients the dynamic changes associated with the pathological progression of these disorders. © 2018 International Parkinson and Movement Disorder Society.

Statins may facilitate Parkinson's disease: Insight gained from a large, national claims database.

OBJECTIVE: Using a large U.S. claims database (MarketScan), we investigated the controversy surrounding the role of statins in Parkinson's disease (PD). METHODS: We performed a retrospective case-control analysis. First, we identified 2322 incident PD cases having a minimum of 2.5 years of continuous enrollment prior to earliest diagnosis code or prescription of antiparkinson medication. A total of 2322 controls were then matched individually by age, gender, and a follow-up window to explore the relationship of statin use with incident PD. RESULTS: Statin usage was significantly associated with PD risk, with the strongest associations being for lipophilic (odds ratio = 1.58, P < .0001) versus hydrophilic (odds ratio = 1.19, P = .25) statins, statins plus nonstatins (odds ratio = 1.95, P < .0001), and for the initial period after starting statins (<1 year odds ratio = 1.82, 1-2.5 years odds ratio = 1.75, and ≥2.5 years odds ratio = 1.37; Ptrend < .0001). CONCLUSION: The use of statin (especially lipophilics) was associated with higher risk of PD, and the stronger association in initial use suggests a facilitating effect. © 2017 International Parkinson and Movement Disorder Society.

Quantitative susceptibility mapping of the midbrain in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is marked pathologically by dopamine neuron loss and iron overload in the substantia nigra pars compacta. Midbrain iron content is reported to be increased in PD based on magnetic resonance imaging (MRI) R2* changes. Because quantitative susceptibility mapping is a novel MRI approach to measure iron content, we compared it with R2* for assessing midbrain changes in PD. METHODS: Quantitative susceptibility mapping and R2* maps were obtained from 47 PD patients and 47 healthy controls. Midbrain susceptibility and R2* values were analyzed by using both voxel-based and region-of-interest approaches in normalized space, and analyzed along with clinical data, including disease duration, Unified Parkinson's Disease Rating Scale (UPDRS) I, II, and III subscores, and levodopa-equivalent daily dosage. All studies were done while PD patients were "on drug." RESULTS: Compared with controls, PD patients showed significantly increased susceptibility values in both right (cluster size = 106 mm(3)) and left (164 mm(3)) midbrain, located ventrolateral to the red nucleus that corresponded to the substantia nigra pars compacta. Susceptibility values in this region were correlated significantly with disease duration, UPDRS II, and levodopa-equivalent daily dosage. Conversely, R2* was increased significantly only in a much smaller region (62 mm(3)) of the left lateral substantia nigra pars compacta and was not significantly correlated with clinical parameters. CONCLUSION: The use of quantitative susceptibility mapping demonstrated marked nigral changes that correlated with clinical PD status more sensitively than R2*. These data suggest that quantitative susceptibility mapping may be a superior imaging biomarker to R2* for estimating brain iron levels in PD.

Statins, plasma cholesterol, and risk of Parkinson's disease: a prospective study.

Previous findings on the association of statins, plasma lipids, and Parkinson's disease (PD) are confounded by the fact that statins also affect lipid profiles. We prospectively examined plasma lipids and statin use in relation to PD in the Atherosclerosis Risk in Communities (ARIC) Study. Statin use and plasma lipids were assessed at baseline (visit 1, 1987-89) and at three triennial visits thereafter (visits 2-4) until 1998. Potential PD cases were identified from multiple sources and validated where possible. The primary analysis was limited to incident PD cases diagnosed between 1998 and 2008. Odds ratios and 95% confidence intervals were derived from multivariate logistic regression models. Statin use was rare at baseline (0.57%) but increased to 11.2% at visit 4. During this time frame, total-cholesterol levels decreased, particularly among statin users. Fifty-six PD cases were identified after 1998. Statin use before 1998 was associated with significantly higher PD risk after 1998 (odds ratio = 2.39, 95% confidence interval 1.11-5.13) after adjusting for total cholesterol and other confounders. Conversely, higher total cholesterol was associated with lower risk for PD after adjustment for statin usage and confounders. Compared with the lowest tertile of average total cholesterol, the odds ratios for PD were 0.56 (0.30-1.04) for the second and 0.43 (0.22-0.87) for the third tertile (P(trend) = 0.02). Statin use may be associated with a higher PD risk, whereas higher total cholesterol may be associated with lower risk. These data are inconsistent with the hypothesis that statins are protective against PD.

Dopamine D1 receptor signaling: does GαQ-phospholipase C actually play a role?

Despite numerous studies showing therapeutic potential, no central dopamine D1 receptor ligand has ever been approved, because of potential limitations, such as hypotension, seizures, and tolerance. Functional selectivity has been widely recognized as providing a potential mechanism to develop novel therapeutics from existing targets, and a highly biased, functionally selective D1 ligand might overcome some of the past limitations. SKF-83959 [6-chloro-3-methyl-1-(m-tolyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7,8-diol] is reported to be a highly biased D1 ligand, having full agonism at D1-mediated activation of phospholipase C (PLC) signaling (via GαQ) and antagonism at D1-mediated adenylate cyclase signaling (via GαOLF/S). For this reason, numerous studies have used this compound to elucidate the physiologic role of D1-PLC signaling, including a novel molecular mechanism (GαQ-PLC activation via D1-D2 heterodimers). There is, however, contradictory literature that suggests that SKF-83959 is actually a partial agonist at both D1-mediated adenylate cyclase and ß-arrestin recruitment. Moreover, the D1-mediated PLC stimulation has also been questioned. This Minireview examines 30 years of relevant literature and proposes that the data strongly favor alternate hypotheses: first, that SKF-83959 is a typical D1 partial agonist; and second, that the reported activation of PLC by SKF-83959 and related benzazepines likely is due to off-target effects, not actions at D1 receptors. If these hypotheses are supported by future studies, it would suggest that caution should be used regarding the role of PLC and downstream pathways in D1 signaling.

The perplexing paradox of paraquat: the case for host-based susceptibility and postulated neurodegenerative effects.

Paraquat is an herbicide used extensively in agriculture and has also been proposed to be a risk factor for Parkinson's disease. To date, experimental, clinical, and epidemiological data on paraquat neurotoxicity have been equivocal. In this short review, we discuss some technical and biological mechanisms that contribute to inconsistencies regarding paraquat neurotoxicity. We hypothesize that individual genetic variations in susceptibility generate major differences in neurotoxic risk and functional outcome. Identifying these heritable sources of variation in host susceptibility, and their role in complex gene-environment interactions, is crucial to identify risk biomarkers and to devise better prevention and treatment for those exposed to paraquat and other potential neurotoxicants.

Dopamine D1 Receptor Agonists Rescue Age-related Decline in Temporal Order Memory.

Dopamine D1 receptor agonists improve spatial working memory, but their effects on temporal order memory, particularly prone to the effects of aging, have not been studied. Two D1 agonists, PF6256142 (PF) and 2-methyldihydrexidine (2MDHX), were examined for their effects in a rodent temporal order recognition task. Our results are consistent with the hypothesis that there is an age-related decline in rodent temporal order memory. The data also show that either agonist rescues the poor memory performance with a large effective size. Interestingly, the optimal effective dose varied among individual rats of different age groups. PF showed greater potency for older rats, whereas 2MDHX showed better overall population effectiveness. Both PF and 2MDHX have high intrinsic activity at rodent D1-mediated cAMP synthesis. Conversely, at D1-mediated ß-arrestin recruitment, PF has essentially no intrinsic activity, whereas 2MDHX is a super-agonist. These findings suggest that D1 agonists have potential to treat age-related cognitive decline, and the pattern of functional selectivity may be useful for developing drugs with an improved therapeutic index.

Effects of mixed metal exposures on MRI diffusion features in the medial temporal lobe.

Background: Environmental exposure to metal mixtures is common and may be associated with increased risk for neurodegenerative disorders including Alzheimer's disease. Objective: This study examined associations of mixed metal exposures with medial temporal lobe (MTL) MRI structural metrics and neuropsychological performance. Methods: Metal exposure history, whole blood metal, and neuropsychological tests were obtained from subjects with/without a history of mixed metal exposure from welding fumes (42 exposed subjects; 31 controls). MTL structures (hippocampus, entorhinal and parahippocampal cortices) were assessed by morphologic (volume, cortical thickness) and diffusion tensor imaging [mean (MD), axial (AD), radial diffusivity (RD), and fractional anisotropy (FA)] metrics. In exposed subjects, correlation, multiple linear, Bayesian kernel machine regression, and mediation analyses were employed to examine effects of single- or mixed-metal predictor(s) and their interactions on MTL structural and neuropsychological metrics; and on the path from metal exposure to neuropsychological consequences. Results: Compared to controls, exposed subjects had higher blood Cu, Fe, K, Mn, Pb, Se, and Zn levels (p's<0.026) and poorer performance in processing/psychomotor speed, executive, and visuospatial domains (p's<0.046). Exposed subjects displayed higher MD, AD, and RD in all MTL ROIs (p's<0.040) and lower FA in entorhinal and parahippocampal cortices (p's<0.033), but not morphological differences. Long-term mixed-metal exposure history indirectly predicted lower processing speed performance via lower parahippocampal FA (p=0.023). Higher whole blood Mn and Cu predicted higher entorhinal diffusivity (p's<0.043) and lower Delayed Story Recall performance (p=0.007) without overall metal mixture or interaction effects. Discussion: Mixed metal exposure predicted MTL structural and neuropsychological features that are similar to Alzheimer's disease at-risk populations. These data warrant follow-up as they may illuminate the path for environmental exposure to Alzheimer's disease-related health outcomes.

Resting-state global brain activity affects early ß-amyloid accumulation in default mode network.

It remains unclear why ß-amyloid (Aß) plaque, a hallmark pathology of Alzheimer's disease (AD), first accumulates cortically in the default mode network (DMN), years before AD diagnosis. Resting-state low-frequency ( < 0.1 Hz) global brain activity recently was linked to AD, presumably due to its role in glymphatic clearance. Here we show that the preferential Aß accumulation in the DMN at the early stage of Aß pathology was associated with the preferential reduction of global brain activity in the same regions. This can be partly explained by its failure to reach these regions as propagating waves. Together, these findings highlight the important role of resting-state global brain activity in early preferential Aß deposition in the DMN.