Custom order entry for Parkinson's medications in the hospital improves timely administration: an analysis of over 31,000 medication doses.

Background: Patients with Parkinson's disease (PD) are at increased risk for hospital acquired complications. Deviations from home medication schedules and delays in administration are major contributing factors. We had previously developed a protocol to ensure adherence to home medication schedules using "custom" ordering. In this study we are assessing the impact this order type may have on reducing delays in PD medication administration in the hospital. Material and methods: We reviewed 31,404 orders placed for PD medications from January 2, 2016 to April 30 2021. We evaluated the orders to determine if they were placed in a Custom format or using a default non-custom order entry. We further evaluated all orders to determine if there was a relationship with the order type and timely administration of medications. We compared medications that were administered within 1 min, 15 min, 30 min and 60 min of due times across custom orders vs. non-custom default orders. We also evaluated the relationship between ordering providers and type of orders placed as well as hospital unit and type of orders placed. Results: 14,204 (45.23%) orders were placed using a custom schedule and 17,200 (54.77%) orders were placed using non-custom defaults. The custom group showed a significantly lower median delay of 3.06 minutes compared to the non-custom group (p<.001). Custom orders had a significantly more recent median date than non-custom default orders (2019-10-07 vs. 2018-01-06, p<0.001). In additional analyses, medication administration delays were significantly improved for custom orders compared to non-custom orders, with likelihoods 1.64 times higher within 1 minute, 1.40 times higher within 15 minutes, and 1.33 times higher within 30 minutes of the due time (p<0.001 for all comparisons). Conclusion: This is the largest study to date examining the effects of order entry type on timely administration of PD medications in the hospital. Orders placed using a custom schedule may help reduce delays in administration of PD medications.

Adherence to a strict medication protocol can reduce length of stay in hospitalized patients with Parkinson's Disease.

BACKGROUND: Patients with Parkinson's Disease (PD) are at higher risk of complications when admitted to the hospital. Delays in PD medications and use of contraindicated medications contribute to the increased risk and prolong their lengths of stay (LOS). Using a hospital-wide PD protocol, we aimed to ensure PD medications were placed with "custom" timing to resemble the home schedules, and also to avoid ordering or administering contraindicated medications. MATERIAL AND METHODS: 569 patients admitted in 2017 and 2018, were reviewed retrospectively. Mean age was 76.5 (SD 10.6), 332 were males and 237 were females. Charts were reviewed to assess if A) PD medications were ordered with custom timing, B) if not, were the orders changed to custom timed C) if contraindicated medications were ordered, and D) if they were administered. We also assessed the actual/expected length of stay during this time period. Chi Square and post hoc analyses were done to compare time points. Poisson regression analysis was done to assess relative improvement of variables. RESULTS: There was a 2.7 fold increase in orders placed with custom timing in 2018 compared to 2017 (RR = 2.651, 95%CI: 1.860-3.780, p < 0.0001), and a 3.2 fold increase in correction of non-custom orders in the same time period (RR = 3.246, 95%CI: 1.875-1.619, p < 0.0001). We also observed a decrease in the actual/expected LOS ratio from 1.54  to 1.32  (p < 0.05). CONCLUSION: By utilizing an established platform for quality improvement, we were able to improve adherence to the home medication regimen timing in admitted PD patients. Our findings also suggests that adherence to a strict medication regimen protocol may decrease LOS for this patient population.

Development of a Joint Commission Disease-Specific Care Certification Program for Parkinson Disease in an Acute Care Hospital.

BACKGROUND: Patients with Parkinson disease (PD) admitted to the hospital for any reason are at a higher risk of hospital-related complications. Frequent causes include delays in administering PD medications or use of contraindicated medications. The Joint Commission Disease-Specific Care (DSC) program has been used to establish a systematic approach to the care of specific inpatient populations. Once obtained, this certification demonstrates a commitment to patient care and safety, which is transparent to the public and can improve quality of care. METHODS: We formalized our efforts to improve the care of hospitalized patients with PD by pursuing Joint Commission DSC. An interprofessional team was assembled to include nurses, therapists, physicians, pharmacists, performance improvement specialists, and data analysts. The team identified quality metrics based on clinical guidelines. In addition, a large educational campaign was undertaken. Application to the Joint Commission for DSC resulted in a successful June 15, 2018 site visit. To our knowledge, this is the first DSC program in PD in an acute care hospital. CONCLUSION: Using the established platform of DSC certification from the Joint Commission, we developed a program based on relevant metrics that aims to address medication management of patients with PD admitted to the hospital. Our hope is to improve the care of this vulnerable patient population.

Weighted brain networks in disease: centrality and entropy in human immunodeficiency virus and aging.

Graph theory models can produce simple, biologically informative metrics of the topology of resting-state functional connectivity (FC) networks. However, typical graph theory approaches model FC relationships between regions (nodes) as unweighted edges, complicating their interpretability in studies of disease or aging. We extended existing techniques and constructed fully connected weighted graphs for groups of age-matched human immunodeficiency virus (HIV) positive (n = 67) and HIV negative (n = 77) individuals. We compared test-retest reliability of weighted versus unweighted metrics in an independent study of healthy individuals (n = 22) and found weighted measures to be more stable. We quantified 2 measures of node centrality (closeness centrality and eigenvector centrality) to capture the relative importance of individual nodes. We also quantified 1 measure of graph entropy (diversity) to measure the variability in connection strength (edge weights) at each node. HIV was primarily associated with differences in measures of centrality, and age was primarily associated with differences in diversity. HIV and age were associated with divergent measures when evaluated at the whole graph level, within individual functional networks, and at the level of individual nodes. Graph models may allow us to distinguish previously indistinguishable effects related to HIV and age on FC.

Unrecognized preclinical Alzheimer disease confounds rs-fcMRI studies of normal aging.

OBJECTIVE: To determine whether, and to what degree, preclinical Alzheimer disease (AD) confounds studies of healthy aging where "healthy" is based on cognitive normality alone. METHODS: We examined the effects of preclinical AD in cognitively normal older individuals using resting-state functional connectivity MRI. We investigated 2 groups of cognitively normal participants: one group with evidence of preclinical AD as assessed by CSF markers of AD and the other group with normal CSF biomarkers. RESULTS: There were significant interactions between age and biomarker status in the default-mode, dorsal attention, and salience resting-state networks. In the group with evidence of preclinical AD, there were dramatic changes in functional connectivity with age. In the group without evidence of preclinical AD, those changes were greatly attenuated. In most regions with significant interactions of age and biomarker status, the age-related change in functional connectivity in the normal biomarker group was indistinguishable from zero. CONCLUSIONS: These results suggest that preclinical AD accounts for a substantial portion of the reported effects of aging in the extant functional connectivity literature.

Functional connectivity in autosomal dominant and late-onset Alzheimer disease.

IMPORTANCE: Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in 3 specific genes in contrast to late-onset Alzheimer disease (LOAD), which has a more polygenetic risk profile. OBJECTIVE: To assess the similarities and differences in functional connectivity changes owing to ADAD and LOAD. DESIGN, SETTING, AND PARTICIPANTS: We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of participants with ADAD (n = 79) and LOAD (n = 444), using resting-state functional connectivity magnetic resonance imaging at multiple international academic sites. MAIN OUTCOMES AND MEASURES: For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity measured by the Clinical Dementia Rating Scale. In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within 5 RSNs. RESULTS: A decrease in functional connectivity with increasing Clinical Dementia Rating scores were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in one type of Alzheimer disease accurately predicted clinical dementia rating scores in the other, further demonstrating the similarity of functional connectivity loss in each disease type. Among participants with ADAD, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared with asymptomatic mutation noncarriers. CONCLUSIONS AND RELEVANCE: Resting-state functional connectivity magnetic resonance imaging changes with progressing AD severity are similar between ADAD and LOAD. Resting-state functional connectivity magnetic resonance imaging may be a useful end point for LOAD and ADAD therapy trials. Moreover, the disease process of ADAD may be an effective model for the LOAD disease process.

The effect of APOE ε4 allele on cholinesterase inhibitors in patients with Alzheimer disease: evaluation of the feasibility of resting state functional connectivity magnetic resonance imaging.

This work is to determine whether apolipoprotein E (APOE) genotype modulates the effect of cholinesterase inhibitor (ChEI) treatment on resting state functional connectivity magnetic resonance imaging (rs-fcMRI) in patients with Alzheimer disease (AD). We retrospectively studied very mild and mild AD participants who were treated (N=25) or untreated (N=19) with ChEIs with respect to rs-fcMRI measure of 5 resting state networks (RSNs): default mode, dorsal attention (DAN), control (CON), salience (SAL), and sensory motor. For each network, a composite score was computed as the mean of Pearson correlations between pairwise time courses extracted from areas comprising this network. The composite scores were analyzed as a function of ChEI treatment and APOE ε4 allele. Across all participants, significant interactions between ChEI treatment and APOE ε4 allele were observed for all 5 RSNs. Within APOE ε4 carriers, significantly greater composite scores were observed in the DAN, CON, and SAL for treated compared with untreated participants. Within APOE ε4 noncarriers, treated and untreated participants did not have significantly different composite scores for all RSNs. These data suggest that APOE genotype affects the response to ChEI using rs-fcMRI. Rs-fcMRI may be useful for assessing the therapeutic effect of medications in AD clinical trials.

Network dysfunction in Alzheimer's disease: refining the disconnection hypothesis.

Much effort in recent years has focused on understanding the effects of Alzheimer's disease (AD) on neural function. This effort has resulted in an enormous number of papers describing different facets of the functional derangement seen in AD. A particularly important tool for these investigations has been resting-state functional connectivity. Attempts to comprehensively synthesize resting-state functional connectivity results have focused on the potential utility of functional connectivity as a biomarker for disease risk, disease staging, or prognosis. While these are all appropriate uses of this technique, the purpose of this review is to examine how functional connectivity disruptions inform our understanding of AD pathophysiology. Here, we examine the rationale and methodological considerations behind functional connectivity studies and then provide a critical review of the existing literature. In conclusion, we propose a hypothesis regarding the development and spread of functional connectivity deficits seen in AD.

Functional connectivity and graph theory in preclinical Alzheimer's disease.

Alzheimer's disease (AD) has a long preclinical phase in which amyloid and tau cerebral pathology accumulate without producing cognitive symptoms. Resting state functional connectivity magnetic resonance imaging has demonstrated that brain networks degrade during symptomatic AD. It is unclear to what extent these degradations exist before symptomatic onset. In this study, we investigated graph theory metrics of functional integration (path length), functional segregation (clustering coefficient), and functional distinctness (modularity) as a function of disease severity. Further, we assessed whether these graph metrics were affected in cognitively normal participants with cerebrospinal fluid evidence of preclinical AD. Clustering coefficient and modularity, but not path length, were reduced in AD. Cognitively normal participants who harbored AD biomarker pathology also showed reduced values in these graph measures, demonstrating brain changes similar to, but smaller than, symptomatic AD. Only modularity was significantly affected by age. We also demonstrate that AD has a particular effect on hub-like regions in the brain. We conclude that AD causes large-scale disconnection that is present before onset of symptoms.

Relationship between Stroop performance and resting state functional connectivity in cognitively normal older adults.

OBJECTIVE: Early biomarkers of Alzheimer's disease (AD) are needed for developing therapeutic interventions. Measures of attentional control in Stroop-type tasks discriminate healthy aging from early stage AD and predict future development of AD in cognitively normal individuals. Disruption in resting state functional connectivity MRI (rs-fcMRI) has been reported in AD and in healthy controls at risk for AD. We explored the relationship among Stroop performance, rs-fcMRI, and CSF Aß42 levels in cognitively normal older adults. METHOD: A computerized Stroop task (along with standard neuropsychological measures), rs-fcMRI, and CSF were obtained in 237 cognitively normal older adults. We compared the relationship between Stroop performance, including measures from reaction distributional analyses, and composite scores from four resting state networks (RSNs; default mode [DMN], salience [SAL], dorsal attention [DAN], and sensory-motor [SMN]), and the modulatory influence of CSF Aß42 levels. RESULTS: A larger Stroop effect in errors was associated with reduced rs-fcMRI within the DMN and SAL. Reaction time (RT) distributional analyses indicated the slow tail of the RT distribution was related to reduced rs-fcMRI functional connectivity within the SAL. Standard psychometric measures were not related to RSN composite scores. A relationship between Stroop performance and DMN (but not SAL) functional connectivity was stronger in CSF Aß42-positive individuals. CONCLUSIONS: A link exists between RSN composite scores and specific attentional performance measures. Both measures may be sensitive biomarkers for AD.

Cerebrospinal fluid Aß42, phosphorylated Tau181, and resting-state functional connectivity.

IMPORTANCE: Resting-state functional connectivity magnetic resonance imaging has great potential for characterizing pathophysiological changes during the preclinical phase of Alzheimer disease. OBJECTIVE: To assess the relationship between default mode network integrity and cerebrospinal fluid biomarkers of Alzheimer disease pathology in cognitively normal older individuals. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional cohort study at The Charles F. and Joanne Knight Alzheimer's Disease Research Center at Washington University in St Louis, St Louis, Missouri, among 207 older adults with normal cognition (Clinical Dementia Rating, 0). MAIN OUTCOMES AND MEASURES: Resting-state functional connectivity magnetic resonance imaging measures of default mode network integrity. RESULTS: Decreased cerebrospinal fluid Aß42 and increased cerebrospinal fluid phosphorylated tau181 were independently associated with reduced default mode network integrity, with the most prominent decreases in functional connectivity observed between the posterior cingulate and medial temporal regions. Observed reductions in functional connectivity were unattributable to age or structural atrophy in the posterior cingulate and medial temporal areas. Similar resting-state functional connectivity magnetic resonance imaging findings in relation to cerebrospinal fluid biomarkers were obtained using region-of-interest analyses and voxelwise correlation mapping. CONCLUSIONS AND RELEVANCE: Both Aß and tau pathology affect default mode network integrity before clinical onset of Alzheimer disease.

Comparison of regional cerebral blood flow responses to hypoglycemia using pulsed arterial spin labeling and positron emission tomography.

Different brain regions sense and modulate the counterregulatory responses that can occur in response to declining plasma glucose levels. The aim of this study was to determine if changes in regional cerebral blood flow (rCBF) during hypoglycemia relative to euglycemia are similar for two imaging modalities-pulsed arterial spin labeling magnetic resonance imaging (PASL-MRI) and positron emission tomography (PET). Nine healthy non-diabetic participants underwent a hyperinsulinemic euglycemic (92±3 mg/dL) - hypoglycemic (53±1 mg/dL) clamp. Counterregulatory hormone levels were collected at each of these glycemic levels and rCBF measurements within the previously described network of hypoglycemia-responsive regions (thalamus, medial prefrontal cortex and globus pallidum) were obtained using PASL-MRI and [(15)O] water PET. In response to hypoglycemia, rCBF was significantly increased in the thalamus, medial prefrontal cortex, and globus pallidum compared to euglycemia for both PASL-MRI and PET methodologies. Both imaging techniques found similar increases in rCBF in the thalamus, medial prefrontal cortex, and globus pallidum in response to hypoglycemia. These brain regions may be involved in the physiologic and symptom responses to hypoglycemia. Compared to PET, PASL-MRI may provide a less invasive, less expensive method for assessing changes in rCBF during hypoglycemia without radiation exposure.

Pathways to neurodegeneration: effects of HIV and aging on resting-state functional connectivity.

OBJECTIVE: Resting-state functional connectivity MRI (rs-fcMRI) may provide insight into the neurophysiology of HIV and aging. METHODS: In this cross-sectional study, we used rs-fcMRI to investigate intra- and internetwork connectivity among 5 functional brain networks in 58 HIV-infected (HIV+) participants (44% receiving highly active antiretroviral therapy) and 53 HIV-uninfected (HIV-) controls. An analysis of covariance assessed the relationship among age, HIV laboratory markers, or degree of cognitive impairment and brain networks. RESULTS: Individuals who were HIV+ had decreased rs-fcMRI intranetwork correlations in the default mode (DMN, p = 0.01), control (CON, p = 0.02), and salience (SAL, p = 0.02) networks, but showed no changes in the sensorimotor (SMN) or dorsal attention (DAN) network. Compared with HIV- controls, participants who were HIV+ had a significant loss of internetwork correlations between the DMN-DAN (p = 0.02), trending loss in DMN-SAL (p = 0.1) and CON-SMN (p = 0.1), and trending increase in CON-SAL (p = 0.1). Neither HIV markers (plasma HIV viral load or CD4(+) cell count) nor degree of cognitive impairment correlated with rs-fcMRI measures. Aging correlated with a decrease in the magnitude of intranetwork functional connectivity within the DMN (p = 0.04) and SAL (p = 0.006) and with decreased magnitude of internetwork functional connectivity between DMN and SAL (p = 0.009) for both HIV+ and HIV- participants. No interaction was observed between HIV and aging. CONCLUSIONS: HIV and aging may cause independent decreases in rs-fcMRI. HIV may lead to a baseline decrease in brain function similar to deterioration that occurs with aging.

Alzheimer disease family history impacts resting state functional connectivity.

OBJECTIVE: Offspring whose parents have Alzheimer disease (AD) are at increased risk for developing dementia. Patients with AD typically exhibit disruptions in the default mode network (DMN). The aim of this study was to investigate the effect of a family history of late onset AD on DMN integrity in cognitively normal individuals. In particular, we determined whether a family history effect is detectable in apolipoprotein E (APOE) ε4 allele noncarriers. METHODS: We studied a cohort of 348 cognitively normal participants with or without family history of late onset AD. DMN integrity was assessed by resting state functional connectivity magnetic resonance imaging. RESULTS: A family history of late onset AD was associated with reduced resting state functional connectivity between particular nodes of the DMN, namely the posterior cingulate and medial temporal cortex. The observed functional connectivity reduction was not attributable to medial temporal structural atrophy. Importantly, we detected a family history effect on DMN functional connectivity in APOE ε4 allele noncarriers. INTERPRETATION: Unknown genetic factors, embodied in a family history of late onset AD, may affect DMN integrity prior to cognitive impairment.

Loss of intranetwork and internetwork resting state functional connections with Alzheimer's disease progression.

Alzheimer's disease (AD) is the most common cause of dementia. Much is known concerning AD pathophysiology but our understanding of the disease at the systems level remains incomplete. Previous AD research has used resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) to assess the integrity of functional networks within the brain. Most studies have focused on the default-mode network (DMN), a primary locus of AD pathology. However, other brain regions are inevitably affected with disease progression. We studied rs-fcMRI in five functionally defined brain networks within a large cohort of human participants of either gender (n = 510) that ranged in AD severity from unaffected [clinical dementia rating (CDR) 0] to very mild (CDR 0.5) to mild (CDR 1). We observed loss of correlations within not only the DMN but other networks at CDR 0.5. Within the salience network (SAL), increases were seen between CDR 0 and CDR 0.5. However, at CDR 1, all networks, including SAL, exhibited reduced correlations. Specific networks were preferentially affected at certain CDR stages. In addition, cross-network relations were consistently lost with increasing AD severity. Our results demonstrate that AD is associated with widespread loss of both intranetwork and internetwork correlations. These results provide insight into AD pathophysiology and reinforce an integrative view of the brain's functional organization.

The effects of HIV and combination antiretroviral therapy on white matter integrity.

OBJECTIVE: HIV preferentially affects white matter in the brain. Although combination antiretroviral therapy (cART) reduces HIV viral load within the brain, continued inflammation can persist. We investigated the effect of HIV and cART on white matter integrity. DESIGN: We used diffusion tensor imaging (DTI) to examine the effects of HIV and cART on white matter integrity within the corpus callosum and centrum semiovale (CSO). METHODS: Neuropsychological testing and DTI measures (fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity) were obtained from 21 HIV-uninfected controls, 21 HIV-infected patients naive to cART (HIV+/cART-), and 21 HIV+ patients receiving stable cART (HIV+/cART+). A subset of the HIV+/cART- individuals (n=10) was assessed before and 6 months after receiving medications. Differences among the cross-sectional groups were assessed using an analysis of variance, whereas paired t-tests evaluated longitudinal changes. RESULTS: HIV+/cART- participants had significantly lower mean diffusivity, axial diffusivity, and radial diffusivity for the corpus callosum and CSO compared to HIV- controls and HIV+/cART+ individuals. No significant difference existed between HIV- controls and HIV+/cART+ patients. cART initiation significantly improved mean diffusivity, radial diffusivity, and axial diffusivity, but not fractional anisotropy, in the corpus callosum and CSO in some HIV-infected patients. CONCLUSION: Observed decreases in DTI parameters between HIV+/cART+ and HIV+/cART- individuals could reflect the presence of inflammatory cells or cytotoxic edema in HIV+/cART- patients. Initiating cART could lead to a reduction in neuro-inflammation and improvement in DTI measures. Future DTI studies may be useful for evaluating the efficacy higher brain penetrating cART regimens.

11C-PiB imaging of human immunodeficiency virus-associated neurocognitive disorder.

OBJECTIVE: To evaluate whether the amyloid-binding agent carbon 11-labeled Pittsburgh Compound B ((11)C-PiB) could differentiate Alzheimer disease (AD) from human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) in middle-aged HIV-positive participants. DESIGN: (11)C-PiB scanning, clinical assessment, and cerebrospinal fluid (CSF) analysis were performed. Both χ(2) and t tests assessed differences in clinical and demographic variables between HIV-positive participants and community-living individuals observed at the Knight Alzheimer's Disease Research Center (ADRC). Analysis of variance assessed for regional differences in amyloid-ß protein 1-42 (Aß42) using (11)C-PiB. SETTING: An ADRC and HIV clinic. PARTICIPANTS: Sixteen HIV-positive participants (11 cognitively normal and 5 with HAND) and 19 ADRC participants (8 cognitively normal and 11 with symptomatic AD). MAIN OUTCOME MEASURES: Mean and regional (11)C-PiB binding potentials. RESULTS: Participants with symptomatic AD were older (P < .001), had lower CSF Aß42 levels (P < .001), and had higher CSF tau levels (P < .001) than other groups. Regardless of degree of impairment, HIV-positive participants did not have increased (11)C-PiB levels. Mean and regional binding potentials were elevated for symptomatic AD participants (P < .001). CONCLUSIONS: Middle-aged HIV-positive participants, even with HAND, do not exhibit increased (11)C-PiB levels, whereas symptomatic AD individuals have increased fibrillar Aß42 deposition in cortical and subcortical regions. Observed dissimilarities between HAND and AD may reflect differences in Aß42 metabolism. (11)C-PiB may provide a diagnostic biomarker for distinguishing symptomatic AD from HAND in middle-aged HIV-positive participants. Future cross-sectional and longitudinal studies are required to assess the utility of (11)C-PiB in older individuals with HAND.