Longitudinal prevalence of neurogenic orthostatic hypotension in the idiopathic Parkinson Progression Marker Initiative (PPMI) cohort.

BACKGROUND: Reported orthostatic hypotension (OH) prevalence in Parkinson's disease (PD) varies widely, with few studies evaluating specifically neurogenic-OH (nOH). The ratio of orthostatic heart rate (HR) to systolic blood pressure (SBP) change (Δ) is a valid screening method to stratify nOH/non-nOH but has had minimal epidemiologic application. OBJECTIVE: To estimate the prevalence of nOH and non-nOH in the PPMI using the ΔHR/ΔSBP ratio and examine associations between nOH and various motor and non-motor measures. METHODS: Longitudinal orthostatic vitals and motor and non-motor measures were extracted (baseline-month 48). Patients were consensus criteria classified as OH+/-, with ΔHR/ΔSBP sub-classification to nOH (ΔHR/ΔSBP < 0.5) or non-nOH (ratio ≥ 0.5). Prevalence was determined across visits. Independent linear mixed models tested associations between nOH/non-nOH and clinical variables. RESULTS: Of N = 907 PD with baseline orthostatic vitals, 3.9 % and 1.8 % exhibited nOH and non-nOH, respectively. Prevalence of nOH/non-nOH increased yearly (P = 0.012, chi-square), though with modest magnitude (baseline: 5.6 % [95 % CI: 4.3-7.3 %]; month 48: 8.6 % [6.4-11.5 %]). nOH patients were older than PD with no OH and nOH was associated with greater impairment of motor and independent functioning than non-nOH/OH- groups. Cognitive function and typical OH symptoms were worse in PD + OH, generally. CONCLUSIONS: nOH prevalence was greater than non-nOH in the PPMI early PD cohort, with modest prevalence increase over time. Our findings are consistent with prior studies of large cohorts that evaluated nOH, specifically. Those with early PD and nOH were likelier to be older and suffer from greater motor and functional impairment, but OH presence was generally associated with more cognitive impairment.

Gender Differences in Pain Threshold, Unpleasantness, and Descending Pain Modulatory Activation Across the Adult Life Span: A Cross Sectional Study.

The neurobiological underpinnings of gender differences in pain perception, and how these differences may be modified by age, are incompletely understood, placing patients at risk of suboptimal pain management. Using functional magnetic resonance imaging, we examined brain responses in the descending pain modulatory system (DPMS, specifically, dorsolateral prefrontal cortex, anterior cingulate cortex, insula, hypothalamus, amygdala, and periaqueductal gray, during an evoked pain task. We investigated the interaction of age and gender in our sample of healthy adults (27 females, 32 males, 30-86 years) on DPMS response. In a perceptually matched thermal pain paradigm, we investigated pain unpleasantness and neural responses for 3 heat pain percepts: just noticeable pain, weak pain, and moderate pain (MP). Females reported just noticeable pain at a lower temperature, but reported less unpleasantness at weak pain and MP percepts, compared to males. There was a significant age-by-gender interaction during moderate pain in the right anterior cingulate cortex and bilateral insula, such that, males had a stronger positive relationship between DPMS response and age compared to females in these regions. Our results indicate that differences in DPMS responses may explain some gender differences in pain perception and that this effect may change across the adult lifespan. PERSPECTIVE: Gender differences in pain have been well-documented but the brain mechanisms for these differences are still unclear. This article describes potential differences in brain functioning during different levels of pain that could explain differences in pain responses between men and women across the adult lifespan.

A Cross-Sectional Study of Pain Sensitivity and Unpleasantness in People with Vascular Dementia.

OBJECTIVE: Advanced age is associated with a higher risk of both pain and dementia, with many studies finding that dementia often heightens sensitivity to pain. Vascular dementia (VaD) is the second most common type of dementia. Only a few observational or retrospective studies have examined pain responsiveness in VaD, suggesting that it could increase pain unpleasantness (i.e., pain affect). This study compared thermal pain psychophysics between a cohort of patients with VaD and healthy control (HC) subjects. DESIGN: Single-center, cross-sectional, between-subjects design. SUBJECTS: Verbally communicative patients with probable VaD (n = 23) and age- and sex-matched HCs (n = 23). METHODS: A thermal psychophysics protocol assessed "mild pain" and "moderate pain" thresholds (temperature in degrees Celsius) and associated unpleasantness ratings (0-20 scale) in both the VaD and HC groups. Psychophysics were compared between groups by way of a mixed-effects analysis, controlling for depressive symptoms. RESULTS: There were no significant differences between groups for pain thresholds (main effect P = 0.086, Cohen's d: mild = 0.55, moderate = 0.27). However, unpleasantness ratings were higher in the VaD group than in the HC group (main effect P = 0.003; mild pain P = 0.022, Cohen's d = 0.79; moderate pain P = 0.057, Cohen's d = 0.6). CONCLUSIONS: These results are consistent with prior observational findings suggesting that VaD could make patients more susceptible to pain, particularly its affective component.

Alzheimer's Disease Progressively Reduces Visual Functional Network Connectivity.

BACKGROUND: Postmortem studies of brains with Alzheimer's disease (AD) not only find amyloid-beta (Aß) and neurofibrillary tangles (NFT) in the visual cortex, but also reveal temporally sequential changes in AD pathology from higher-order association areas to lower-order areas and then primary visual area (V1) with disease progression. OBJECTIVE: This study investigated the effect of AD severity on visual functional network. METHODS: Eight severe AD (SAD) patients, 11 mild/moderate AD (MAD), and 26 healthy senior (HS) controls undertook a resting-state fMRI (rs-fMRI) and a task fMRI of viewing face photos. A resting-state visual functional connectivity (FC) network and a face-evoked visual-processing network were identified for each group. RESULTS: For the HS, the identified group-mean face-evoked visual-processing network in the ventral pathway started from V1 and ended within the fusiform gyrus. In contrast, the resting-state visual FC network was mainly confined within the visual cortex. AD disrupted these two functional networks in a similar severity dependent manner: the more severe the cognitive impairment, the greater reduction in network connectivity. For the face-evoked visual-processing network, MAD disrupted and reduced activation mainly in the higher-order visual association areas, with SAD further disrupting and reducing activation in the lower-order areas. CONCLUSION: These findings provide a functional corollary to the canonical view of the temporally sequential advancement of AD pathology through visual cortical areas. The association of the disruption of functional networks, especially the face-evoked visual-processing network, with AD severity suggests a potential predictor or biomarker of AD progression.

Associations between advertisement-supported media exposure and dietary quality among preschool-age children.

Foods of low nutritional quality are heavily marketed to children, and exposure to food ads shapes children's preferences and intake towards advertised foods. Whether food ad exposure independently relates to an overall lower diet quality among children remains unclear. We examined the association between ad-supported media use, a proxy for food ad exposure, and diet quality using the baseline data (2014-2015) from 535 3-5-year-olds in a community-based cohort study. Parents reported their child's dietary intake over 3 days via a diary, and diet quality was assessed with the Healthy Eating Index (HEI-2015) where higher scores reflect greater adherence to USDA dietary guidelines. Children's media exposure was measured through online parent surveys. Mean HEI score was 54.5 (SD = 9.4). In models adjusted for sociodemographic characteristics and metrics of parent diet quality, children's HEI scores were 0.5 points lower (adjusted beta = -0.5 [95% CI: 0.8, -0.1]; P < 0.01) for each 1-h increment in weekly viewing of ad-supported children's TV networks. Children's use of media that may have food ads (e.g., apps, online games) also related to a lower diet quality yet to a lesser extent (adjusted beta -0.2 [-0.2, -0.1]; P < 0.01). In contrast, children's ad-free media use was not associated with diet quality (P = 0.21). Findings support the premise that exposure to food advertisements via media may result in a lower quality diet among children independently of other risk factors.

Alzheimer's Disease Progressively Alters the Face-Evoked Visual-Processing Network.

BACKGROUND: Postmortem studies of Alzheimer's disease (AD) brains not only find amyloid-ß (Aß) and neurofibrillary tangles (NFT) in the primary and associative visual cortical areas, but also reveal a temporally successive sequence of AD pathology beginning in higher-order visual association areas, followed by involvement of lower-order visual processing regions with disease progression, and extending to primary visual cortex in late-stage disease. These findings suggest that neuronal loss associated with Aß and NFT aggregation in these areas may alter not only the local neuronal activation but also visual neural network activity. OBJECTIVE: Applying a novel method to identify the visual functional network and investigate the association of the network changes with disease progression. METHODS: To investigate the effect of AD on the face-evoked visual-processing network, 8 severe AD (SAD) patients, 11 mild/moderate AD (MAD), and 26 healthy senior (HS) controls undertook a task-fMRI study of viewing face photos. RESULTS: For the HS, the identified group-mean visual-processing network in the ventral pathway started from V1 and ended within the fusiform gyrus. In contrast, this network was disrupted and reduced in the AD patients in a disease-severity dependent manner: for the MAD patients, the network was disrupted and reduced mainly in the higher-order visual association areas; for the SAD patients, the network was nearly absent in the higher-order association areas, and disrupted and reduced in the lower-order areas. CONCLUSION: This finding is consistent with the current canonical view of the temporally successive sequence of AD pathology through visual cortical areas.

Sudden Onset Fluent Aphasia: Stroke or Seizure?

Conventional understanding of acute onset language deficits indicates that fluent aphasias are due to perisylvian lesions in the dominant hemisphere, most often in the setting of acute stroke. Case studies and retrospective analyses, however, suggest the need to keep ictal phenomena as an alternative diagnostic possibility. The following case illustrates an epileptic mechanism of sudden onset fluent aphasia mimicking an acute stroke presentation. We utilize the case to illustrate means by which to differentiate stroke versus ictal etiology by way of electroencephalography/response to antiseizure drugs as well as perfusion/diffusion imaging. We review the literature case reports to demonstrate that isolated fluent aphasia typically localizes to left-hemispheric, temporal foci. Finally, we provide a brief synthesis of potential neurologic mechanisms by which left temporal lesions may cause fluent aphasia.

Thermal Psychophysics and Associated Brain Activation Patterns Along a Continuum of Healthy Aging.

OBJECTIVE: To examine psychophysical and brain activation patterns to innocuous and painful thermal stimulation along a continuum of healthy older adults. DESIGN: Single center, cross-sectional, within-subjects design. METHODS: Thermal perceptual psychophysics (warmth, mild, and moderate pain) were tested in 37 healthy older adults (65-97 years, median = 73 years). Percept thresholds (oC) and unpleasantness ratings (0-20 scale) were obtained and then applied during functional magnetic resonance imaging scanning. General linear modeling assessed effects of age on psychophysical results. Multiple linear regressions were used to test the main and interaction effects of brain activation against age and psychophysical reports. Specifically, differential age effects were examined by comparing percent-signal change slopes between those above/below age 73 (a median split). RESULTS: Advancing age was associated with greater thresholds for thermal perception (z = 2.09, P = 0.037), which was driven by age and warmth detection correlation (r = 0.33, P = 0.048). Greater warmth detection thresholds were associated with reduced hippocampal activation in "older" vs "younger" individuals (>/<73 years; beta < 0.40, P < 0.01). Advancing age, in general, was correlated with greater activation of the middle cingulate gyrus (beta > 0.44, P < 0.01) during mild pain. Differential age effects were found for prefrontal activation during moderate pain. In "older" individuals, higher moderate pain thresholds and greater degrees of moderate pain unpleasantness correlated with lesser prefrontal activation (anterolateral prefrontal cortex and middle-frontal operculum; beta < -0.39, P < 0.009); the opposite pattern was found in "younger" individuals. CONCLUSIONS: Advancing age may lead to altered thermal sensation and (in some circumstances) altered pain perception secondary to age-related changes in attention/novelty detection and cognitive functions.

Prenatal arsenic exposure alters the placental expression of multiple epigenetic regulators in a sex-dependent manner.

BACKGROUND: Prenatal exposure to arsenic has been linked to a range of adverse health conditions in later life. Such fetal origins of disease are frequently the result of environmental effects on the epigenome, leading to long-term alterations in gene expression. Several studies have demonstrated effects of prenatal arsenic exposure on DNA methylation; however the impact of arsenic on the generation and decoding of post-translational histone modifications (PTHMs) is less well characterized, and has not been studied in the context of prenatal human exposures. METHODS: In the current study, we examined the effect of exposure to low-to-moderate levels of arsenic in a US birth cohort, on the expression of 138 genes encoding key epigenetic regulators in the fetal portion of the placenta. Our candidate genes included readers, writers and erasers of PTHMs, and chromatin remodelers. RESULTS: Arsenic exposure was associated with the expression of 27 of the 138 epigenetic genes analyzed. When the cohort was stratified by fetal sex, arsenic exposure was associated with the expression of 40 genes in male fetal placenta, and only 3 non-overlapping genes in female fetal placenta. In particular, we identified an inverse relationship between arsenic exposure and expression of the gene encoding the histone methyltransferase, PRDM6 (p < 0.001). Mutation of PRDM6 has been linked to the congenital heart defect, patent ductus arteriosus. CONCLUSIONS: Our findings suggest that prenatal arsenic exposure may have sex-specific effects on the fetal epigenome, which could plausibly contribute to its subsequent health impacts.

Sex Differences in the Psychophysical Response to Contact Heat in Moderate Cognitive Impairment Alzheimer's Disease: A Cross-Sectional Brief Report.

BACKGROUND: People with Alzheimer's disease (AD) report pain less frequently and receive less pain medication than people without AD. Recent studies have begun to elucidate how pain may be altered in those with AD. However, potential sex differences in pain responsiveness have never been explored in these patients. It is unclear whether sex differences found in prior studies of healthy young and older individuals extend to people with AD. OBJECTIVE: The purpose of this study was to examine sex differences in the psychophysical response to experimental thermal pain in people with AD. METHODS: Cross-sectional analysis of 14 male and 14 female age-matched (≥65 years of age, median = 74) and AD severity-matched (Mini-Mental State Exam score <24, median = 16) communicative people who completed thermal psychophysics. RESULTS: There was a statistically significant main effect of sex for both temperature and unpleasantness ratings that persisted after controlling for average and current pain (mixed-effects general liner model: temperature: p = 0.004, unpleasantness: p < 0.001). Females reported sensing mild pain and moderate pain percepts at markedly lower temperatures than did males (mild: Cohen's d = 0.72, p = 0.051, moderate: Cohen's d = 0.80, p = 0.036). By contrast, males rated mild and moderate thermal pain stimuli as more unpleasant than did females (mild: Cohen's d = 0.80, p = 0.072, moderate: Cohen's d = 1.32, p = 0.006). There were no statistically significant correlations of temperature with perceived unpleasantness for mild or moderate pain (rs = 0.29 and rs = 0.20 respectively, p > 0.05). CONCLUSIONS: Results suggest experimental pain-related sex differences persist in older adults with AD in a different manner than those previously demonstrated in cognitively intact older adults. These findings could potentially aid in developing targeted pain management approaches in this vulnerable population. Further studies are warranted to replicate the findings from this pilot work.

Altered Behavioral and Autonomic Pain Responses in Alzheimer's Disease Are Associated with Dysfunctional Affective, Self-Reflective and Salience Network Resting-State Connectivity.

While pain behaviors are increased in Alzheimer's disease (AD) patients compared to healthy seniors (HS) across multiple disease stages, autonomic responses are reduced with advancing AD. To better understand the neural mechanisms underlying these phenomena, we undertook a controlled cross-sectional study examining behavioral (Pain Assessment in Advanced Dementia, PAINAD scores) and autonomic (heart rate, HR) pain responses in 24 HS and 20 AD subjects using acute pressure stimuli. Resting-state fMRI was utilized to investigate how group connectivity differences were related to altered pain responses. Pain behaviors (slope of PAINAD score change and mean PAINAD score) were increased in patients vs. CONTROLS: Autonomic measures (HR change intercept and mean HR change) were reduced in severe vs. mildly affected AD patients. Group functional connectivity differences associated with greater pain behavior reactivity in patients included: connectivity within a temporal limbic network (TLN) and between the TLN and ventromedial prefrontal cortex (vmPFC); between default mode network (DMN) subcomponents; between the DMN and ventral salience network (vSN). Reduced HR responses within the AD group were associated with connectivity changes within the DMN and vSN-specifically the precuneus and vmPFC. Discriminant classification indicated HR-related connectivity within the vSN to the vmPFC best distinguished AD severity. Thus, altered behavioral and autonomic pain responses in AD reflects dysfunction of networks and structures subserving affective, self-reflective, salience and autonomic regulation.

The Impact of Alzheimer's Disease on the Resting State Functional Connectivity of Brain Regions Modulating Pain: A Cross Sectional Study.

BACKGROUND: It is currently unknown why people with Alzheimer's disease (AD) receive less pain medication and report pain less frequently. OBJECTIVE: The purpose of this study was to determine the impact of AD on thermal psychophysics and resting-state functional connectivity (RSFC) among sensory, affective, descending modulatory, and default mode structures. METHODS: Controls (n = 23, 13 = female) and age-matched people with AD (n = 23, 13 = females) underwent psychophysical testing to rate perceptions of warmth, mild, and moderate pain and then completed resting-state fMRI. Between groups analysis in psychophysics and RSFC were conducted among pre-defined regions of interest implicated in sensory and affective dimensions of pain, descending pain modulation, and the default mode network. RESULTS: People with AD displayed higher thermal thresholds for warmth and mild pain but similar moderate pain thresholds to controls. No between-group differences were found for unpleasantness at any percept. Relative to controls, people with AD demonstrated reduced RSFC between the right posterior insula and left anterior cingulate and also between right amygdala and right secondary somatosensory cortex. Moderate pain unpleasantness reports were associated with increased RSFC between right dorsolateral prefrontal cortex and left ACC in controls only. CONCLUSIONS: While AD had little effect on unpleasantness, people with AD had increased thermal thresholds, altered RSFC, and no association of psychophysics with RSFC in pain regions. Findings begin to elucidate that in people with AD, altered integration of pain sensation, affect, and descending modulation may, in part, contribute to decreased verbal pain reports and thus decreased analgesic administration.

Effects of Alzheimer Disease on the Facial Expression of Pain.

OBJECTIVES: Facial expression may be a surrogate marker of pain in Alzheimer disease (AD) when self-report of pain is compromised. Recent studies have demonstrated increased pain sensitivity in AD; however, experimental pain studies analyzing facial expressions in AD are limited and report inconsistent results. The aims of this study were to examine facial expression of pain in AD patients and its relationship to sum-scored measures of multiple pain behavioral domains and subjective pain ratings. MATERIALS AND METHODS: The Facial Action Coding System (FACS) was used to characterize facial expressions in 35 AD patients and 33 healthy seniors during pressure algometry. To improve pain specificity, facial responses were categorized as pain-relevant or pain-irrelevant before group analyses. We also assessed the relationship of AD severity to differential facial responsiveness by correlating FACS-based results with clinical pain scales (portions of the Pain Assessment in Advanced Dementia scale and the Faces Pain Scale-Revised [FPS-R]). RESULTS: No significant relationship was found between AD severity and FACS scores. Pain-relevant, but not irrelevant, FACS scores were increased in AD patients compared with seniors without AD. Pain Assessment in Advanced Dementia scale stimulus-response slopes were correlated with those of pain-relevant FACS and FPS-R in both the groups. Pain-relevant FACS slopes showed no relationship with those of the FPS-R in either group. DISCUSSION: Pain sensitivity is increased across all severities of AD when measured using the FACS. Clinical observational pain scales support the relevance of facial expression as a partial compensatory pain communication modality for AD. However, measures of pain behavior that sum across objective coding of several domains provide a better indicator of subjective pain than measures of facial expression alone.

Autonomic, Behavioral, and Subjective Pain Responses in Alzheimer's Disease.

OBJECTIVE: To compare autonomic, behavioral, and subjective pain responses of patients with Alzheimer's disease (AD) to those of healthy seniors (HS). As few studies have examined patients with severe Alzheimer's disease (sAD), we emphasized inclusion of these patients together with mild/moderate Alzheimer's disease (mAD) patients to characterize pain responses potentially affected by disease severity. DESIGN: A controlled cross-sectional study involving repeated measures behavioral pain testing. SETTING: An outpatient clinical setting and local nursing facilities. SUBJECTS: Community dwelling HS controls (N = 33) and individuals with chart-confirmed diagnoses of AD (N = 38, Diagnostic and Statistical Manual-IV criteria). METHODS: HS and AD groups were compared in their responses to repeated applications of five pressure intensities (1-5 kg) on the distal forearm. Autonomic responses (heart rate [HR]), pain behaviors (vocal, facial, and bodily as scored by the Pain Assessment in Advanced Dementia [PAINAD] scale), and subjective pain ratings (Faces Pain Scale-Revised) were measured. RESULTS: HR responses to pressure stimuli were differentially affected based on AD severity: sAD patients had generally decreased HR reactivity compared with other groups (P < 0.01). In contrast, pain behaviors were increased in AD regardless of severity (P < 0.001), compared with HS, for all but the lowest pressure intensity. Increased behaviors occurred in all measured domains of the PAINAD (P < 0.005). While sAD were unreliable subjective reporters, mAD patients (N = 17) rated low level pressures as more painful than HS (P < 0.01). CONCLUSION: These findings provide behavioral and subjective-report evidence of increased acute pain sensitivity in AD, which should be taken into consideration with respect to pain management across the spectrum of AD severity.

Induction of cellular growth by the axon guidance regulators netrin A and semaphorin-1a.

Although neurite outgrowth has been linked to axon guidance regulators, the effects of guidance molecules on cellular growth are not well understood. Use of the Drosophila wing imaginal disc, an epithelial tissue and a well-characterized system for analysis of cellular growth regulation, permits analysis of the impacts of guidance molecules on cellular growth in a setting in which axon guidance is not a confounding factor. In this investigation, the impacts of Netrin A (NetA) and Semaphorin-1a (Sema1a) signaling on cellular growth are examined during wing development. Levels of these genes were modulated in somatic clones in the developing wing disc, and clone areas, as well as individual sizes of clonal cells were assessed. NetA and Sema1a signaling were found to induce cellular growth in these assays. Furthermore, immunohistochemical analyses indicated that NetA and Sema1a signaling induce expression of several growth regulators, including myc, cycD, cdk4, PCNA, and MapK in the wing disc. These data illustrate that NetA and Sema1a can specifically promote growth through induction of key cellular growth regulators. The abilities of NetA and Sema1a to regulate cellular growth are likely critical to their functions in both nervous system development and oncogenesis.

Conservation of arthropod midline netrin accumulation revealed with a cross-reactive antibody provides evidence for midline cell homology.

Although many similarities in arthropod CNS development exist, differences in axonogenesis and the formation of midline cells, which regulate axon growth, have been observed. For example, axon growth patterns in the ventral nerve cord of Artemia franciscana differ from that of Drosophila melanogaster. Despite such differences, conserved molecular marker expression at the midline of several arthropod species indicates that midline cells may be homologous in distantly related arthropods. However, data from additional species are needed to test this hypothesis. In this investigation, nerve cord formation and the putative homology of midline cells were examined in distantly related arthropods, including: long- and short-germ insects (D. melanogaster, Aedes aeygypti, and Tribolium castaneum), branchiopod crustaceans (A. franciscana and Triops longicauditus), and malacostracan crustaceans (Porcellio laevis and Parhyale hawaiensis). These comparative analyses were aided by a cross-reactive antibody generated against the Netrin (Net) protein, a midline cell marker and regulator of axonogenesis. The mechanism of nerve cord formation observed in Artemia is found in Triops, another branchiopod, but is not found in the other arthropods examined. Despite divergent mechanisms of midline cell formation and nerve cord development, Net accumulation is detected in a well-conserved subset of midline cells in branchiopod crustaceans, malacostracan crustaceans, and insects. Notably, the Net accumulation pattern is also conserved at the midline of the amphipod P. hawaiensis, which undergoes split germ-band development. Conserved Net accumulation patterns indicate that arthropod midline cells are homologous, and that Nets function to regulate commissure formation during CNS development of Tetraconata.