Unique Pain Responses in Different Etiological Subgroups of Intellectual and Developmental Disabilities.

We studied whether there exist variations in pain responses between different intellectual and developmental disability (IDD) etiologies. Self-reports and facial expressions (Facial Action Coding System = FACS) were recorded during experimental pressure stimuli and compared among 31 individuals with IDD-13 with cerebral palsy (CP), nine with Down syndrome (DS), nine with unspecified origin (UIDD)-and among 15 typically developing controls (TDCs). The CP and DS groups had higher pain ratings and FACS scores compared to the UIDD and TDC groups, and steeper stimulus-response functions. The DS group exhibited the most diverse facial expressions. There were variations in the foci of facial expressions between groups. It appears that different IDD etiologies display distinct pain responses.

Pain Behavior of People with Intellectual and Developmental Disabilities Coded with the New PAIC-15 and Validation of Its Arabic Translation.

Pain management necessitates assessment of pain; the gold standard being self-report. Among individuals with intellectual and developmental disabilities (IDD), self-report may be limited and therefore indirect methods for pain assessment are required. A new, internationally agreed upon and user-friendly observational tool was recently published-the Pain Assessment in Impaired Cognition (PAIC-15). The current study's aims were: to test the use of the PAIC-15 in assessing pain among people with IDD and to translate the PAIC-15 into Arabic for dissemination among Arabic-speaking professionals. Pain behavior following experimental pressure stimuli was analyzed among 30 individuals with IDD and 15 typically developing controls (TDCs). Translation of the PAIC followed the forward-backward approach; and reliability between the two versions and between raters was calculated. Observational scores with the PAIC-15 exhibited a stimulus-response relationship with pressure stimulation. Those of the IDD group were greater than those of the TDC group. The overall agreement between the English and Arabic versions was high (ICC = 0.89); single items exhibited moderate to high agreement levels. Inter-rater reliability was high (ICC = 0.92). Both versions of the PAIC-15 are feasible and reliable tools to record pain behavior in individuals with IDD. Future studies using these tools in clinical settings are warranted.

From virus to diabetes therapy: Characterization of a specific insulin-degrading enzyme inhibitor for diabetes treatment.

Inhibition of insulin-degrading enzyme (IDE) is a possible target for treating diabetes. However, it has not yet evolved into a medical intervention, mainly because most developed inhibitors target the zinc in IDE's catalytic site, potentially causing toxicity to other essential metalloproteases. Since IDE is a cellular receptor for the varicella-zoster virus (VZV), we constructed a VZV-based inhibitor. We computationally characterized its interaction site with IDE showing that the peptide specifically binds inside IDE's central cavity, however, not in close proximity to the zinc ion. We confirmed the peptide's effective inhibition on IDE activity in vitro and showed its efficacy in ameliorating insulin-related defects in types 1 and 2 diabetes mouse models. In addition, we suggest that inhibition of IDE may ameliorate the pro-inflammatory profile of CD4+ T-cells toward insulin. Together, we propose a potential role of a designed VZV-derived peptide to serve as a selectively-targeted and as an efficient diabetes therapy.

Specific Behavioral Responses Rather Than Autonomic Responses Can Indicate and Quantify Acute Pain among Individuals with Intellectual and Developmental Disabilities.

Individuals with intellectual and developmental disabilities (IDD) are at a high risk of experiencing pain. Pain management requires assessment, a challenging mission considering the impaired communication skills in IDD. We analyzed subjective and objective responses following calibrated experimental stimuli to determine whether they can differentiate between painful and non-painful states, and adequately quantify pain among individuals with IDD. Eighteen adults with IDD and 21 healthy controls (HC) received experimental pressure stimuli (innocuous, mildly noxious, and moderately noxious). Facial expressions (analyzed with the Facial Action Coding System (FACS)) and autonomic function (heart rate, heart rate variability (HRV), pulse, and galvanic skin response (GSR)) were continuously monitored, and self-reports using a pyramid and a numeric scale were obtained. Significant stimulus-response relationships were observed for the FACS and pyramid scores (but not for the numeric scores), and specific action units could differentiate between the noxious levels among the IDD group. FACS scores of the IDD group were higher and steeper than those of HC. HRV was overall lower among the IDD group, and GSR increased during noxious stimulation in both groups. In conclusion, the facial expressions and self-reports seem to reliably detect and quantify pain among individuals with mild-moderate IDD; their enhanced responses may indicate increased pain sensitivity that requires careful clinical consideration.

Orally Administered Cinnamon Extract Attenuates Cognitive and Neuronal Deficits Following Traumatic Brain Injury.

The present paper shows how cinnamon extract (CE) consumption mitigates neuronal loss and memory impairment following traumatic brain injury (TBI), one of the world's most common neurodegenerative diseases. TBI patients suffer short- and long-term behavioral, cognitive, and emotional impairments, including difficulties in concentration, memory loss, and depression. Research shows that CE application can mitigate cognitive and behavioral impairments in animal models for Alzheimer's and Parkinson's disease, whose pathophysiology is similar to that of TBI. This study builds on prior research by showing similar results in TBI mice models. After drinking CE for a week, mice were injured using our 70-g weight drop TBI device. For 2 weeks thereafter, the mice continued drinking CE alongside standard lab nutrition. Subsequently, the mice underwent behavioral tests to assess their memory, motor activity, and anxiety. The mice brains were harvested for immunohistochemistry staining to evaluate overall neuronal survival. Our results show that CE consumption almost completely mitigates memory impairment and decreases neuronal loss after TBI. Mice that did not consume CE demonstrated impaired memory. Our results also show that CE consumption attenuated neuronal loss in the temporal cortex and the dentate gyrus. Mice that did not consume CE suffered a significant neuronal loss. There were no significant differences in anxiety levels and motor activity between all groups. These findings show a new therapeutic approach to improve cognitive function and decrease memory loss after TBI.

Increased Evoked Potentials and Behavioral Indices in Response to Pain Among Individuals with Intellectual Disability.

OBJECTIVE: Previous studies on the sensitivity and reactivity to pain of individuals with intellectual disability (ID) are inconsistent. The inconsistency may result from the reliance on self-reports and facial expressions of pain that are subject to internal and external biases. The aim was therefore to evaluate the reactivity to pain of individuals with ID by recording pain-evoked potentials (EPs), here for the first time, and testing their association with behavioral pain indices. SUBJECT: Forty-one healthy adults, 16 with mild-moderate ID and 25 controls. METHODS: Subjects received series of phasic heat stimuli and rated their pain on self-report scales. Changes in facial expressions and in pain EPs were recorded and analyzed offline. RESULTS: Pain self-reports, facial expressions, and the N2P2 amplitudes of the EPs exhibited stimulus-response relationship with stimulation intensity in both groups. The facial expressions and N2P2 amplitudes of individuals with ID were increased and N2P2 latency prolonged compared with controls. N2P2 amplitudes correlated with self-reports only in controls. CONCLUSIONS: Individuals with ID are hypersensitive/reactive to pain, a finding bearing clinical implications. Although pain EPs may reflect a somewhat different aspect of pain than the behavioral indices do, there is evidence to support their use to record pain in noncommunicative individuals, pending further validation.

Physiological and Behavioral Responses to Calibrated Noxious Stimuli Among Individuals with Cerebral Palsy and Intellectual Disability.

Objective: As individuals with intellectual disability (ID) due to cerebral palsy (CP) are at high risk of experiencing pain, measuring their pain is crucial for adequate treatment. While verbal reports are the gold standard in pain measurements, they may not be sufficient in ID. The aim was to detect behavioral/autonomic responses that may indicate the presence and intensity of pain in individuals with CP and ID, using calibrated stimuli, here for the first time. Subjects: Thirteen adults with CP and ID (CPID), 15 healthy controls (HC), and 5 adults with CP with no ID (CPNID). Methods: Subjects received pressure stimuli of various intensities. Self-reports (using a pyramid scale), facial expressions (retrospectively analyzed with Facial Action Coding System = FACS), and autonomic function (heart rate, heart rate variability, pulse, galvanic skin response) were analyzed. Results: Self-reports and facial expressions but not the autonomic function exhibited stimulus-response relationship to pressure stimulation among all groups. The CPID group had increased pain ratings and facial expressions compared with controls. In addition, the increase in facial expressions along the increase in noxious stimulation was larger than in controls. Freezing in response to pain was frequent in CPID. Conclusions: 1) Individuals with CP and ID have increased responses to pain; 2) facial expressions and self-reports, but not autonomic variables can reliably indicate their pain intensity; 3) the pyramid scale is suitable for self-report in this population. Although facial expressions may replace verbal reports, increased facial expressions at rest among these individuals may mask pain, especially at lower intensities.

Changes in the basal membrane of dorsal root ganglia Schwann cells explain the biphasic pattern of the peripheral neuropathy in streptozotocin-induced diabetic rats.

Peripheral neuropathy is one of the main complications of diabetes mellitus. The current study demonstrated the bimodal pattern of diabetic peripheral neuropathy found in the behavioral study of pain perception in parallel to the histopathological findings in dorsal root ganglia (DRGs) neurons and satellite Schwann cell basement membranes. A gradual decrease in heparan sulfate content, with a reciprocal increase in deposited laminin in the basement membranes of dorsal root ganglia Schwann cells, was shown in streptozotocin-treated rats. In addition, the characteristic biphasic pain profiles were demonstrated in diabetic rats, as shown by hypersensitivity at the third week and hyposensitivity at the tenth week post-streptozotocin injection, accompanied by a continuous decrease in the sciatic nerve conduction velocity. It appears that these basal membrane abnormalities in content of heparan sulfate and laminin, noticed in diabetic rats, may underline the primary damage in dorsal ganglion sensory neurons, simultaneously with the bimodal painful profile in diabetic peripheral neuropathy, simulating the scenario of filtration rate in diabetic kidney.

Insulin-degrading enzyme deficiency accelerates cerebrovascular amyloidosis in an animal model.

Cerebrovascular amyloidosis (CA) may result in intraparenchymal bleeding and cognitive impairment. It was previously shown that transforming growth factor-ß1 (TGF-ß1) expression under an astrocyte promoter resulted in congophilic vascular deposits and vascular pathology. A reduction in insulin-degrading enzyme (IDE) activity was previously suggested to play a role in the accumulation of congophilic vascular deposits in the microvasculature of Alzheimer's disease (AD) cases. Here, we aim to investigate the link between TGF-ß1 and IDE activity in the development of CA. We found that TGF-ß1 can reduce IDE expression in a mouse brain endothelial cell line (ECs). Furthermore, we discovered that IDE activity in the brains of TGF-ß1 transgenic (Tg) mice was significantly reduced compared with that of the control mice in an age-dependent manner. In addition, TGF-ß1/IDE(-/-) mice showed significantly greater levels of cerebrovascular pathology compared with TGF-ß1 mice. We have previously shown that 16-month-old TGF-ß1 mice have a significant reduction in synaptophysin protein levels, which may lead to cognitive impairment. Here we discovered a significant reduction in synaptophysin protein already at the age of seven in the hippocampus of TGF-ß1/IDE(-/-) mice compared with TGF-ß1 mice. Further investigation of TGF-ß1-mediated IDE activity in ECs may provide useful therapeutic intervention targets for cerebrovascular diseases such as CA.

Immunotherapy of cerebrovascular amyloidosis in a transgenic mouse model.

Cerebrovascular amyloidosis is caused by amyloid accumulation in walls of blood vessel walls leading to hemorrhagic stroke and cognitive impairment. Transforming growth factor-ß1 (TGF-ß1) expression levels correlate with the degree of cerebrovascular amyloid deposition in Alzheimer's disease (AD) and TGF-ß1 immunoreactivity in such cases is increased along the cerebral blood vessels. Here we show that a nasally administered proteosome-based adjuvant activates macrophages and decreases vascular amyloid in TGF-ß1 mice. Animals were nasally treated with a proteosome-based adjuvant on a weekly basis for 3 months beginning at age 13 months. Using magnetic resonance imaging (MRI) we found that while control animals showed a significant cerebrovascular pathology, proteosome-based adjuvant prevents further brain damage and prevents pathological changes in the blood-brain barrier. Using an object recognition test and Y-maze, we found significant improvement in cognition in the treated group. Our findings support the potential use of a macrophage immunomodulator as a novel approach to reduce cerebrovascular amyloid, prevent microhemorrhage, and improve cognition.

Orally administrated cinnamon extract reduces ß-amyloid oligomerization and corrects cognitive impairment in Alzheimer's disease animal models.

An increasing body of evidence indicates that accumulation of soluble oligomeric assemblies of ß-amyloid polypeptide (Aß) play a key role in Alzheimer's disease (AD) pathology. Specifically, 56 kDa oligomeric species were shown to be correlated with impaired cognitive function in AD model mice. Several reports have documented the inhibition of Aß plaque formation by compounds from natural sources. Yet, evidence for the ability of common edible elements to modulate Aß oligomerization remains an unmet challenge. Here we identify a natural substance, based on cinnamon extract (CEppt), which markedly inhibits the formation of toxic Aß oligomers and prevents the toxicity of Aß on neuronal PC12 cells. When administered to an AD fly model, CEppt rectified their reduced longevity, fully recovered their locomotion defects and totally abolished tetrameric species of Aß in their brain. Furthermore, oral administration of CEppt to an aggressive AD transgenic mice model led to marked decrease in 56 kDa Aß oligomers, reduction of plaques and improvement in cognitive behavior. Our results present a novel prophylactic approach for inhibition of toxic oligomeric Aß species formation in AD through the utilization of a compound that is currently in use in human diet.