The relationship between gross motor function impairment in cerebral palsy and sleeping issues of children and caregivers

AimTo investigate, among children and adolescents with cerebral palsy (CP), the relationship between impairment of the gross motor function and: (i) child sleep disorders; (ii) the need for nocturnal support; and (iii) the quality of sleep of their caregivers.MethodsFor children, we considered their scores on the gross motor function measure (GMFM-88) and on the sleep disturbance scale for children (SDSC), besides analyzing qualitative features about their sleep. For caregivers, we considered their scores in the Pittsburgh sleep quality index (PSQI).ResultsOur sample was comprised of 87 participants with mean age of 11.4 years old (±3.4). We observed correlations between GMFM-88 and disorders of initiating and maintaining sleep (DIMS) (r = −0.22; p = 0.039), sleep–wake transition disorders (SWTD) (r = 0.26; p = 0.017) and disorders of arousal (DA) (r = 0.23; p = 0.033). Children receiving nocturnal support presented lower scores in the GMFM-88 (p = 0.001) and higher scores in the SDSC (p = 0.029). For the caregivers, we found no correlation between GMFM-88 and PSQI. Nonetheless, their PSQI scores correlated with the SDSC scores (r = 0.24; p = 0.027).ConclusionImpairment of the gross motor function correlated with DIMS and the need for nocturnal support but might not have an impact on the caregivers’ sleep, which in turn correlated with child sleep disorders.     

Human in vivo neuroimaging to detect reprogramming of the cerebral immune response following repeated systemic inflammation

Despite increasing evidence that immune training within the brain may affect the clinical course of neuropsychiatric diseases, data on cerebral immune tolerance are scarce. This study in healthy volunteers examined the trajectory of the immune response systemically and within the brain following repeated lipopolysaccharide (LPS) challenges. Five young males underwent experimental human endotoxemia (intravenous administration of 2 ng/kg LPS) twice with a 7-day interval. The systemic immune response was assessed by measuring plasma cytokine levels. Four positron emission tomography (PET) examinations, using the translocator protein (TSPO) ligand ¹⁸F-DPA-714, were performed in each participant, to assess brain immune cell activation prior to and 5 hours after both LPS challenges. The first LPS challenge caused a profound systemic inflammatory response and resulted in a 53% [95%CI 36–71%] increase in global cerebral ¹⁸F-DPA-714 binding (p < 0.0001). Six days after the first challenge, ¹⁸F-DPA-714 binding had returned to baseline levels (p = 0.399). While the second LPS challenge resulted in a less pronounced systemic inflammatory response (i.e. 77 ± 14% decrease in IL-6 compared to the first challenge), cerebral inflammation was not attenuated, but decreased below baseline, illustrated by a diffuse reduction of cerebral ¹⁸F-DPA-714 binding (-38% [95%CI -47 to -28%], p < 0.0001). Our findings constitute evidence for in vivo immunological reprogramming in the brain following a second inflammatory insult in healthy volunteers, which could represent a neuroprotective mechanism. These results pave the way for further studies on immunotolerance in the brain in patients with systemic inflammation-induced cerebral dysfunction.     

Early childhood adversity in adult patients with metastatic lung cancer: Cross-sectional analysis of symptom burden and inflammation

ObjectivePsychological and physical symptoms commonly occur in patients with metastatic lung cancer and are associated with reduced quality of life and decreased survival. Previous work has associated these symptoms with inflammation. The experience of Early Childhood Adversity (ECA) is linked to chronic inflammation and may identify adult cancer patients who are at-risk for psychological and physical symptoms. We thus hypothesized that ECA in lung cancer patients would be associated with increased psychological symptoms (distress, anxiety, and depression) and physical symptoms and that this relationship would be explained by inflammation.MethodsPatients with metastatic lung cancer (n = 92) were evaluated for ECA using the Risky Families Questionnaire. Concomitant assessments were made of distress (Distress Thermometer and Problem List [DT&PL]), anxiety (Generalized Anxiety Disorder-7), depression (Patient Hospital Questionniare-9), physical symptoms (DT&PL), and inflammation (C-reactive protein [CRP]). Multivariate models were created to explain associations of ECA with depression, anxiety, distress, number of physical problems, and inflammation.ResultsECA was associated with distress (r = 0.24, p = .03), anxiety (r = 0.30, p = .004), depression (r = 0.35, p = .001), greater physical problems (r = 0.25, p = .03), younger age (r = -0.29, p = .006), and elevated CRP (r = 0.22, p = .04). Multivariate analyses of outcomes found that depression severity was independently explained by both ECA and inflammation (β = 0.37, p = .001) but not distress or anxiety, while controlling for age and sex. Number of physical problems were also associated with ECA (β = 0.35, p = .004) but not inflammation. The association between ECA and physical problems was not significant after controlling for depression.ConclusionECA is associated with increased depression and physical symptoms independent of inflammation. Moreover, depression appears to mediate the impact of ECA on physical symptoms. ECA may identify patients at risk for psychological and physical symptoms.     

Utility of quantitative EEG in early Lewy body disease

IntroductionThe reduction of background activity and the increase of low-frequency powers on electroencephalogram (EEG) correlate with cognitive impairment and have been suggested to be underpinned by cholinergic deficit. We aimed to investigate the ratio between α and θ band power (α/θ ratio), as a synoptic index of quantitative EEG (qEEG) slowing-down, in a peculiar group of patients with mild cognitive impairment (MCI) due to an early-stage Lewy body disease (MCI-LBD), as compared to de novo PD patients without cognitive impairment (PD-MOT), to patients with MCI due to Alzheimer's disease (MCI-AD), and to healthy controls (HC).MethodsTwelve patients with MCI-LBD (8 males; mean age 74.8 ± 3.6), 11 PD-MOT, 11 MCI-AD and 24 HC subjects undergoing qEEG were matched for gender, age, and education. Following logarithmic transformation, the α/θ ratio was compared among groups and brain regions by repeated measures ANOVA, also exploring group*regions interactions.ResultsA significant effect of group (p = 0.0003), regions (p = 0.0001), and group*regions interaction (p = 0.0001) on the α/θ ratio was observed. At post-hoc analysis, α/θ ratio was significantly lower in MCI-LBD (p = 0.001) and in PD-MOT (p = 0.02) compared to HC, and in MCI-LBD than MCI-AD (p = 0.05). No significant differences were found between MCI-AD and HC, as well as between MCI-LBD and PD-MOT.ConclusionThe α/θ power ratio as a synoptic index of EEG background slowing-down could be a simple and easy-to-use qEEG index which might indirectly mirror a cholinergic failure, useful to pick-up those MCI patients at higher risk of developing a Lewy-body disease.     

Elevated tau and interleukin-6 concentrations in adults with obstructive sleep apnea

Obstructive sleep apnea (OSA) is characterized by apneas and hypopneas that result in hypoxia, cerebral hypoperfusion, endothelial dysfunction, inflammation, and oxidative stress. These pathophysiologic processes likely contribute to neuronal damage. Tau is a protein that stabilizes microtubules and, along with amyloid beta (Aβ), is associated with neurodegenerative processes. We sought to determine if tau and other biomarkers of inflammation were related to OSA severity.Concentrations of tau, Aβ40, Aβ42, c-reactive protein (CRP), TNF-α, interleukin (IL)-6, and IL-10 were measured in blood and compared between participants with moderate-severe OSA (n = 28), those with mild OSA (n = 22), and healthy controls (n = 24). The cohort included relatively young, primarily male active duty military personnel without a history of traumatic brain injury or neurodegenerative disease. Total biomarker concentrations were determined from plasma samples using an ultra-sensitive detection method, Simoa™, and CRP was assayed by ELISA. Total tau and IL-6 concentrations were elevated in participants with moderate-severe OSA, with a mean apnea-hypopnea index (AHI) of 26.1/h, compared to those with mild OSA (mean AHI 8.6/h) and healthy controls (mean AHI 2.1/h). Tau concentrations were also significantly correlated with the AHI (r = 0.342, p = 0.004). Our findings show that tau is elevated in the blood of young patients with moderate-severe OSA, suggesting that this degree of sleep-disordered breathing is a contributing factor in the development of neurodegenerative disorders. The finding of increased IL-6 further suggests that inflammatory biomarkers are present early in the course of this chronic disease.     

Skin capillary amylin deposition resembles brain amylin vasculopathy in rats

Background and purposeHuman amylin is a 37 amino-acid pancreatic peptide that forms neuro-toxic aggregates that deposit in the endothelium of brain capillaries of patients with diabetes, potentially contributing to cerebral small vessel ischemic injury. Pathogenic amylin also deposits in the capillary endothelium in other organs, including the skin. The aim of this study was to test the hypothesis that skin capillary amylin deposition correlates with cerebral small vessel amylin deposition, potentially providing a clinically useful marker of cerebral amylin deposition.MethodsImmunohistochemistry (IHC) was performed for human amylin and collagen IV in brain and skin sections of rats (age 15–16 months) with pancreatic overexpression of amyloidogenic human amylin polypeptide (HIP rats), and control rats (Wild type; WT; rats that express non-amyloidogenic rat amylin) using antibodies binding amylin (n = 5 male and 5 female rats for each group) and antibodies binding Hypoxia inducing factor (HIF)-1α and HIF-2α (n = 3 for each group). The reactive amylin-aldehyde 4-hydroxynonenal (4-HNE) adduct was measured in skin homogenates. (n = 4 for each group)ResultsBrain capillaries isolated from HIP rats had higher amylin content compared to WT rats using Western blot with anti-amylin antibody (p = 0.0010). The HIF-1α and HIF-2α immunoreactivity signals in skin from HIP and WT rats were similar (p = 0.2 for HIF-1 α, and p = 0.75 for HIF-2α). Amylin-4HNE adduct formation was higher in HIP rats compared to WT rats (p = 0.0014). There was phenotypic similarity between brain and skin capillary amylin based on co-staining for human amylin and collagen IV in both HIP and WT rats.ConclusionSkin and brain capillary amylin deposition are similar providing evidence that a skin biopsy might be providing a potential biomarker for diabetes-associated intracranial vasculopathy.     

Does REM sleep behavior disorder change in the progression of Parkinson’s disease?

Objectives/backgroundRapid eye movement (REM) Sleep Behavior Disorder (RBD) in Parkinson's disease (PD) may be associated with a malignant phenotype. Despite its prognostic value, little is known about the time course of RBD in PD. In this study, we aimed to ascertain whether or not RBD is a stable feature in PD. In this study, we prospectively evaluated clinical and neurophysiological features of RBD, including REM Sleep Without Atonia (RSWA), in PD patients with RBD at baseline and after three years then assessed whether the changes in measures of RSWA parallel the progression of PD.Patients/methodsIn sum, 22 (17M, mean age 64.0 ± 6.9 years) moderate-to-advanced PD patients (mean PD duration at baseline:7.6±4.8 years) with RBD, underwent a video-polysomnography (vPSG) recording and clinical and neuropsychological assessment at baseline and after three years.ResultsAt follow-up, the self-assessed frequency of RBD symptoms increased in six patients, decreased in six and remained stable in 10, while RSWA measures significantly increased in all subjects. At follow-up, patients showed worse H&Y stage (p = 0.02), higher dopaminergic doses (p = 0.05) and they performed significantly worse in phonetic and semantic fluency tests (p = 0.02; p = 0.04). Changes in RSWA correlated significantly with the severity in levodopa-induced dyskinesia (r = 0.61,p = 0.05) and motor fluctuation (r = 0.54,p = 0.03) scores, and with the worsening of executive functions (r = 0.78,p = 0.001) and visuo-spatial perception (r = −0.57,p = 0.04).ConclusionDespite the subjective improvement of RBD symptoms in one-fourth of PD patients, all RSWA measures increased significantly at follow-up, and their changes correlated with the clinical evolution of motor and non-motor symptoms. RBD is a long-lasting feature in PD and RSWA is a marker of the disease's progression.     

Alpha power decrease in quantitative EEG detects development of cerebral infarction after subarachnoid hemorrhage early

ObjectiveIn subarachnoid hemorrhage (SAH), transcranial Doppler/color-coded-duplex sonography (TCD/TCCS) is used to detect delayed cerebral ischemia (DCI). In previous studies, quantitative electroencephalography (qEEG) also predicted imminent DCI. This study aimed to compare and analyse the ability of qEEG and TCD/TCCS to early identify patients who will develop later manifest cerebral infarction.MethodsWe analysed cohorts of two previous qEEG studies. Continuous six-channel-EEG with artefact rejection and a detrending procedure was applied. Alpha power decline of ≥ 40% for ≥ 5 hours compared to a 6-hour-baseline was defined as significant EEG event. Median reduction and duration of alpha power decrease in each channel was determined. Vasospasm was diagnosed by TCD/TCCS, identifying the maximum frequency and days of vasospasm in each territory.Results34 patients were included (17 male, mean age 56 ± 11 years, Hunt and Hess grade: I–V, cerebral infarction: 9). Maximum frequencies in TCD/TCCS and alpha power reduction in qEEG were correlated (r = 0.43; p = 0.015). Patients with and without infarction significantly differed in qEEG parameters (maximum alpha power decrease: 78% vs 64%, p = 0.019; summed hours of alpha power decline: 236 hours vs 39 hours, p = 0.006) but showed no significant differences in TCD/TCCS parameters.ConclusionsThere was a moderate correlation of TCD/TCCS frequencies and qEEG alpha power reduction but only qEEG differentiated between patients with and without cerebral infarction.SignificanceqEEG represents a non-invasive, continuous tool to identify patients at risk of cerebral infarction.     

Impact of Integrated Care Pathways Within the Framework of Collaborative Care on Older Adults With Anxiety,Depression, or Mild Cognitive Impairment

ObjectivesTo evaluate the impact of an Integrated Care Pathway (ICP) within a collaborative care framework for anxiety, depression and mild cognitive impairment (MCI) on clinical outcomes, quality of life, and time to treatment initiation.DesignProspective Cohort study.SettingPrimary care practices in Toronto and Hamilton, Ontario, Canada.ParticipantsPatients of participating primary care practices born in the years 1950 to 1958.Sample SizeTarget 150 participants, 75 in ICP and 75 in Treatment-As-Usual (TAU) arm.InterventionICP within a collaborative care framework and TAU.Methods and ResultsOne hundred forty-five participants with anxiety, depression or MCI, from five primary care practices were enrolled: 69 were managed as per ICP and 76 as per TAU. All underwent outcome assessments at 6, 12, 18, and 24 months. Compared to TAU, ICP participants had a significantly higher rate of improvement in depression symptoms (β = ?0.620, F (1, 256) = 4.10, p = 0.044), anxiety symptoms (β = ?0.593, F (1, 223) = 4.00, p = 0.047), and quality of life (β = 1.351, F(1, 358) = 6.58, p = 0.011). The ICP group had also a significantly higher “hazard” of treatment initiation (HR = 3.557; 95% CI: [2.228, 5.678]; p < 0.001) after controlling for age, gender and baseline severity of symptoms compared to TAU group.ConclusionsUse of an ICP within a collaborative care framework in primary care settings for anxiety, depression and MCI among older adults, results in faster reductions in clinical symptoms and improvement in quality of life compared to usual care, as well as faster access to recommended treatments.     

Detecting inspiratory flow limitation with temporal features of nasal airflow

BackgroundInspiratory flow limitation is a breathing pattern during sleep caused by upper airway (UA) narrowing that occurs during snoring and various degrees of obstructive sleep apnea (OSA). Clinical examination of flow limitation relies on identifying patterns of airflow contour, however this process is subjective and lacks physiological evidence of UA narrowing. Our objective is to derive the temporal features of nasal airflow contour that characterize flow limitation. The features that correlate with UA narrowing can be used to develop machine learning classifiers to detect flow limitation with physiological support.MethodsSixteen healthy adult men underwent full daytime polysomnography where the nasal airflow was recorded. Before and after sleep, we measured UA anatomical parameters including neck circumference (NC) and upper-airway cross-sectional area (UA-XSA). We extracted various temporal features of airflow and investigated their relationships with the UA anatomical parameters.ResultsWe found that three features were correlated with the anatomical parameters associated with UA narrowing: deviation index vs. baseline UA-XSA (r = −0.67, p = 0.01), peak amplitude variability vs. baseline UA-XSA (r = −0.69, p < 0.01), peak amplitude variability vs. ΔNC (r = 0.74, p < 0.01) and peak number vs. baseline UA-XSA (r = −0.54, p = 0.04).ConclusionsTemporal features of airflow were associated with UA narrowing. Future studies could utilize the features to develop classifiers to detect flow limitation and assess the severity of breathing disorders during sleep in high-risk populations such as pregnant women and children.     

BDNF levels and nigrostriatal degeneration in “drug naïve” Parkinson's disease patients. An “in vivo” study using I-123-FP-CIT SPECT

IntroductionParkinson's Disease (PD) is a common neurodegenerative disorder, characterized by a progressive loss of dopaminergic neurons and whose cause remains unclear. Brain-Derived Neurotrophic factor (BDNF) is a protein involved in dopaminergic cells survival. Previous studies have shown decreased serum BDNF levels in PD patients.Aim and objectivesThe aim of the study was to evaluate serum BDNF levels in a group of recently diagnosed non-medicated PD patients and its relationship with the nigrostriatal system degeneration using I-123-FP-CIT.Methods30 recently diagnosed, unmedicated PD patients were included in this study. Serum BDNF levels were measured twice using a sandwich enzyme linked immunoabsorbent assay and compared with levels of 27 unrelated Caucasian healthy adults.A I-123-FP-CIT SPECT was performed in all PD Patients in order to assess the association between serum BDNF levels and I-123-FP CIT uptake in several brain areas using a volumetric semi-automatic method.ResultsPD patients showed lower serum BDNF levels (Median = 49.61, IQ range: 43.55 to 61.82) than the controls (Median = 68.82, IQ range: 51.87 to 88.14) (U = 211.00, z = -3.10, p = 0.002). BDNF levels in PD patients correlated with both caudate (Spearman r = 0.58, p = 0.001 for ispilateral and r 0.55, p = 0.002 for contralateral) and putamen (Spearman r = 0.68, p < 0.001 for ipsilateral and r = 0.80, p < 0.001 for contralateral) I-123-FP-CIT uptake ratios.ConclusionsSerum BDNF levels were lower in recently diagnosed, untreated PD patients compared to controls. These lower levels were significantly correlated with the I-123-FP-CIT uptake ratios.     

Comparative study of the substantia nigra echogenicity and 123I-Ioflupane SPECT in patients with synucleinopathies with and without REM sleep behavior disorder

ObjectivesHyperechogenicity of the substantia nigra (SN) and abnormal dopamine transporter-single-photon emission computed tomography (DAT-SPECT) are biomarkers commonly used in the assessment of prodromal synucleinopathy. Our goals were as follows: (1) to compare echogenicity of SN in idiopathic rapid eye movement (REM) behavior disorder (iRBD), Parkinson's disease (PD) without RBD (PD-noRBD), PD with RBD (PD + RBD), and control subjects; and (2) to examine association between SN degeneration assessed by DAT-SPECT and SN echogenicity.Patients/methodsA total of 61 subjects with confirmed iRBD were examined using Movement Disorders Society-unified PD rating scale (MDS-UPDRS), TCS (transcranial sonography) and DAT-SPECT. The results were compared with 44 patients with PD (25% PD + RBD) and with 120 age-matched healthy subjects.Results and conclusionThe abnormal SN area was found in 75.5% PD, 23% iRBD and 7.3% controls. Median SN echogenicity area in PD (0.27 ± 0.22 cm²) was higher compared to iRBD (0.07 ± 0.07 cm²; p < 0.0001) and controls (0.05 ± 0.03 cm²; p < 0.0001). SN echogenicity in PD + RBD was not significantly different from PD-noRBD (0.30 vs. 0.22, p = 0.15).Abnormal DAT-SPECT was found in 16 iRBD (25.4%) and 44 PD subjects (100%). No correlation between the larger SN area and corresponding putaminal binding index was found in iRBD (r = −0.13, p = 0.29), nor in PD (r = −0.19, p = 0.22).The results of our study showed that: (1) SN echogenicity area in iRBD was higher compared to controls, but the hyperechogenicity was present only in a minority of iRBD patients; (2) SN echogenicity and DAT-SPECT binding index did not correlate in either group; and (3) SN echogenicity does not differ between PD with/without RBD.     

Valproate but not levetiracetam slows the EEG alpha peak frequency – A pharmaco-EEG study

ObjectiveStudies of the effect of valproate (VPA) on the background EEG have shown varying results. Therefore, we compared the effect of VPA and levetiracetam (LEV) on the EEG alpha peak frequency (APF).MethodsWe retrospectively examined the APF in resting-state EEG of patients undergoing inpatient video-EEG monitoring (VEM) during withdrawal of VPA or LEV. We assessed APF trends by computing linear fits across individual patients’ APF as a function of consecutive days, and correlated the APF and daily antiseizure medication (ASM) doses on a single-patient and group level.ResultsThe APF in the VPA-group significantly increased over days with falling VPA doses (p = 0.005, n = 13), but did not change significantly in the LEV-group (p = 0.47, n = 18). APF correlated negatively with daily ASM doses in the VPA-group (average of r = −0.74 ± 0.12 across patients, p = 0.0039), but not in the LEV-group (average of r = −0.17 ± 0.18 across patients, p = 0.4072).ConclusionsOur results suggest that VPA treatment slows the APF. This APF reduction correlates with the daily dose of VPA and is not present in LEV treatment.SignificanceOur study identifies a VPA-related slowing of the APF even in patients without electroencephalographic or overt clinical signs of encephalopathy.     

Sleep positions in children with Down syndrome and obstructive sleep apnea

ObjectivesTo assess sleep positions in children with both Down syndrome (DS) and obstructive sleep apnea (OSA) and determine if there is a preferred sleep position by severity of apnea.MethodsA single-center retrospective review of patients with both DS and OSA was performed. Caregivers reported sleep position utilized greater than 50% of observed sleep time. Accuracy of this report was confirmed through review of hypnograms from polysomnography studies.ResultsEighty-two patients met inclusion criteria. Median body mass index (BMI) was 26.6 and 56% of patients had a prior tonsillectomy and/or adenoidectomy. The mean obstructive AHI (OAHI) was 25.33 with 90.4% having severe OSA, 9.6% having moderate OSA, and no patients having mild OSA. Reported sleep positions were skewed towards lateral/decubitus (82.9%) compared to prone (11.0%) and supine (6.1%). This was consistent with hypnogram data where 71% of total sleep time in lateral/decubitus positions compared to prone (13%) and supine (6%). The median changes in sleep position per patient was 5 (IQR: 3–6). Lower BMI (p < 0.001, 95% CI: 0.32–1.13) and tonsillectomy (p < 0.001, 95% CI: 7.7–18.19) were associated with lower OAHI. Sleep position was not associated with age (p = 0.19), sex (p = 0.66), race (p = 0.10), ethnicity (p = 0.68) nor history of tonsillectomy (p = 0.34). Preferred sleep position was not correlated with OAHI (p = 0.78, r = 0.03) or OSA severity (p = 0.72, r = 0.03).ConclusionsThis study highlights the possibility that children with DS may have preferential sleep positions that cater to optimized airflow in the context of OSA although further prospective study is needed.     

Exploring three levels of interoception in people with functional motor disorders

IntroductionA three-level model of interoception has recently been defined. We aim to study the interoceptive processing in individuals with functional motor disorder (FMD).MethodsTwenty-two patients with FMD were compared to 23 healthy controls. They underwent a protocol measuring different levels of interoception including: accuracy (a heart-beat tracking task), awareness (participant's confidence level) and sensibility (the Body Awareness Questionnaire-BAQ). Depression, anxiety and alexithymia were assessed by means of validated clinical scales.ResultsThe FMD group showed a lower cardiac interoceptive accuracy and sensibility than healthy controls but they did not differ in terms of awareness (p = 0.03 and 0.005 respectively). They were aware of their poor performance in the accuracy task. Cardiac interoceptive accuracy positively correlated with the BAQ sub-scales “Predict Body Reaction” (r = 0.49, p = 0.001) and “Sleep-Wake Cycle” (r = 0.52, p < 0.001). A mediation analysis showed a significant indirect effect of group on cardiac interoceptive accuracy through BAQ “Predict Body Reaction” (b = −2.95, 95% BCa CI[-7.2;-0.2]). The direct effect of group on “Predict Body Reaction” was still significant (b = − 6.95, p = 0.02, 95% CI[-13.18;-0.73]).ConclusionsPeople with FMD have impaired cardiac interoceptive accuracy and sensibility but no difference in metacognitive interoception compared to healthy controls.     

Effects of modifying the electrode placement and pulse width on cognitive side effects with unilateral ECT: A pilot randomised controlled study with computational modelling

BackgroundThe electrode placement and pulse width for electroconvulsive therapy (ECT) are important treatment parameters associated with ECT related retrograde memory side-effects. Modification of these parameters with right unilateral (RUL) ECT may have utility for further reducing these side-effects.ObjectiveThis study explored use of the frontoparietal (FP) placement for reducing retrograde memory side effects with ECT. We hypothesised that superior retrograde memory outcomes would occur with FP compared to temporoparietal (TP) placement and with ultrabrief (UB: 0.3 ms) compared to brief pulse (BP: 1.0 ms) width ECT.MethodsIn this randomised cross-over, double-blinded study, participants received a single treatment of BP TP, BP FP, UB TP and UB FP ECT. Neuropsychological testing was conducted prior to and immediately following each treatment. Computational modelling was conducted to explore associations between E-fields in regions-of-interest associated with memory.ResultsNine participants completed the study. The FP placement was not superior to TP for retrograde memory outcomes. For both electrode placements UB pulse width was associated with significantly better visual retrograde memory compared to BP (p < .05). With TP ECT, higher E-fields in regions-of-interest were significantly associated with greater visual retrograde memory side-effects (hippocampi: r = −0.77, p = .04; inferior frontal gyri: r = −0.92, p < .01; middle frontal gyri: r = −0.84, p = .02).ConclusionsModification of pulse-width had greater effects than electrode placement for reducing retrograde memory side-effects with RUL ECT. Preliminary findings suggested that higher E-fields may be associated with greater cognitive side-effects with ECT.     

LTP-like cortical plasticity predicts conversion to dementia in patients with memory impairment

BackgroundNew diagnostic criteria consider Alzheimer’s disease (AD) as a clinico-biological entity identifiable in vivo on the presence of specific patterns of CSF biomarkers.ObjectiveHere we used transcranial magnetic stimulation to investigate the mechanisms of cortical plasticity and sensory-motor integration in patients with hippocampal-type memory impairment admitted for the first time in the memory clinic stratified according to CSF biomarkers profile.MethodsSeventy-three patients were recruited and divided in three groups according to the new diagnostic criteria: 1) Mild Cognitive Impaired (MCI) patients (n = 21); Prodromal AD (PROAD) patients (n = 24); AD with manifest dementia (ADD) patients (n = 28). At time of recruitment all patients underwent CSF sampling for diagnostic purposes. Repetitive and paired-pulse transcranial magnetic stimulation protocols were performed to investigate LTP-like and LTD-like cortical plasticity, short intracortical inhibition (SICI) and short afferent inhibition (SAI). Patients were the followed up during three years to monitor the clinical progression or the conversion to dementia.ResultsMCI patients showed a moderate but significant impairment of LTP-like cortical plasticity, while ADD and PROAD groups showed a more severe loss of LTP-like cortical plasticity. No differences were observed for LTD-like cortical plasticity, SICI and SAI protocols. Kaplan-Meyer analyses showed that PROAD and MCI patients converting to dementia had weaker LTP-like plasticity at time of first evaluation.ConclusionLTP-like cortical plasticity could be a novel biomarker to predict the clinical progression to dementia in patients with memory impairment at prodromal stages of AD identifiable with the new diagnostic criteria based on CSF biomarkers.     

Treelet transform analysis to identify clusters of systemic inflammatory variance in a population with moderate-to-severe traumatic brain injury

BackgroundInflammatory cascades following traumatic brain injury (TBI) can have both beneficial and detrimental effects on recovery. Single biomarker studies do not adequately reflect the major arms of immunity and their relationships to long-term outcomes. Thus, we applied treelet transform (TT) analysis to identify clusters of interrelated inflammatory markers reflecting major components of systemic immune function for which substantial variation exists among individuals with moderate-to-severe TBI.MethodsSerial blood samples from 221 adults with moderate-to-severe TBI were collected over 1–6 months post-injury (n = 607 samples). Samples were assayed for 33 inflammatory markers using Millipore multiplex technology. TT was applied to standardized mean biomarker values generated to identify latent patterns of correlated markers. Treelet clusters (TC) were characterized by biomarkers related to adaptive immunity (TC1), innate immunity (TC2), soluble molecules (TC3), allergy immunity (TC4), and chemokines (TC5). For each TC, a score was generated as the linear combination of standardized biomarker concentrations and cluster load for each individual in the cohort. Ordinal logistic or linear regression was used to test associations between TC scores and 6- and 12-month Glasgow Outcome Scale (GOS), Disability Rating Scale (DRS), and covariates.ResultsWhen adjusting for clinical covariates, TC5 was significantly associated with 6-month GOS (odds ratio, OR = 1.44; p-value, p = 0.025) and 6-month DRS scores (OR = 1.46; p = 0.013). TC5 relationships were attenuated when including all TC scores in the model (GOS: OR = 1.29, p = 0.163; DRS: OR = 1.33, p = 0.100). When adjusting for all TC scores and covariates, only TC3 was associated with 6- and 12-month GOS (OR = 1.32, p = 0.041; OR = 1.39, p = 0.002) and also 6- and 12-month DRS (OR = 1.38, p = 0.016; OR = 1.58, p = 0.0002). When applying TT to inflammation markers significantly associated with 6-month GOS, multivariate modeling confirmed that TC3 remained significantly associated with GOS. Biomarker cluster membership remained consistent between the GOS-specific dendrogram and overall dendrogram.ConclusionsTT effectively characterized chronic, systemic immunity among a cohort of individuals with moderate-to-severe TBI. We posit that chronic chemokine levels are effector molecules propagating cellular immune dysfunction, while chronic soluble receptors are inflammatory damage readouts perpetuated, in part, by persistent dysfunctional cellular immunity to impact neuro-recovery.     

DNA methylation changes at TREM2 intron 1 and TREM2 mRNA expression in patients with Alzheimer's disease

ObjectivesRecent genome-wide association studies revealed that Triggering receptor expressed on myeloid cells 2 (TREM2) was associated with Alzheimer's disease (AD) and other neurodegenerative diseases. We previously reported that TREM2 mRNA is highly expressed in leukocytes of AD patients compared to those in healthy controls. However, the mechanism of TREM2 expression change is still not known. In this study, we examined the involvement of the DNA methylation status of TREM2 in its high gene expression.Materials and methodsFifty AD subjects and age- and sex-matched control subjects were recruited (25 males, 25 females; 79.9 ± 5.27 and 79.4 ± 3.92 years old, respectively). TREM2 mRNA expression and the percentage of DNA methylation at four CpG sites in intron 1 of TREM2 were studied using their peripheral leukocytes.ResultsWe confirmed that TREM2 mRNA expression in leukocytes was significantly higher in AD patients than in controls (p = 0.007). The percentage methylation at three CpG sites in TREM2 intron 1 was significantly lower in AD subjects than in control: CpG1, 9.4 ± 3.2 vs 11.9 ± 4.0 (p = 0.001); CpG2, 15.4 ± 4.9 vs 19.1 ± 4.8 (p = 0.001); CpG3, 20.8 ± 5.5 vs 25.5 ± 5.4 (p < 0.001); and the average percentage methylation of all CpG sites: 13.5 ± 3.7 vs 16.1 ± 3.8 (p = 0.002), respectively. In addition, there were significant negative correlations between TREM2 mRNA expression and the percentage DNA methylation of each of CpG sites (CpG1, r = −0.416, p < 0.001; CpG2, r = −0.510, p < 0.001; CpG3, r = −0.504, p < 0.001; CpG4, r = −0.356, p < 0.001).ConclusionsLower DNA methylation at TREM2 intron 1 caused higher TREM2 mRNA expression in the leukocytes of AD subjects versus controls and may be a biomarker for AD.     

Hippocampal and insula volume in mild cognitive impairment with Lewy bodies

IntroductionDiagnostic criteria for prodromal dementia with Lewy bodies have recently been published. These include the use of imaging biomarkers to distinguish mild cognitive impairment with Lewy bodies (MCI-LB) from MCI due to other causes. Two potential biomarkers listed, though not formally included in the diagnostic criteria, due to insufficient evidence, are relatively preserved hippocampi, and atrophy of the insula cortex on structural brain imaging.MethodsIn this report, we sought to investigate these imaging biomarkers in 105 research subjects, including well characterised groups of patients with MCI-LB (n = 38), MCI with no core features of Lewy body disease (MCI-AD; n = 36) and healthy controls (N = 31). Hippocampal and insula volumes were determined from T1 weighted structural MRI scans, using grey matter segmentation performed with SPM software.ResultsAdjusting for age, sex and intracranial volume, there were no differences in hippocampal or insula volume between MCI-AD and MCI-LB, although in both conditions volumes were significantly reduced relative to controls.ConclusionOur results do not support the use of either hippocampal or insula volume to identify prodromal dementia with Lewy bodies.