Background
Fibromyalgia (FM) is a disabling chronic pain syndrome with unknown pathophysiology. Functional magnetic resonance imaging studies on FM have suggested altered brain connectivity between ...the insula and the default mode network (DMN). However, this connectivity change has not been characterized through direct neural signals for exploring the embedded spectrotemporal features and the pertinent clinical relevance.
Methods
We recorded the resting-state magnetoencephalographic activities of 28 patients with FM and 28 age- and sex-matched controls, and analyzed the source-based functional connectivity between the insula and the DMN at 1–40 Hz by using the minimum norm estimates and imaginary coherence methods. We also measured the connectivity between the DMN and the primary visual (V1) and somatosensory (S1) cortices as intrapatient negative controls. Connectivity measurement was further correlated with the clinical parameters of FM.
Results
Compared with the controls, patients with FM reported more tender points (15.2±2.0 vs. 5.9±3.7) and higher total tenderness score (TTS; 29.1±7.0 vs. 7.7±5.5; both
p
< 0.001); they also had decreased insula–DMN connectivity at the theta band (4–8 Hz; left,
p
= 0.007; right,
p
= 0.035), but displayed unchanged V1–DMN and S1–DMN connectivity (
p
> 0.05). When patients with FM and the controls were combined together, the insula-DMN theta connectivity was negatively correlated with the number of tender points (left insula,
r
= −0.428,
p
= 0.001; right insula,
r
= −0.4,
p
= 0.002) and TTS score (left insula,
r
= −0.429,
p
= 0.001; right insula,
r
= −0.389,
p
= 0.003). Furthermore, in patients with FM, the right insula–DMN connectivity at the beta band (13–25 Hz) was negatively correlated with the number of tender points (
r
= −0.532,
p
= 0.004) and TTS (
r
= −0.428,
p
= 0.023), and the bilateral insula–DMN connectivity at the delta band (1–4 Hz) was negatively correlated with FM Symptom Severity (left:
r
= −0.423,
p
= 0.025; right:
r
= −0.437,
p
= 0.020) and functional disability (Fibromyalgia Impact Questionnaire; left:
r
= −0.415,
p
= 0.028; right:
r
= −0.374,
p
= 0.050).
Conclusions
We confirmed the frequency-specific reorganization of the insula–DMN connectivity in FM. The clinical relevance of this connectivity change may warrant future studies to elucidate its causal relationship and potential as a neurological signature for FM.
Patients with amnestic mild cognitive impairment (aMCI) demonstrate significant cognitive deficits, especially in the memory aspect. The memory deficiency might be attributed to the difficulties in ...the inhibitory function to suppress redundant stimuli. Sensory gating (SG) refers to the attenuation of neural responses to the second identical stimulus in a paired-click paradigm, in which auditory stimuli are delivered in pairs with inter-stimulus intervals (ISI) of 500 ms and inter-pair intervals of 6-8 s. It is considered as an electrophysiological signal to reflect the brain's automatic response to gate out repetitive sensory inputs. However, there has been no study systematically investigating SG function in aMCI patients. Thus, the present study used magnetoencephalography (MEG) to record neuromagnetic responses to a paired-click paradigm in 23 healthy controls (HC) and 26 aMCI patients. The Stimulus 2/Stimulus 1 (S2/S1) amplitude ratio was used to represent the SG function. Compared to HC, aMCI patients showed M50 SG deficits in the left inferior frontal gyrus (IFG) and right inferior parietal lobule (IPL). M100 SG defects were also observed in the right IPL. Based on the ROIs showing significant between-group SG differences, we found that a more deficient M50 SG function in the right IPL was associated with poorer performance in the immediate recall of Logic Memory (LM), Chinese Version Verbal Learning Test (CVVLT) and Digit Span Backward (DSB) Test. Furthermore, the M50 SG ratios of the right IPL together with the neuropsychological performance of LM and CVVLT demonstrated very good accuracy in the discrimination of aMCI from HC. In conclusion, compared to HC, aMCI patients showed a significant SG deficit in the right IPL, which was correlated with the auditory short-term memory function. We suggest the combination of SG in the right IPL, LM and CVVLT to be sensitive indicators to differentiate aMCI patients from HC.
Mild cognitive impairment (MCI) is considered an intermediate state between normal aging and early dementia. Fear of falling (FOF) could be considered a risk indicator for falls and quality of life ...in individuals with MCI. Our objective was to explore factors associated with FOF in those with MCI due to Alzheimer’s disease (AD-MCI) and mild cognitive impairment in Parkinson’s disease (PD-MCI). Seventy-one participants were separated into two groups, AD-MCI (n = 37) and PD-MCI (n = 34), based on the disease diagnosis. FOF was assessed using the Activities-specific Balance Confidence scale. The neuropsychological assessment and gait assessment were also measured. FOF was significantly correlated with global cognitive function, attention and working memory, executive function, Tinetti assessment scale scores, gait speed, and stride length in the AD-MCI group. Moreover, attention and working memory were the most important factors contributing to FOF. In the PD-MCI group, FOF was significantly correlated with gait speed, and time up and go subtask performance. Furthermore, turn-to-walk was the most important factor contributing to FOF. We noted that FOF in different types of MCI was determined by different factors. Therapies that aim to lower FOF in AD-MCI and PD-MCI populations may address attention and working memory and turn-to-walk, respectively.
Severe carotid stenosis is associated with cognitive impairment, which may be attributed to asymptomatic microembolism and/or chronic hypoperfusion. We aim to evaluate the long-term cognitive and ...brain connectivity outcomes of carotid artery stenting (CAS) for asymptomatic ≥70% stenosis of the extracranial internal carotid artery (ICA).
We conducted a non-randomized controlled study to compare intensive medical therapy alone (Med) or in combination with carotid artery stenting for the composite vascular events, neuropsychological, and multimodal magnetic resonance perfusion imaging and diffusion tensor imaging outcomes.
Sixty-nine patients were followed for a mean of 2.3 years (31 Med, 38 CAS) and 11 patients had composite vascular events of all-cause death, ischemic stroke, or myocardial infarction (6 Med vs 5 CAS). Forty-six asymptomatic subjects completed neuropsychological and multimodality imaging follow-ups (23 Med, 23 CAS). Compared to the Med group, the CAS group had a modest improvement of 12-item delayed verbal memory (8.9 ± 2.4 to 9.8 ± 2.7 vs 9.0 ± 2.1 to 8.9 ± 2.3, p = 0.04), but not in global cognition, attention or executive function, which was associated with increased structural connectivity of fractional anisotropy at the ipsilateral deep white matter. Importantly, the memory improvement was correlated with the perfusion increment at the ipsilateral middle cerebral artery territory.
For asymptomatic extracranial carotid steno-occlusion, successful carotid revascularization in addition to intensive medical treatment may potentially benefit cognitive reserve and connectivity strength which are partly attributed to restoration of non-critical hypoperfusion.
Both amyloid plaques and neurofibrillary tangles are pathological hallmarks in the brains of patients with Alzheimer’s disease (AD). However, the constituents of these hallmarks, amyloid beta (Aβ) ...40, Aβ42, and total Tau (t-Tau), have been detected in the blood of cognitively normal subjects by using an immunomagnetic reduction (IMR) assay. Whether these levels are age dependent is not known, and their interrelation remains undefined. We determined the levels of these biomarkers in cognitively normal subjects of different age groups. A total of 391 cognitively normal subjects aged 23 to 91 were enrolled from hospitals in Asia, Europe, and North America. Healthy cognition was evaluated by NIA-AA guidelines to exclude subjects with mild cognitive impairment (MCI) and AD and by cognitive assessment using the Mini Mental State Examination and Clinical Dementia Rating. We examined the effect of age on plasma levels of Aβ40, Aβ42, and t-Tau and the relationship between these biomarkers during aging. Additionally, we explored age-related reference intervals for each biomarker. Plasma t-Tau and Aβ42 levels had modest but significant correlations with chronological age (r = 0.127, p = 0.0120 for t-Tau; r = -0.126, p = 0.0128 for Aβ42), ranging from ages 23 to 91. Significant positive correlations were detected between Aβ42 and t-Tau in the groups aged 50 years and older, with Rho values ranging from 0.249 to 0.474. Significant negative correlations were detected between Aβ40 and t-Tau from age 40 to 91 (r ranged from -0.293 to -0.582) and between Aβ40 and Aβ42 in the age groups of 30-39 (r = -0.562, p = 0.0235), 50-59 (r = -0.261, p = 0.0142), 60-69 (r = -0.303, p = 0.0004), and 80-91 (r = 0.459, p = 0.0083). We also provided age-related reference intervals for each biomarker. In this multicenter study, age had weak but significant effects on the levels of Aβ42 and t-Tau in plasma. However, the age group defined by decade revealed the emergence of a relationship between Aβ40, Aβ42, and t-Tau in the 6th and 7th decades. Validation of our findings in a large-scale and longitudinal study is warranted.
Introduction
Pyroglutamate‐modified amyloid β (AβpE3) could be a biomarker for Aβ plaque pathology in the brain. An ultra‐high‐sensitive assay is needed for detecting AβpE3‐40.
Methods
Immunomagnetic ...reduction was used for quantification of AβpE3‐40 in plasma from 46 participants. The concentrations of AβpE3‐40 of these subjects were compared with 18F‐florbetapir positron emission tomography (PET) images.
Results
AβpE3‐40 concentration was 44.1 ± 28.2 fg/mL in PET‐ (n = 28) and 91.6 ± 54.6 fg/mL in PET+ (n = 18; P < .05). The cutoff value of AβpE3‐40 for discriminating PET‐ from PET+ was 55.5 fg/mL, resulting in a sensitivity of 83.3%, a specificity of 71.4%. The concentration of AβpE3‐40 showed a moderate correlation (r = 0.437) with PET standardized uptake value ratio.
Discussion
We did not enroll pre‐clinical AD subject with normal cognition but Aβ PET+. It would be an important issue to explore the feasibility of using AβpE3‐40 for screening pre‐clinical subjects.
Conclusion
These results reveal the feasibility of detecting Aβ pathology using quantification of a plaque‐derived Aβ molecule in plasma.
Objective
Mutations in the colony‐stimulating factor 1 receptor gene (CSF1R) were identified as a cause of adult‐onset inherited leukoencephalopathy. The present study aims at investigating the ...frequency, clinical characteristics, and functional effects of CSF1R mutations in Taiwanese patients with adult‐onset leukoencephalopathy.
Methods
Mutational analysis of CSF1R was performed in 149 unrelated individuals with leukoencephalopathy by a targeted resequencing panel covering the entire coding regions of CSF1R. In vitro analysis of the CSF1‐induced autophosphorylation activities of mutant CSF1R proteins was conducted to assess the pathogenicity of the CSF1R mutations.
Results
Among the eight CSF1R variants identified in this study, five mutations led to a loss of CSF1‐induced autophosphorylation of CSF1R proteins. Four mutations (p.K586*, p.G589R, p.R777Q, and p.R782C) located within the tyrosine kinase domain of CSF1R, whereas the p.T79M mutation resided in the immunoglobulin‐like domain. The five patients carrying the CSF1R mutations developed cognitive decline at age 41, 43, 50, 79, and 86 years, respectively. Psychiatric symptoms and behavior changes were observed in four of the five patients. The executive function and processing speed were severely impaired at an early stage, and their cognitive function deteriorated rapidly within 3–4 years. Diffusion‐restricted lesions at the subcortical regions and bilateral corticospinal tracts were found in three patients.
Interpretation
CSF1R mutations account for 3.5% (5/149) of the adult‐onset leukoencephalopathy in Taiwan. CSF1R mutations outside the tyrosine kinase domain may also disturb the CSF1R function and lead to the clinical phenotype. Molecular functional validation is important to determine the pathogenicity of novel CSF1R variants.
Objective
The etiology of age‐related white matter changes is unclear. Cerebral white matter changes on magnetic resonance imaging (MRI) and progressive dementia have been reported in patients with ...dural arteriovenous fistulas of the sigmoid sinus. The frequency of jugular venous reflux, which mimics a dural arteriovenous fistula, significantly increases with age. We investigated whether jugular venous reflux was associated with the severity of age‐related white matter changes in 97 persons (aged 55–90 years, mean standard deviation: 75.77 8.19 years; 55 men) from a medical center memory clinic.
Methods
MRI (1.5T) and the semiquantitative Scheltens scale were used to investigate the severity of white matter changes. Subjects were classified into 3 groups (no, mild, and severe jugular venous reflux) by duplex ultrasonography.
Results
Subjects with severe jugular venous reflux had more severe age‐related white matter changes in occipital subcortical, thalamus, pontine, and summed infratentorial regions compared with subjects with no jugular venous reflux (all corrected p
< 0.0166), especially subjects aged ≥75 years (corrected p
< 0.0166 in occipital subcortical; corrected p
< 0.0001 in pontine and summed infratentorial regions). In subjects ≥75 years, we further noted that the whole brain age‐related white matter changes rating scores were higher in the severe jugular venous reflux group than the no and mild jugular venous reflux groups (corrected p
< 0.0166).
Interpretation
People with severe jugular venous reflux exhibit more severe age‐related white matter changes, especially in caudal brain regions. We also demonstrate age‐dependent jugular venous reflux effects on the severity of age‐related white matter changes. These findings may provide new clues into the pathophysiology of age‐related white matter changes. ANN NEUROL 2011
A better understanding of factors associated with caregiver burden might facilitate the construction of coping strategies to improve their clinical outcomes and the comprehensive care model for ...dementia.
To investigate the cognitive and neuropsychiatric domains that contribute to caregiver burden in three types of neurodegenerative disorders: Parkinson's disease (PD), Alzheimer's disease (AD), and frontotemporal disease (FTD).
Eight hundred and fourteen patients and their caregivers were invited to participate; among them, 235 had PD with cognitive impairment; 429 had AD, and 150 had FTD. The evaluation protocol included the Neuropsychiatric Inventory (NPI), the Mini-Mental State Examination, the Chinese Version Verbal Learning Test, the modified Trail Making Test B, semantic fluency, and a geriatric depression score. Statistical comparisons of the cognitive tests, NPI total scores, and caregiver burden among the three diagnosed types of dementia, matched for a Clinical Dementia Rating (CDR) of 0.5 or 1, were performed, and multivariate linear regression models were used to evaluate the parameter significance.
Caregivers for patients with PD and FTD showed significant burden increments when the CDR scores changes from 0.5 to 1. For CDR = 0.5, the PD group had significantly lower caregiver burdens than the AD group, but the NPI total scores were significantly higher. Factors related to caregiver burden were the presence of delusion among all diagnosis groups, while the impact of NPI total scores related to caregiver burden was the highest in FTD, followed by AD and PD.
At the mild to moderate stages, our results suggested different degrees of significance in terms of the cognitive test scores or NPI subdomains for predicting caregiver stress among the three types of dementia.
To assess whether high cerebral microbleeds (CMBs) are associated with carotid intima-media thickness (CIMT), a marker of systemic atherosclerosis, we cross-sectionally evaluated participants from a ...community-based study, the I-Lan Longitudinal Aging Study. The participants' demographics and cardiovascular risk factors were determined by questionnaire and/or laboratory measurements. CIMT was measured by ultrasonography. CMBs were assessed by susceptibility-weighted-imaging on 3 T MRI. Of the 962 subjects 62.5(8.6) years, 44.2% men included, CMBs were found in 134(14.0%) subjects. Among the subjects with identified CMB's, 85(63.4%) had deep or infratentorial (DI) and 49(36.6%) had strictly lobar(SL) CMBs. After the results were adjusted for age and sex, the analysis revealed that hypertension, hyperlipidemia, obesity, and higher triglyceride levels correlated with DI but not SL CMBs. The subjects with DI CMBs also had a higher mean CIMT and higher prevalence of top quartile CIMT. The multivariate analysis demonstrated that high CIMT (top quartile) significantly predicted the presence of DI CMBs (odds ratio = 2.1; 95% confidence interval = 1.3-3.4; P = 0.004), independent of age, sex, cardiovascular risk factors, and other cerebral small vessel diseases, lacune, and white matter hyperintensity. There was no association between CIMT and SL CMBs. Our results support that there are distinct pathogenesis in DI and SL CMBs.
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