Elderly Controls Research Articles

Distinct changes in all major components of the neurovascular unit across different neuropathological stages of Alzheimer's disease.

In the brain capillaries, endothelial cells, pericytes, astrocytes and microglia form a structural and functional complex called neurovascular unit (NVU) which is critically involved in maintaining neuronal homeostasis. In the present study, we applied a comprehensive immunohistochemical approach to investigate the structural alterations in the NVU across different Alzheimer's disease (AD) neuropathological stages. Post-mortem human cortical and hippocampal samples derived from AD patients and non-demented elderly control individuals were immunostained using a panel of markers representing specific components of the NVU including Collagen IV (basement membrane), PDGFR-β (pericytes), GFAP (astrocytes), Iba1 (microglia), MRC1 (perivascular macrophages) and lectin as an endothelial cell label. Astrocytes (GFAP) and microglia (Iba1) were quantified both in the whole visual-field and specifically within the NVU, and the sample set was additionally analyzed using anti-tau (AT8) and three different anti-Aβ (clones G2-10, G2-11, 4G8) antibodies. Analyses of lectin labeled sections showed an altered vascular distribution in AD patients as revealed by a reduced nearest distance between capillaries. Within the NVU, a Braak-stage dependent reduction in pericyte coverage was identified as the earliest structural alteration during AD progression. In comparison to non-demented elderly controls, AD patients showed a significantly higher astrocyte coverage within the NVU, which was paralleled by a reduced microglial coverage around capillaries. Assessment of perivascular macrophages moreover demonstrated a relocation of these cells from leptomeningeal arteries to penetrating parenchymal vessels in AD patients. Collectively, the results of our study represent a comprehensive first in-depth analysis of AD-related structural changes in the NVU and suggest distinct alterations in all components of the NVU during AD progression.

Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls.

Inherited pathogenic variants account for 5% to 10% of all breast cancer (BC) and colorectal cancer (CRC) cases. Here, we sought to profile the pathogenic variants in 25 cancer susceptibility genes in Turkish population. Germline pathogenic variants were screened in 732 BC patients, 189 CRC patients and 490 cancer-free elderly controls, using next-generation sequencing-based multigene panel testing and multiplex ligation-dependent probe amplification testing. Pathogenic variants were detected in 17.2% of high-risk BC patients and 26.4% of high-risk CRC patients. More than 95% of these variants were clinically actionable. BRCA1/2 and mismatch repair genes (MLH1, MSH2 and MSH6) accounted for two-thirds of all pathogenic variants detected in high-risk BC and CRC patients, respectively. Pathogenic variants in PALB2, CHEK2, ATM and TP53 were also prevalent in high-risk BC patients (4.5%). BRCA1 exons 17-18 deletion and CHEK2 c.592+3A>T were the most common variants predisposing to BC, and they are likely to be founder variants. Three frequent MUTYH pathogenic variants (c.884C>T, c.1437_1439delGGA and c.1187G>A) were responsible for all MUTYH biallelic cases (4.4% of high-risk CRC patients). The total pathogenic variant frequency was very low in controls (2.4%) and in low-risk BC (3.9%) and CRC (6.1%) patients. Our study depicts the pathogenic variant spectrum and prevalence in Turkish BC and CRC patients, guiding clinicians and health authorities for genetic testing applications and variant classification in Turkish population.

Cognitive and functional changes in prediagnostic phase of Parkinson disease: A population-based study

IntroductionProdromal non-motor symptoms precede, often by decades, motor signs and diagnosis of Parkinson's disease. It is however still uncertain if cognitive changes belong to the spectrum of non-motor prodromal Parkinson's disease. Thanks to the very long-term follow-up of the PAQUID population-based cohort, we assessed trajectories of cognitive complaints and functioning over a 13-year period before the diagnosis of late onset Parkinson's disease. MethodsThis study relies on a matched nested case-control sample selected from the cohort. Of the 3777 initial subjects of the cohort, 43 developed incident Parkinson's disease over the follow-up. The mean age at diagnosis was 78.0 (standard deviation = 5.8) years and 46.5% were men. These cases were matched to 86 elderly control subjects. Scores of different cognitive domains, daily function, and depressive symptoms were described throughout the follow-up using mixed-effects models. ResultsNo significant global cognitive decline preceded the diagnosis of late onset Parkinson's disease. However, psychomotor speed appeared significantly slower 2 years before the diagnosis and depressive symptoms 12 years before. Global score of instrumental activities of daily living became altered 2–3 years preceding the diagnosis of late onset Parkinson's disease, including the use of public transportation that was altered ten years before the diagnosis. ConclusionIn late onset Parkinson's disease, while global cognitive functions seem preserved, psychomotor speed starts to decline 2 years before the diagnosis and activities of daily living are also impacted. Depressive symptoms appear very early in the prediagnosic phase.

No Association Between a Genetic Variant of FOXO3 and Risk of Type 2 Diabetes Mellitus in the Elderly Population of North India.

Aging can be considered an evolutionary process that is modulated by various genetic and biochemical processes. Therefore the genetic variants may interplay a role in human longevity as well as age related illness. Forkhead Box O (FOXO) gene is one of the major defensive genes that are known for ameliorating lifespan. FOXO proteins act as nuclear transcription factors that facilitate the action of insulin or insulin-like growth factor (IGF-1) in various physiological processes. The rationale of our study is to find out association between genetic variant rs2253310 of FOXO3 and risk of Type 2 Diabetes Mellitus (T2DM) in elderly population. This case control study involved 172 age sex matched elderly subjects while patients were recruited as per IDF criteria. Clinical, biochemical, ELISA methods were employed for assesement of clinical samples while Taqman method was used for genotyping analysis. Our results revealed that there was no significant difference in genotypic and allelic frequencies for the tested SNP (p > 0.05) between elderly T2DM patients and controls. The SNP rs2253310 was not associated with risk of T2DM in any genetic model. Also no association was found among the studied group between FOXO3 variant and HOMA-IR, HOMA-B index and Fasting plasma glucose. Serum level of inflammatory markers like CRP and TNF-α was significantly higher in patients but its not associated with SNP rs2253310. Our study concluded that, this intronic longevity-associated variant rs2253310 in FOXO3 is not associated with type 2 diabetes in geriatric patients of northern India.

Cortical diffusivity investigation in posterior cortical atrophy and typical Alzheimer\u2019s disease

ObjectivesTo investigate the global cortical and regional quantitative features of cortical neural architecture in the brains of patients with posterior cortical atrophy (PCA) and typical Alzheimer’s disease (tAD) compared with elderly healthy controls (HC).MethodsA novel diffusion MRI method, that has been shown to correlate with minicolumnar organization changes in the cerebral cortex, was used as a surrogate of neuropathological changes in dementia. A cohort of 15 PCA patients, 23 tAD and 22 healthy elderly controls (HC) were enrolled to investigate the changes in cortical diffusivity among groups. For each subject, 3 T MRI T1-weighted images and diffusion tensor imaging (DTI) scans were analysed to extract novel cortical DTI derived measures (AngleR, PerpPD and ParlPD). Receiver operating characteristics (ROC) curve analysis and the area under the curve (AUC) were used to assess the group discrimination capability of the method.ResultsThe results showed that the global cortical DTI derived measures were able to detect differences, in both PCA and tAD patients compared to healthy controls. The AngleR was the best measure to discriminate HC from tAD (AUC = 0.922), while PerpPD was the best measure to discriminate HC from PCA (AUC = 0.961). Finally, the best global measure to differentiate the two patient groups was ParlPD (AUC = 0.771). The comparison between PCA and tAD patients revealed a different pattern of damage within the AD spectrum and the regional comparisons identified significant differences in key regions including parietal and temporal lobe cortical areas. The best AUCs were shown by PerpPD right lingual cortex (AUC = 0.856), PerpPD right superior parietal cortex (AUC = 0.842) and ParlPD right lateral occipital cortex (AUC = 0.826).ConclusionsDiagnostic group differences were found, suggesting that the new cortical DTI analysis method may be useful to investigate cortical changes in dementia, providing better characterization of neurodegeneration, and potentially aiding differential diagnosis and prognostic accuracy.

Association of epileptiform abnormalities and seizures in Alzheimer disease.

To examine the relationship between scalp EEG biomarkers of hyperexcitability in Alzheimer disease (AD) and to determine how these electric biomarkers relate to the clinical expression of seizures in AD. In this cross-sectional study, we performed 24-hour ambulatory scalp EEGs on 43 cognitively normal elderly healthy controls (HC), 41 participants with early-stage AD with no history or risk factors for epilepsy (AD-NoEp), and 15 participants with early-stage AD with late-onset epilepsy related to AD (AD-Ep). Two epileptologists blinded to diagnosis visually reviewed all EEGs and annotated all potential epileptiform abnormalities. A panel of 9 epileptologists blinded to diagnosis was then surveyed to generate a consensus interpretation of epileptiform abnormalities in each EEG. Epileptiform abnormalities were seen in 53% of AD-Ep, 22% of AD-NoEp, and 4.7% of HC. Specific features of epileptiform discharges, including high frequency, robust morphology, right temporal location, and occurrence during wakefulness and REM, were associated with clinical seizures in AD. Multiple EEG biomarkers concordantly demonstrated a pattern of left temporal lobe hyperexcitability in early stages of AD, whereas clinical seizures in AD were often associated with bitemporal hyperexcitability. Frequent small sharp spikes were specifically associated with epileptiform EEGs and thus identified as a potential biomarker of hyperexcitability in AD. Epileptiform abnormalities are common in AD but not all equivalent. Specific features of epileptiform discharges are associated with clinical seizures in AD. Given the difficulty recognizing clinical seizures in AD, these EEG features could provide guidance on which patients with AD are at high risk for clinical seizures.

Dopamine and reward hypersensitivity in Parkinson's disease with impulse control disorder.

Impulse control disorders in Parkinson's disease are common neuropsychiatric complications associated with dopamine replacement therapy. Some patients treated with dopamine agonists develop pathological behaviours, such as gambling, compulsive eating, shopping, or disinhibited sexual behaviours, which can have a severe impact on their lives and that of their families. In this study we investigated whether hypersensitivity to reward might contribute to these pathological behaviours and how this is influenced by dopaminergic medication. We asked participants to shift their gaze to a visual target as quickly as possible, in order to obtain reward. Critically, the reward incentive on offer varied over trials. Motivational effects were indexed by pupillometry and saccadic velocity, and patients were tested ON and OFF dopaminergic medication, allowing us to measure the effect of dopaminergic medication changes on reward sensitivity. Twenty-three Parkinson's disease patients with a history of impulse control disorders were compared to 26 patients without such behaviours, and 31 elderly healthy controls. Intriguingly, behavioural apathy was reported alongside impulsivity in the majority of patients with impulse control disorders. Individuals with impulse control disorders also exhibited heightened sensitivity to exogenous monetary rewards cues both ON and OFF (overnight withdrawal) dopamine medication, as indexed by pupillary dilation in anticipation of reward. Being OFF dopaminergic medication overnight did not modulate pupillary reward sensitivity in impulse control disorder patients, whereas in control patients reward sensitivity was significantly reduced when OFF dopamine. These effects were independent of cognitive impairment or total levodopa equivalent dose. Although dopamine agonist dose did modulate pupillary responses to reward, the pattern of results was replicated even when patients with impulse control disorders on dopamine agonists were excluded from the analysis. The findings suggest that hypersensitivity to rewards might be a contributing factor to the development of impulse control disorders in Parkinson's disease. However, there was no difference in reward sensitivity between patient groups when ON dopamine medication, suggesting that impulse control disorders may not emerge simply because of a direct effect of dopaminergic drug level on reward sensitivity. The pupillary reward sensitivity measure described here provides a means to differentiate, using a physiological measure, Parkinson's disease patients with impulse control disorder from those who do not experience such symptoms. Moreover, follow-up of control patients indicated that increased pupillary modulation by reward can be predictive of the risk of future emergence of impulse control disorders and may thereby provide the potential for early identification of patients who are more likely to develop these symptoms.

The impact of folate and vitamin B12 status on cognitive function and brain atrophy in healthy elderly and demented Austrians, a retrospective cohort study.

Background: Dementia, and in particular Alzheimer’s disease (AD), is a debilitating progressive disease with high prevalence in our society. Vitamin B12 and folate deficiency are potential modifiable risk factors. However, previous studies reported inconsistent results.Results: The average concentrations of all biochemical markers were within the respective reference ranges. Cross-sectional and longitudinal analyses did not reveal significant associations between biochemical markers and cognitive function, global or regional brain volume, cortical thickness or cortical surface area, neither in controls nor in AD patients.Conclusions: Variations of direct and indirect markers of B12 and folate status are not associated with cognitive dysfunction and brain atrophy.Methods: This retrospective study explored the association between biochemical markers of B12 and folate status, cognitive function and MRI-based brain atrophy in cognitive normal elderly (controls) and AD patients. Folate, total and active vitamin B12 and MMA were measured in blood samples from 378 controls and 217 AD patients. Neuropsychiatric tests capturing memory, executive function and visuopractical skills were performed in all participants. Brain atrophy was assessed by MRI in 155 controls and 217 AD patients. In a subset of participants cognitive testing (n=234) and MRI (n=182) was repeated after an average median between 1.25 and 6.25 years.

Peripheral TREM2 mRNA levels in early and late-onset Alzheimer disease's patients.

'Triggering receptor expressed on myeloid cells 2' (TREM2) gene is involved in Alzheimer's disease (AD) and TREM2 mRNA expression is known to be increased in the peripheral blood cells of AD patients. In this study, we examined the expression levels of TREM2 mRNA in peripheral leukocytes of early and late-onset AD patients. We have also investigated the effect of the presence of APOE ε4 allele on TREM2 expression. TREM2 mRNA expression was analyzed in 30 early-onset AD (EOAD) patients, 38 late-onset AD (LOAD) patients, and in their age-matched controls by using quantitative real-time polymerase chain reaction. TREM2 levels in LOAD patients were higher than EOAD. Also, in elderly controls significantly higher TREM2 levels were found compared with young controls. Moreover, APOE ε4 carriers in LOAD patients exhibited significantly higher TREM2 expression levels than APOE ε4 non-carriers and elderly controls. Also, correlation analysis showed that TREM2 mRNA expression was increased by age. The differential expression of TREM2 mRNA levels between EOAD and LOAD patients might be independent of the AD disease status and results from an age-related increase in TREM2 expression. In LOAD patients, increased age and the presence of APOE ε4 allele further increase TREM2 expression. Taken together, we can suggest that age is a factor that increases TREM2 expression, and TREM2 and APOE ε4 may interact together in the pathogenesis of LOAD.

Esophageal Dysmotility is Common in Patients With Multiple System Atrophy.

Esophageal dysmotility (ED) in patients with multiple system atrophy (MSA) are poorly understood. This study aimed to investigate the prevalence of ED in patients with MSA and to assess the relationship of esophageal abnormalities with other clinical findings and characteristics in these patients. A retrospective chart review was conducted to identify patients with MSA and to compare them to the elderly controls without MSA (65+ years) who underwent a videofluorographic esophagram from 2014 to 2019. Disease type, disease severity, vocal fold mobility impairment, abnormal deglutitive proximal esophageal contraction (ADPEC), and intra-esophageal stasis (IES) were reviewed and compared between groups. Thirty-seven patients with MSA were identified. The median age was 63 and 26 (70%) were male. These patients were matched to 22 elderly adults with presbylarynx but not MSA (median age 77, 68% male). In MSA patients, cerebellar variant type was predominant (59%), and ADPEC was recognized in 18 patients (49%). Disease severity level (P = 0.028) and existence of IES (P = 0.046) were associated with higher risks of developing ADPEC. The prevalence of IES was significantly higher in patients with MSA (95%) compared to controls without MSA (46%) (P < 0.001). Disease severity level and the existence of IES were significantly associated with the presence of ADPEC (p < 0.05). ADPEC and IES were significantly more common in MSA than in elderly subjects without MSA. MSA severity is associated with the development of ADPEC. The data suggest that esophageal motility is predominantly affected in MSA. 3 Laryngoscope, 131:832-838, 2021.

Cardiorespiratory and Vascular Variability Analysis to Classify Patients with Ischemic and Dilated Cardiomyopathy.

Heart diseases are the leading cause of death in developed countries. Ascertaining the etiology of cardiomyopathies is still a challenge. The objective of this study was to classify cardiomyopathy patients through cardio, respiratory and vascular variability analysis, considering the vascular activity as the input and output of the baroreflex response. Forty-one cardiomyopathy patients (CMP) classified as ischemic (ICM, 24 patients) and dilated (DCM, 17 patients) were analyzed. Thirty-nine elderly control subjects (CON) were used as reference. From the electrocardiographic, respiratory flow, and blood pressure signals, following temporal series were extracted: beat-to-beat intervals (BBI), total respiratory cycle time series (TT), and end- systolic (SBP) and diastolic (DBP) blood pressure amplitudes, respectively. Three-dimensional representation of the cardiorespiratory and vascular activities was characterized geometrically, by fitting a polygon that contains 95% of data, and by statistical descriptive indices. The best classifiers were used to build support vector machine models. The optimal model to classify ICM versus DCM patients achieved 92.7% accuracy, 94.1% sensitivity, and 91.7% specificity. When comparing CMP patients and CON subjects, the best model achieved 86.2% accuracy, 82.9% sensitivity, and 89.7% specificity. These results suggest a limited ability of cardiac and respiratory systems response to regulate the vascular variability in these patients.

Long-term survival of elderly patients after intensive care unit admission for acute respiratory infection: a population-based, propensity score-matched cohort study

BackgroundIntensive care unit (ICU) hospitalisations of elderly patients with acute respiratory infection have increased, yet the long-term effects of ICU admission among elderly individuals remain unknown. We examined differences over the 2 years after discharge in mortality, healthcare utilisation and frailty score between elderly survivors of ARI in the ICU and an elderly control population.MethodsWe used 2009–2017 data from 39 hospital discharge databases. Patients ≥ 80 years old discharged alive from ICU hospitalisation for acute respiratory infection were propensity score-matched with controls (cataract surgery) discharged from the hospital at the same time and adjusted for age, sex and comorbidities present before hospitalisation. We reported 2-year mortality and compared healthcare utilisation and frailty scores in the 2-year periods before and after ICU hospitalisation.ResultsOne thousand two hundred and twenty elderly survivors of acute respiratory infection in the ICU were discharged, and 988 were successfully matched with controls. After discharge, patients had a 10.1-fold [95% CI, 6.1–17.3] higher risk of death at 6 months and 3.6-fold [95% CI, 2.9–4.6] higher risk of death at 2 years compared with controls. They also had a 2-fold increase in both healthcare utilisation and frailty score in the 2 years after hospital discharge, whereas healthcare utilisation and frailty scores among controls were stable before and after hospitalisation.ConclusionsWe observed a substantially increased rate of death in the years following ICU hospitalisation for elderly patients along with elevated healthcare resource use and accelerated age-associated decline as assessed by frailty score. These findings provide data for better informed goals-of-care discussions and may help target post-ICU discharge services.

Lack of association between LGMN and Alzheimer's disease in the Southern Han Chinese population.

Recently, functional studies have demonstrated that legumain (LGMN) cleaves both amyloid β-protein precursor and tau, promoting senile plaques and formation of neurofibrillary tangles, which may play a crucial role in the pathogenesis of Alzheimer's disease (AD). However, the genetic role of LGMN in AD has not been clearly elucidated. Here, we used Sanger sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effects of variants in the LGMN gene as potential susceptibility factors for AD, in a cohort comprising 676 AD cases and 365 elderly controls from the Han population of South China. In single-variant association analysis, none of the common variants in LGMN were statistically significant. In gene-based analysis, the LGMN gene also showed no association with AD. The results of our replication study in the Alzheimer's Disease Neuroimaging Initiative cohort also showed no association between LGMN and AD. These findings suggest that the LGMN gene may not be a critical factor for AD development.

Oxygen extraction fraction mapping with multi-parametric quantitative BOLD MRI: Reduced transverse relaxation bias using 3D-GraSE imaging

Magnetic resonance imaging (MRI)-based quantification of the blood-oxygenation-level-dependent (BOLD) effect allows oxygen extraction fraction (OEF) mapping. The multi-parametric quantitative BOLD (mq-BOLD) technique facilitates relative OEF (rOEF) measurements with whole brain coverage in clinically applicable scan times. Mq-BOLD requires three separate scans of cerebral blood volume and transverse relaxation rates measured by gradient-echo (1/T2∗) and spin-echo (1/T2). Although the current method is of clinical merit in patients with stroke, glioma and internal carotid artery stenosis (ICAS), there are relaxation measurement artefacts that impede the sensitivity of mq-BOLD and artificially elevate reported rOEF values.We posited that T2-related biases caused by slice refocusing imperfections during rapid 2D-GraSE (Gradient and Spin Echo) imaging can be reduced by applying 3D-GraSE imaging sequences, because the latter requires no slice selective pulses. The removal of T2-related biases would decrease overestimated rOEF values measured by mq-BOLD. We characterized effects of T2-related bias in mq-BOLD by comparing the initially employed 2D-GraSE and two proposed 3D-GraSE sequences to multiple single spin-echo reference measurements, both in vitro and in vivo. A phantom and 25 participants, including young and elderly healthy controls as well as ICAS-patients, were scanned. We additionally proposed a procedure to reliably identify and exclude artefact affected voxels. In the phantom, 3D-GraSE derived T2 values had 57% lower deviation from the reference. For in vivo scans, the formerly overestimated rOEF was reduced by −27% (p ​< ​0.001). We obtained rOEF ​= ​0.51, which is much closer to literature values from positron emission tomography (PET) measurements. Furthermore, increased sensitivity to a focal rOEF elevation in an ICAS-patient was demonstrated.In summary, the application of 3D-GraSE improves the mq-BOLD-based rOEF quantification while maintaining clinically feasible scan times. Thus, mq-BOLD with non-slice selective T2 imaging is highly promising to improve clinical diagnostics of cerebrovascular diseases such as ICAS.

Rare Genetic Variants in Complement Factor I Lead to Low FI Plasma Levels Resulting in Increased Risk of Age-Related Macular Degeneration.

PurposeRare genetic variants in complement factor I (CFI) that cause low systemic levels of the protein (FI) have been reported as a strong risk factor for advanced age-related macular degeneration (AMD). This study set out to replicate these findings.MethodsFI levels were measured by sandwich ELISA in an independent cohort of 276 patients with AMD and 205 elderly controls. Single-nucleotide polymorphism genotyping and Sanger sequencing were used to assess genetic variability.ResultsThe median FI level was significantly lower in those individuals with AMD and a rare CFI variant (28.3 µg/mL) compared to those with AMD without a rare CFI variant (38.8 µg/mL, P = 0.004) or the control population with (41.7 µg/mL, P = 0.0085) or without (41.5 µg/mL, P < 0.0001) a rare CFI variant. Thirty-six percent of patients with AMD with a rare CFI variant had levels below the fifth percentile, compared to 6% in controls with CFI variants. Multiple regression analyses revealed a decreased FI level associated with a rare CFI variant was a risk factor for AMD (early or late AMD: odds ratio [OR] 12.05, P = 0.03; early AMD: OR 30.3, P = 0.02; late AMD: OR 10.64, P < 0.01). Additionally, measurement of FI in aqueous humor revealed a large FI concentration gradient between systemic circulation and the eye (∼286-fold).ConclusionsRare genetic variants in CFI causing low systemic FI levels are strongly associated with AMD. The impermeability of the Bruch's membrane to FI will have implications for therapeutic replacement of FI in individuals with CFI variants and low FI levels at risk of AMD.

Evoked and induced EEG oscillations to visual targets reveal a differential pattern of change along the spectrum of cognitive decline in Alzheimer's Disease

In recent years, quantitative variables derived from the electroencephalogram (EEG) attract an increasing interest for the evaluation of neurodegenerative diseases, as EEG registers the neuro-electric activity with a high temporal resolution and provides a cost-effective and easily accessible, non-invasive method. Event-related oscillations (EROs) as oscillatory responses in the EEG to specific events further provide the possibility to track the cognitive decline in a task-specific manner. Current study in search for potential ERO biomarkers to distinguish different stages of cognitive decline along the Alzheimer's Disease (AD) continuum re-analyzed a combined set of data collected and analyzed in previous studies by Başar and coworkers. Target responses of a visual oddball experiment recorded from 33 AD patients, 46 Mild Cognitive Impairment (MCI) patients and 48 age, gender, and education matched normal elderly controls were analyzed for both evoked (phase-locked) and total (phase-locked + non-phase-locked) ERO powers in delta, theta, alpha, beta and gamma bands by applying continuous wavelet transform (WT) on averaged and single trial data, respectively. The cluster-based nonparametric permutation test implemented in the FieldTrip toolbox revealed significant differences among the three groups. While the total delta and theta responses already significantly declined in the MCI stage with further spatial expansion of the decline in AD, the evoked delta response reached a statistically significant reduction level in the AD stage. We obtained no significant difference among groups for alpha, beta and gamma frequency bands. These results suggest that total delta and theta EROs to oddball targets may be useful for early detection of the disease in MCI stage, while the evoked delta response allows detecting the conversion to AD.

Defective Granuloma Formation in Elderly Infected Patients.

Granulomas are compact structures formed in tissues by the immune system in response to aggressions. The in vitro formation of granulomas using circulating mononuclear cells is an innovative method to easily assess the immune response of patients. Monitoring the efficiency of mononuclear cells from patients to form granulomas in vitro would help improve their therapeutic management. Circulating mononuclear cells from 23 elderly patients with sepsis and 24 elderly controls patients were incubated with Sepharose beads coated with either BCG or Coxiella burnetii extracts. The formation of granulomas was measured over 9 days. Most healthy elderly patients (92%) were able to form granulomas in response to BCG and Coxiella burnetii extracts compared to only 48% of infected elderly patients. Undernutrition was significantly associated with impaired granuloma formation in healthy and infected patients. Granulomas typically comprise epithelioid cells and multinucleated giant cells, however, these cells were not detected in samples obtained from patients unable to form granulomas. We also found that the impairment of granuloma formation was associated with reduced production of tumor necrosis factor without overproduction of interleukin-10. Finally, all genes specifically modulated in granulomatous cells were down-modulated in patients with defective granuloma formation. TNFSF10 was the only M1 gene markedly upregulated in patients who did not form granulomas. Our study suggest that defective granuloma formation may be a measurement of altered activation of immune cells which can predispose to nosocomial infections in elderly patients.

Impaired Structural Network Properties Caused by White Matter Hyperintensity Related to Cognitive Decline.

Purpose: There is a high correlation between white matter hyperintensity (WMH) and cognitive impairment (CI) in elderly people. However, not all WMH will develop into CI, and the potential mechanism of WMH-related CI is still unclear. This study aimed to investigate the topological properties of white matter structural network in WMH-related CI.Methods: Forty-one WMH subjects with CI (WMH-CI), 42 WMH subjects without CI (WMH-no-CI), and 52 elderly healthy controls (HC) were recruited. Diffusion tensor imaging (DTI) fiber tractography and graph theoretical analysis were applied to construct the structural network. We compared network properties and clinical features among the three groups. Multiple linear regression analysis was performed to investigate the relationships among WMH volumes, impaired network properties, and cognitive functions in the WMH-CI group.Results: Compared with the controls, both WMH groups showed decreased network strength, global efficiency, and increased characteristic path length (Lp) at the level of the whole brain. The WMH-CI group displayed more profound impairments of nodal efficiency and nodal path length (NLp) within multiple regions including precentral, cingulate, and medial temporal gyrus. The disrupted network properties were associated with CI and WMH burdens in the WMH-CI group. Furthermore, a mediation effect of NLp in the left inferior frontal gyrus was observed for the association between periventricular WMH (PWMH) and memory deficit.Conclusions: Brain structural network in WMH-CI is significantly disturbed, and this disturbance is related to the severity of WMH and CI. Increased NLp in the left opercular part of inferior frontal gyrus (IFGoperc.L) was shown to be a mediation framework between PWMH and WMH-related memory, which shed light on investigating the underlying mechanisms of CI caused by WMH.

The role of brain structural magnetic resonance imaging in the assessment of hippocampal subfields in Alzheimer\u2019s disease

BackgroundVolumetric MR neuroimaging can visualize the pattern of hippocampal subfield atrophic changes in AD. This can be used as a biomarker in early diagnosis of AD and allow early treatment to improve memory, behavioral symptoms, and delay the cognitive deterioration. The aim of this work is to assess the role of the volumetric study of different hippocampal subfields as a post-processing technique of structural MR imaging in patients with Alzheimer’s disease of different severity of cognitive functions. The regional ethics committee approved the study and written informed consent was obtained from all participants. In the duration from 2016 to 2018, a cross-sectional study was conducted on 30 patients (17 males and 13 females) and 15 healthy elderly controls (9 males and 6 females) referred to the Radiodiagnosis Department from the Neuropsychiatry Department. Patients were diagnosed with AD by clinical examination and using the Mini Mental State Examination (MMSE) and the Clinical Dementia Rating scale (CDR) as a measure of general cognitive performance.ResultsCA1 and subiculum subfields were significantly reduced in size in patients with Alzheimer’s disease in relation to the age-matched control group (P < 0.05). This finding was positively correlated with the MMSE score and negatively correlated with CDR clinical tests. No significant atrophy was found among other hippocampal subfields in the patients’ group.ConclusionThis study proposed a new approach to detect atrophy in hippocampal subfields, using MR volumetric study of high-resolution T1 images, that can be used as a biomarker in the diagnosis of AD patients and differentiating them from elderly control subjects which is important in early diagnosis of AD and hence the proper treatment to improve the prognosis of the cognitive function.

Automated voxel- and region-based analysis of gray matter and cerebrospinal fluid space in primary dementia disorders

PurposePrevious studies showed voxel-based volumetry as a helpful tool in detecting pathologic brain atrophy. Aim of this study was to investigate whether the inclusion of CSF volume improves the imaging based diagnostic accuracy using combined automated voxel- and region-based volumetry. MethodsIn total, 120 individuals (30 healthy elderly, 30 frontotemporal dementia (FTD), 30 Alzheimer’s dementia (AD) and 30 Lewy body dementia (LBD) patients) were analyzed with voxel-based morphometry and compared to a reference group of 360 healthy elderly controls. Abnormal GM and CSF volumes were visualized via z-scores. Volumetric results were finally evaluated by ROC analyses. ResultsBased on the volume of abnormal GM and CSF voxels high accuracy was shown in separating dementia from normal ageing (AUC 0.93 and 0.91, respectively) within 5 different brain regions per hemisphere (frontal, medial temporal, temporal, parietal, occipital). Accuracy for separating FTD and AD was higher based on CSF volume (FTD: AUC 0.80 vs. 0.75 in frontal regions; AD: AUC 0.78 vs. 0.68 in parietal regions based on CSF and GM respectively). ConclusionsDifferentiation of dementia patients from normal ageing persons shows high accuracy when based on automatic volumetry alone. Evaluating volumes of abnormal CSF performed better than volumes of abnormal GM, especially in AD and FTD patients.