Language-Related Brain Activation in Cognitive Decline and Aging: An fNIRS-Based Literature Review

Decision letter: Stage-dependent differential influence of metabolic and structural networks on memory across Alzheimer’s disease continuum

BackgroundRepressor element 1-silencing transcription (REST)/neuron-restrictive silencer factor is considered a new therapeutic target for neurodegenerative disorders such as Alzheimer’s disease (AD). However, the relationship between AD and REST remains unclear. This study aimed to 1) examine plasma REST levels and REST gene levels in AD patients and 2) further explore the pathological relationships between REST protein levels and cognitive decline in clinical conditions, including medial temporal lobe atrophy.MethodsParticipants (n = 252, mean age 68.95 ± 8.78 years) were recruited in Beijing, China, and then divided into a normal cognition (NC) group (n = 89), an amnestic mild cognitive impairment (aMCI) group (n = 79), and an AD dementia group (n = 84) according to diagnostic criteria. All participants underwent neuropsychological assessments, laboratory tests, and neuroimaging scans (magnetic resonance imaging) at baseline. Plasma REST protein levels and the distribution of REST single nucleotide polymorphisms (SNPs) were compared among the three groups. Correlations between cognitive function, neuro-imaging results, and REST levels were determined by a multivariate linear regression analysis.ResultsThe plasma REST levels in both the NC group (430.30 ± 303.43)pg/ml and aMCI group (414.27 ± 263.39)pg/ml were significantly higher than that in the AD dementia group (NC vs AD dementia group, p = 0.034; aMCI vs AD dementia group, p = 0.033). There was no significant difference between the NC and aMCI groups (p = 0.948). No significant difference was found among the three groups regarding the genotype distribution (rs2227902 and rs3976529 SNPs) of the REST gene. The REST level was correlated with the left medial temporal lobe atrophy index (r = 0.306, p = 0.023). After 6 months of follow-up, the REST level in the NC group was positively correlated with the change in the Mini-Mental State Examination score (r = 0.289, p = 0.02).ConclusionThe plasma REST protein level is decreased in AD dementia patients, which is associated with memory impairment and left temporal lobe atrophy and may have potential value for clinical diagnosis of AD dementia.

Cerebral small vessel disease (SVD) is the leading cause of vascular dementia. However, it is unclear whether the individual SVD or global SVD progression correlates with cognitive decline across mild cognitive impairment (MCI) subjects. To investigate the association of small vessel disease progression with longitudinal cognitive decline across MCI. We included 432 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, with 151 participants in the cognitively normal (CN) group and 281 participants in the MCI group. We evaluated magnetic resonance imaging-based SVD markers in both CN and MCI groups and explored their associations with 12-and 24-month cognitive decline using linear mixing effect (LME) models. In the CN group, cerebral microbleed (CMB) progression was associated with the decline in language function (p < 0.05), and deep white matter hyperintensity (WMH) progression was associated with a decline in memory function (p < 0.05). In the MCI group, CMB progression was associated with a decline in memory function (p < 0.05) and lacunes progression was associated with executive function (p < 0.05), whereas the progression of global SVD score was not related to longitudinal cognitive function. The progression of CMB and WMH had an impact on cognitive decline in both CN and MCI groups, and lacunes progression only had an association with cognitive decline in the MCI group. Our study suggested that individual SVD markers may have a higher predictive value in longitudinal cognition compared with global SVD burden.

BackgroundResearch has shown disrupted structural network measures related to cognitive decline and future cortical atrophy during the progression of Alzheimer’s disease (AD). However, evidence regarding the individual variability of gray matter network measures and the associations with concurrent cognitive decline and cortical atrophy related to AD is still sparse.ObjectiveTo investigate whether alterations in single-subject gray matter networks are related to concurrent cognitive decline and cortical gray matter atrophy during AD progression.MethodsWe analyzed structural MRI data from 185 cognitively normal (CN), 150 mild cognitive impairment (MCI), and 153 AD participants, and calculated the global network metrics of gray matter networks for each participant. We examined the alterations of single-subject gray matter networks in patients with MCI and AD, and investigated the associations of network metrics with concurrent cognitive decline and cortical gray matter atrophy.ResultsThe small-world properties including gamma, lambda, and sigma had lower values in the MCI and AD groups than the CN group. AD patients had reduced degree, clustering coefficient, and path length than the CN and MCI groups. We observed significant associations of cognitive ability with degree in the CN group, with gamma and sigma in the MCI group, and with degree, connectivity density, clustering coefficient, and path length in the AD group. There were significant correlation patterns between sigma values and cortical gray matter volume in the CN, MCI, and AD groups.ConclusionThese findings suggest the individual variability of gray matter network metrics may be valuable to track concurrent cognitive decline and cortical atrophy during AD progression. This may contribute to a better understanding of cognitive decline and brain morphological alterations related to AD.

Familial hypercholesterolemia (FH) is characterized by elevated LDL cholesterol (LDL-C) levels that promote atherosclerosis progression. Limited data exist on the link between elevated LDL-C and cognitive impairment. The aim of this study was to assess the prevalence of cognitive impairment in FH subjects and its association with subclinical vascular damage. In this cross-sectional observational study, we evaluated 253 genetically confirmed FH subjects aged between 18 and 75 years and without previous documented cognitive disorders. Clinical evaluation, biochemical analyses and vascular profile assessment were obtained from all subjects. Cognitive function was assessed using the Short Blessed Test (SBT). Participants were stratified into two groups according to SBT: normal cognition (NC) group (n = 202) and impaired cognition (IC) group (n = 51). The IC group was older and had higher prevalence of hypertension than the NC group. Dutch Lipid Clinical Network (DLCN) score at diagnosis was higher in the IC group than the NC group. Pulse wave velocity (PWV) and intima-media thickness (IMT) were significantly elevated in the IC group than the NC group (PWV: 8.64±0.43 vs 7.24±0.13 m/s, p = 0.0001; IMT: 0.78±0.02 vs 0.68±0.01 mm, p = 0.0003). Logistic regression showed that cognitive impairment was independently associated with increased PWV (OR 1.32 [1.06-1.66], p = 0.012). FH subjects with cognitive impairment exhibited increased PWV and IMT. These findings suggest that subclinical vascular damage may independently contribute to the cognitive decline in FH subjects.

Normal brain aging is commonly associated with neural activity alteration, β-amyloid (Aβ) deposition, and tau aggregation, driving a progressive cognitive decline in normal elderly individuals. Positron emission tomography (PET) with radiotracers targeting these age-related changes has been increasingly employed to clarify the sequence of their occurrence and the evolution of clinically cognitive deficits. Herein, we reviewed recent literature on PET-based imaging of normal human brain aging in terms of neural activity, Aβ, and tau. Neural hypoactivity reflected by decreased glucose utilization with PET imaging has been predominately reported in the frontal, cingulate, and temporal lobes of the normal aging brain. Aβ PET imaging uncovers the pathophysiological association of Aβ deposition with cognitive aging, as well as the potential mechanisms. Tau-associated cognitive changes in normal aging are likely independent of but facilitated by Aβ as indicated by tau and Aβ PET imaging. Future longitudinal studies using multi-radiotracer PET imaging combined with other neuroimaging modalities, such as magnetic resonance imaging (MRI) morphometry, functional MRI, and magnetoencephalography, are essential to elucidate the neuropathological underpinnings and interactions in normal brain aging.

To explore the use of approximate entropy (ApEn) as an index of the complexity and the synchronicity of resting state blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in normal aging and cognitive decline associated with familial Alzheimer's disease (fAD).Resting state BOLD fMRI data were acquired at 3T from two independent cohorts of subjects consisting of healthy young (age 23 ± 2 years, n = 8) and aged volunteers (age 66 ± 3 years, n = 8), as well as 22 fAD associated subjects (14 mutation carriers, age 41.2 ± 15.8 years; and eight nonmutation carrying family members, age 28.8 ± 5.9 years). Mean ApEn values were compared between the two age groups and correlated with cognitive performance in the fAD group. Cross-ApEn (C-ApEn) was further calculated to assess the asynchrony between precuneus and the rest of the brain.Complexity of brain activity measured by mean ApEn in gray and white matter decreased with normal aging. In the fAD group, cognitive impairment was associated with decreased mean ApEn in gray matter as well as decreased regional ApEn in right precuneus, right lateral parietal regions, left precentral gyrus, and right paracentral gyrus. A pattern of asynchrony between BOLD fMRI series emerged from C-ApEn analysis, with significant regional anti-correlation with cross-correlation coefficient of functional connectivity analysis.ApEn and C-ApEn may be useful for assessing the complexity and synchronicity of brain activity in normal aging and cognitive decline associated with neurodegenerative diseases.

China Alzheimer's Disease and Neurodegenerative Disorder Research (CANDOR) -A Prospective Cohort Study for Alzheimer's Disease and Vascular Cognitive Impairment.

BackgroundSubjective cognitive decline (SCD) is a state in which individuals complain of cognitive impairment; however, they perform normally on standard neuropsychological tests. SCD is considered a diagnostic entity of risk for mild cognitive impairment (MCI) and dementia. SCD and MCI correspond to stages 2 and 3, respectively, in the clinical staging of the continuum of the Alzheimer's disease (AD). Portability of APOEε4 allele increases AD's risk, and its interaction with SCD might raise the cognitive impairment's risk. Herein, we aimed to explore the relationship between SCD, MCI and APOEε4 status in Mexican‐mestizo older adults.Method84 Mexican‐mestizo older adults (86.9% females) were included after consent was obtained (protocol INNN_139/23). Three comparable groups by age (69.37±6.51 y.o.) and years of schooling (13.46±2.92) were formed, n = 28/group, as follows: participants with normal cognition (NC), SCD and MCI. The MoCA and the Cognitive Complaint Questionnaire (CCQ) cut point scores at enrollment were used to classify the groups. APOE genotyping was assessed by allelic discrimination and SPSS was used for statistical analysis.ResultSignificant differences were observed in the cognitive performance between the NC and MCI groups (27.36±1.47 vs. 22.21± 2.06, p <0.001). Regarding the cognitive complaint, NC group showed the lowest score, followed by the DCS and MCI groups (11.71± 6.54, 28.18± 5.75 and 26.66± 9.89, p <0.001) (Table 1). The distribution of APOE genotype and allele frequencies of the studied sample was within Hardy–Weinberg equilibrium. Comparison of APOEε4 allele frequency was different between NC vs. SCD and MCI (p <0.005), while SCD and MCI groups behaved similarly (p >0.05). Being carrier of APOEε4 increased the risk of SCD (OR=5.17, CI95%=1.06‐25.13, p = 0.04) and MCI (OR=6.60, CI95%=1.39‐31.34, p = 0.02), compared to the NC group (Figure 1).ConclusionAn association between SCD, MCI and APOEε4 was identified in our sample of mestizo‐Mexican older adults; of note, no differences were found for APOEε4 allele between the SCD and MCI groups. The risk of portability of APOEe4 was comparable in SCD and MCI, highlighting SCD as a clinical risk prediction entity in the AD continuum. The relevance of SCD should be further studied in the prevention of dementia by improving early detection.

Primary cultures of neurons for testing neuroprotective drug effects.- Regulation of proteolytic processing of the amyloid ?-protein precursor in Alzheimer's disease in transfected cell lines and in brain slices.- Glutamate, beta-amyloid precursor proteins, and calcium mediated neurofibrillary degeneration.- An aggregate brain cell culture model for studying neuronal degeneration and regeneration.- The organotypic entorhinal-hippocampal complex slice culture of adolescent rats. A model to study transcellular changes in a circuit particularly vulnerable in neurodegenerative disorders.- The use of ion-sensitive electrodes and fluorescence imaging in hippocampal slices for studying pathological changes of intracellular Ca2+ regulation.- The cultured fibroblast model.- Psychometric testing in rats during normal ageing. Procedures and results.- Ultrastructural changes in brain parenchyma during normal aging and in animal models of aging.- Morphological hippocampal changes during normal aging and their relation to cognitive deterioration.- The function of the NMDA-receptor during normal brain aging.- Age-related alterations by chronic intermittent hypoxia on cerebral synaptosomal ATPase activities.- Impairment in memory function and neurodegenerative changes in the cholinergic basal forebrain system induced by chronic intake of ethanol.- Dysfunction of the brain cholinergic system during aging and after lesions of the nucleus basalis of Meynert.- Receptor function in cortical rat brain regions after lesion of nucleus basalis.- Trophic factors during normal brain aging and after functional damage.- Alzheimer's disease and transgenic mice.- An aspect of Alzheimer neuropathology after suicide transport damage.- AF64A-induced brain damage and its relation to dementia.- Desensitization of brain insulin receptor. Effect on glucose/energy and related metabolism.

ObjectiveThis study aims to investigate the activation of frontotemporal functional brain areas in patients with Obsessive-Compulsive Disorder (OCD) during a Verbal Fluency Task (VFT), and to compare their brain functional connectivity in a resting state with that of healthy controls. The goal is to deepen our understanding of the neuropathological mechanisms underlying OCD.Methods32 patients with OCD and 32 controls matched for age, gender, handedness, and years of education participated in this study, they were divided into OCD group and healthy comtrol group. We conducted VFT task tests and 10-minute resting state tests on both groups by using functional Near-Infrared Spectroscopy (fNIRS). The VFT was utilized to assess the activation (beta values) and the integral and centroid values of the frontal and bilateral temporal lobes, including brain areas BA9 and 46 (dorsolateral prefrontal cortex), BA10 (frontal pole), BA45 (inferior frontal gyrus), BA21 (middle temporal gyrus), and BA22 (superior temporal gyrus). We evaluated the functional connectivity levels of these areas during the resting state. Differences in these measures between OCD patients and healthy controls were analyzed using two-sample independent t-tests and non-parametric Mann-Whitney U tests.ResultsDuring VFT, OCD had smaller integral values(z=5.371, p<0.001; t=4.720, p<0.001), and larger centroid values(t=-2.281, p=0.026; z=-2.182, p=0.029) compared to healthy controls, along with a reduced number of activated channels detected by fNIRS. Additionally, activation values (β) in various functional brain areas, including BA9, BA46, BA10, BA45, BA21, and BA22, were significantly lower in the OCD group (all p< 0.01). In the resting state, notable disparities in functional connectivity were observed between the inferior frontal gyrus (IFG) and dorsolateral prefrontal cortex (DLPFC) in the OCD group, in comparison to the control group. Specifically, there was a significant increase in connectivity between the left IFG and right DLPFC, suggesting the presence of altered connectivity patterns in these areas.ConclusionsThe study highlights significant disparities in neural activation and functional connectivity between OCD patients and healthy controls during VFT. Specifically, reduced activation was noted in the frontal and bilateral temporal lobes of OCD patients, alongside alterations in resting-state functional connectivity between the IFG and DLPFC. These findings contribute to our understanding of the neurobiological underpinnings of OCD and may guide future therapeutic strategies.

Early detection of mild cognitive impairment (MCI) is crucial for preventing Alzheimer's disease (AD). This study aims to explore alterations in brain co-functional connectivity between cognitively healthy individuals and those with cognitive impairment during a verbal fluency task (VFT) using functional near-infrared spectroscopy (fNIRS). The investigation examines changes in brain activation patterns in both MCI patients and healthy controls during the VFT and 1-back task, and identifies correlations between cognitive function and brain activation areas using fNIRS technology. This study evaluated markers for screening MCI by performing the VFT and 1-back task using a 67-channel fNIRS to measure changes in oxyhemoglobin (HbO) levels in the bilateral prefrontal and temporal lobes of 108 healthy controls (HC) and 103 participants with MCI. The severity of patients' symptoms was assessed using the Montreal Cognitive Assessment (MoCA) scale, neuropsychiatric symptoms were evaluated with the Symptom Checklist-90 (SCL-90), and sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Compared with the HC group, the MCI group showed a significant reduction in MoCA scores, with no significant differences in education level, PSQI, and SCL-90 scores. There was no significant difference in brain activation levels between the MCI and HC groups during the VFT. However, during the 1-back task, the MCI group exhibited significantly reduced activation levels in channels 33, 54, 49, and 47, as well as in the dorsolateral prefrontal cortex (DLPFC) and frontal eye fields (FEF). Moreover, the mean HbO levels in these channels, DLPFC, and FEF during the 1-back task were found to be significantly correlated with MoCA scores. When performing the VFT and 1-back task, our study found that patients with MCI exhibited reduced brain activity levels in the DLPFC and FEF only during the 1-back task. This diminished task-induced brain activity was significantly positively correlated with MoCA scores and was less influenced by mental health and sleep quality. The 1-back task may be a more optimal paradigm for the early detection of MCI compared to the VFT.

Neurodegenerative changes in the preclinical stage of Alzheimer’s disease (AD) have recently been the focus of attention because they may present a range of treatment opportunities. A total of 134 elderly volunteers who lived in a local community were investigated and grouped into preclinical and mild cognitive impairment stages according to the Clinical Dementia Rating test; we also estimated amyloid deposition in the brain using positron emission tomography (PET). A significant interaction between clinical stage and amyloid PET positivity on cerebral atrophy was observed in the bilateral parietal lobe, parahippocampal gyri, hippocampus, fusiform gyrus, and right superior and middle temporal gyri, as previously reported. Early AD-specific voxel of interest (VOI) analysis was also applied and averaged Z-scores in the right, left, bilateral, and right minus left medial temporal early AD specific area were computed. We defined these averaged Z-scores in the right, left, bilateral, and right minus left early AD specific VOI in medial temporal area as R-MedT-Atrophy-score, L-MedT-Atrophy-score, Bil-MedT-Atrophy-score, and R_L-MedT-Atrophy-score, respectively. It revealed that the R_L-MedT-Atrophy-scores were significantly larger in the amyloid-positive than in the amyloid-negative cognitively normal (CN) elderly group, that is, the right medial temporal areas were smaller than left in amyloid positive CN group and these left-right differences were significantly larger in amyloid positive than amyloid negative CN elderly group. The L-MedT-Atrophy-score was slightly larger (p = 0.073), that is, the left medial temporal area was smaller in the amyloid-negative CN group than in the amyloid-positive CN group. Conclusively, the left medial temporal area could be larger in CN participants with amyloid deposition than in those without amyloid deposition. The area under the receiver operating characteristic curve for differentiating amyloid positivity among CN participants using the R_L-MedT-Atrophy-scores was 0.73; the sensitivity and specificity were 0.828 and 0.606, respectively. Although not significant, a negative correlation was observed between the composite cerebral standardized uptake value ratio in amyloid PET images and L-MedT-Atrophy-score in CN group. The left medial temporal volume might become enlarged because of compensatory effects against AD pathology occurring at the beginning of the amyloid deposition.

We investigated the relationship between urinary Alzheimer-associated neuronal thread protein (AD7c-NTP) levels and apolipoprotein epsilon 4 (ApoE ɛ4) alleles, as well as other factors that cause cognitive decline, in the cognitively normal population. We recruited 329 cognitively normal right-handed Han Chinese subjects who completed ApoE gene testing and urinary AD7c-NTP testing. There was no significant difference in urinary AD7c-NTP levels between the normal control and subjective cognitive decline groups. Urinary AD7c-NTP levels were significantly higher in subjects with ApoE ɛ3/4 and 4/4 [0.6074 (0.6541) ng/mL] than in subjects without ApoE ɛ4 [0.4368 (0.3392) ng/mL and 0.5287 (0.3656) ng/mL], and urinary AD7c-NTP levels positively correlated with ApoE genotype grade (r = 0.165, p = 0.003). There were significant differences in urinary AD7c-NTP levels between subjects with and without a history of coronary heart disease or diabetes. Urinary AD7c-NTP levels were not related to years of education, nature of work, family history of dementia, a history of hypertension, stroke, anemia, or thyroid dysfunction. Urinary AD7c-NTP levels were positively correlated with ApoE grade in the cognitively normal population. The relationship between risk factors of cognitive decline and urinary AD7c-NTP levels provides a new way for us to understand AD and urinary AD7c-NTP.

Dementia, characterized by loss of cognitive abilities in the elderly, poses a significant global health challenge. This study explores the role of astrocytes, one of most representative glial cells in the brain, in mitigating cognitive decline. Specifically, we investigated the impact of Hevin (also known as SPARC-like1/SPARCL-1), a secreted glycoprotein, on cognitive decline in both normal and pathological brain aging. By using adeno-associated viruses, we overexpressed Hevin in hippocampal astrocytes of middle-aged APP/PSEN mice, an established Alzheimer's disease (AD) model. Results demonstrated that Hevin overexpression attenuates cognitive decline, as evidenced by cognitive tests, increased pre- and postsynaptic markers colocalization, and altered expression of synaptic mediators, as revealed by proteomic profiling. Importantly, Hevin overexpression did not influence the deposition of Aβ plaques in the hippocampus, a hallmark of AD pathology. Furthermore, the study extended its findings to middle-aged wild-type animals, revealing improved cognitive performance following astrocytic Hevin overexpression. In conclusion, our results propose astrocytic Hevin as a potential therapeutic target for age-associated cognitive decline.