Neuropsychiatric symptoms associated multimodal brain networks in Alzheimer's disease.

Concomitant neuropsychiatric symptoms (NPS) are associated with accelerated Alzheimer's disease (AD) progression. Identifying multimodal brain imaging patterns associated with NPS may help understand pathophysiology correlates AD. Based on the AD continuum, a supervised learning strategy was used to guide four-way multimodal neuroimaging fusion (Amyloid, Tau, gray matter volume, brain function) by using NPS total score as the reference. Loadings of the identified multimodal patterns were compared across the AD continuum. Then, regression analyses were performed to investigate its predictability of longitudinal cognition performance. Furthermore, the fusion analysis was repeated in the four NPS subsyndromes. Here, an NPS-associated pathological-structural-functional covaried pattern was observed in the frontal-subcortical limbic circuit, occipital, and sensor-motor region. Loading of this multimodal pattern showed a progressive increase with the development of AD. The pattern significantly correlates with multiple cognitive domains and could also predict longitudinal cognitive decline. Notably, repeated fusion analysis using subsyndromes as references identified similar patterns with some unique variations associated with different syndromes. Conclusively, NPS was associated with a multimodal imaging pattern involving complex neuropathologies, which could effectively predict longitudinal cognitive decline. These results highlight the possible neural substrate of NPS in AD, which may provide guidance for clinical management.

The association of enlarged perivascular space with microglia-related inflammation and Alzheimer's pathology in cognitively normal elderly.

BACKGROUND: Glymphatic dysfunction may contribute to the accumulation of Alzheimer's disease (AD) pathologies. Conversely, AD pathologic change might also cause neuroinflammation and aggravate glymphatic dysfunction, forming a loop that accelerates AD progression. In vivo validations are needed to confirm their relationships. METHODS: In this study, we included 144 cognitively normal participants with AD pathological biomarker data (baseline CSF Aß1-42, T-Tau, P-Tau181; plasma P-Tau181 at baseline and at least one follow-up) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Each subject had completed structural MRI scans. Among them, 117 subjects have available neuroinflammatory biomarker (soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and 123 subjects have completed two times [18F]-florbetapir PET. The enlarged PVS (EPVS) visual rating scores in basal ganglia (BG) and centrum semiovale (CS) were assessed on T1-weighted images to reflect glymphatic dysfunction. Intracranial volume and white matter hyperintensities (WMH) volume were also calculated for further analysis. We performed stepwise linear regression models and mediation analyses to estimate the association between EPVS severity, sTREM2, and AD biomarkers. RESULTS: CS-EPVS degree was associated with CSF sTREM2, annual change of plasma P-tau181 and total WMH volume, whereas BG-EPVS severity was associated with age, gender and intracranial volume. The sTREM2 mediated the association between CSF P-tau181 and CS-EPVS. CONCLUSION: Impaired glymphatic dysfunction could contribute to the accumulation of pathological tau protein. The association between tauopathy and glymphatic dysfunction was mediated by the microglia inflammatory process. These findings may provide evidence for novel treatment strategies of anti-neuroinflammation therapy in the early stage.

Progressive Memory Circuit Impairments along with Alzheimer's Disease Neuropathology Spread: Evidence from in vivo Neuroimaging.

During the progression of Alzheimer's disease (AD), neuropathology may propagate transneuronally, cause disruption in memory circuit, and lead to memory impairment. However, there is a lack of in vivo evidence regarding this process. Thus, we aim to simulate and observe the progression of neuropathology in AD continuum. We included cognitively normal (CN), mild cognitive impairments (MCI), and AD subjects, and further classified them using the A/T/N scheme (Group 0: CN, A - T-; Group 1: CN, A + T-; Group 2: CN, A + T+; Group 3: MCI, A + T+; Group 4: AD, A + T+). We investigated alterations of three core memory circuit structures: hippocampus (HP) subfields volume, cingulum-angular bundles (CAB) fiber integrity, and precuneus cortex volume. HP subfields volume showed the trend of initially increased and then decreased (starting from Group 2), while precuneus volume decreased in Groups 3 and 4. The CAB integrity degenerated in Groups 3 and 4 and aggravated with higher disease stages. Further, memory circuit impairments were correlated with neuropathology biomarkers and memory performance. Conclusively, our results demonstrated a pattern of memory circuit impairments along with AD progression: starting from the HP, then propagating to the downstream projection fiber tract and cortex. These findings support the tau propagation theory to some extent.

Distinct resting-state functional connectivity patterns of Anterior Insula affected by smoking in mild cognitive impairment.

Smoking is a modifiable risk factor for Alzheimer's disease (AD). The insula plays a vital role in both smoking and cognition. However, the smoking effects on insula-related networks in cognitively normal controls (CN) and mild cognitive impairment (MCI) patients remain unknown. We identified 129 CN (85 non-smokers and 44 smokers) and 83 MCI (54 non-smokers and 29 smokers). Each underwent neuropsychological assessment and MRI (structural and resting-state functional). Seed-based functional analyses in the anterior and posterior insula were performed to calculate the functional connectivity (FC) with voxels in the whole brain. Mixed-effect analyses were performed to explore the interactive effects on smoking and cognitive status. Associations between FC and neuropsychological scales were assessed. Mixed-effect analyses revealed the FC differences between the right anterior insula (RAI) with the left middle temporal gyrus (LMTG) and that with the right inferior parietal lobule (RIPL) (p < 0.01, cluster level < 0.05, two-tailed, gaussian random field correction). The FC of RAI in both LMTG and RIPL sees a significant decrease in MCI smokers (p < 0.01). Smoking affects insula FC differently between MCI and CN, and could decrease the insula FC in MCI patients. Our study provides evidence of neural mechanisms between smoking and AD.

Distinct cerebral small vessel disease impairment in early- and late-onset Alzheimer's disease.

OBJECTIVE: This study investigated cerebral small vessel disease (CSVD) damage patterns in early-onset and late-onset Alzheimer's disease (EOAD and LOAD) and their effects on cognitive function. METHODS: This study included 93 participants, 45 AD patients (14 EOAD and 31 LOAD), and 48 normal controls (13 YNC and 35 ONC) from the ADNI database. All participants had diffusion tensor imaging data; some had amyloid PET and plasma p-tau181 data. The study used peak width of skeletonized mean diffusivity (PSMD) to measure CSVD severity and compared PSMD between patients and age-matched controls. The effect of age on the relationship between PSMD and cognition was also examined. The study also repeated the analysis in amyloid-positive AD patients and amyloid-negative controls in another independent database (31 EOAD and 38 LOAD), and the merged database. RESULTS: EOAD and LOAD showed similar cognitive function and disease severity. PSMD was validated as a reliable correlate of cognitive function. In the ADNI database, PSMD was significantly higher for LOAD and showed a tendency to increase for EOAD; in the independent and merged databases, PSMD was significantly higher for both LOAD and EOAD. The impact of PSMD on cognitive function was notably greater in the younger group (YNC and EOAD) than in the older group (ONC and LOAD), as supported by the ADNI and merged databases. INTERPRETATION: EOAD has less CSVD burden than LOAD, but has a greater impact on cognition. Proactive cerebrovascular prevention strategies may have potential clinical value for younger older adults with cognitive decline.

Exploration of the Mechanism Underlying the Association of Incident Microinfarct and Motor Deficit: A Preliminary Functional MRI Study.

BACKGROUND: Cerebral microinfarcts (CMIs) might cause measurable disruption to brain connections and are associated with cognitive decline, but the association between CMIs and motor impairment is still unclear. OBJECTIVE: To assess the CMIs effect on motor function in vivo and explore the potential neuropathological mechanism based on graph-based network method. METHODS: We identified 133 non-demented middle-aged and elderly participants who underwent MRI scanning, cognitive, and motor assessment. The short physical performance battery (SPPB) assessed motor function, including balance, walking speed, and chair stand. We grouped participants into 34 incident CMIs carriers and 99 non-CMIs carriers as controls, depending on diffusion-weighted imaging. Then we assessed the independent CMIs effects on motor function and explored neural mechanisms of CMIs on motor impairment via mapping of degree centrality (DC) and eigenvector centrality (EC). RESULTS: CMIs carriers had worse motor function than non-carriers. Linear regression analyses showed that CMIs independently contributed to motor function. CMIs carriers had decreased EC in the precuneus, while increased DC and EC in the middle temporal gyrus and increased DC in the inferior frontal gyrus compared to controls (p < 0.05, corrected). Correlation analyses showed that EC of precuneus was related to SPPB (r = 0.25) and balance (r = 0.27); however, DC (r = -0.25) and EC (r = -0.25) of middle temporal gyrus was related with SPPB in all participants (p < 0.05, corrected). CONCLUSION: CMIs represent an independent risk factor for motor dysfunction. The relationship between CMIs and motor function may be attributed to suppression of functional hub region and compensatory activation of motor-related regions.

Effects of Anosognosia on Static and Dynamic Amplitudes of Low-Frequency Fluctuation in Mild Cognitive Impairment.

Background: Anosognosia is a significant symptom in patients with mild cognitive impairment (MCI) while the underlying neurological mechanism behind it is still unclear. Methods: A total of 121 subjects were included and classified into three groups, including 39 normal controls (NCs), 42 individuals with MCI without anosognosia (MCI-NA), and 40 individuals with MCI with anosognosia (MCI-A), based on their everyday cognition (ECog) questionnaire (discrepancy score). Resting-state functional MRIs were acquired from all the subjects, and the static amplitudes of low-frequency fluctuation (sALFF) and dynamic ALFF (dALFF) variance were investigated to evaluate the intrinsic functional network strength and stability, respectively, and both were corrected by age, sex, education, and gray matter volume. Eventually, correlation analyses were conducted to explore the relationship between brain activity changes and cognitive status in all the subjects. Results: No significant difference was found between MCI-A and MCI-NA (P > 0.05) in cognitive ability. Regarding intrinsic brain activity, MCI-A had increased sALFF and dALFF variance in the anterior cingulate cortex (ACC) relative to MCI-NA, as well as decreased sALFF and dALFF variance in the precuneus relative to MCI-NA and controls. Moreover, MCI-A had decreased sALFF in the inferior temporal gyrus (ITG) and paracentral lobule (PCL) compared to MCI-NA. Among all the subjects, correlation analyses showed that the sALFF and dALFF variance in the precuneus was related to the Ecog discrepancy score (r = 0.232 and 0.235, respectively), immediate story recall (r = 0.200 and 0.277, respectively), and delayed story recall (r = 0.255 and 0.298, respectively). Conclusion: Alterations of intrinsic brain activation in the ACC and precuneus seem to be associated with the anosognosia symptom in patients with MCI.

Effects of APOE ε2 on the Fractional Amplitude of Low-Frequency Fluctuation in Mild Cognitive Impairment: A Study Based on the Resting-State Functional MRI.

BACKGROUND: Apolipoprotein E (APOE) ε2 is a protective genetic factor for Alzheimer's disease (AD). However, the potential interaction effects between the APOE ε2 allele and disease status on the intrinsic brain activity remain elusive. METHODS: We identified 73 healthy control (HC) with APOE ε3/ε3, 61 mild cognitive impairment (MCI) subjects with APOE ε3/ε3, 24 HC with APOE ε2/ε3, and 10 MCI subjects with APOE ε2/ε3 from the ADNI database. All subjects underwent a resting-state functional MRI and Fluoro-deoxy-glucose positron emission tomography (FDG-PET). We used a fractional amplitude of low-frequency fluctuation (fALFF) to explore the spontaneous brain activity. Based on the mixed-effects analysis, we explored the interaction effects between the APOE ε2 allele versus disease status on brain activity and metabolism in a voxel-wise fashion (GRF corrected, p < 0.01), followed by post hoc two-sample t-tests (Bonferroni corrected, p < 0.05). We then investigated the relationship between the mean imaging metrics and cognitive abilities. RESULTS: There are no significant differences in gender, age, or education among the four groups. The interaction effect on brain activity was located in the inferior parietal lobule (IPL). Post hoc analysis showed that APOE ε2/ε3 MCI had an increased IPL fALFF than APOE ε3/ε3 MCI. Regarding the APOE ε2 allele effects, we found that ε2 carriers had a decreased fALFF in the transverse temporal gyrus than non-carriers. Also, FDG-PET results showed a lower SUVR of the frontal lobe in APOE ε2 carriers than non-carriers. Furthermore, fALFF of IPL was correlated with the visuospatial function (r = -0.16, p < 0.05). CONCLUSION: APOE ε2 carriers might have a better brain reservation when coping with AD-related pathologies.

Intrinsic Brain Activity of Inferior Temporal Region Increased in Prodromal Alzheimer's Disease With Hearing Loss.

BACKGROUND AND OBJECTIVE: Hearing loss (HL) is one of the modifiable risk factors for Alzheimer's disease (AD). However, the underlying mechanism behind HL in AD remains elusive. A possible mechanism is cognitive load hypothesis, which postulates that over-processing of degraded auditory signals in the auditory cortex leads to deficits in other cognitive functions. Given mild cognitive impairment (MCI) is a prodromal stage of AD, untangling the association between HL and MCI might provide insights for potential mechanism behind HL. METHODS: We included 85 cognitively normal (CN) subjects with no hearing loss (NHL), 24 CN with HL, 103 mild cognitive impairment (MCI) patients with NHL, and 23 MCI with HL from the ADNI database. All subjects underwent resting-state functional MRI and neuropsychological scale assessments. Fractional amplitude of low-frequency fluctuation (fALFF) was used to reflect spontaneous brain activity. The mixed-effects analysis was applied to explore the interactive effects between HL and cognitive status (GRF corrected, voxel p-value <0.005, cluster p-value < 0.05, two-tailed). Then, the FDG data was included to further reflect the regional neuronal abnormalities. Finally, Pearson correlation analysis was performed between imaging metrics and cognitive scores to explore the clinical significance (Bonferroni corrected, p < 0.05). RESULTS: The interactive effects primarily located in the left superior temporal gyrus (STG) and bilateral inferior temporal gyrus (ITG). Post-hoc analysis showed that NC with HL had lower fALFF in bilateral ITG compared to NC with NHL. NC with HL had higher fALFF in the left STG and decreased fALFF in bilateral ITG compared to MCI with HL. In addition, NC with HL had lower fALFF in the right ITG compared to MCI with NHL. Correlation analysis revealed that fALFF was associated with MMSE and ADNI-VS, while SUVR was associated with MMSE, MoCA, ADNI-EF and ADNI-Lan. CONCLUSION: HL showed different effects on NC and MCI stages. NC had increased spontaneous brain activity in auditory cortex while decreased activity in the ITG. Such pattern altered with disease stage changing and manifested as decreased activity in auditory cortex along with increased activity in ITG in MCI. This suggested that the cognitive load hypothesis may be the underlying mechanism behind HL.

Distinct impaired patterns of intrinsic functional network centrality in patients with early- and late-onset Alzheimer's disease.

Early-onset Alzheimer's disease (EOAD) involves multiple cognitive domains and shows more rapid progression than late-onset Alzheimer's disease (LOAD). However, the difference in pathogenesis between EOAD and LOAD is still unclear. Accordingly, we applied intrinsic network analysis to explore the potential neuropathological mechanism underlying distinct clinical phenotypes. According to the cut-off age of 65, we included 20 EOAD patients, 20 LOAD patients, and 36 age-matched controls (19 young and 17 old controls). We employed resting-state functional MRI and network centrality analysis to explore the local (degree centrality (DC)) and global (eigenvector centrality (EC)) functional integrity. Two-sample t-test analysis was performed, with gray matter volume, age, gender, and education as covariates. Furthermore, we performed a correlation analysis between network metrics and cognition. Compared to young controls, EOAD patients exhibited lower DC in the middle temporal gyrus (MTG), parahippocampal gyrus (PHG), superior temporal gyrus (STG), and lower EC in the MTG, PHG, and postcentral gyrus. In contrast, LOAD patients exhibited lower DC in the STG and anterior cingulum gyrus and higher DC in the middle frontal gyrus compared to old controls. No significant difference in EC was observed in LOAD patients. Furthermore, both DC and EC correlated with cognitive performance. Our study demonstrated divergent functional network impairments in EOAD and LOAD patients. EOAD patients showed more complex network damage involving both local and global centrality properties, while LOAD patients mainly featured local functional connectivity changes. Such centrality impairments are related to poor cognition, especially regarding memory performance.

Distinct Atrophy Pattern of Hippocampal Subfields in Patients with Progressive and Stable Mild Cognitive Impairment: A Longitudinal MRI Study.

BACKGROUND: Predicting the prognosis of mild cognitive impairment (MCI) has outstanding clinical value, and the hippocampal volume is a reliable imaging biomarker of AD diagnosis. OBJECTIVE: We aimed to longitudinally assess hippocampal sub-regional difference (volume and asymmetry) among progressive MCI (pMCI), stable MCI (sMCI) patients, and normal elderly. METHODS: We identified 29 pMCI, 52 sMCI, and 102 normal controls (NC) from the ADNI database. All participants underwent neuropsychological assessment and 3T MRI scans three times. The time interval between consecutive MRI sessions was about 1 year. Volumes of hippocampal subfield were measured by Freesurfer. Based on the analysis of variance, repeated measures analyses, and receiver operating characteristic curves, we compared cross-sectional and longitudinal alteration sub-regional volume and asymmetry index. RESULTS: Compared to NC, both MCI groups showed significant atrophy in all subfields. At baseline, pMCI have a smaller volume than sMCI in the bilateral subiculum, molecular layer (ML), the molecular and granule cell layers of the dentate gyrus, cornu ammonis 4, and right tail. Furthermore, repeated measures analyses revealed that pMCI patients showed a faster volume loss than sMCI in bilateral subiculum and ML. After controlling for age, gender, and education, most results remained unchanged. However, none of the hippocampal sub-regional volumes performed better than the whole hippocampus in ROC analyses, and no asymmetric difference between pMCI and sMCI was found. CONCLUSION: The faster volume loss in subiculum and ML suggest a higher risk of disease progression in MCI patients. The hippocampal asymmetry may have smaller value in predicting the MCI prognosis.

Effects of Smoking on Regional Homogeneity in Mild Cognitive Impairment: A Resting-State Functional MRI Study.

BACKGROUND: Smoking is a modifiable risk factor for Alzheimer's disease (AD). However, smoking-related effects on intrinsic brain activity in high-risk AD population are still unclear. OBJECTIVE: We aimed to explore differences in smoking effects on brain function between healthy elderly and amnestic mild cognitive impairment (aMCI) patients using ReHo mapping. METHODS: We identified 64 healthy elderly controls and 116 aMCI patients, including 98 non-smoking and 18 smoking aMCI. Each subject underwent structural and resting-state functional MRI scanning and neuropsychological evaluations. Regional homogeneity (ReHo) mapping was used to assess regional brain synchronization. After correction for age, gender, education, and gray matter volume, we explored the difference of ReHo among groups in a voxel-wise way based on analysis of covariance (ANCOVA), followed by post hoc two-sample analyses (p < 0.05, corrected). Further, we correlated the mean ReHo with neuropsychological scales. RESULTS: Three groups were well-matched in age, gender, and education. Significant ReHo differences were found among three groups, located in the left supramarginal gyrus (SMG) and left angular gyrus (AG). Specifically, non-smoking aMCI had lower ReHo in SMG and AG than smoking aMCI and controls. By contrast, smoking aMCI had greater AG ReHo than healthy controls (p < 0.05). Across groups, correlation analyses showed that left AG ReHo correlated with MMSE (r = 0.18, p = 0.015), clock drawing test (r = 0.20, p = 0.007), immediate recall (r = 0.36, p < 0.001), delayed recall (r = 0.34, p < 0.001), and auditory verbal learning test (r = 0.20, p = 0.007). CONCLUSION: Smoking might pose compensatory or protective effects on intrinsic brain activity in aMCI patients.