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BACKGROUND: The nucleus basalis of Meynert (NBM) is known to play a crucial role in the development and pathogenesis of Alzheimer's Disease (AD), particularly the cholinergic system within the NBM. However, the relationship between synaptic loss in the NBM and the clinical profile of AD remains unclear. METHODS: In our study, we included 44 Aß-negative normal controls (CN) and 76 Aß-positive participants with cognitive impairment (CI). All participants underwent structural and diffusion magnetic resonance imaging (MRI), as well as positron emission tomography (PET) imaging to measure synaptic vesicle glycoprotein 2 A (SV2A) levels (Trial registration: NCT05623124. Registered 21 November 2022). The SV2A standardized uptake value ratios (SUVR) distribution in the NBM of CN participants was used as the reference norm. We investigated the association between NBM synaptic density and clinical performance, traditional AD biomarkers, and white matter tracts that passed the NBM. RESULTS: Participants with cognitive impairment (CI) who had NBM synaptic density below 1.5 standard deviations (SD) or 0.5 SD of the norm exhibited worse cognitive performance compared to cognitively normal (CN) individuals. Crucially, the extent of deviation in synaptic density from the norm was directly proportional to the severity of cognitive impairment and neurodegeneration biomarkers. Furthermore, among patients with cognitive impairment, synaptic loss in the NBM was associated with potential impairment in the density and organization of neurites within the white matter tracts connected to the NBM. Finally, neurite density index in the medial tracts may play a mediating role in the relationship between NBM synaptic density and MMSE scores. CONCLUSION: The extent that synaptic density in NBM deviated from the norm suggested the extent of worse cognitive performance and severe neurodegeneration. Furthermore, cognitive impairment associated with synaptic loss in the NBM may be mediated by its pathological impact on NBM white matter tracts.
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INTRODUCTION: We investigated the association between white matter hyperintensities (WMH) and regional cortical thickness, amyloid and tau deposition, and synaptic density in the WMH-connected cortex using multimodal images. METHODS: We included 107 participants (59 with Alzheimer's disease [AD]; 27 with mild cognitive impairment; 21 cognitively normal controls) with amyloid beta (Aß) positivity on amyloid positron emission tomography (PET). The cortex connected to WMH was identified using probabilistic tractography. RESULTS: We found that WMH connected to the cortex with more severe regional degeneration as measured by cortical thickness, Aß and tau deposition, and synaptic vesicle glycoprotein 2 A (SV2A) density using 18F-SynVesT-1 PET. In addition, higher ratios of Aß in the deep WMH-connected versus WMH-unconnected cortex were significantly related to lower cognitive scores. Last, the cortical thickness of WMH-connected cortex reduced more than WMH-unconnected cortex over 12 months. DISCUSSION: Our results suggest that WMH may be associated with AD-intrinsic processes of degeneration, in addition to vascular mechanisms. HIGHLIGHTS: We studied white matter hyperintensities (WMHs) and WMH-connected cortical changes. WMHs are associated with more severe regional cortical degeneration. Findings suggest WMHs may be associated with Alzheimer's disease-intrinsic processes of degeneration.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Positron-Emission Tomography , White Matter , Humans , Alzheimer Disease/pathology , Alzheimer Disease/diagnostic imaging , Male , Female , White Matter/pathology , White Matter/diagnostic imaging , Aged , Amyloid beta-Peptides/metabolism , Cognitive Dysfunction/pathology , Cognitive Dysfunction/diagnostic imaging , Synapses/pathology , Synapses/metabolism , Magnetic Resonance Imaging , tau Proteins/metabolism , Cerebral Cortical Thinning/pathology , Cerebral Cortical Thinning/diagnostic imaging , Cerebral Cortex/pathology , Cerebral Cortex/diagnostic imaging , Aged, 80 and overABSTRACT
The associations of synaptic loss with amyloid-ß (Aß) and tau pathology measured by positron emission tomography (PET) and plasma analysis in Alzheimer's disease (AD) patients are unknown. Seventy-five participants, including 26 AD patients, 19 mild cognitive impairment (MCI) patients, and 30 normal controls (NCs), underwent [18F]SynVesT-1 PET/MR scans to assess synaptic density and [18F]florbetapir and [18F]MK6240 PET/CT scans to evaluate Aß plaques and tau tangles. Among them, 19 AD patients, 12 MCI patients, and 29 NCs had plasma Aß42/40 and p-tau181 levels measured by the Simoa platform. Twenty-three individuals, 6 AD patients, 4 MCI patients, and 13 NCs, underwent [18F]SynVesT-1 PET/MRI and [18F]MK6240 PET/CT scans during a one-year follow-up assessment. The associations of Aß and tau pathology with cross-sectional and longitudinal synaptic loss were investigated using Pearson correlation analyses, generalized linear models and mediation analyses. AD patients exhibited lower synaptic density than NCs and MCI patients. In the whole cohort, global Aß deposition was associated with synaptic loss in the medial (r = -0.431, p < 0.001) and lateral (r = -0.406, p < 0.001) temporal lobes. Synaptic density in almost all regions was related to the corresponding regional tau tangles independent of global Aß deposition in the whole cohort and stratified groups. Synaptic density in the medial and lateral temporal lobes was correlated with plasma Aß42/40 (r = 0.300, p = 0.020/r = 0.289, p = 0.025) and plasma p-tau 181 (r = -0.412, p = 0.001/r = -0.529, p < 0.001) levels in the whole cohort. Mediation analyses revealed that tau tangles mediated the relationship between Aß plaques and synaptic density in the whole cohort. Baseline tau pathology was positively associated with longitudinal synaptic loss. This study suggested that tau burden is strongly linked to synaptic density independent of Aß plaques, and also can predict longitudinal synaptic loss.
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INTRODUCTION: We aimed to investigate the effect of apolipoprotein E4 (APOE) ε4 on synaptic density in cognitively impaired (CI) participants. METHODS: One hundred ten CI participants underwent amyloid positron emission tomography (PET) with 18F-florbetapir and synaptic density PET with 18F-SynVesT-1. We evaluated the influence of APOE ε4 allele on synaptic density and investigated the effects of ε4 genotype on the associations of synaptic density with Alzheimer's disease (AD) biomarkers. The mediation effects of AD biomarkers on ε4-associated synaptic density loss were analyzed. RESULTS: Compared with non-carriers, APOE ε4 allele carriers exhibited significant synaptic loss in the medial temporal lobe. Amyloid beta (Aß) and tau pathology mediated the effects of APOE ε4 on synaptic density to different extents. The associations between synaptic density and tau pathology were regulated by the APOE ε4 genotype. DISCUSSION: The APOE ε4 allele was associated with decreased synaptic density in CI individuals and may be driven by AD biomarkers.
Subject(s)
Amyloid beta-Peptides , Apolipoprotein E4 , Cognitive Dysfunction , Positron-Emission Tomography , Synapses , Humans , Male , Female , Apolipoprotein E4/genetics , Aged , Cognitive Dysfunction/genetics , Cognitive Dysfunction/pathology , Synapses/pathology , Synapses/metabolism , Amyloid beta-Peptides/metabolism , tau Proteins/genetics , tau Proteins/metabolism , Genotype , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Alzheimer Disease/diagnostic imaging , Biomarkers , Middle Aged , Alleles , Aged, 80 and over , Brain/pathology , Brain/diagnostic imagingABSTRACT
Recent efforts demonstrated the efficacy of identifying early-stage neuropathology of Alzheimer's disease (AD) through lumbar puncture cerebrospinal fluid assessment and positron emission tomography (PET) radiotracer imaging. These methods are effective yet are invasive, expensive, and not widely accessible. We extend and improve the multiscale structural mapping (MSSM) procedure to develop structural indicators of ß-amyloid neuropathology in preclinical AD, by capturing both macrostructural and microstructural properties throughout the cerebral cortex using a structural MRI. We find that the MSSM signal is regionally altered in clear positive and negative cases of preclinical amyloid pathology (N = 220) when cortical thickness alone or hippocampal volume is not. It exhibits widespread effects of amyloid positivity across the posterior temporal, parietal, and medial prefrontal cortex, surprisingly consistent with the typical pattern of amyloid deposition. The MSSM signal is significantly correlated with amyloid PET in almost half of the cortex, much of which overlaps with regions where beta-amyloid accumulates, suggesting it could provide a regional brain 'map' that is not available from systemic markers such as plasma markers.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Humans , Amyloid beta-Peptides/metabolism , Brain/metabolism , Alzheimer Disease/pathology , Positron-Emission Tomography/methods , Magnetic Resonance Imaging/methods , Amyloid/metabolismABSTRACT
BACKGROUND: Tai Chi was found to improve motor symptoms in Parkinson's disease (PD). Whether long-term Tai Chi training could improve non-motor symptoms (NMS) and the related mechanisms were unknown. OBJECTIVE: To investigate Tai Chi's impact on non-motor symptoms in PD and related mechanisms. METHODS: 95 early-stage PD patients were recruited and randomly divided into Tai Chi (N = 32), brisk walking (N = 31), and no-exercise groups (N = 32). All subjects were evaluated at baseline, 6 months, and 12 months within one-year intervention. Non-motor symptoms (including cognition, sleep, autonomic symptoms, anxiety/depression, and quality of life) were investigated by rating scales. fMRI, plasma cytokines and metabolomics, and blood Huntingtin interaction protein 2 (HIP2) mRNA levels were detected to observe changes in brain networks and plasma biomarkers. RESULTS: Sixty-six patients completed the study. Non-motor functions assessed by rating scales, e.g. PD cognitive rating scale (PDCRS) and Epworth Sleepiness scale (ESS), were significantly improved in the Tai Chi group than the control group. Besides, Tai Chi had advantages in improving NMS-Quest and ESS than brisk walking. Improved brain function was seen in the somatomotor network, correlating with improved PDCRS (p = 0.003, respectively). Downregulation of eotaxin and upregulation of BDNF demonstrated a positive correlation with improvement of PDCRS and PDCRS-frontal lobe scores (p ≤ 0.037). Improvement of energy and immune-related metabolomics (p ≤ 0.043), and elevation of HIP2 mRNA levels (p = 0.003) were also found associated with the improvement of PDCRS. CONCLUSIONS: Tai Chi improved non-motor symptoms in PD, especially in cognition and sleep. Enhanced brain network function, downregulation of inflammation, and enhanced energy metabolism were observed after Tai Chi training.
Subject(s)
Parkinson Disease , Tai Ji , Humans , Parkinson Disease/complications , Parkinson Disease/therapy , Quality of Life , Research Design , RNA, MessengerABSTRACT
Cortical gray to white matter signal intensity ratio (GWR) measured from T1-weighted magnetic resonance (MR) images was associated with neurodegeneration and dementia. We characterized topological patterns of GWR during AD pathogenesis and investigated its association with cognitive decline. The study included a cross-sectional dataset and a longitudinal dataset. The cross-sectional dataset included 60 cognitively healthy controls, 61 mild cognitive impairment (MCI), and 63 patients with dementia. The longitudinal dataset included 26 participants who progressed from cognitively normal to dementia and 26 controls that remained cognitively normal. GWR was compared across the cross-sectional groups, adjusted for amyloid PET. The correlation between GWR and cognition performance was also evaluated. The longitudinal dataset was used to investigate GWR alteration during the AD pathogenesis. Dementia with ß-amyloid deposition group exhibited the largest area of increased GWR, followed by MCI with ß-amyloid deposition, MCI without ß-amyloid deposition, and controls. The spatial pattern of GWR-increased regions was not influenced by ß-amyloid deposits. Correlation between regional GWR alteration and cognitive decline was only detected among individuals with ß-amyloid deposition. GWR showed positive correlation with tau PET in the left supramarginal, lateral occipital gyrus, and right middle frontal cortex. The longitudinal study showed that GWR increased around the fusiform, inferior/superior temporal lobe, and entorhinal cortex in MCI and progressed to larger cortical regions after progression to AD. The spatial pattern of GWR-increased regions was independent of ß-amyloid deposits but overlapped with tauopathy. The GWR can serve as a promising biomarker of neurodegeneration in AD.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Dementia , White Matter , Humans , White Matter/pathology , Longitudinal Studies , Cross-Sectional Studies , Plaque, Amyloid/complications , Amyloid beta-Peptides/metabolism , Cognitive Dysfunction/pathology , Cognition , Magnetic Resonance Imaging , Dementia/diagnostic imaging , Alzheimer Disease/pathology , Positron-Emission Tomography , tau Proteins/metabolismABSTRACT
Background: Alzheimer's disease (AD) is a multi-gene inherited disease, and apolipoprotein E (APOE) É4 is a strong risk factor. Other genetic factors are important but limited. Objective: This study aimed to investigate the relationship between 17 single-nucleotide polymorphisms (SNPs) and AD in the Southern Chinese populations. Methods: We recruited 242 AD patients and 208 controls. The SNaPshot technique was used to detect the SNPs. Results: Adjusted for sex and age, we found rs6572869 (FERMT2), rs11604680 (CELF1), and rs1317149 (CELF1) were associated with AD risk in the dominant (rs6572869: pâ=â0.022, ORâ=â1.55; rs11604680: pâ=â0.007, ORâ=â1.68; rs1317149: pâ=â0.033, ORâ=â1.50) and overdominant models (rs6572869: pâ=â0.001, ORâ=â1.96; rs11604680: pâ=â0.002, ORâ=â1.82; rs1317149: pâ=â0.003, ORâ=â1.80). rs9898218 (COPI) was associated with AD risk in the overdominant model (pâ=â0.004, ORâ=â1.81). Further, rs2741342 (CHRNA2) was associated with AD protection in the dominant (pâ=â0.002, ORâ=â0.5) and additive models (pâ=â0.002, ORâ=â0.64). Mutations in rs10742814 (CELF1), rs11039280 (CELF1), and rs3752242 (ABCA7) contributed to AD protection. Among them, rs10742814 (CELF1), rs3752242 (ABCA7), and rs11039280 (CELF1) were more significantly associated with AD carrying APOE É4, whereas rs1317149 (CELF1) showed an opposite trend. Interestingly, rs4147912 (ABCA7) and rs2516049 (HLA-DRB1) were identified to be relevant with AD carrying APOE É4. Using expression quantitative trait locus analysis, we found polymorphisms in CELF1 (rs10742814 and rs11039280), ABCA7 (rs4147912), HLA-DRB1 (rs2516049), and ADGRF4 (rs1109581) correlated with their corresponding gene expression in the brain. Conclusions: We identified four risk and four protective SNPs associated with AD in the Southern Chinese population, with different correlations between APOE É4 carriers and non-carriers. rs4147912 (ABCA7) and rs2516049 (HLA-DRB1) were associated with AD carrying APOE É4.
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OBJECTIVES: Amyloid deposition is considered the initial pathology in Alzheimer's disease (AD). Personalized management requires investigation of amyloid pathology and the risk factors for both amyloid pathology and cognitive decline in the Chinese population. We aimed to investigate amyloid positivity and deposition in AD patients, as well as factors related to amyloid pathology in Chinese cities. METHODS: This cross-sectional multicenter study was conducted in Shanghai and Zhengzhou, China. All participants were recruited from urban communities and memory clinics. Amyloid positivity and deposition were analyzed based on amyloid positron emission tomography (PET). We used partial least squares (PLS) models to investigate how related factors contributed to amyloid deposition and cognitive decline. RESULTS: In total, 1026 participants were included: 768 participants from the community-based cohort (COMC) and 258 participants from the clinic-based cohort (CLIC). The overall amyloid-positive rates in individuals with clinically diagnosed AD, mild cognitive impairment (MCI), and normal cognition (NC) were 85.8%, 44.5%, and 26.9%, respectively. The global amyloid deposition standardized uptake value ratios (SUVr) (reference: cerebellar crus) were 1.44 ± 0.24, 1.30 ± 0.22, and 1.24 ± 0.14, respectively. CLIC status, apolipoprotein E (ApoE) ε4, and older age were strongly associated with amyloid pathology by PLS modeling. CONCLUSION: The overall amyloid-positive rates accompanying AD, MCI, and NC in the Chinese population were similar to those in published cohorts of other populations. ApoE ε4 and CLIC status were risk factors for amyloid pathology across the AD continuum. Education was a risk factor for amyloid pathology in MCI. Female sex and age were risk factors for amyloid pathology in NC. CLINICAL RELEVANCE STATEMENT: This study provides new details about amyloid pathology in the Chinese population. Factors related to amyloid deposition and cognitive decline can help to assess patients' AD risk. KEY POINTS: ⢠We studied amyloid pathology and related risk factors in the Chinese population. ⢷The overall amyloid-positive rates in individuals with clinically diagnosed AD, MCI, and NC were 85.8%, 44.5%, and 26.9%, respectively. ⢠These overall amyloid-positive rates were in close agreement with the corresponding prevalence for other populations.
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AIMS: To compare the fecal levels of short-chain fatty acids (SCFAs) in patients with mild cognitive impairment (MCI) and normal controls (NCs) and to examine whether fecal SCFAs could be used as the biomarker for the identification of patients with MCI. To examine the relationship between fecal SCFAs and amyloid-ß (Aß) deposition in the brain. METHODS: A cohort of 32 MCI patients, 23 Parkinson's disease (PD) patients, and 27 NC were recruited in our study. Fecal levels of SCFAs were measured using chromatography and mass spectrometry. Disease duration, ApoE genotype, body mass index, constipation, and diabetes were evaluated. To assess cognitive impairment, we used the Mini-Mental Status Examination (MMSE). To assess brain atrophy, the degree of medial temporal atrophy (MTA score, Grade 0-4) was measured by structural MRI. Aß positron emission tomography with 18 F-florbetapir (FBP) was performed in seven MCI patients at the time of stool sampling and in 28 MCI patients at an average of 12.3 ± 0.4 months from the time of stool sampling to detect and quantify Aß deposition in the brain. RESULTS: Compared with NC, MCI patients had significantly lower fecal levels of acetic acid, butyric acid, and caproic acid. Among fecal SCFAs, acetic acid performed the best in discriminating MCI from NC, achieved an AUC of 0.752 (p = 0.001, 95% CI: 0.628-0.876), specificity of 66.7%, and sensitivity of 75%. By combining fecal levels of acetic acid, butyric acid, and caproic acid, the diagnostic specificity was significantly improved, reaching 88.9%. To better verify the diagnostic performance of SCFAs, we randomly assigned 60% of participants into training dataset and 40% into testing dataset. Only acetic acid showed significantly difference between these two groups in the training dataset. Based on the fecal levels of acetic acid, we achieved the ROC curve. Next, the ROC curve was evaluated in the independent test data and 61.5% (8 in 13) of patients with MCI, and 72.7% (8 in 11) of NC could be identified correctly. Subgroup analysis showed that reduced fecal SCFAs in MCI group were negatively associated with Aß deposition in cognition-related brain regions. CONCLUSION: Reductions in fecal SCFAs were observed in patients with MCI compared with NC. Reduced fecal SCFAs were negatively associated with Aß deposition in cognition-related brain regions in MCI group. Our findings suggest that gut metabolite SCFAs have the potential to serve as early diagnostic biomarkers for distinguishing patients with MCI from NC and could serve as potential targets for preventing AD.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Humans , Caproates , Butyric Acid , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/complications , Amyloid beta-Peptides/metabolism , Positron-Emission Tomography/methods , Fatty Acids, Volatile , Acetates , Atrophy/complications , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/complicationsSubject(s)
MicroRNAs , Presenilins , Mice , Animals , Calcium , Signal Transduction , Neurons , MicroRNAs/genetics , Presenilin-1ABSTRACT
Synapse loss has been considered as a major pathological change in Alzheimer's disease (AD). It remains unclear about whether and how synapse loss relates to functional and structural connectivity dysfunction in AD. We measured synaptic vesicle glycoprotein 2 A (SV2A) binding using 18F-SynVesT-1 PET to evaluate synaptic alterations in 33 participants with AD, 31 with mild cognitive impairment (MCI), and 30 controls. We examined the correlation between synaptic density and cognitive function. Functional MRI was performed to analyze functional connectivity in lower synaptic density regions. We tracked the white matter tracts between impaired functional connectivity regions using Diffusion MRI. In AD group, lower synaptic density in bilateral cortex and hippocampus was found when compared with controls. The synaptic density changes in right insular cortex and bilateral caudal middle frontal gyrus (MFG) were correlated with cognitive decline. Among them, right MFG synaptic density was positively associated with right MFG - bilateral superior frontal gyrus (SFG) functional connectivity. AD had lower probability of tract (POT) between right MFG and SFG than controls, which was significantly associated with global cognition. These findings provide evidence supporting synapse loss contributes to functional and related structural connectivity alterations underlying cognitive impairment of AD.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Humans , Alzheimer Disease/metabolism , Pyridines , Cognitive Dysfunction/pathology , Cognition , Magnetic Resonance ImagingSubject(s)
MicroRNAs , Presenilins , Mice , Animals , Calcium , Signal Transduction , Neurons , MicroRNAs/genetics , Presenilin-1ABSTRACT
INTRODUCTION: Cognitive training and physical exercise have shown positive effects on delaying progression of mild cognitive impairment (MCI) to dementia. METHODS: We explored the enhancing effect from Tai Chi when it was provided with cognitive training for MCI. In the first 12 months, the cognitive training group (CT) had cognitive training, and the mixed group (MixT) had additional Tai Chi training. In the second 12 months, training was only provided for a subgroup of MixT. RESULTS: In the first 12 months, MixT and CT groups were benefited from training. Compared to the CT group, MixT had additional positive effects with reference to baseline. In addition, Compared to short-time training, prolonged mixed training further delayed decline in global cognition and memory. Functional magnetic resonance imaging showed more increased regional activity in both CT and MixT. DISCUSSION: Tai Chi enhanced cognitive training effects in MCI. Moreover, Tai Chi and cognitive mixed training showed effects on delaying cognitive decline.
Subject(s)
Cognitive Dysfunction , Tai Ji , Humans , Tai Ji/methods , Tai Ji/psychology , Cognitive Training , Treatment Outcome , Cognitive Dysfunction/therapy , Cognitive Dysfunction/psychology , CognitionABSTRACT
BACKGROUND: The relationship between switching rate of multilayer functional network and cognitive ability in mild cognitive impairment (MCI) and Alzheimers' disease remains unclear. METHODS: We followed up MCI patients for one year and analyzed the association of switching rates with cognitive decline. The iterative and ordinal Louvain algorithm tracked the switching of functional networks, while elastic network regression and Bayesian belief networks were used to test the relationship between network switching rate and cognitive performance cross-sectionally and longitudinally. RESULTS: The switching rate of the default mode network positively correlated with better cognitive function, while that of salience and executive control network was negatively associated with memory and executive function. The lower default mode network (DMN) switching rate predicted MCI progression to dementia, while the lower sensorimotor network switching rate heralded in slower cognitive decline. CONCLUSIONS: The present study investigated the predictive effect of switching rate on cognitive performance, as well as MCI progression to dementia. The inverse effect from different functional networks may become useful for early diagnosis and revealing the mechanism of neural networks in cognitive decline.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Humans , Cross-Sectional Studies , Bayes Theorem , Nerve Net , Magnetic Resonance Imaging , Cognitive Dysfunction/diagnosis , CognitionABSTRACT
Parkinson's disease (PD) is a movement disorder characterized by the early loss of nigrostriatal dopaminergic pathways producing significant network changes impacting motor coordination. Recently three motor stages of PD have been proposed (a silent period when nigrostriatal loss begins, a prodromal motor period with subtle focal manifestations, and clinical PD) with evidence that motor cortex abnormalities occur to produce clinical PD[8]. We directly assess structural changes in the primary motor cortex and corticospinal tract using parallel analyses of longitudinal clinical and cross-sectional pathological cohorts thought to represent different stages of PD. 18F-FP-CIT positron emission tomography and subtle motor features identified patients with idiopathic rapid-eye-movement sleep behaviour disorder (n = 8) that developed prodromal motor signs of PD. Longitudinal diffusion tensor imaging before and after the development of prodromal motor PD showed higher fractional anisotropy in motor cortex and corticospinal tract compared to controls, indicating adaptive structural changes in motor networks in concert with nigrostriatal dopamine loss. Histological analyses of the white matter underlying the motor cortex showed progressive disorientation of axons with segmental replacement of neurofilaments with α-synuclein, enlargement of myelinating oligodendrocytes and increased density of their precursors. There was no loss of neurons in the motor cortex in early or late pathologically confirmed motor PD compared to controls, although there were early cortical increases in neuronal neurofilament light chain and myelin proteins in association with α-synuclein accumulation. Our results collectively provide evidence of a direct impact of PD on primary motor cortex and its output pathways that begins in the prodromal motor stage of PD with structural changes confirmed in early PD. These adaptive structural changes become considerable as the disease advances potentially contributing to motor PD.
Subject(s)
Motor Cortex , Parkinson Disease , White Matter , Cross-Sectional Studies , Diffusion Tensor Imaging , Dopamine , Humans , Motor Cortex/metabolism , Parkinson Disease/pathology , Prodromal Symptoms , White Matter/pathology , alpha-Synuclein/metabolismABSTRACT
Mushroom spine loss and calcium dyshomeostasis are early hallmark events of age-related neurodegeneration, such as Alzheimer's disease (AD), that are connected with neuronal hyperactivity in early pathology of cognitive brain areas. However, it remains elusive how these key events are triggered at the molecular level for the neuronal abnormality that occurs at the initial stage of disease. Here, we identify downregulated miR-339-5p and its upregulated target protein, neuronatin (Nnat), in cortex neurons from the presenilin-1 M146V knockin (PSEN1-M146V KI) mouse model of familial AD (FAD). Inhibition of miR-339-5p or overexpression of Nnat recapitulates spine loss and endoplasmic reticulum calcium overload in cortical neurons with the PSEN1 mutation. Conversely, either overexpression of miR-339-5p or knockdown of Nnat restores spine morphogenesis and calcium homeostasis. We used fiber photometry recording during the object-cognitive process to further demonstrate that the PSEN1 mutant causes defective habituation in neuronal reaction in the retrosplenial cortex and that this can be rescued by restoring the miR-339-5p/Nnat pathway. Our findings thus reveal crucial roles of the miR-339-5p/Nnat pathway in FAD that may serve as potential diagnostic and therapeutic targets for early pathogenesis.
Subject(s)
Alzheimer Disease , MicroRNAs , Animals , Mice , Alzheimer Disease/pathology , Calcium/metabolism , MicroRNAs/genetics , Neurons/metabolism , Presenilin-1/genetics , Presenilin-1/metabolismABSTRACT
CSF1R-related leukoencephalopathy is an adult-onset white matter disease with high disability and mortality, while little is known about its pathogenesis. This study introduced amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) based on resting-state functional magnetic resonance imaging(rsfMRI) to compare the spontaneous brain activities of patients and healthy controls, aiming to enhance our understanding of the disease. RsfMRI was performed on 16 patients and 23 healthy controls, and preprocessed for calculation of ALFF and ReHo. Permutation tests with threshold free cluster enhancement (TFCE) was applied for comparison (number of permutations = 5,000). The TFCE significance threshold was set at [Formula: see text] < 0.05. In addition, 10 was set as the minimum cluster size. Compared to healthy controls, the patient group showed decreased ALFF in right paracentral lobule, and increased ALFF in bilateral insula, hippocampus, thalamus, supramarginal and precentral gyrus, right inferior, middle and superior frontal gyrus, right superior and middle occipital gyrus, as well as left parahippocampal gyrus, fusiform, middle occipital gyrus and angular gyrus. ReHo was decreased in right supplementary motor area, paracentral lobule and precentral gyrus, while increased in right superior occipital gyrus and supramarginal gyrus, left parahippocampal gyrus, hippocampus, fusiform, middle occipital gyrus and angular gyrus, as well as bilateral middle occipital gyrus and midbrain. These results revealed altered spontaneous brain activities in CSF1R-related leukoencephalopathy, especially in limbic system and motor cortex, which may shed light on underlying mechanisms.