Cortical lipid metabolic pathway alteration of early Alzheimer's disease and candidate drugs screen.

BACKGROUND: Lipid metabolism changes occur in early Alzheimer's disease (AD) patients. Yet little is known about metabolic gene changes in early AD cortex. METHODS: The lipid metabolic genes selected from two datasets (GSE39420 and GSE118553) were analyzed with enrichment analysis. Protein-protein interaction network construction and correlation analyses were used to screen core genes. Literature analysis and molecular docking were applied to explore potential therapeutic drugs. RESULTS: 60 lipid metabolic genes differentially expressed in early AD patients' cortex were screened. Bioinformatics analyses revealed that up-regulated genes were mainly focused on mitochondrial fatty acid oxidation and mediating the activation of long-chain fatty acids, phosphoproteins, and cholesterol metabolism. Down-regulated genes were mainly focused on lipid transport, carboxylic acid metabolic process, and neuron apoptotic process. Literature reviews and molecular docking results indicated that ACSL1, ACSBG2, ACAA2, FABP3, ALDH5A1, and FFAR4 were core targets for lipid metabolism disorder and had a high binding affinity with compounds including adenosine phosphate, oxidized Photinus luciferin, BMS-488043, and candidate therapeutic drugs especially bisphenol A, benzo(a)pyrene, ethinyl estradiol. CONCLUSIONS: AD cortical lipid metabolism disorder was associated with the dysregulation of the PPAR signaling pathway, glycerophospholipid metabolism, adipocytokine signaling pathway, fatty acid biosynthesis, fatty acid degradation, ferroptosis, biosynthesis of unsaturated fatty acids, and fatty acid elongation. Candidate drugs including bisphenol A, benzo(a)pyrene, ethinyl estradiol, and active compounds including adenosine phosphate, oxidized Photinus luciferin, and BMS-488043 have potential therapeutic effects on cortical lipid metabolism disorder of early AD.

Cortical thickness reveals sex differences in verbal and visuospatial memory.

Although previous studies have reported the sex differences in behavior/cognition and the brain, the sex difference in the relationship between memory abilities and the underlying neural basis in the aging process remains unclear. In this study, we used a machine learning model to estimate the association between cortical thickness and verbal/visuospatial memory in females and males and then explored the sex difference of these associations based on a community-elderly cohort (n = 1153, age ranged from 50.42 to 86.67 years). We validated that females outperformed males in verbal memory, while males outperformed females in visuospatial memory. The key regions related to verbal memory in females include the medial temporal cortex, orbitofrontal cortex, and some regions around the insula. Further, those regions are more located in limbic, dorsal attention, and default-model networks, and are associated with face recognition and perception. The key regions related to visuospatial memory include the lateral prefrontal cortex, anterior cingulate gyrus, and some occipital regions. They overlapped more with dorsal attention, frontoparietal and visual networks, and were associated with object recognition. These findings imply the memory performance advantage of females and males might be related to the different memory processing tendencies and their associated network.

Divergent brain regional atrophy and associated fiber disruption in amnestic and non-amnestic MCI.

BACKGROUND: Understanding the pathological characteristics of various mild cognitive impairment (MCI) subtypes is crucial for the differential diagnosis of dementia. The purpose of this study was to feature divergent symptom-deficit profiles in amnestic MCI (aMCI) and non-amnestic MCI (naMCI). METHODS: T1 and DTI MRI data from a total of 158 older adults with 50 normal controls, 56 aMCI, and 52 naMCI were included. The voxel-wise gray matter volumes and the number of seed-based white matter fiber bundles were compared among these three groups. Furthermore, correlation and mediation analyses between the neuroimaging indices and cognitive measures were performed. RESULTS: The aMCI with specific memory abnormalities was characterized by volumetric atrophy of the left hippocampus but not by damage in the linked white matter fiber bundles. Conversely, naMCI was characterized by both the altered volume of the right inferior frontal gyrus and the significant damage to fiber bundles traversing the region in all three directions, not only affecting fibers around the atrophied area but also distant fibers. Mediation analyses of gray matter-white matter-cognition showed that gray matter atrophy affects the number of fiber bundles and further affects attention and executive function. Meanwhile, fiber bundle damage also affects gray matter volume, which further affects visual processing and language. CONCLUSIONS: The divergent structural damage patterns of the MCI subtypes and cognitive dysfunctions highlight the importance of detailed differential diagnoses in the early stages of pathological neurodegenerative diseases to deepen the understanding of dementia subtypes and inform targeted early clinical interventions.

The preservation of right cingulum fibers in subjective cognitive decline of preclinical phase of Alzheimer's disease.

Introduction: Subjective cognitive decline (SCD) with a positive amyloid burden has been recognized as the earliest clinical symptom of the preclinical phase of Alzheimers disease (AD), providing invaluable opportunities to improve our understanding of the natural history of AD and determine strategies for early therapeutic interventions. Methods: The microstructure of white matter in patients showing SCD in the preclinical phase of AD (SCD of pre-AD) was evaluated using diffusion images, and voxel-wise fractional anisotropy (FA), mean diffusivity (MD), and axial and radial diffusivities were assessed and compared among participant groups. Significant clusters in the tracts were extracted to determine their associations with alterations in the cognitive domains. Results: We found that individuals with SCD of pre-AD may have subclinical episodic memory impairment associated with the global amyloid burden. Meanwhile, we found significantly reduced FA and λ1 in the right cingulum (cingulate and hippocampus) in AD dementia, while significantly increased FA and decreased MD as well as λ23 in the SCD of pre-AD group in comparison with the HC group. Discussion: In conclusion, increased white matter microstructural integrity in the right cingulum (cingulate and hippocampus) may indicate compensation for short-term episodic memory in individuals with SCD of pre-AD in comparison with individuals with AD and healthy elderly individuals.

Unlocking potential: low frequency subthalamic nucleus stimulation enhances executive function in Parkinson's disease patients with postural instability/gait disturbance.

Postural instability/gait disturbance (PIGD) is very common in advanced Parkinson's disease, and associated with cognitive dysfunction. Research suggests that low frequency (5-12 Hz) subthalamic nucleus-deep brain stimulation (STN-DBS) could improve cognition in patients with Parkinson's disease (PD). However, the clinical effectiveness of low frequency stimulation in PIGD patients has not been explored. This study was designed in a double-blinded randomized cross-over manner, aimed to verify the effect of low frequency STN-DBS on cognition of PIGD patients. Twenty-nine PIGD patients with STN-DBS were tested for cognitive at off (no stimulation), low frequency (5 Hz), and high frequency (130 Hz) stimulation. Neuropsychological tests included the Stroop Color-Word Test (SCWT), Verbal fluency test, Symbol Digital Switch Test, Digital Span Test, and Benton Judgment of Line Orientation test. For conflict resolution of executive function, low frequency stimulation significantly decreased the completion time of SCWT-C (p = 0.001) and Stroop interference effect (p < 0.001) compared to high frequency stimulation. However, no significant differences among stimulation states were found for other cognitive tests. Here we show, low frequency STN-DBS improved conflict resolution of executive function compared to high frequency. Our results demonstrated the possibility of expanding the treatment coverage of DBS to cognitive function in PIGD, which will facilitate integration of low frequency stimulation into future DBS programming.

Brain Network Organization and Aging.

Despite recent substantial progress in neuroscience, the mechanisms and principles of the complex structure, functions, and the relationship between the brain and cognitive functions have not been fully understood. The modeling method of brain network can provide a new perspective for neuroscience research, and it is possible to provide new solutions to the related research problems. On this basis, the researchers define the concept of human brain connectome to highlight and emphasize the importance of network modeling methods in neuroscience. For example, using diffusion-weighted magnetic resonance imaging (dMRI) technology and fiber tractography methods, a white matter connection network of the whole brain can be constructed. From the perspective of brain function, functional magnetic resonance imaging (fMRI) data can build the brain functional connection network. A structural covariation modeling method is used to obtain a brain structure covariation network, and it appears to reflect developmental coordination or synchronized maturation between areas of the brain. In addition, network modeling and analysis methods can also be applied to other types of image data, such as positron emission tomography (PET), electroencephalogram (EEG), and magnetoencephalography (MEG). This chapter mainly reviews the research progress of researchers on brain structure, function, and other aspects at the network level in recent years.

The Aging Patterns of Brain Structure, Function, and Energy Metabolism.

The normal aging process brings changes in brain structure, function, and energy metabolism, which are presumed to contribute to the age-related decline in brain function and cognitive ability. This chapter aims to summarize the aging patterns of brain structure, function, and energy metabolism to distinguish them from the pathological changes associated with neurodegenerative diseases and explore protective factors in aging. We first described the normal atrophy pattern of cortical gray matter with age, which is negatively affected by some neurodegenerative diseases and is protected by a healthy lifestyle, such as physical exercise. Next, we summarized the main types of age-related white matter lesions, including white matter atrophy and hyperintensity. Age-related white matter changes mainly occurred in the frontal lobe, and white matter lesions in posterior regions may be an early sign of Alzheimer's disease. In addition, the relationship between brain activity and various cognitive functions during aging was discussed based on electroencephalography, magnetoencephalogram, and functional magnetic resonance imaging. An age-related reduction in occipital activity is coupled with increased frontal activity, which supports the posterior-anterior shift in aging (PASA) theory. Finally, we discussed the relationship between amyloid-ß deposition and tau accumulation in the brain, as pathological manifestations of neurodegenerative disease and aging.

Visit-to-visit HbA1c variability, dementia, and hippocampal atrophy among adults without diabetes.

OBJECTIVES: Adults without diabetes are not completely healthy; they are probably heterogeneous with several potential health problems. The management of hemoglobin A1c (HbA1c) is crucial among patients with diabetes; but whether similar management strategy is needed for adults without diabetes is unclear. Thus, this study aimed to investigate the associations of visit-to-visit HbA1c variability with incident dementia and hippocampal volume among middle-aged and older adults without diabetes, providing potential insights into this question. METHODS: We conducted a prospective analysis for incident dementia in 10,792 participants (mean age 58.9 years, 47.8 % men) from the UK Biobank. A subgroup of 3793 participants (mean age 57.8 years, 48.6 % men) was included in the analysis for hippocampal volume. We defined HbA1c variability as the difference in HbA1c divided by the mean HbA1c over the 2 sequential visits ([latter - former]/mean). Dementia was identified using hospital inpatient records with ICD-9 codes. T1-structural brain magnetic resonance imaging was conducted to derive hippocampal volume (normalized for head size). The nonlinear and linear associations were examined using restricted cubic spline (RCS) models, Cox regression models, and multiple linear regression models. RESULTS: During a mean follow-up (since the second round) of 8.4 years, 90 (0.8 %) participants developed dementia. The RCS models suggested no significant nonlinear associations of HbA1c variability with incident dementia and hippocampal volume, respectively (All P > 0.05). Above an optimal cutoff of HbA1c variability at 0.08, high HbA1c variability (increment in HbA1c) was associated with an increased risk of dementia (Hazard Ratio, 1.88; 95 % Confidence Interval, 1.13 to 3.14, P = 0.015), and lower hippocampal volume (coefficient, -96.84 mm3, P = 0.037), respectively, in models with adjustment of covariates including age, sex, etc. Similar results were found for a different cut-off of 0. A series of sensitivity analyses verified the robustness of the findings. CONCLUSIONS: Among middle-aged and older adults without diabetes, increasing visit-to-visit HbA1c variability was associated with an increased dementia risk and lower hippocampal volume. The findings highlight the importance of monitoring and controlling HbA1c fluctuation in apparently healthy adults without diabetes.

Lesion Network Mapping for Neurological Deficit in Acute Ischemic Stroke.

OBJECTIVE: To create a comprehensive map of strategic lesion network localizations for neurological deficits, and identify prognostic neuroimaging biomarkers to facilitate the early detection of patients with a high risk of poor functional outcomes in acute ischemic stroke (AIS). METHODS: In a large-scale multicenter study of 7,807 patients with AIS, we performed voxel-based lesion-symptom mapping, functional disconnection mapping (FDC), and structural disconnection mapping (SDC) to identify distinct lesion and network localizations for National Institutes of Health Stroke Scale (NIHSS) score. Impact scores were calculated based on the odds ratios or t-values of voxels from voxel-based lesion-symptom mapping, FDC, and SDC results. Ordinal regression models were used to investigate the predictive value of the impact scores on functional outcome (defined as the modified Rankin score at 3 months). RESULTS: We constructed lesion, FDC, and SDC maps for each item of the NIHSS score, which provided insights into the neuroanatomical substrate and network localization of neurological function deficits after AIS. The lesion impact score of limb ataxia, the SDC impact score of limb deficit, and FDC impact score of sensation and dysarthria were significantly associated with modified Rankin Scale at 3 months. Adding the SDC impact score, FDC impact score, and lesion impact score to the NIHSS total score improved the performance in predicting functional outcomes, as compared with using the NIHSS score alone. INTERPRETATION: We constructed comprehensive maps of strategic lesion network localizations for neurological deficits that were predictive of functional outcomes in AIS. These results may provide specifically localized targets for future neuromodulation therapies. ANN NEUROL 2023;94:572-584.

SORL1 rs1699102 Moderates the Effect of Sex on Language Network.

BACKGROUND: Language ability differs between the sexes. However, it is unclear how this sex difference is moderated by genetic factors and how the brain interacts with genetics to support this specific language capacity. Previous studies have demonstrated that the sorting protein-related receptor (SORL1) polymorphism influences cognitive function and brain structure differently in males and females and is associated with Alzheimer's disease risk. OBJECTIVE: The aim of this study was to investigate the effects of sex and the SORL1 rs1699102 (CC versus T carriers) genotype on language. METHODS: 103 non-demented Chinese older adults from Beijing Aging Brain Rejuvenation Initiative (BABRI) database were included in this study. Participants completed language tests, T1-weighted structural magnetic resonance imaging (MRI) and resting-state functional MRI. Language test performance, gray matter volume, and network connections were compared between genotype and sex groups. RESULTS: The rs1699102 polymorphism moderated the effects of sex on language performance, with the female having reversed language advantages in T carriers. The T allele carriers had lower gray matter volume in the left precentral gyrus. The effect of sex on language network connections was moderated by rs1699102; male CC homozygotes and female T carriers had higher internetwork connections, which were negatively correlated with language performance. CONCLUSION: These results suggest that SORL1 moderates the effects of sex on language, with T being a risk allele, especially in females. Our findings underscore the importance of considering the influence of genetic factors when examining sex effects.

Naoxin'an capsules protect brain function and structure in patients with vascular cognitive impairment.

Introduction: Vascular cognitive impairment (VCI) is one of the most common types of dementia. Naoxin'an capsule (NXA), a traditional Chinese medicine compound, has been used to treat VCI for a long time in the clinic. Previous studies proved that the NXA capsules could ameliorate the cerebral mitochondrion deficits of VCI animals. This study aimed to investigate the protectiveness of NXA on human brain structure and function in patients with VCI. Methods: In total, 100 VCI patients were enrolled in this 24-week trial and randomly divided into the NXA capsules group (n = 50) and the ginkgo biloba capsules control group (n = 50). Before and after the treatment, cognitive behavior tests and multimodal brain magnetic resonance imaging were analyzed to comprehensively evaluate the effectiveness of NXA treatment on VCI patients after 24 weeks. Results: We found that the NXA group significantly improved overall cognitive ability (Alzheimer's Disease Assessment Scale-Cognitive section, p = 0.001; Mini-Mental Status Examination, p = 0.003), memory (Rey-Osterrieth Complex Figure test, p < 0.001) and executive function (Trail Making Test-A, p = 0.024) performance after treatment compared with the control group. For brain function, the degree of centrality in the left middle frontal gyrus, right postcentral gyrus, and left supplementary motor area increased in the NXA group and decreased in the ginkgo biloba group after treatment. The fractional amplitude of low-frequency fluctuation (fALFF) of the left precentral and right superior parietal gyrus increased, and the fALFF of the right parahippocampal and left inferior temporal gyrus decreased in the NXA group after treatment. For brain structure, the gray matter density of the left postcentral gyrus increased in the NXA group after treatment, and the total volume of white matter hyperintensity showed a decreasing trend but was not statistically significant. Furthermore, the improvement effect of NXA on executive function was associated with changes in brain function. Conclusion: These findings suggest that the NXA capsules improved cognitive performance and multiregional brain function, as well as gray matter structure in the postcentral gyrus.

From local properties to brain-wide organization: A review of intraregional temporal features in functional magnetic resonance imaging data.

Based on the fluctuations ensembled over neighbouring neurons, blood oxygen level-dependent (BOLD) signal is a mesoscale measurement of brain signals. Intraregional temporal features (IRTFs) of BOLD signal, extracted from regional neural activities, are utilized to investigate how the brain functions in local brain areas. This literature highlights four types of IRTFs and their representative calculations including variability in the temporal domain, variability in the frequency domain, entropy, and intrinsic neural timescales, which are tightly related to cognitions. In the brain-wide spatial organization, these brain features generally organized into two spatial hierarchies, reflecting structural constraints of regional dynamics and hierarchical functional processing workflow in brain. Meanwhile, the spatial organization gives rise to the link between neuronal properties and cognitive performance. Disrupted or unbalanced spatial conditions of IRTFs emerge with suboptimal cognitive states, which improved our understanding of the aging process and/or neuropathology of brain disease. This review concludes that IRTFs are important properties of the brain functional system and IRTFs should be considered in a brain-wide manner.

Tau as a biomarker of cognitive impairment and neuropsychiatric symptom in Alzheimer's disease.

The A/T/N research framework has been proposed for the diagnosis and prognosis of Alzheimer's disease (AD). However, the spatial distribution of ATN biomarkers and their relationship with cognitive impairment and neuropsychiatric symptoms (NPS) need further clarification in patients with AD. We scanned 83 AD patients and 38 cognitively normal controls who independently completed the mini-mental state examination and Neuropsychiatric Inventory scales. Tau, Aß, and hypometabolism spatial patterns were characterized using Statistical Parametric Mapping together with [18F]flortaucipir, [18F]florbetapir, and [18F]FDG positron emission tomography. Piecewise linear regression, two-sample t-tests, and support vector machine algorithms were used to explore the relationship between tau, Aß, and hypometabolism and cognition, NPS, and AD diagnosis. The results showed that regions with tau deposition are region-specific and mainly occurred in inferior temporal lobes in AD, which extensively overlaps with the hypometabolic regions. While the deposition regions of Aß were unique and the regions affected by hypometabolism were widely distributed. Unlike Aß, tau and hypometabolism build up monotonically with increasing cognitive impairment in the late stages of AD. In addition, NPS in AD were associated with tau deposition closely, followed by hypometabolism, but not with Aß. Finally, hypometabolism and tau had higher accuracy in differentiating the AD patients from controls (accuracy = 0.88, accuracy = 0.85) than Aß (accuracy = 0.81), and the combined three were the highest (accuracy = 0.95). These findings suggest tau pathology is superior over Aß and glucose metabolism to identify cognitive impairment and NPS. Its results support tau accumulation can be used as a biomarker of clinical impairment in AD.

The characteristics of glucose metabolism and functional connectivity in posterior default network during nondemented aging: relationship with executive function performance.

BACKGROUND: Understanding the characteristics of intrinsic connectivity networks (ICNs) in terms of both glucose metabolism and functional connectivity (FC) is important for revealing cognitive aging and neurodegeneration, but the relationships between these two aspects during aging has not been well established in older adults. OBJECTIVE: This study is to assess the relationship between age-related glucose metabolism and FC in key ICNs, and their direct or indirect effects on cognitive deficits in older adults. METHODS: We estimated the individual-level standard uptake value ratio (SUVr) and FC of eleven ICNs in 59 cognitively unimpaired older adults, then analyzed the associations of SUVr and FC of each ICN and their relationships with cognitive performance. RESULTS: The results showed both the SUVr and FC in the posterior default mode network (pDMN) had a significant decline with age, and the association between them was also significant. Moreover, both decline of metabolism and FC in the pDMN were significantly correlated with executive function decline. Finally, mediation analysis revealed the glucose metabolism mediated the FC decline with age and FC mediated the executive function deficits. CONCLUSIONS: Our findings indicated that covariance between glucose metabolism and FC in the pDMN is one of the main routes that contributes to age-related executive function decline.

Contributions of early-life cognitive reserve and late-life leisure activity to successful and pathological cognitive aging.

BACKGROUND: The identification of factors that specifically influence pathological and successful cognitive aging is a prerequisite for implementing disease prevention and promoting successful aging. However, multi-domain behavioral factors that characterize the difference between successful and pathological cognitive aging are not clear yet. METHODS: A group of community-dwelling older adults (N = 1347, aged 70-88 years) in Beijing was recruited in this cross-sectional study, and a sub-cohort was further divided into successful cognitive aging (SCA, N = 154), mild cognitive impairment (MCI, N = 256), and cognitively normal control (CNC, N = 173) groups. Analyses of variance, regression models with the Shapley value algorithm, and structural equation model (SEM) analyses were conducted to determine specific influencing factors and to evaluate their relative importance and interacting relationships in altering cognitive performance. RESULTS: We found that abundant early-life cognitive reserve (ECR, including the level of education and occupational attainment) and reduced late-life leisure activity (LLA, including mental, physical, and social activities) were distinct characteristics of SCA and MCI, respectively. The level of education, age, mental activity, and occupational attainment were the top four important factors that explained 31.6% of cognitive variability. By SEM analyses, we firstly found that LLA partially mediated the relationship between ECR and cognition; and further multi-group SEM analyses showed ECR played a more direct role in the SCA group than in the MCI group: in the SCA group, only the direct effect of ECR on cognition was significant, and in the MCI group, direct effects between ECR, LLA and cognition were all significant. CONCLUSIONS: Results of this large-sample community-based study suggest it is important for older adults to have an abundant ECR for SCA, and to keep a high level of LLA to prevent cognitive impairment. This study clarifies the important rankings of behavioral characteristics of cognitive aging, and the relationship that ECR has a long-lasting effect on LLA and finally on cognition, providing efficient guidance for older adults to improve their cognitive function and new evidence to explain the heterogeneity of cognitive aging.

Spatial Distribution and Hierarchical Clustering of ß-Amyloid and Glucose Metabolism in Alzheimer's Disease.

Increased amyloid burden and decreased glucose metabolism are important characteristics of Alzheimer's disease (AD), but their spatial distribution and hierarchical clustering organization are still poorly understood. In this study, we explored the distribution and clustering organization of amyloid and glucose metabolism based on 18F-florbetapir and 18F-fluorodeoxyglucose PET data from 68 AD patients and 20 cognitively normal individuals. We found that: (i) cortical regions with highest florbetapir binding were the regions with high glucose metabolism; (ii) the percentage changes of amyloid deposition were greatest in the frontal and temporal areas, and the hypometabolism was greatest in the parietal and temporal areas; (iii) brain areas can be divided into three hierarchical clusters by amyloid and into five clusters by metabolism using a hierarchical clustering approach, indicating that adjacent regions are more likely to be grouped into one sub-network; and (iv) there was a significant positive correlation in any pair of amyloid-amyloid and metabolism-metabolism sub-networks, and a significant negative correlation in amyloid-metabolism sub-networks. This may suggest that the influence forms and brain regions of AD on different pathological markers may not be synchronous, but they are closely related.

Detection Anomaly in Video Based on Deep Support Vector Data Description.

Video surveillance systems have been widely deployed in public places such as shopping malls, hospitals, banks, and streets to improve the safety of public life and assets. In most cases, how to detect video abnormal events in a timely and accurate manner is the main goal of social public safety risk prevention and control. Due to the ambiguity of anomaly definition, the scarcity of anomalous data, as well as the complex environmental background and human behavior, video anomaly detection is a major problem in the field of computer vision. Existing anomaly detection methods based on deep learning often use trained networks to extract features. These methods are based on existing network structures, instead of designing networks for the goal of anomaly detection. This paper proposed a method based on Deep Support Vector Data Description (DSVDD). By learning a deep neural network, the input normal sample space can be mapped to the smallest hypersphere. Through DSVDD, not only can the smallest size data hypersphere be found to establish SVDD but also useful data feature representations and normal models can be learned. In the test, the samples mapped inside the hypersphere are judged as normal, while the samples mapped outside the hypersphere are judged as abnormal. The proposed method achieves 86.84% and 73.2% frame-level AUC on the CUHK Avenue and ShanghaiTech Campus datasets, respectively. By comparison, the detection results achieved by the proposed method are better than those achieved by the existing state-of-the-art methods.

Specific structuro-metabolic pattern of thalamic subnuclei in fatal familial insomnia: A PET/MRI imaging study.

BACKGROUND: Dysfunction of the thalamus has been proposed as a core mechanism of fatal familial insomnia. However, detailed metabolic and structural alterations in thalamic subnuclei are not well documented. We aimed to address the multimodal structuro-metabolic pattern at the level of the thalamic nuclei in fatal familial insomnia patients, and investigated the clinical presentation of primary thalamic alterations. MATERIALS AND METHODS: Five fatal familial insomnia patients and 10 healthy controls were enrolled in this study. All participants underwent neuropsychological assessments, polysomnography, electroencephalogram, and cerebrospinal fluid tests. MRI and fluorodeoxyglucose PET were acquired on a hybrid PET/MRI system. Structural and metabolic changes were compared using voxel-based morphometry analyses and standardized uptake value ratio analyses, focusing on thalamic subnuclei region of interest analyses. Correlation analysis was conducted between gray matter volume and metabolic decrease ratios, and clinical features. RESULTS: The whole-brain analysis showed that gray matter volume decline was confined to the bilateral thalamus and right middle temporal pole in fatal familial insomnia patients, whereas hypometabolism was observed in the bilateral thalamus, basal ganglia, and widespread cortices, mainly in the forebrain. In the regions of interest analysis, gray matter volume and metabolism decreases were prominent in bilateral medial dorsal nuclei, anterior nuclei, and the pulvinar, which is consistent with neuropathological and clinical findings. A positive correlation was found between gray matter volume and metabolic decrease ratios. CONCLUSIONS: Our study revealed specific structuro-metabolic pattern of fatal familial insomnia that demonstrated the essential roles of medial dorsal nuclei, anterior nuclei, and pulvinar, which may be a potential biomarker in diagnosis. Also, primary thalamic subnuclei alterations may be correlated with insomnia, neuropsychiatric, and autonomic symptoms sparing primary cortical involvement.

Brain structural and functional anomalies associated with simultanagnosia in patients with posterior cortical atrophy.

Simultanagnosia is a common symptom of posterior cortical atrophy, and its association with brain structural and functional changes remains unclear. In our study, 18 posterior cortical atrophy patients with simultanagnosia, 29 patients with Alzheimer's disease and 20 cognitively normal controls were recruited and subjected to full neuropsychological evaluation, including simultanagnosia tests, and structural and resting-state functional MRI. The gray matter volume was assessed by voxel-based morphometry, while the intrinsic functional connectivity was evaluated using the reduced gray matter volume regions of interest as the seed. In contrast to the patients with Alzheimer's disease, those with posterior cortical atrophy showed the following: (1) markedly lower simultanagnosia test scores, (2) an altered regional gray matter volume of the left middle occipital gyrus and ventral occipital areas, and (3) lowered intrinsic functional connectivity with the left middle occipital gyrus, left lingual gyrus and right middle occipital gyrus separately. Additionally, the gray matter volume of the left middle occipital gyrus and left inferior occipital gyrus were each correlated with simultanagnosia in posterior cortical atrophy patients. The intrinsic functional connectivity of the left middle occipital gyrus with the right superior occipital gyrus and that of the right middle occipital gyrus with the left superior parietal gyrus were also correlated with simultanagnosia in posterior cortical atrophy patients. In summary, this study indicated that simultanagnosia is associated with gray matter reductions and decreased functional connectivity in the left middle occipital gyrus and the left inferior occipital gyrus in patients with posterior cortical atrophy.