＜Editors' Choice＞ Pattern of THK 5351 retention in normal aging involves core regions of resting state networks associated with higher cognitive function.

We aimed to elucidate the distribution pattern of the positron emission tomography probe [18F]THK 5351, a marker for astrogliosis and tau accumulation, in healthy aging. We also assessed the relationship between THK5351 retention and resting state networks. We enrolled 62 healthy participants in this study. All participants underwent magnetic resonance imaging/positron emission tomography scanning consisting of T1-weighted images, resting state functional magnetic resonance imaging, Pittsburgh Compound-B and THK positron emission tomography. The preprocessed THK images were entered into a scaled subprofile modeling/principal component analysis to extract THK distribution patterns. Using the most significant THK pattern, we generated regions of interest, and performed seed-based functional connectivity analyses. We also evaluated the functional connectivity overlap ratio to identify regions with high between-network connectivity. The most significant THK distributions were observed in the medial prefrontal cortex and bilateral putamen. The seed regions of interest in the medial prefrontal cortex had a functional connectivity map that significantly overlapped with regions of the dorsal default mode network. The seed regions of interest in the putamen showed strong overlap with the basal ganglia and anterior salience networks. The functional connectivity overlap ratio also showed that three peak regions had the characteristics of connector hubs. We have identified an age-related spatial distribution of THK in the medial prefrontal cortex and basal ganglia in normal aging. Interestingly, the distribution's peaks are located in regions of connector hubs that are strongly connected to large-scale resting state networks associated with higher cognitive function.

Associations of Alzheimer's-related plasma biomarkers with cognitive decline in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is associated with cognitive decline through multiple mechanisms, including Alzheimer's disease (AD) pathology and cortical Lewy body involvement. However, its underlying mechanisms remain unclear. Recently, AD-related plasma biomarkers have emerged as potential tools for predicting abnormal pathological protein accumulation. We aimed to investigate the association between AD-related plasma biomarkers and cognitive decline in PD patients. METHODS: Plasma biomarkers were measured in 70 PD patients (49 with nondemented Parkinson's disease (PDND) and 21 with Parkinson's disease dementia (PDD)) and 38 healthy controls (HCs) using a single-molecule array. The study evaluated (1) the correlation between plasma biomarkers and clinical parameters, (2) receiver operating characteristic curves and areas under the curve to evaluate the discrimination capacity of plasma biomarkers among groups, and (3) a generalized linear model to analyze associations with Addenbrooke's Cognitive Examination-Revised and Montreal Cognitive Assessment-Japanese version scores. RESULTS: Plasma glial fibrillary acidic protein significantly correlated with cognitive function tests, including all subdomains, with a notable increase in the PDD group compared with the HC and PDND groups, while plasma neurofilament light chain captured both cognitive decline and disease severity in the PDND and PDD groups. Plasma beta-amyloid 42/40 and pholphorylated-tau181 indicated AD pathology in the PDD group, but plasma beta-amyloid 42/40 was increased in the PDND group compared with HCs and decreased in the PDD group compared with the PDND group. CONCLUSIONS: AD-related plasma biomarkers may predict cognitive decline in PD and uncover underlying mechanisms suggesting astrocytic pathologies related to cognitive decline in PD.

Enzymatic properties and clinical associations of serum alpha-galactosidase A in Parkinson's disease.

OBJECTIVE: Recent studies have revealed an association between Parkinson's disease (PD) and Fabry disease, a lysosomal storage disorder; however, the underlying mechanisms remain to be elucidated. This study aimed to investigate the enzymatic properties of serum alpha-galactosidase A (GLA) and compared them with the clinical parameters of PD. METHODS: The study participants consisted of 66 sporadic PD patients and 52 controls. We measured serum GLA activity and calculated the apparent Michaelis constant (Km ) and maximal velocity (Vmax ) by Lineweaver-Burk plot analysis. Serum GLA protein concentration was measured by enzyme-linked immunosorbent assay. We examined the potential correlations between serum GLA activity and GLA protein concentration and clinical features and the plasma neurofilament light chain (NfL) level. RESULTS: Compared to controls, PD patients showed significantly lower serum GLA activity (P < 0.0001) and apparent Vmax (P = 0.0131), but no change in the apparent Km value. Serum GLA protein concentration was lower in the PD group (P = 0.0168) and was positively associated with GLA activity. Serum GLA activity and GLA protein concentration in the PD group showed a negative correlation with age. Additionally, serum GLA activity was negatively correlated with the motor severity score and the level of plasma NfL, and was positively correlated with the score of frontal assessment battery. INTERPRETATION: This study highlights that the lower serum GLA activity in PD is the result of a quantitative decrement of GLA protein in the serum and that it may serve as a biomarker of disease severity.

Comparative examination of the pons and corpus callosum as reference regions for quantitative evaluation in positron emission tomography imaging for Alzheimer's disease using 11C-Pittsburgh Compound-B.

OBJECTIVES: Standardised uptake value ratio (SUVR) is usually obtained by dividing the SUV of the region of interest (ROI) by that of the cerebellar cortex. Cerebellar cortex is not a valid reference in cases where amyloid ß deposition or lesions are present. Only few studies have evaluated the use of other regions as references. We compared the validity of the pons and corpus callosum as reference regions for the quantitative evaluation of brain positron emission tomography (PET) using 11C-PiB compared to the cerebellar cortex. METHODS: We retrospectively evaluated data from 86 subjects with or without Alzheimer's disease (AD). All subjects underwent magnetic resonance imaging, PET imaging, and cognitive function testing. For the quantitative analysis, three-dimensional ROIs were automatically placed, and SUV and SUVR were obtained. We compared these values between AD and healthy control (HC) groups. RESULTS: SUVR data obtained using the pons and corpus callosum as reference regions strongly correlated with that using the cerebellar cortex. The sensitivity and specificity were high when either the pons or corpus callosum was used as the reference region. However, the SUV values of the corpus callosum were different between AD and HC (p < 0.01). CONCLUSIONS: Our data suggest that the pons and corpus callosum might be valid reference regions.

Convenient Auditory-Based Language and Executive Function Test for Patients With Amyotrophic Lateral Sclerosis: A Pilot Study.

OBJECTIVE: About 30%-50% of patients with amyotrophic lateral sclerosis (ALS) show cognitive impairment ranging from mild dysexecutive syndrome to frontotemporal dementia. We aimed to develop a brief cognitive test, convenient auditory-based language and executive function test (CABLET), for rapid detection of cognitive impairment in ALS, with reduced load on motor function. METHOD: The CABLET comprises two tests using auditory verbal stimuli: Test 1, assessing word repetition and lexical judgment, and Test 2, evaluating verbal short-term memory and semantics knowledge. The administration time of Test 1 and Test 2 was 1 and 3-5 min, respectively. Overall, 61 patients with ALS and 46 age-, sex-, and education-matched healthy controls participated in this study. All participants underwent existing neuropsychological tests and the CABLET. We investigated the applicability of the CABLET to detect ALS with cognitive impairment (ALSci) from normal cognition. RESULTS: Receiver operating characteristic analyses showed that both the CABLET total and Test 2 had good diagnostic accuracy (area under the curve [AUC]: total = 0.894, Test 2 = 0.893). Test 2 had the highest sensitivity (100% sensitivity and 71.4% specificity). No significant difference existed in the AUC between the analyses with and without age, education, and disease severity as covariates. Correlations were observed between the CABLET and established neuropsychological tests, supporting its good convergent validity. CONCLUSIONS: Our findings indicated that the CABLET could be useful in identifying ALSci quickly without adjusting for confounding factors. Further validation is required to evaluate it in larger groups and compare with ALS-specific cognitive screen.

Connectivity impairment of cerebellar and sensorimotor connector hubs in Parkinson's disease.

Cognitive and movement processes involved integration of several large-scale brain networks. Central to these integrative processes are connector hubs, brain regions characterized by strong connections with multiple networks. Growing evidence suggests that many neurodegenerative and psychiatric disorders are associated with connector hub dysfunctions. Using a network metric called functional connectivity overlap ratio, we investigated connector hub alterations in Parkinson's disease. Resting-state functional MRI data from 99 patients (male/female = 44/55) and 99 age- and sex-matched healthy controls (male/female = 39/60) participating in our cross-sectional study were used in the analysis. We have identified two sets of connector hubs, mainly located in the sensorimotor cortex and cerebellum, with significant connectivity alterations with multiple resting-state networks. Sensorimotor connector hubs have impaired connections primarily with primary processing (sensorimotor, visual), visuospatial, and basal ganglia networks, whereas cerebellar connector hubs have impaired connections with basal ganglia and executive control networks. These connectivity alterations correlated with patients' motor symptoms. Specifically, values of the functional connectivity overlap ratio of the cerebellar connector hubs were associated with tremor score, whereas that of the sensorimotor connector hubs with postural instability and gait disturbance score, suggesting potential association of each set of connector hubs with the disorder's two predominant forms, the akinesia/rigidity and resting tremor subtypes. In addition, values of the functional connectivity overlap ratio of the sensorimotor connector hubs were highly predictive in classifying patients from controls with an accuracy of 75.76%. These findings suggest that, together with the basal ganglia, cerebellar and sensorimotor connector hubs are significantly involved in Parkinson's disease with their connectivity dysfunction potentially driving the clinical manifestations typically observed in this disorder.

Functional connector hubs in the cerebellum.

Accumulating evidence from anatomical and neuroimaging studies suggests that the cerebellum is engaged in a variety of motor and cognitive tasks. Given its various functions, a key question is whether the cerebellum also plays an important role in the brain's integrative functions. Here, we hypothesize the existence of connector regions, also known as connector hubs, where multiple resting state networks converged in the cerebellum. To verify this, we employed a recently developed voxel-level network measure called functional connectivity overlap ratio (FCOR), which could be used to quantify the spatial extent of a region's connection to several large-scale cortical networks. Using resting state functional MRI data from 101 healthy participants, cerebellar FCOR maps were constructed and used to identify the locations of connector hubs in the cerebellum. Results showed that a number of cerebellar regions exhibited strong connectivity with multiple functional networks, verifying our hypothesis. These highly connected regions were located in the posterior cerebellum, especially in lobules VI, VII, and IX, and mainly connected to the core neurocognitive networks such as default mode and executive control networks. Regions associated with the sensorimotor network were also localized in lobule V, VI, and VIII, albeit in small clusters. These cerebellar connector hubs may play an essential role in the processing of information across the core neurocognitive networks.

Reserve and Maintenance in the Aging Brain: A Longitudinal Study of Healthy Older Adults.

The aging brain undergoes structural changes even in very healthy individuals. Quantifying these changes could help disentangle pathologic changes from those associated with the normal human aging process. Using longitudinal magnetic resonance imaging (MRI) data from 227 carefully selected healthy human cohort with age ranging from 50 to 80 years old at baseline scan, we quantified age-related volumetric changes in the brain of healthy human older adults. Longitudinally, the rates of tissue loss in total gray matter (GM) and white matter (WM) were 2497.5 and 2579.8 mm3 per year, respectively. Across the whole brain, the rates of GM decline varied with regions in the frontal and parietal lobes having faster rates of decline, whereas some regions in the occipital and temporal lobes appeared relatively preserved. In contrast, cross-sectional changes were mainly observed in the temporal-occipital regions. Similar longitudinal atrophic changes were also observed in subcortical regions including thalamus, hippocampus, putamen, and caudate, whereas the pallidum showed an increasing volume with age. Overall, regions maturing late in development (frontal, parietal) are more vulnerable to longitudinal decline, whereas those that fully mature in the early stage (temporal, occipital) are mainly affected by cross-sectional changes in healthy older cohort. This may suggest that, for a successful healthy aging, the former needs to be maximally developed at an earlier age to compensate for the longitudinal decline later in life and the latter to remain relatively preserved even in old age, consistent with both concepts of reserve and brain maintenance.

Fiber-specific white matter analysis reflects upper motor neuron impairment in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: To clarify the relationship between fiber-specific white matter changes in amyotrophic lateral sclerosis (ALS) and clinical signs of upper motor neuron (UMN) involvement, we performed a fixel-based analysis (FBA), a novel framework for diffusion-weighted imaging analysis. METHODS: We enrolled 96 participants, including 48 nonfamilial ALS patients and 48 age- and sex-matched healthy controls (HCs), in this study and conducted whole-brain FBA and voxel-based morphometry analysis. We compared the fiber density (FD), fiber morphology (fiber cross-section [FC]), and a combined index of FD and FC (FDC) between the ALS and HC groups. We performed a tract-of-interest analysis to extract FD values across the significant regions in the whole-brain analysis. Then, we evaluated the associations between FD values and clinical variables. RESULTS: The bilateral corticospinal tracts (CSTs) and the corpus callosum (CC) showed reduced FD and FDC in ALS patients compared with HCs (p < 0.05, familywise error-corrected), and the comparison of FCs revealed no region that was significantly different from another. Voxel-based morphometry showed cortical volume reduction in the regions, including the primary motor area. Clinical scores showed correlations with FD values in the CSTs (UMN score: rho = -0.530, p < 0.001; central motor conduction time [CMCT] in the upper limb: rho = -0.474, p = 0.008; disease duration: rho = -0.383, p = 0.007; ALS Functional Rating Scale-Revised: rho = 0.340, p = 0.018). In addition, patients whose CMCT was not calculated due to unevoked waves also showed FD reduction in the CSTs. CONCLUSIONS: Our findings suggest that FD values in the CST estimated via FBA can be potentially used in evaluating UMN impairments.

Characteristics of Neural Network Changes in Normal Aging and Early Dementia.

To understand the mechanisms underlying preserved and impaired cognitive function in healthy aging and dementia, respectively, the spatial relationships of brain networks and mechanisms of their resilience should be understood. The hub regions of the brain, such as the multisensory integration and default mode networks, are critical for within- and between-network communication, remain well-preserved during aging, and play an essential role in compensatory processes. On the other hand, these brain hubs are the preferred sites for lesions in neurodegenerative dementias, such as Alzheimer's disease. Disrupted primary information processing networks, such as the auditory, visual, and sensorimotor networks, may lead to overactivity of the multisensory integration networks and accumulation of pathological proteins that cause dementia. At the cellular level, the brain hub regions contain many synapses and require a large amount of energy. These regions are rich in ATP-related gene expression and had high glucose metabolism as demonstrated on positron emission tomography (PET). Importantly, the number and function of mitochondria, which are the center of ATP production, decline by about 8% every 10 years. Dementia patients often have dysfunction of the ubiquitin-proteasome and autophagy-lysosome systems, which require large amounts of ATP. If there is low energy supply but the demand is high, the risk of disease can be high. Imbalance between energy supply and demand may cause accumulation of pathological proteins and play an important role in the development of dementia. This energy imbalance may explain why brain hub regions are vulnerable to damage in different dementias. Here, we review (1) the characteristics of gray matter network, white matter network, and resting state functional network changes related to resilience in healthy aging, (2) the mode of resting state functional network disruption in neurodegenerative dementia, and (3) the cellular mechanisms associated with the disruption.

Resting State Networks Related to the Maintenance of Good Cognitive Performance During Healthy Aging.

Purpose: Maintenance of cognitive performance is important for healthy aging. This study aims to elucidate the relationship between brain networks and cognitive function in subjects maintaining relatively good cognitive performance. Methods: A total of 120 subjects, with equal number of participants from each age group between 20 and 70 years, were included in this study. Only participants with Addenbrooke's Cognitive Examination - Revised (ACE-R) total score greater than 83 were included. Anatomical T1-weighted MR images and resting-state functional MR images (rsfMRIs) were taken from all participants using a 3-tesla MRI scanner. After preprocessing, several factors associated with age including the ACE-R total score, scores of five domains, sub-scores of ACE-R, and brain volumes were tested. Morphometric changes associated with age were analyzed using voxel based morphometry (VBM) and changes in resting state networks (RSNs) were examined using dual regression analysis. Results: Significant negative correlations with age were seen in the total gray matter volume (GMV, r = -0.58), and in the memory, attention, and visuospatial domains. Among the different sub-scores, the score of the delayed recall (DR) showed the highest negative correlation with age (r = -0.55, p < 0.001). In VBM analysis, widespread regions demonstrated negative correlation with age, but none with any of the cognitive scores. Quadratic approximations of cognitive scores as functions of age showed relatively delayed decline compared to total GMV loss. In dual regression analysis, some cognitive networks, including the dorsal default mode network, the lateral dorsal attention network, the right / left executive control network, the posterior salience network, and the language network, did not demonstrate negative correlation with age. Some regions in the sensorimotor networks showed positive correlation with the DR, memory, and fluency scores. Conclusion: Some domains of the cognitive test did not correlate with age, and even the highly correlated sub-scores such as the DR score, showed delayed decline compared to the loss of total GMV. Some RSNs, especially involving cognitive control regions, were relatively maintained with age. Furthermore, the scores of memory, fluency, and the DR were correlated with the within-network functional connectivity values of the sensorimotor network, which supported the importance of exercise for maintenance of cognition.

Bridging large-scale cortical networks: Integrative and function-specific hubs in the thalamus.

The thalamus is critical for the brain's integrative hub functions; however, the localization and characterization of the different thalamic hubs remain unclear. Using a voxel-level network measure called functional connectivity overlap ratio (FCOR), we examined the thalamus' association with large-scale resting-state networks (RSNs) to elucidate its connector hub roles. Connections to the core-neurocognitive networks were localized in the anterior and medial parts, such as the anteroventral and mediodorsal nuclei areas. Regions functionally connected to the sensorimotor network were distinctively located around the lateral pulvinar nucleus but to a limited extent. Prominent connector hubs include the anteroventral, ventral lateral, and mediodorsal nuclei with functional connections to multiple RSNs. These findings suggest that the thalamus, with extensive connections to most of the RSNs, is well placed as a critical integrative functional hub and could play an important role for functional integration facilitating brain functions associated with primary processing and higher cognition.

Individual voxel-based morphometry adjusting covariates in multiple system atrophy.

INTRODUCTION: This study aimed to evaluate whether novel individual voxel-based morphometry adjusting covariates (iVAC), such as age, sex, and total intracranial volume, could increase the accuracy of a diagnosis of multiple system atrophy (MSA) and enable the differentiation of MSA from Parkinson's disease (PD). METHODS: We included 53 MSA patients (MSA-C: 33, MSA-P: 20), 53 PD patients, and 189 healthy controls in this study. All participants underwent high-resolution T1-weighted imaging (WI) and T2-WI with a 3.0-T MRI scanner. We evaluated the occurrence of significant atrophic findings in the pons/middle cerebellar peduncle (MCP) and putamen on iVAC and compared these findings with characteristic changes on T2-WI. RESULTS: On iVAC, abnormal findings were observed in the pons/MCP of 96.2% of MSA patients and in the putamen of 80% of MSA patients; however, on T2-WI, they were both observed at a frequency of 60.4% in MSA patients. On iVAC, all but one MSA-P patient (98.1%) showed significant atrophic changes in the pons/MCP or putamen. By contrast, 69.8% of patients with MSA showed abnormal signal changes in the pons/MCP or putamen on T2-WI. iVAC yielded 95.0% sensitivity and 96.2% specificity for differentiating MSA-P from PD. CONCLUSION: iVAC enabled us to recognize the morphological characteristics of MSA visually and with high accuracy compared to T2-WI, indicating that iVAC is a potential diagnostic screening tool for MSA.

Clinicoradiological features in amyotrophic lateral sclerosis patients with olfactory dysfunction.

Objective: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by motor neuron involvement. Although olfactory dysfunction has been described in ALS, clinicoradiological features associated with the olfactory dysfunction remain poorly understood. Methods: We enrolled 30 patients with ALS and age- and sex-matched 53 healthy controls (HCs). All participants underwent the odor stick identification test for Japanese (OSIT-J) and clinical assessments, including disease duration, ALSFRS-R, site of onset, forced vital capacity, and cognitive examinations that reflected the general, executive, memory and language function. We investigated the associations between OSIT-J score and clinical features and examined atrophic changes by voxel-based morphometry (VBM) analysis to MRI. Results: The OSIT-J score was significantly lower in ALS patients than HCs (6.9 ± 3.2 vs. 9.8 ± 1.9, p < 0.001). In ALS, there were significant relationships between OSIT-J score and age at examination, frontal assessment battery, word fluencies, digit span forward, and ADAS-Jcog recognition, but not education, disease type, duration, ALSFRS-R and, %VC. Multiple regression analysis with stepwise method showed the only ADAS-Jcog recognition substantially predicted OSIT-J score. VBM analysis with age, sex, total intracranial volume, and ADAS-Jcog recognition as covariates showed OSIT-J scores were substantially correlated with atrophic changes of left orbital cortex consisting of gyrus rectus and medial orbital gyrus and right hippocampus in ALS. Conclusion: ALS patients could show substantial olfactory dysfunction in association with orbital cortex and hippocampus involvements. The olfactory examination could be a useful marker for screening of frontotemporal alteration in ALS.

Aging Impacts the Overall Connectivity Strength of Regions Critical for Information Transfer Among Brain Networks.

Recent studies have demonstrated that connector hubs, regions considered critical for the flow of information across neural systems, are mostly involved in neurodegenerative dementia. Considering that aging can significantly affect the brain's intrinsic connectivity, identifying aging's impact on these regions' overall connection strength is important to differentiate changes associated with healthy aging from neurodegenerative disorders. Using resting state functional magnetic resonance imaging data from a carefully selected cohort of 175 healthy volunteers aging from 21 to 86 years old, we computed an intrinsic connectivity contrast (ICC) metric, which quantifies a region's overall connectivity strength, for whole brain, short-range, and long-range connections and examined age-related changes of this metric over the adult lifespan. We have identified a limited number of hub regions with ICC values that showed significant negative relationship with age. These include the medial precentral/midcingulate gyri and insula with both their short-range and long-range (and thus whole-brain) ICC values negatively associated with age, and the angular, middle frontal, and posterior cingulate gyri with their long-range ICC values mainly involved. Seed-based connectivity analyses further confirmed that these regions are connector hubs with connectivity profile that strongly overlapped with multiple large-scale brain networks. General cognitive performance was not associated with these hubs' ICC values. These findings suggest that even healthy aging could negatively impact the efficiency of regions critical for facilitating information transfer among different functional brain networks. The extent of the regions involved, however, was limited.

The neural network basis of altered decision-making in patients with amyotrophic lateral sclerosis.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a multisystem disorder associated with motor impairment and behavioral/cognitive involvement. We examined decision-making features and changes in the neural hub network in patients with ALS using a probabilistic reversal learning task and resting-state network analysis, respectively. METHODS: Ninety ALS patients and 127 cognitively normal participants performed this task. Data from 62 ALS patients and 63 control participants were fitted to a Q-learning model. RESULTS: ALS patients had anomalous decision-making features with little shift in choice until they thought the value of the two alternatives had become equal. The quantified parameters (Pαß) calculated by logistic regression analysis with learning rate and inverse temperature well represented the unique choice pattern of ALS patients. Resting-state network analysis demonstrated a strong correlation between Pαß and decreased degree centrality in the anterior cingulate gyrus and frontal pole. INTERPRETATION: Altered decision-making in ALS patients may be related to the decreased hub function of medial prefrontal areas.

Cerebello-basal ganglia connectivity fingerprints related to motor/cognitive performance in Parkinson's disease.

INTRODUCTION: The role of the cerebellum in Parkinson's disease (PD) has attracted increasing attention; however, the role of functional connectivity (FC) between the basal ganglia and particular cerebellar subregions remains to be elucidated. We aimed to clarify the FC and its contribution to motor and cognitive performances in patients with PD. METHODS: We included 99 patients with PD and 99 age- and sex-matched healthy controls in this study. We created a cerebellar functional parcellation by performing cerebellum-only independent component analysis. Using the functional parcellation map, we performed seed-based connectivity analysis using each region as a seed and extracted the mean correlation coefficients within the thalamus and basal ganglia, including the caudate, pallidum, putamen and subthalamic nucleus. We examined the group differences and correlations with the motor and general cognitive scores. In addition, we conducted a mediation analysis to clarify the relationship among FC, motor severity, and cognition. RESULTS: The PD group showed decreased FC between a wide range of cerebellar subregions and the basal ganglia. Motor severity was correlated with FC between the subthalamic nucleus and posterior Crus I/II, and general cognitive performance scores correlated with FC between the caudate nucleus and medial-posterior part of the Crus I/II (p < 0.05, corrected for multiple comparisons). The cerebello-caudate network had a direct effect on cognitive performance (p = 9.0 × 10-3), although partially mediated by motor performance (p = 8.2 × 10-3). CONCLUSION: FC between cerebellar Crus I/II and divergent basal ganglia related to motor and cognitive performance in PD.

Individual changes in visual performance in non-demented Parkinson's disease patients: a 1-year follow-up study.

Cognitive deficits in Parkinson's disease (PD) are heterogeneous entities, and the cognitive status fluctuates over time. However, individual changes in longitudinal cognitive performance in PD are not fully understood. We evaluated three visual indices (visuoperception, visuoconstruction, and visuospatial ability) and four cognitive domains (attention/working memory, executive function, memory, and language) at baseline (Time1) and at 1-year follow-up (Time2) in 36 patients with PD and 32 healthy controls (HCs). To explore the magnitude and frequency of cognitive changes, we analyzed data using the simple difference method and the standardized regression-based method. We also explored the correlations between changes in test scores and several clinical predictors, using logistic regression analysis. At 1 year, patients with PD showed higher rates of change in scores on several cognitive tests, especially the Incomplete Letters test of visuoperception, compared to HCs. After adjusting for demographic variables, the visuoperceptual change was 61.1% overall, with the largest effect size. The changes in scores of visuoperception correlated with those of memory (r = 0.672, p < 0.001), language (r = 0.389, p < 0.05), and visuospatial ability (r = 0.379, p < 0.05). The severity of olfactory disturbance, the MDS-UPDRS Part I score, and younger PD onset predicted the significant changes observed in the Incomplete Letters test scores. Visuoperception changed more in non-demented PD patients than in HCs at 1-year follow-up. The changes in visuoperception could relate to involvement of the ventral occipitotemporal pathway, the more widespread temporal lobe, and brain reserve in PD.

Identifying the brain's connector hubs at the voxel level using functional connectivity overlap ratio.

Neuroimaging studies have shown that the brain is functionally organized into several large-scale brain networks. Within these networks are regions that are widely connected to several other regions within and/or outside the network. Regions that connect to several other networks, known as connector hubs, are believed to be crucial for information transfer and between-network communication within the brain. To identify regions with high between-network connectivity at the voxel level, we introduced a novel metric called functional connectivity overlap ratio (FCOR), which quantifies the spatial extent of a region's connection to a given network. Using resting state functional magnetic resonance imaging data, FCOR maps were generated for several well-known large-scale resting state networks (RSNs) and used to examine the relevant associations among different RSNs, identify connector hub regions in the cerebral cortex, and elucidate the hierarchical functional organization of the brain. Constructed FCOR maps revealed a strong association among the core neurocognitive networks (default mode, salience, and executive control) as well as among primary processing networks (sensorimotor, auditory, and visual). Prominent connector hubs were identified in the bilateral middle frontal gyrus, posterior cingulate, lateral parietal, middle temporal, dorsal anterior cingulate, and anterior insula, among others, regions mostly associated with the core neurocognitive networks. Finally, clustering the whole brain using FCOR features yielded a topological organization that arranges brain regions into a hierarchy of information processing systems with the primary processing systems at one end and the heteromodal systems comprising connector hubs at the other end.

Changes in white matter fiber density and morphology across the adult lifespan: A cross-sectional fixel-based analysis.

White matter (WM) fiber bundles change dynamically with age. These changes could be driven by alterations in axonal diameter, axonal density, and myelin content. In this study, we applied a novel fixel-based analysis (FBA) framework to examine these changes throughout the adult lifespan. Using diffusion-weighted images from a cohort of 293 healthy volunteers (89 males/204 females) from ages 21 to 86 years old, we performed FBA to analyze age-related changes in microscopic fiber density (FD) and macroscopic fiber morphology (fiber cross section [FC]). Our results showed significant and widespread age-related alterations in FD and FC across the whole brain. Interestingly, some fiber bundles such as the anterior thalamic radiation, corpus callosum, and superior longitudinal fasciculus only showed significant negative relationship with age in FD values, but not in FC. On the other hand, some segments of the cerebello-thalamo-cortical pathway only showed significant negative relationship with age in FC, but not in FD. Analysis at the tract-level also showed that major fiber tract groups predominantly distributed in the frontal lobe (cingulum, forceps minor) exhibited greater vulnerability to the aging process than the others. Differences in FC and the combined measure of FD and cross section values observed between sexes were mostly driven by differences in brain sizes although male participants tended to exhibit steeper negative linear relationship with age in FD as compared to female participants. Overall, these findings provide further insights into the structural changes the brain's WM undergoes due to the aging process.