Cingulum Bundle Research Articles

Properties of the prefrontal tracts and cingulum bundle in children with prenatal alcohol exposure

BackgroundPrenatal alcohol exposure (PAE) significantly impacts brain structure and function, including cognition and behavior. The cingulum bundle and frontal lobe mediate social-, emotional- and cognitive-related functioning that are affected by PAE. However, the neurobehavioural development of the cingulum and intra-frontal tracts has not been examined in people with PAE. MethodsWe recruited 29 children and adolescents with PAE and 42 age- and gender-matched unexposed controls. Diffusion magnetic resonance imaging (MRI) data were acquired on a 3 T scanner. The rostral, dorsal and parahippocampal cingulum as well as medio-orbitofrontal, lateral-orbitofrontal, dorsolateral-prefrontal and medial-prefrontal tracts, were delineated and their fractional anisotropy and mean (MD), radial (RD), and axial (AD) diffusivities were calculated using constrained spherical deconvolution and deterministic tractography. We measured behavioural and emotional difficulties using the Behavior Assessment System for Children, 2nd Edition, Parent Rating Scale, and then explored their associations with diffusion metrics that differed between groups. ResultsWe found lower MD, RD, and AD in the right parahippocampal cingulum and multiple intra-frontal tracts in youth with PAE compared to controls; however, these differences did not withstand correction for multiple comparisons. While, youth with PAE showed significantly more emotional and behavioural difficulties compared to unexposed controls, these challenges were not associated with differences in diffusion metrics between groups. ConclusionPAE may be weakly associated with restricted diffusion in the right parahippocampal cingulum and multiple intra-frontal tracts. However, diffusivity changes related to PAE might not be the primary contributor to emotional and behavioural challenges in children and adolescents with PAE.

Glymphatic function assessment with diffusion tensor imaging along the perivascular space in patients with major depressive disorder and its relation to cerebral white-matter alteration.

The link between glymphatic system function in the brain and alterations in white-matter microstructure among individuals with major depressive disorder (MDD) remains unclear. This study aimed to examine the assessment of glymphatic system function in patients with MDD using the diffusion tensor imaging along the perivascular space (DTI-ALPS) index and to evaluate its association with cerebral-white-matter abnormalities and neuropsychological scores. From February 2023 to November 2023, this cross-sectional study recruited 35 patients with MDD from the Psychosomatic Diseases Department of the First Affiliated Hospital of Dalian Medical University. In this time period, 23 healthy controls (HCs) were enlisted from the community and matched with the MDD cohort in terms of years of education, gender, and age. All participants underwent magnetic resonance imaging, depression, anxiety, and cognitive assessments. The tract-based spatial statistics (TBSS) analyzed DTI parameters and identified significant clusters. Automated fiber quantification (AFQ) was used to automatically identify fiber bundles with statistical differences. Mann-Whitney tests or two-sample t-tests were used for comparisons. Interobserver consistency of the DTI-ALPS measurements was evaluated using the interclass correlation coefficient (ICC). Partial correlation analyses and linear regression analyses were used to examine relationships. A comparison of the DTI-ALPS index was made between the two groups. Correlations among diffusion characteristics, neuropsychological scores, and the DTI-ALPS index were analyzed. Compared to HCs, patients with MDD exhibited a lower DTI-ALPS score (P=0.001). According to using linear regression analysis, the ALPS index was found to be an independent predictor of the Hamilton Depression Rating Scale [B=-25.32; P=0.001; 95% confidence interval (CI): -40.35 to -11.55], Hamilton Anxiety Rating Scale (B=-33.48; P=0.003; 95% CI: -55.38 to -11.24), and Montreal Cognitive Assessment total score (B=8.59; P=0.008; 95% CI: 2.38 to 14.79). According to the TBSS analysis, there were clusters of increased axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) in patients with MDD as compared to HCs (all P values <0.05). A lower DTI-ALPS score was correlated with higher AD (r=-0.592; P<0.001), MD (cluster 1: r=-0.567, P=0.001; cluster 2: r=-0.581, P<0.001), and RD (r=-0.491; P=0.004) values. AFQ analysis identified the significantly different diffusion indicators in the left cingulum bundle (CB_L), left inferior longitudinal fasciculus (ILF_L), and left uncinate fasciculus (UF_L) between the two groups (all false discovery rate P values <0.05). DTI-ALPS score was negatively correlated with the AD value of CB_L (r=-0.304; P=0.024), ILF_L (r=-0.35; P=0.008), and UF_L (r=-0.354; P=0.008) in AFQ tract-level analysis. In point-wise analysis, the MD value of CB_L at nodes 33 to 36 was negatively correlated with DTI-ALPS score (r ranging from -0.504 to -0.535; P<0.01). Our results indicated a decrease in DTI-ALPS index score in patients with MDD. DTI-ALPS score was associated with depression, anxiety, declined cognitive ability, and white-matter microstructural abnormalities and may thus be a promising biomarker for the partial evaluation of glymphatic system function in patients with MDD.

No significant alteration in white matter microstructure in first-degree relatives of patients with obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is characterized by structural alteration within white matter tissues of cortico-striato-thalamo-cortical, temporal and occipital circuits. However, the presence of microstructural changes in the white matter tracts of unaffected first-degree relatives of patients with OCD as a vulnerability marker remains unclear. Therefore, here, diffusion-tensor magnetic resonance imaging (DTI) data were obtained from 29 first-degree relatives of patients with OCD and 59 healthy controls. We investigated the group differences in FA using whole-brain analysis (DTI analysis). For additional regions of interest (ROI) analysis, we focused on the posterior thalamic radiation and sagittal stratum, shown in recent meta-analysis of patients with OCD. In both whole-brain and ROI analyses, using a strict statistical threshold (family-wise error rate [FWE] corrected p<.05 for whole-brain analyses, and p<.0125 (0.05/4) with Bonferroni correction for ROI analyses), we found no significant group differences in FA. Subtle reductions were observed in the anterior corona radiata, forceps minor, cingulum bundle, and corpus callosum only when a lenient statistical was applied (FWE corrected p<.20). These findings suggest that alterations in the white matter microstructure of first-degree relatives, as potential vulnerability markers for OCD, are likely subtle.

Diffusion spectrum imaging in patients with idiopathic normal pressure hydrocephalus: correlation with ventricular enlargement

BackgroundTo investigate the association between white matter changes and ventricular expansion in idiopathic normal pressure hydrocephalus (iNPH) based on diffusion spectrum imaging (DSI).MethodsWe included 32 patients with iNPH who underwent DSI using a 3T MRI scanner. The lateral ventricles were manually segmented, and ventricular volumes were measured. Two methods were utilised in the study: manual region-of-interest (ROI) delineation and tract diffusion profile analysis. General fractional anisotropy (GFA) and fractional anisotropy (FA) were extracted in different white matter regions, including the bilateral internal capsule (anterior and posterior limbs) and corpus callosum (body, genu, and splenium) with manual ROI delineation. The 18 main tracts in the brain of each patient were extracted; the diffusion metrics of 100 equidistant nodes on each fibre were calculated, and Spearman’s correlation coefficient was used to determine the correlation between diffusion measures and ventricular volume of iNPH patients.ResultsThe GFA and FA of all ROI showed no significant correlation with lateral ventricular volume. However, in the tract diffusion profile analysis, lateral ventricular volume was positively correlated with part of the cingulum bundle, left corticospinal tract, and bilateral thalamic radiation posterior, whereas it was negatively correlated with the bilateral cingulum parahippocampal (all p < 0.05).ConclusionsThe effect of ventricular enlargement in iNPH on some white matter fibre tracts around the ventricles was limited and polarizing, and most white matter fibre tract integrity changes were not associated with ventricular enlargement; this reflects that multiple pathological mechanisms may have been combined to cause white matter alterations in iNPH.

Brain white matter microstructural alterations in Behcet's syndrome correlate with cognitive impairment and disease severity: A diffusion tensor imaging study

ObjectivesTo evaluate the microstructural integrity of brain white matter tracts in patients with Neuro-Behcet's syndrome (NBS) and Behcet's syndrome (BS) without neurological manifestations using diffusion tensor imaging (DTI) and to investigate potential utility of DTI as a surrogate biomarker of neurocognitive functioning and disease severity. MethodsThis cross-sectional study comprised 34 NBS patients and 32 BS patients without neurological involvement, identified based on the International Study Group of the Behcet's disease (ISGBD) and the International Consensus Recommendation (ICR) criteria, as well as 33 healthy controls. Cognitive functions, including attention, memory, language, abstraction, executive control, visuospatial skills, and sensorimotor performance were assessed using standardized questionnaires. DTI data were analyzed using tract-based spatial statistics (TBSS) and automated probabilistic tractography to investigate inter-group differences. Subsequently, correlations between tensor-derived parameters of white matter tracts, neurocognitive test scores, and disease severity measures were examined. ResultsDTI revealed decreased fractional anisotropy and increased radial diffusivity, mean diffusivity, and axial diffusivity in both supratentorial and infratentorial white matter in NBS patients, indicating widespread loss of microstructural integrity. Moreover, this loss of integrity was also observed in BS patients without neurological manifestations, albeit to a lesser extent. In NBS patients, certain white matter tracts, including cingulum bundle, were associated with poor cognitive performance across multiple domains and disease severity. DiscussionDTI findings might potentially serve as a neuroimaging marker to predict the extent of neurocognitive impairment and disease severity associated with central nervous system involvement in BS.

Structural and functional connectivity associations with anterior cingulate sulcal variability

Sulcation of the anterior cingulate may be defined by presence of a paracingulate sulcus, a tertiary sulcus developing during the third gestational trimester with implications on cognitive function and disease. In this cross-sectional study we examine task-free resting state functional connectivity and diffusion-weighted tract segmentation data from a cohort of healthy adults (< 60-year-old, n = 129), exploring the impact of ipsilateral paracingulate sulcal presence on structural and functional connectivity. Presence of a left paracingulate sulcus was associated with reduced fractional anisotropy in the left cingulum bundle and the left peri-genual and dorsal bundle segments, suggesting reduced structural organisational coherence in these tracts. This association was not observed in the offsite temporal cingulum bundle segment. Left paracingulate sulcal presence was associated with increased left peri-genual radial diffusivity and tract volume possibly suggesting increased U-fibre density in this region. Greater network dispersity was identified in individuals with an absent left paracingulate sulcus by presence of a significant, predominantly intraregional, frontal component of resting state functional connectivity which was not present in individuals with a present left paracingulate sulcus. Seed-based functional connectivity in pre-defined networks was not associated with paracingulate sulcal presence. These results identify a novel association between sulcation and structural connectivity in a healthy adult population with implications for conditions where this variation is of interest. Presence of a left paracingulate sulcus appears to alter local structural and functional connectivity, possibly as a result of the presence of a local network reliant on short association fibres.

High angular resolution diffusion-weighted imaging and higher order tractography of the white matter tracts in the anterior thalamic area: Insights into deep brain stimulation targeting

BackgroundDeep brain stimulation of the anterior nucleus of the thalamus (ANT) is emerging EU/US-approved form of therapy for drug-resistant focal epilepsy. Its mechanism of action is not yet fully understood, and the patient outcomes in epilepsy appear less consistent compared to for instance movement disorders. Furthermore, very little anatomy-based information, such as tractography of relevant fiber systems, exists guiding DBS therapy at present. ObjectiveTo demonstrate ANT-related fiber systems based on histology in vivo employing multi-shell/multi-tissue constrained spherical deconvolution (MSMT-CSD) based deterministic and probabilistic tractography using a sophisticated scanning protocol of 3T high angular resolution diffusion-weighted imaging (HARDI) data in healthy volunteers. MethodHARDI data was acquired from five healthy volunteers in a 3T Siemens MAGNETOM Skyra Magnetic resonance imaging (MRI) machine using multiple b-values (1000, 2000, and 3000), 64 directions, and further preprocessed for tractography. MSMT-CSD-based deterministic and probabilistic tractography was performed from selected fiber systems based on existing literature. ResultsMultiple fiber systems were identified: The anterior thalamic radiation (ANT), the thalamo-cingulate tract, the inferior thalamic peduncle (with remote termination areas in the amygdala, the ventral tegmental area, and the occipital cortex), and the mammillothalamic tract. In addition, we observed three parallel connections to the hippocampus (via the cingulum bundle, the fornix, and the temporo-pulvinar pathway). Interestingly, different seed areas in ANT complex mimicking DBS contact locations resulted in visualization of different fiber systems. DiscussionThe connections of the ANT are complex and different stimulation sites are likely to affect different networks depending on lead locations and the selection of the active contact. ConclusionsIn-depth understanding of the network of anatomical structures related to the ANT is likely to influence therapy outcomes. A hypothetical model of neuronal networks affected by different DBS lead contact locations is proposed. A more profound understanding of neuroanatomic characteristics may guide stereotactic implantation and subsequent programming to optimize outcomes.

Clinical characteristics of post-stroke basal ganglia aphasia and the study of language-related white matter tracts based on diffusion spectrum imaging

BackgroundStroke often damages the basal ganglia, leading to atypical and transient aphasia, indicating that post-stroke basal ganglia aphasia (PSBGA) may be related to different anatomical structural damage and functional remodeling rehabilitation mechanisms. The basal ganglia contain dense white matter tracts (WMTs). Hence, damage to the functional tract may be an essential anatomical structural basis for the development of PSBGA. MethodsWe first analyzed the clinical characteristics of PSBGA in 28 patients and 15 healthy controls (HCs) using the Western Aphasia Battery and neuropsychological test batteries. Moreover, we investigated white matter injury during the acute stage using diffusion magnetic resonance imaging scans for differential tractography. Finally, we used multiple regression models in correlation tractography to analyze the relationship between various language functions and quantitative anisotropy (QA) of WMTs. ResultsCompared with HCs, patients with PSBGA showed lower scores for fluency, comprehension (auditory word recognition and sequential commands), naming (object naming and word fluency), reading comprehension of sentences, Mini-Mental State Examination, and Montreal Cognitive Assessment, along with increased scores in Hamilton Anxiety Scale-17 and Hamilton Depression Scale-17 within 7 days after stroke onset (P < 0.05). Differential tractography revealed that patients with PSBGA had damaged fibers, including in the body fibers of the corpus callosum, left cingulum bundles, left parietal aslant tracts, bilateral superior longitudinal fasciculus II, bilateral thalamic radiation tracts, left fornix, corpus callosum tapetum, and forceps major, compared with HCs (FDR < 0.02). Correlation tractography highlighted that better comprehension was correlated with a higher QA of the left inferior fronto-occipital fasciculus (IFOF), corpus callosum forceps minor, and left extreme capsule (FDR < 0.0083). Naming was positively associated with the QA of the left IFOF, forceps minor, left arcuate fasciculus, and uncinate fasciculus (UF) (FDR < 0.0083). Word fluency of naming was also positively associated with the QA of the forceps minor, left IFOF, and thalamic radiation tracts (FDR < 0.0083). Furthermore, reading was positively correlated with the QA of the forceps minor, left IFOF, and UF (FDR < 0.0083). ConclusionPSBGA is primarily characterized by significantly impaired word fluency of naming and preserved repetition abilities, as well as emotional and cognitive dysfunction. Damaged limbic pathways, dorsally located tracts in the left hemisphere, and left basal ganglia pathways are involved in PSBGA pathogenesis. The results of connectometry analysis further refine the current functional localization model of higher-order neural networks associated with language functions.

Long-term calorie restriction reduces oxidative DNA damage to oligodendroglia and promotes homeostatic microglia in the aging monkey brain

Calorie restriction (CR) is a robust intervention that can slow biological aging and extend lifespan. In the brain, terminally differentiated neurons and glia accumulate oxidative damage with age, reducing their optimal function. We investigated if CR could reduce oxidative DNA damage to white matter oligodendrocytes and microglia. This study utilized post-mortem brain tissue from rhesus monkeys that died after decades on a 30 % reduced calorie diet. We found that CR subjects had significantly fewer cells with oxidative damage within the corpus callosum and the cingulum bundle. Oligodendrocytes specifically showed the greatest response to CR with a robust reduction in DNA damage. Additionally, we observed alterations in microglia morphology with CR subjects having a higher proportion of ramified, homeostatic microglia and fewer pro-inflammatory, hypertrophic microglia relative to controls. Furthermore, we determined that the observed attenuation in damaged DNA occurs primarily within mitochondria. Overall, these data suggest that long-term CR can reduce oxidative DNA damage and offer a neuroprotective effect in a cell-type-specific manner in the aging monkey brain.

Diffusion imaging markers of accelerated aging of the lower cingulum in subjective cognitive decline.

Alzheimer's Disease (AD) typically starts in the medial temporal lobe, then develops into a neurodegenerative cascade which spreads to other brain regions. People with subjective cognitive decline (SCD) are more likely to develop dementia, especially in the presence of amyloid pathology. Thus, we were interested in the white matter microstructure of the medial temporal lobe in SCD, specifically the lower cingulum bundle that leads into the hippocampus. Diffusion tensor imaging (DTI) has been shown to differentiate SCD participants who will progress to mild cognitive impairment from those who will not. However, the biology underlying these DTI metrics is unclear, and results in the medial temporal lobe have been inconsistent. To better characterize the microstructure of this region, we applied DTI to cognitively normal participants in the Cam-CAN database over the age of 55 with cognitive testing and diffusion MRI available (N = 325, 127 SCD). Diffusion MRI was processed to generate regional and voxel-wise diffusion tensor values in bilateral lower cingulum white matter, while T1-weighted MRI was processed to generate regional volume and cortical thickness in the medial temporal lobe white matter, entorhinal cortex, temporal pole, and hippocampus. SCD participants had thinner cortex in bilateral entorhinal cortex and right temporal pole. No between-group differences were noted for any of the microstructural metrics of the lower cingulum. However, correlations with delayed story recall were significant for all diffusion microstructure metrics in the right lower cingulum in SCD, but not in controls, with a significant interaction effect. Additionally, the SCD group showed an accelerated aging effect in bilateral lower cingulum with MD, AxD, and RD. The diffusion profiles observed in both interaction effects are suggestive of a mixed neuroinflammatory and neurodegenerative pathology. Left entorhinal cortical thinning correlated with decreased FA and increased RD, suggestive of demyelination. However, right entorhinal cortical thinning also correlated with increased AxD, suggestive of a mixed pathology. This may reflect combined pathologies implicated in early AD. DTI was more sensitive than cortical thickness to the associations between SCD, memory, and age. The combined effects of mixed pathology may increase the sensitivity of DTI metrics to variations with age and cognition.

Fixel-Based Analysis Reveals Tau-Related White Matter Changes in Early Stages of Alzheimer's Disease.

Several studies have shown white matter (WM) abnormalities in Alzheimer's disease (AD) using diffusion tensor imaging (DTI). Nonetheless, robust characterization of WM changes has been challenging due to the methodological limitations of DTI. We applied fixel-based analyses (FBA) to examine microscopic differences in fiber density (FD) and macroscopic changes in fiber cross-section (FC) in early stages of AD (N = 393, 212 females). FBA was also compared with DTI, free-water corrected (FW)-DTI and diffusion kurtosis imaging (DKI). We further investigated the correlation of FBA and tensor-derived metrics with AD pathology and cognition. FBA metrics were decreased in the entire cingulum bundle, uncinate fasciculus and anterior thalamic radiations in Aβ-positive patients with mild cognitive impairment compared to control groups. Metrics derived from DKI, and FW-DTI showed similar alterations whereas WM degeneration detected by DTI was more widespread. Tau-PET uptake in medial temporal regions was only correlated with reduced FC mainly in the parahippocampal cingulum in Aβ-positive individuals. This tau-related WM alteration was also associated with impaired memory. Despite the spatially extensive between-group differences in DTI-metrics, the link between WM and tau aggregation was only revealed using FBA metrics implying high sensitivity but low specificity of DTI-based measures in identifying subtle tau-related WM degeneration. No relationship was found between amyloid load and any diffusion-MRI measures. Our results indicate that early tau-related WM alterations in AD are due to macrostructural changes specifically captured by FBA metrics. Thus, future studies assessing the effects of AD pathology in WM tracts should consider using FBA metrics.

Subcallosal cingulate deep brain stimulation evokes two distinct cortical responses via differential white matter activation

Subcallosal cingulate (SCC) deep brain stimulation (DBS) is an emerging therapy for refractory depression. Good clinical outcomes are associated with the activation of white matter adjacent to the SCC. This activation produces a signature cortical evoked potential (EP), but it is unclear which of the many pathways in the vicinity of SCC is responsible for driving this response. Individualized biophysical models were built to achieve selective engagement of two target bundles: either the forceps minor (FM) or cingulum bundle (CB). Unilateral 2 Hz stimulation was performed in seven patients with treatment-resistant depression who responded to SCC DBS, and EPs were recorded using 256-sensor scalp electroencephalography. Two distinct EPs were observed: a 120 ms symmetric response spanning both hemispheres and a 60 ms asymmetrical EP. Activation of FM correlated with the symmetrical EPs, while activation of CB was correlated with the asymmetrical EPs. These results support prior model predictions that these two pathways are predominantly activated by clinical SCC DBS and provide first evidence of a link between cortical EPs and selective fiber bundle activation.

Brain identification of IBS patients based on GBDT and multiple imaging techniques.

The brain biomarker of irritable bowel syndrome (IBS) patients is still lacking. The study aims to explore a new technology studying the brain alterations of IBS patients based on multi-source brain data. In the study, a decision-level fusion method based on gradient boosting decision tree (GBDT) was proposed. Next, 100 healthy subjects were used to validate the effectiveness of the method. Finally, the identification of brain alterations and the pain evaluation in IBS patients were carried out by the fusion method based on the resting-state fMRI and DWI for 46 patients and 46 controls selected randomly from 100 healthy subjects. The results showed that the method can achieve good classification between IBS patients and controls (accuracy = 95%) and pain evaluation of IBS patients (mean absolute error = 0.1977). Moreover, both the gain-based and the permutation-based evaluation instead of statistical analysis showed that left cingulum bundle contributed most significantly to the classification, and right precuneus contributed most significantly to the evaluation of abdominal pain intensity in the IBS patients. The differences seem to suggest a probable but unexplored separation about the central regions between the identification and progression of IBS. This finding may provide one new thought and technology for brain alteration related to IBS.

Tract-based analyses of white matter in schizophrenia, bipolar disorder, aging, and dementia using high spatial and directional resolution diffusion imaging: a pilot study.

Structural brain connectivity abnormalities have been associated with several psychiatric disorders. Schizophrenia (SCZ) is a chronic disabling disorder associated with accelerated aging and increased risk of dementia, though brain findings in the disorder have rarely been directly compared to those that occur with aging. We used an automated approach to reconstruct key white matter tracts and assessed tract integrity in five participant groups. We acquired one-hour-long high-directional diffusion MRI data from young control (CON, n =28), bipolar disorder (BPD, n =21), and SCZ (n =22) participants aged 18-30, and healthy elderly (ELD, n =15) and dementia (DEM, n =9) participants. Volume, fractional (FA), radial diffusivity (RD) and axial diffusivity (AD) of seven key white matter tracts (anterior thalamic radiation, ATR; dorsal and ventral cingulum bundle, CBD and CBV; corticospinal tract, CST; and the three superior longitudinal fasciculi: SLF-1, SLF-2 and SLF-3) were analyzed with TRACULA. Group comparisons in tract metrics were performed using multivariate and univariate analyses. Clinical relationships of tract metrics with recent and chronic symptoms were assessed in SCZ and BPD participants. A MANOVA showed group differences in FA (λ=0.5; p=0.0002) and RD (λ=0.35; p<0.0001) across the seven tracts, but no significant differences in tract AD and volume. Post-hoc analyses indicated lower tract FA and higher RD in ELD and DEM groups compared to CON, BPD and SCZ groups. Lower FA and higher RD in SCZ compared to CON did not meet statistical significance. In SCZ participants, a significant negative correlation was found between chronic psychosis severity and FA in the SLF-1 (r= -0.45; p=0.035), SLF-2 (r= -0.49; p=0.02) and SLF-3 (r= -0.44; p=0.042). Our results indicate impaired white matter tract integrity in elderly populations consistent with myelin damage. Impaired tract integrity in SCZ is most prominent in patients with advanced illness.

Multi-modal morphometric association study of subclinical depressive symptoms using voxel-based morphometry, cortical thickness, and diffusion tensor imaging (DTI)

BackgroundCase-control studies in major depression have established numerous regional grey and white matter effects in fronto-limbic brain regions. Yet, brain structural studies of dimensional depressive psychopathology within the subclinical spectrum are still limited, in particular for multi-modal imaging approaches. MethodsUsing voxel-based and surface-based morphometry (cortical thickness) in combination with diffusion tensor imaging (DTI) in a large non-clinical sample (N = 300), we correlated grey and white matter structural variation with subclinical depressive symptoms assessed with Beck's Depression inventory (BDI). ResultsWe found a significant decrease of axial diffusivity associated with higher BDI scores in the left hippocampal part of the cingulum bundle (p < 0.05, threshold free cluster enhanced [TFCE] p-value) and some grey matter trend results e.g., a non-linear negative correlation of cortical thickness with depressive symptom load in the right pre/postcentral cortex (pFWE = 0.054, family wise error [FWE] peak level corrected) and a trend in grey matter volume decrease in women in the inferior frontal gyrus (pFWE = 0.054). LimitationsSince all grey matter effects disappear after FWE correction, we assume more stable effects in a larger, less homogenous sample enriched by help-seeking subjects covering a wider range of subclinical psychopathology. ConclusionOur study adds correlations between single depressive symptoms and brain structure to a growing literature. Since subclinical depression is increasingly recognised to be relevant in our understanding of manifest depression, early detection and identification of potential brain correlates of minor depressive symptoms has the potential to expand and reveal possible biomarkers and early psychological treatment.

Advanced Cognitive Patterns in Multiple System Atrophy Compared to Parkinson’s Disease: An Individual Diffusion Tensor Imaging Study

Although both Multiple system atrophy (MSA) and Parkinson's disease (PD) belong to alpha-synucleinopathy, they have divergent clinical courses and prognoses. The degeneration of white matter has a considerable impact on cognitive performance, yet it is uncertain how PD and MSA affect its functioning in a similar or different manner. In this study, a total of 116 individuals (37 PD with mild cognitive impairment (PD-MCI), 37 MSA (parkinsonian variant) with mild cognitive impairment (MSA-MCI), and 42 healthy controls) underwent diffusion tensor imaging (DTI) and cognitive assessment. Utilizing probabilistic fiber tracking, association fibers, projection fibers, and thalamic fibers were reconstructed. Subsequently, regression, support vector machine, and SHAP (Shapley Addictive exPlanations) analyzes were conducted to evaluate the association between microstructural diffusion metrics and multiple cognitive domains, thus determining the white matter predictors of MCI. MSA-MCI patients exhibited distinct white matter impairment extending to the middle cerebellar peduncle, corticospinal tract, and cingulum bundle. Furthermore, the fractional anisotropy (FA) and mean diffusivity (MD)values of the right anterior thalamic radiation were significantly associated with global efficiency (FA: B=0.69, P<0.001, VIF=1.31; MD: B=-0.53, P=0.02, VIF=2.50). The diffusion metrics of white matter between PD-MCI and MSA-MCI proved to be an effective predictor of the MCI, with an accuracy of 0.73 (P<0.01), and the most predictive factor being the MD of the anterior thalamic radiation. Our results demonstrated that MSA-MCI had a more noticeable deterioration in white matter, which potentially linked to various cognitive domain connections. Diffusion MRI could be a useful tool in comprehending the neurological basis of cognitive impairment in Parkinsonian disorders.

Dysregulated C1q and CD47 in the aging monkey brain: association with myelin damage, microglia reactivity, and cognitive decline.

Normal aging, though lacking widespread neurodegeneration, is nevertheless characterized by cognitive impairment in learning, memory, and executive function. The aged brain is spared from neuron loss, but white matter is lost and damage to myelin sheaths accumulates. This myelin damage is strongly associated with cognitive impairment. Although the cause of the myelin damage is not known, microglia dysregulation is a likely contributor. Immunologic proteins interact with microglial receptors to modulate microglia-mediated phagocytosis, which mediates myelin damage clearance and turn-over. Two such proteins, "eat me" signal C1q and "don't eat me" signal CD47, act in opposition with microglia. Both C1q and CD47 have been implicated inMultiple Sclerosis, a demyelinating disease, but whether they play a role in age-related myelin pathology is currently unknown. The present study investigates C1q and CD47 in relation to age-related myelin degeneration using multilabel immunofluorescence, RNAscope, and confocal microscopy in the cingulum bundle of male and female rhesus monkeys across the lifespan. Our findings showed significant age-related elevation in C1q localized to myelin basic protein, and this increase is associated with more severe cognitive impairment. In contrast, CD47 localization to myelin decreased in middle age and oligodendrocyte expression of CD47 RNA decreased with age. Lastly, microglia reactivity increased with age in association with the changes in C1q and CD47. Together, these results suggest disruption in the balance of "eat me" and "don't eat me" signals during normal aging, biasing microglia toward increased reactivity and phagocytosis of myelin, resulting in cognitive deficits.

Alzheimer’s disease biomarkers of amyloid and tau influence white matter neurite alterations in dementia with Lewy bodies: a NODDI study

AbstractBackgroundCo‐morbid Alzheimer’s disease (AD) pathology in the form of amyloid‐ß plaques and tau neurofibrillary tangles are frequently observed in people with probable dementia with Lewy bodies (DLB). Neurite Orientation Dispersion and Density Imaging (NODDI) is an emerging technique to characterize white matter (WM) tissue microstructure, although NODDI alterations and associations with AD biomarkers remain undefined in DLB. The objectives of this study are to compare NODDI and DTI parameters between DLB and controls and (ii) evaluate the pattern of DTI and NODDI changes associated with amyloid and tau deposition.MethodConsecutive patients within the DLB spectrum (n = 45), including probable DLB (n = 32) and probable Mild Cognitive Impairment with Lewy bodies (MCI‐LB) (n = 13) from the Mayo Clinic ADRC underwent multi‐shell diffusion MRI, [18F]‐Flortaucipir and [11C]‐PiB PET. A comparison group of 45 age‐ and gender‐matched clinically unimpaired controls (CU) was included. Voxelwise non‐parametric permutation models were used to determine pair‐wise group differences and assess the associations of AD biomarkers with fractional anisotropy (FA), mean diffusivity (MD), tissue‐weighted neurite density index (tNDI; NDI x (1 – Free water fraction)) and orientation dispersion index (ODI), controlling for age. Complementary analyses were performed using regions‐of‐interest (ROI) obtained from the JHU atlas.ResultCompared to CU, the DLB spectrum group exhibited widespread decreases in FA and tNDI and increases in MD and ODI, with the most pronounced effects in the cingulum bundles, uncinate, inferior and superior longitudinal fasciculi (Fig. 1). Greater [18F]‐Flortaucipir uptake was also associated with lower FA and tNDI, and higher MD and ODI in the DLB spectrum compared to CU, independently of age and [11C]‐PiB uptake (Fig. 2). In contrast, no associations were found between [11C]‐PiB uptake and any of the DTI or NODDI parameters. Complementary ROI analyses corroborated these findings.ConclusionWidespread loss of WM integrity was observed on DTI and NODDI in probable DLB and prodromal DLB. These findings were associated with greater cortical tau, but not with amyloid‐ß deposition. Although alpha‐synuclein pathology underlies the loss of WM integrity in DLB, amyloid‐independent tau pathology may also be an important influence on white matter integrity within the DLB spectrum.

Sex differences in white matter bundle properties across menopausal transition states

AbstractBackgroundWomen develop Alzheimer’s disease (AD) at a 2:1 rate compared to men. Changes associated with menopause exacerbate a midlife bioenergetic crisis that, when unsuccessfully resolved, leads to white matter degradation and ultimately brain atrophy. Understanding how white matter structural properties differ between sexes and evolve over midlife transitions may provide insight into the exacerbated AD risk for women. Here, we report differences in white matter bundle properties comparing pre‐ (n = 40, 44.1±3.34y), peri‐ (n = 60, 49.6±3.90y), and post‐menopausal women (n = 70, 56.0±4.12y) to age‐matched males.MethodDiffusion weighted MRI was acquired for each participant. Data were preprocessed with QSIPrep and analyzed using a fixel‐based approach implemented in MRtrix (v. 3.0.3). Fiber density (FD), cross‐section (FC), and a combined density/cross‐section metric (FDC) were compared between sexes after controlling for age, education, APOE ε4 carrier status, and total brain volume (FC and FDC only). Continuous covariates were standardized to 2 standard deviations. Analyses were conducted using connectivity‐enhanced fixel‐based permutation analyses and thresholded at family‐wise error corrected p&lt;0.05.ResultPre‐, peri‐, and post‐ menopausal women exhibited greater FD and FDC in the corpus callosum, inferior occipto‐frontal fasciculus, cortico‐spinal, and cingulum bundles. By contrast, males had greater fiber cross section in the splenium of the corpus callosum (compared to pre‐), (compared to peri‐), and in fibers near the left uncinate fasciculus and inferior longitudinal fasciculus (compared to both peri‐ and post‐menopausal women). After controlling for age, education, total brain volume, and APOE ε4 carrier status, a smaller cluster of fibers in the left splenium survived multiple comparisons correction demonstrating greater fiber cross‐section in post‐menopausal women compared to peri‐menopausal women.ConclusionWomen across menopausal transition states exhibited greater fiber density than their age‐matched male counterparts in commissural and association tracts, which agrees with previous work demonstrating stronger inter‐hemispheric connections in women. However, peri‐ and post‐menopausal females exhibited 4‐8% decrease in fiber cross section in uncinate fasciculus fibers, which have been implicated in Alzheimer’s related cognitive decline. These findings suggest that reductions in white matter cross‐section, particularly in regions associated with Alzheimer’s disease, may begin for women in menopause and be an early indicator of neurodegenerative risk.

Clinical and biomarker correlates of region‐specific diffusion MRI metrics in a short‐term, Phase 1b clinical trial for XPro1595 in Alzheimer’s disease

AbstractBackgroundXPro1595 is a selective, brain penetrant neutralizer of soluble TNF with potent anti‐neuroinflammatory effects recently assessed for safety and pharmacological activity in a 12‐week, phase‐1b open‐label dose finding study in patients with AD (NCT03943264). An unbiased screen of imaging outcomes revealed signals for target engagement in gray matter (GM) cortices documented in the literature as regions most frequently affected by accumulation of amyloid‐beta (Aβ) in early and late phases of AD (Mattsson et al. 2019). Post‐hoc analyses were conducted to further investigate these signals.MethodStudy results for patients (n = 9; MMSE range: 8‐27) with analyzable dMRIs who completed 12‐weeks of treatment with XPro1595 [0.3 mg/kg; n = 3) or (1.0 mg/kg; n = 6)] met inclusion criteria. Correlation matrices (uncorrected Pearson’s r) were created to compare key secondary and exploratory imaging outcomes to clinical characteristics and CSF biomarkers of AD specific pathology (Roche Elecsys NeuroToolKit). Imaging outcomes included white matter free‐water (WM‐FW) as a prespecified proxy for neuroinflammation, and GM PerpPD+. PerpPD+ represents the diffusion components perpendicular to cortical GM minicolumns and serves as an indicator of worsening GM microarchitecture when increased in AD. Due to the small sample size, the threshold for identification of informative values was set at P&lt;0.05.ResultAt baseline, PerpPD in GM regions associated with early Aβ accumulation (insula, precuneus, isthmus and posterior cingulate, and lateral‐orbitofrontal cortices), and WM‐FW in the cingulum bundle, showed strong associations with CSF biomarkers of neurodegeneration (pTau and tTau), inflammatory gliosis (YKL‐40, GFAP and sTREM2), cognitive status (MMSE scores) and disease duration (Table1). Week‐12 results showed decreased PerpPD+ and WM‐FW in these regions, with a dose‐dependent signal concentrated in the isthmus cingulate GM and cingulum WM. Isthmus cingulate PerpPD+ ∆ (%) correlated positively with baseline Aβ42/40 and MMSE (Figure1), and negatively with duration of disease and cingulum WM‐FW, whereas cingulum WM‐FW ∆ (%) corelated with baseline pTau and tTau (Table 2).ConclusionPerpPD+ in isthmus cingulate GM and WM‐FW in cingulum WM represent potential indicators of disease activity sensitive to early treatment effects in small, proof of concept clinical trials for AD. Additional research is warranted to further elucidate these signals.