Divergent functional connectivity changes associated with white matter hyperintensities.

Age-related white matter hyperintensities are a common feature and are known to be negatively associated with structural integrity, functional connectivity, and cognitive performance. However, this has yet to be fully understood mechanistically. We analyzed multiple MRI modalities acquired in 465 non-demented individuals from the Swedish BioFINDER study including 334 cognitively normal and 131 participants with mild cognitive impairment. White matter hyperintensities were automatically quantified using fluid-attenuated inversion recovery MRI and parameters from diffusion tensor imaging were estimated in major white matter fibre tracts. We calculated fMRI resting state-derived functional connectivity within and between predefined cortical regions structurally linked by the white matter tracts. How change in functional connectivity is affected by white matter lesions and related to cognition (in the form of executive function and processing speed) was explored. We examined the functional changes using a measure of sample entropy. As expected hyperintensities were associated with disrupted structural white matter integrity and were linked to reduced functional interregional lobar connectivity, which was related to decreased processing speed and executive function. Simultaneously, hyperintensities were also associated with increased intraregional functional connectivity, but only within the frontal lobe. This phenomenon was also associated with reduced cognitive performance. The increased connectivity was linked to increased entropy (reduced predictability and increased complexity) of the involved voxels' blood oxygenation level-dependent signal. Our findings expand our previous understanding of the impact of white matter hyperintensities on cognition by indicating novel mechanisms that may be important beyond this particular type of brain lesions.

Elevated plasma neurofilament light and glial fibrillary acidic protein in epilepsy versus nonepileptic seizures and nonepileptic disorders.

OBJECTIVE: Research suggests that recurrent seizures may lead to neuronal injury. Neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAP) levels increase in cerebrospinal fluid and blood in response to neuroaxonal damage, and they have been hypothesized as potential biomarkers for epilepsy. We examined plasma NfL and GFAP levels and their diagnostic utility in differentiating patients with epilepsy from those with psychogenic nonepileptic seizures (PNES) and other nonepileptic disorders. METHODS: We recruited consecutive adults admitted for video-electroencephalographic monitoring and formal neuropsychiatric assessment. NfL and GFAP levels were quantified and compared between different patient groups and an age-matched reference cohort (n = 1926) and correlated with clinical variables in patients with epilepsy. RESULTS: A total of 138 patients were included, of whom 104 were diagnosed with epilepsy, 22 with PNES, and 12 with other conditions. Plasma NfL and GFAP levels were elevated in patients with epilepsy compared to PNES, adjusted for age and sex (NfL p = .04, GFAP p = .04). A high proportion of patients with epilepsy (20%) had NfL levels above the 95th age-matched percentile compared to the reference cohort (5%). NfL levels above the 95th percentile of the reference cohort had a 95% positive predictive value for epilepsy. Patients with epilepsy who had NfL levels above the 95th percentile were younger than those with lower levels (37.5 vs. 43.8 years, p = .03). SIGNIFICANCE: An elevated NfL or GFAP level in an individual patient may support an underlying epilepsy diagnosis, particularly in younger adults, and cautions against a diagnosis of PNES alone. Further examination of the association between NfL and GFAP levels and specific epilepsy subtypes or seizure characteristics may provide valuable insights into disease heterogeneity and contribute to the refinement of diagnosis, understanding pathophysiological mechanisms, and formulating treatment approaches.

Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders.

OBJECTIVE: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. METHODS: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). RESULTS: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. CONCLUSIONS: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings.

Plasma and CSF neurofilament light chain distinguish neurodegenerative from primary psychiatric conditions in a clinical setting.

INTRODUCTION: People with neurodegenerative disorders (ND) frequently face diagnostic delay and misdiagnosis. We investigated blood and cerebrospinal fluid (CSF) neurofilament light chain (NfL) to distinguish ND from primary psychiatric disorders (PPD), a common challenge in clinical settings. METHODS: Plasma and CSF NfL levels were measured and compared between groups, adjusting for age, sex, and weight. RESULTS: A total of 337 participants were included: 136 ND, 77 PPD, and 124 Controls. Plasma NfL was 2.5-fold elevated in ND compared to PPD and had strong diagnostic performance (area under the curve, [AUC]: 0.86, 81%/85% specificity/sensitivity) that was comparable to CSF NfL (2-fold elevated, AUC: 0.89, 95%/71% specificity/sensitivity). Diagnostic performance was especially strong in younger people (40- < 60 years). Additional findings were cutoffs optimized for sensitivity and specificity, and issues important for future clinical translation. CONCLUSIONS: This study adds important evidence for a simple blood-based biomarker to assist as a screening test for neurodegeneration and distinction from PPD, in clinical settings. HIGHLIGHTS: NfL levels were significantly higher in ND versus PPD. Plasma NfL showed strong diagnostic performance, comparable to CSF NfL, to distinguish ND from PPD. Diagnostic performance was higher in younger people, where diagnostic challenges are greater. Further research is needed on analytical and reference range factors, for clinical translation. These findings support a simple screening blood test for neurodegeneration.

Clinical recognition of frontotemporal dementia with right anterior temporal predominance: A multicenter retrospective cohort study.

INTRODUCTION: Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype. METHODS: Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments. RESULTS: Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word-finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face-recognition deficits (60%). Real-life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations. DISCUSSION: This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real-life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients. HIGHLIGHTS: This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses.

Plasma neurofilament light chain is increased in Niemann-Pick Type C but glial fibrillary acidic protein remains normal.

OBJECTIVE: Niemann-Pick Type C (NPC) is a genetic neurodegenerative lysosomal storage disorder commonly associated with psychiatric symptoms and delays to accurate diagnosis and treatment. This study investigated biomarker levels and diagnostic utility of plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in NPC compared to healthy controls. METHODS: Patients with NPC were recruited from a specialist assessment and management service. Data was available from an age and sex-matched healthy control group. NfL and GFAP were measured on Quanterix Simoa HD-X analysers and groups compared using generalised linear models. NfL levels were compared to, and percentiles derived from, recently developed NfL reference ranges. RESULTS: Plasma NfL was significantly elevated in 11 patients with NPC compared to 25 controls (mean 17.1 vs. 7.4 pg/ml, p < 0.001), and reference ranges (all >98th percentile). NfL distinguished NPC from controls with high accuracy. GFAP levels were not elevated in NPC (66.6 vs. 75.1 pg/ml). DISCUSSION: The study adds important evidence on the potential diagnostic utility of plasma NfL in NPC, extends the literature of NfL as a diagnostic tool to differentiate neurodegenerative from primary psychiatric disorders, and adds support to the pathology in NPC primarily involving neuronal, particularly axonal, degeneration.

Cerebrospinal fluid neurofilament light predicts longitudinal diagnostic change in patients with psychiatric and neurodegenerative disorders.

OBJECTIVE: People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. METHODS: We collected longitudinal diagnostic information (mean = 36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other) and PSY. We pre-specified NfL > 582 pg/mL as indicative of ND/MCI/other. RESULTS: Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. CONCLUSIONS: CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.

[18F]RO948 tau positron emission tomography in genetic and sporadic frontotemporal dementia syndromes.

PURPOSE: To examine [18F]RO948 retention in FTD, sampling the underlying protein pathology heterogeneity. METHODS: A total of 61 individuals with FTD (n = 35), matched cases of AD (n = 13) and Aß-negative cognitively unimpaired individuals (n = 13) underwent [18F]RO948PET and MRI. FTD included 21 behavioral variant FTD (bvFTD) cases, 11 symptomatic C9orf72 mutation carriers, one patient with non-genetic bvFTD-ALS, one individual with bvFTD due to a GRN mutation, and one due to a MAPT mutation (R406W). Tracer retention was examined using a region-of-interest and voxel-wise approaches. Two individuals (bvFTD due to C9orf72) underwent postmortem neuropathological examination. Tracer binding was additionally assessed in vitro using [3H]RO948 autoradiography in six separate cases. RESULTS: [18F]RO948 retention across ROIs was clearly lower than in AD and comparable to that in Aß-negative cognitively unimpaired individuals. Only minor loci of tracer retention were seen in bvFTD; these did not overlap with the observed cortical atrophy in the cases, the expected pattern of atrophy, nor the expected or verified protein pathology distribution. Autoradiography analyses showed no specific [3H]RO948 binding. The R406W MAPT mutation carriers were clear exceptions with AD-like retention levels and specific in-vitro binding. CONCLUSION: [18F]RO948 uptake is not significantly increased in the majority of FTD patients, with a clear exception being specific MAPT mutations.

Clinical value of cerebrospinal fluid neurofilament light chain in semantic dementia.

BACKGROUND: Semantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD. METHODS: This large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset). RESULTS: CSF NfL levels were significantly higher in patients with SD (median: 2326 pg/mL, IQR: 1628-3593) than in controls (577 (446-766), p<0.001). Higher CSF NfL levels were moderately associated with naming impairment as measured by the Boston Naming Test (rs =-0.32, p=0.002) and with smaller grey matter volume of the parahippocampal gyri (rs =-0.31, p=0.004). However, cross-sectional CSF NfL levels were not associated with progression of grey matter atrophy and did not predict survival. CONCLUSION: CSF NfL is a promising biomarker in the diagnostic process of SD, although it has limited cross-sectional monitoring or prognostic abilities.

Regional structural hypo- and hyperconnectivity of frontal-striatal and frontal-thalamic pathways in behavioral variant frontotemporal dementia.

Behavioral variant frontotemporal dementia (bvFTD) has been predominantly considered as a frontotemporal cortical disease, with limited direct investigation of frontal-subcortical connections. We aim to characterize the grey and white matter components of frontal-thalamic and frontal-striatal circuits in bvFTD. Twenty-four patients with bvFTD and 24 healthy controls underwent morphological and diffusion imaging. Subcortical structures were manually segmented according to published protocols. Probabilistic pathways were reconstructed separately from the dorsolateral, orbitofrontal and medial prefrontal cortex to the striatum and thalamus. Patients with bvFTD had smaller cortical and subcortical volumes, lower fractional anisotropy, and higher mean diffusivity metrics, which is consistent with disruptions in frontal-striatal-thalamic pathways. Unexpectedly, regional volumes of the striatum and thalamus connected to the medial prefrontal cortex were significantly larger in bvFTD (by 135% in the striatum, p = .032, and 217% in the thalamus, p = .004), despite smaller dorsolateral prefrontal cortex connected regional volumes (by 67% in the striatum, p = .002, and 65% in the thalamus, p = .020), and inconsistent changes in orbitofrontal cortex connected regions. These unanticipated findings may represent compensatory or maladaptive remodeling in bvFTD networks. Comparisons are made to other neuropsychiatric disorders suggesting a common mechanism of changes in frontal-subcortical networks; however, longitudinal studies are necessary to test this hypothesis.

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.

Plasma neurofilament light chain is not elevated in people with first-episode psychosis or those at ultra-high risk for psychosis.

INTRODUCTION: Neurofilament light chain (NfL), a blood biomarker of neuronal injury, shows promise in distinguishing neurodegenerative disorders from psychiatric conditions. This is especially relevant in psychosis, given neurological conditions such as autoimmune encephalitis and Niemann Pick Type C disease (NPC) may initially present with psychotic symptoms. Whilst NfL levels have been studied in established schizophrenia cases, their levels in first-episode psychosis (FEP) and ultra-high risk (UHR) for psychosis individuals remain largely unexplored. This study aimed to compare plasma NfL in people with FEP or UHR with healthy controls, as well as explore its associations with clinical data. METHOD: We retrospectively analysed plasma NfL in 63 participants, consisting of 29 individuals with FEP, 10 individuals with UHR, and 24 healthy controls. We used general linear models (GLM), which were bootstrapped, to compute bias-corrected and accelerated (BCa) 95 % confidence intervals (CIs). RESULTS: Mean NfL levels were 5.2 pg/mL in FEP, 4.9 pg/mL in UHR, and 5.9 pg/mL in healthy controls. Compared to healthy controls, there were no significant differences in NfL levels in the FEP group (ß = -0.22, 95 % CI [-0.86, 0.39], p = 0.516) nor UHR group (ß = -0.37, 95 % CI [-0.90, 0.19], p = 0.182). There were no significant associations between NfL levels and clinical variables in the FEP group. DISCUSSION: Our study is the first to demonstrate that plasma NfL levels are not significantly elevated in individuals at UHR for psychosis compared to healthy controls, a finding also observed in the FEP cohort. These findings bolster the potential diagnostic utility of NfL in differentiating between psychiatric and neurodegenerative disorders.

Structural and functional connectivity associations with anterior cingulate sulcal variability.

Background: 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. Methods: In this retrospective analysis 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. Results: Presence of a left paracingulate sulcus was associated with reduced fractional anisotropy in the left cingulum (P = 0.02) bundle and the peri-genual (P = 0.002) and dorsal (P = 0.03) but not the temporal cingulum bundle segments. Left paracingulate sulcal presence was associated with increased left peri-genual radial diffusivity (P = 0.003) and tract volume (P = 0.012). A significant, predominantly intraregional frontal component of altered resting state functional connectivity was identified in individuals possessing a left PCS (P = 0.01). Seed-based functional connectivity in pre-defined networks was not associated with paracingulate sulcal presence. Conclusion: These results identify a novel association between neurodevelopmentally derived sulcation and altered structural connectivity in a healthy adult population with implications for conditions where this variation is of interest. Furthermore, they provide evidence of a link between the structural and functional connectivity of the brain in the presence of a paracingulate sulcus which may be mediated by a highly connected local functional network reliant on short association fibres.

Plasma neurofilament light protein is differentially associated with age in individuals with treatment-resistant schizophrenia and bipolar affective disorder compared to controls.

Accelerated brain ageing has been observed in multiple psychiatric disorders. This study examined whether relationships between age and plasma neurofilament light (NfL) protein differed in individuals with psychiatric disorders (major depressive disorder (n = 42), bipolar affective disorder (n = 121), treatment-resistant schizophrenia (TRS, n = 82)) compared to two healthy control (HC) groups (n = 1,926 and n = 59). Compared to two independent HC samples, individuals with TRS demonstrated a stronger positive relationship between age and NfL levels. Individuals with BPAD had a stronger negative relationship between age and NfL levels compared to the large normative HC cohort, but not locally-acquired HCs. These findings show that plasma NfL levels are differentially associated with age in individuals with TRS and BPAD compared to healthy individuals.

Associations between structural brain changes and blood neurofilament light chain protein in treatment-resistant schizophrenia.

Background and Hypothesis: Around 30% of people with schizophrenia are refractory to antipsychotic treatment (treatment-resistant schizophrenia; TRS). While abnormal structural neuroimaging findings, in particular volume and thickness reductions, are often observed in schizophrenia, it is anticipated that biomarkers of neuronal injury like neurofilament light chain protein (NfL) can improve our understanding of the pathological basis underlying schizophrenia. The current study aimed to determine whether people with TRS demonstrate different associations between plasma NfL levels and regional cortical thickness reductions compared with controls. Study Design: Measurements of plasma NfL and cortical thickness were obtained from 39 individuals with TRS, and 43 healthy controls. T1-weighted magnetic resonance imaging sequences were obtained and processed via FreeSurfer. General linear mixed models adjusting for age and weight were estimated to determine whether the interaction between diagnostic group and plasma NfL level predicted lower cortical thickness across frontotemporal structures and the insula. Study Results: Significant (false discovery rate corrected) cortical thinning of the left (p = 0.001, η2p = 0.104) and right (p < 0.001, η2p = 0.167) insula was associated with higher levels of plasma NfL in TRS, but not in healthy controls. Conclusions: The association between regional thickness reduction of the insula bilaterally and plasma NfL may reflect a neurodegenerative process during the course of TRS. The findings of the present study suggest that some level of cortical degeneration localised to the bilateral insula may exist in people with TRS, which is not observed in the normal population.

Altered empathy processing in frontotemporal dementia A task-based fMRI study.

A lack of empathy, and particularly its affective components, is a core symptom of behavioural variant frontotemporal dementia (bvFTD). Visual exposure to images of a needle pricking a hand (pain condition) and Q-tips touching a hand (control condition) is an established functional magnetic resonance imaging (fMRI) paradigm used to investigate empathy for pain (EFP; pain condition minus control condition). EFP has been associated with increased blood oxygen level dependent (BOLD) signal in regions known to become atrophic in the early stages in bvFTD, including the anterior insula and the anterior cingulate. We therefore hypothesized that patients with bvFTD would display altered empathy processing in the EFP paradigm. Here we examined empathy processing using the EFP paradigm in 28 patients with bvFTD and 28 sex and age matched controls. Participants underwent structural MRI, task-based and resting-state fMRI. The Interpersonal Reactivity Index (IRI) was used as a measure of different facets of empathic function outside the scanner. The EFP paradigm was analysed at a whole brain level and using two regions-of-interest approaches, one based on a metanalysis of affective perceptual empathy versus cognitive evaluative empathy and one based on the controls activation pattern. In controls, EFP was linked to an expected increase of BOLD signal that displayed an overlap with the pattern of atrophy in the bvFTD patients (insula and anterior cingulate). Additional regions with increased signal were the supramarginal gyrus and the occipital cortex. These latter regions were the only ones that displayed increased BOLD signal in bvFTD patients. BOLD signal increase under the affective perceptual empathy but not the cognitive evaluative empathy region of interest was significantly greater in controls than in bvFTD patients. The controls rating on their empathic concern subscale of the IRI was significantly correlated with the BOLD signal in the EFP paradigm, as were an informants ratings of the patients empathic concern subscale. This correlation was not observed on other subscales of the IRI or when using the patient's self-ratings. Finally, controls and patients showed different connectivity patterns in empathy related networks during resting-state fMRI, mainly in nodes overlapping the ventral attention network. Our results indicate that reduced neural activity in regions typically affected by pathology in bvFTD is associated with reduced empathy processing, and a predictor of patients capacity to experience affective empathy.

Structural and microstructural thalamocortical network disruption in sporadic behavioural variant frontotemporal dementia.

BACKGROUND: Using multi-block methods we combined multimodal neuroimaging metrics of thalamic morphology, thalamic white matter tract diffusion metrics, and cortical thickness to examine changes in behavioural variant frontotemporal dementia. (bvFTD). METHOD: Twenty-three patients with sporadic bvFTD and 24 healthy controls underwent structural and diffusion MRI scans. Clinical severity was assessed using the Clinical Dementia Rating scale and behavioural severity using the Frontal Behaviour Inventory by patient caregivers. Thalamic volumes were manually segmented. Anterior and posterior thalamic radiation fractional anisotropy and mean diffusivity were extracted using Tract-Based Spatial Statistics. Finally, cortical thickness was assessed using Freesurfer. We used shape analyses, diffusion measures, and cortical thickness as features in sparse multi-block partial least squares (PLS) discriminatory analyses to classify participants within bvFTD or healthy control groups. Sparsity was tuned with five-fold cross-validation repeated 10 times. Final model fit was assessed using permutation testing. Additionally, sparse multi-block PLS was used to examine associations between imaging features and measures of dementia severity. RESULTS: Bilateral anterior-dorsal thalamic atrophy, reduction in mean diffusivity of thalamic projections, and frontotemporal cortical thinning, were the main features predicting bvFTD group membership. The model had a sensitivity of 96%, specificity of 68%, and was statistically significant using permutation testing (p = 0.012). For measures of dementia severity, we found similar involvement of regional thalamic and cortical areas as in discrimination analyses, although more extensive thalamo-cortical white matter metric changes. CONCLUSIONS: Using multimodal neuroimaging, we demonstrate combined structural network dysfunction of anterior cortical regions, cortical-thalamic projections, and anterior thalamic regions in sporadic bvFTD.

Anterior cingulate sulcation is associated with onset and survival in frontotemporal dementia.

Frontotemporal dementia is the second most common form of early onset dementia (<65 years). Despite this, there are few known disease-modifying factors. The anterior cingulate is a focal point of pathology in behavioural variant frontotemporal dementia. Sulcation of the anterior cingulate is denoted by the presence of a paracingulate sulcus, a tertiary sulcus developing, where present during the third gestational trimester and remaining stable throughout life. This study aims to examine the impact of right paracingulate sulcal presence on the expression and prognosis of behavioural variant frontotemporal dementia. This retrospective analysis drew its population from two clinical samples recruited from memory clinics at university hospitals in the USA and The Netherlands. Individuals with sporadic behavioural variant frontotemporal dementia were enrolled between 2000 and 2022 and followed up for an average of 7.71 years. T1-MRI data were evaluated for hemispheric paracingulate sulcal presence in accordance with an established protocol by two blinded raters. Outcome measures included age at onset, survival, cortical thickness and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating determined clinical disease progression. The study population consisted of 186 individuals with sporadic behavioural variant frontotemporal dementia (113 males and 73 females), mean age 63.28 years (SD 8.32). The mean age at onset was 2.44 years later in individuals possessing a right paracingulate sulcus [60.2 years (8.54)] versus individuals who did not [57.76 (8.05)], 95% confidence interval > 0.41, P = 0.02. Education was not associated with age at onset (ß = -0.05, P = 0.75). The presence of a right paracingulate sulcus was associated with an 83% increased risk of death per year after age at onset (hazard ratio 1.83, confidence interval [1.09-3.07], P < 0.02), whilst the mean age at death was similar for individuals with a present and absent right paracingulate sulcus (P = 0.7). Right paracingulate sulcal presence was not associated with baseline cortical thickness. Right paracingulate sulcal presence is associated with disease expression and survival in sporadic behavioural variant frontotemporal dementia. Findings provide evidence of neurodevelopmental brain reserve in behavioural variant frontotemporal dementia that may be important in the design of trials for future therapeutic approaches.

Anterior cingulate sulcation is associated with onset and survival in frontotemporal dementia.

Background: Frontotemporal dementia is the second most common form of early onset dementia (< 65 years). Despite this there are few known disease modifying factors. The anterior cingulate is a focal point of pathology in behavioural variant frontotemporal dementia. Sulcation of the anterior cingulate is denoted by the presence of a paracingulate sulcus, a tertiary sulcus developing, where present during the third gestational trimester and remaining stable throughout life. This study aims to examine the impact of right paracingulate sulcal presence on the expression and prognosis of behavioural variant Frontotemporal Dementia. Methods: This retrospective analysis drew it's population from two clinical samples recruited from memory clinics at University Hospitals in The United States of America and The Netherlands. Individuals with sporadic behavioural variant Frontotemporal Dementia were enrolled between 2004 and 2022 and followed up for an average of 7.71 years. T1-MRI data were evaluated for hemispheric paracingulate sulcal presence in accordance with an established protocol by two blinded raters. Outcome measures included age at onset, survival, cortical thickness, and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating determined clinical disease progression. Results: The study population consisted of 186 individuals with sporadic behavioural variant Frontotemporal Dementia, (113 males and 73 females) mean age 63.28 years (SD 8.32). The mean age at onset was 2.44 years later in individuals possessing a right paracingulate sulcus (60.2 years (SD 8.54)) versus individuals who did not (57.76 (8.05)), 95% CI >0.41, P = 0.02. Education was not associated with age at onset (ß = -0.05, P =0.75). Presence of a right paracingulate sulcus was associated with a 119% increased risk of death per year after age at onset (HR 2.19, CI [1.21 - 3.96], P <0.01), whilst the mean age at death was similar for individuals with a present and absent right paracingulate sulcus ( P = 0.7). Right paracingulate sulcal presence was not associated with baseline cortical thickness. Conclusion: Right paracingulate sulcal presence is associated with disease expression and survival in sporadic behavioural variant Frontotemporal Dementia. Findings provide evidence of neurodevelopmental brain reserve in behavioural variant Frontotemporal Dementia which may be important in the design of trials for future therapeutic approaches.