Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results.

GRN mutations cause progranulin haploinsufficiency, which eventually leads to frontotemporal dementia (FTD-GRN). PR006 is an investigational gene therapy delivering the granulin gene (GRN) using an adeno-associated virus serotype 9 (AAV9) vector. In non-clinical studies, PR006 transduced neurons derived from induced pluripotent stem cells of patients with FTD-GRN, resulted in progranulin expression and improvement of lipofuscin, lysosomal and neuroinflammation pathologies in Grn-knockout mice, and was well tolerated except for minimal, asymptomatic dorsal root ganglionopathy in non-human primates. We initiated a first-in-human phase 1/2 open-label trial. Here we report results of a pre-specified interim analysis triggered with the last treated patient of the low-dose cohort (n = 6) reaching the 12-month follow-up timepoint. We also include preliminary data from the mid-dose cohort (n = 7). Primary endpoints were safety, immunogenicity and change in progranulin levels in cerebrospinal fluid (CSF) and blood. Secondary endpoints were Clinical Dementia Rating (CDR) plus National Alzheimer's Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) rating scale and levels of neurofilament light chain (NfL). One-time administration of PR006 into the cisterna magna was generally safe and well tolerated. All patients developed treatment-emergent anti-AAV9 antibodies in the CSF, but none developed anti-progranulin antibodies. CSF pleocytosis was the most common PR006-related adverse event. Twelve serious adverse events occurred, mostly unrelated to PR006. Deep vein thrombosis developed in three patients. There was one death (unrelated) occurring 18 months after treatment. CSF progranulin increased after PR006 treatment in all patients; blood progranulin increased in most patients but only transiently. NfL levels transiently increased after PR006 treatment, likely reflecting dorsal root ganglia toxicity. Progression rates, based on the CDR scale, were within the broad ranges reported for patients with FTD. These data provide preliminary insights into the safety and bioactivity of PR006. Longer follow-up and additional studies are needed to confirm the safety and potential efficacy of PR006. ClinicalTrials.gov identifier: NCT04408625 .

Longitudinal cerebral perfusion in presymptomatic genetic frontotemporal dementia: GENFI results.

INTRODUCTION: Effective longitudinal biomarkers that track disease progression are needed to characterize the presymptomatic phase of genetic frontotemporal dementia (FTD). We investigate the utility of cerebral perfusion as one such biomarker in presymptomatic FTD mutation carriers. METHODS: We investigated longitudinal profiles of cerebral perfusion using arterial spin labeling magnetic resonance imaging in 42 C9orf72, 70 GRN, and 31 MAPT presymptomatic carriers and 158 non-carrier controls. Linear mixed effects models assessed perfusion up to 5 years after baseline assessment. RESULTS: Perfusion decline was evident in all three presymptomatic groups in global gray matter. Each group also featured its own regional pattern of hypoperfusion over time, with the left thalamus common to all groups. Frontal lobe regions featured lower perfusion in those who symptomatically converted versus asymptomatic carriers past their expected age of disease onset. DISCUSSION: Cerebral perfusion is a potential biomarker for assessing genetic FTD and its genetic subgroups prior to symptom onset. HIGHLIGHTS: Gray matter perfusion declines in at-risk genetic frontotemporal dementia (FTD). Regional perfusion decline differs between at-risk genetic FTD subgroups . Hypoperfusion in the left thalamus is common across all presymptomatic groups. Converters exhibit greater right frontal hypoperfusion than non-converters past their expected conversion date. Cerebral hypoperfusion is a potential early biomarker of genetic FTD.

Symptom-based staging for logopenic variant primary progressive aphasia.

BACKGROUND AND PURPOSE: Logopenic variant primary progressive aphasia (lvPPA) is a major variant presentation of Alzheimer's disease (AD) that signals the importance of communication dysfunction across AD phenotypes. A clinical staging system is lacking for the evolution of AD-associated communication difficulties that could guide diagnosis and care planning. Our aim was to create a symptom-based staging scheme for lvPPA, identifying functional milestones relevant to the broader AD spectrum. METHODS: An international lvPPA caregiver cohort was surveyed on symptom development under an 'exploratory' survey (34 UK caregivers). Feedback from this survey informed the development of a 'consolidation' survey (27 UK, 10 Australian caregivers) in which caregivers were presented with six provisional clinical stages and feedback was analysed using a mixed-methods approach. RESULTS: Six clinical stages were endorsed. Early symptoms included word-finding difficulty, with loss of message comprehension and speech intelligibility signalling later-stage progression. Additionally, problems with hearing in noise, memory and route-finding were prominent early non-verbal symptoms. 'Milestone' symptoms were identified that anticipate daily-life functional transitions and care needs. CONCLUSIONS: This work introduces a new symptom-based staging scheme for lvPPA, and highlights milestone symptoms that could inform future clinical scales for anticipating and managing communication dysfunction across the AD spectrum.

Extending the phenotypic spectrum assessed by the CDR plus NACC FTLD in genetic frontotemporal dementia.

INTRODUCTION: We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD). METHODS: Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD-NM scale. This was assessed in 522 mutation carriers and 310 mutation-negative controls from the Genetic Frontotemporal dementia Initiative (GENFI). RESULTS: The new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales. DISCUSSION: Adding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely. Highlights: The new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD-NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS).No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD-NM rating scale.Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains.A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales.

Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.

Diagnostic accuracy of research criteria for prodromal frontotemporal dementia.

BACKGROUND: The Genetic Frontotemporal Initiative Staging Group has proposed clinical criteria for the diagnosis of prodromal frontotemporal dementia (FTD), termed mild cognitive and/or behavioral and/or motor impairment (MCBMI). The objective of the study was to validate the proposed research criteria for MCBMI-FTD in a cohort of genetically confirmed FTD cases against healthy controls. METHODS: A total of 398 participants were enrolled, 117 of whom were carriers of an FTD pathogenic variant with mild clinical symptoms, while 281 were non-carrier family members (healthy controls (HC)). A subgroup of patients underwent blood neurofilament light (NfL) levels and anterior cingulate atrophy assessment. RESULTS: The core clinical criteria correctly classified MCBMI vs HC with an AUC of 0.79 (p < 0.001), while the addition of either blood NfL or anterior cingulate atrophy significantly increased the AUC to 0.84 and 0.82, respectively (p < 0.001). The addition of both markers further increased the AUC to 0.90 (p < 0.001). CONCLUSIONS: The proposed MCBMI criteria showed very good classification accuracy for identifying the prodromal stage of FTD.

Novel avenues of tau research.

INTRODUCTION: The pace of innovation has accelerated in virtually every area of tau research in just the past few years. METHODS: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation. RESULTS: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research. DISCUSSION: The virtual meeting provided an opportunity to foster cross-sector collaboration and partnerships as well as a forum for updating colleagues on research-advancing tools and programs that are steadily moving the field forward.

Binary reversals: a diagnostic sign in primary progressive aphasia.

BACKGROUND: Binary reversals (exemplified by 'yes'/'no' confusions) have been described in patients with primary progressive aphasia (PPA) but their diagnostic value and phenotypic correlates have not been defined. METHODS: We conducted a retrospective cohort study analysing demographic, clinical, neuropsychological, linguistic and behavioural data from patients representing all major PPA syndromes (non-fluent/agrammatic variant, nfvPPA; logopenic variant, lvPPA; semantic variant, svPPA) and behavioural variant frontotemporal dementia (bvFTD). The prevalence of binary reversals and behavioural abnormalities, illness duration, parkinsonian features and neuropsychological test scores were compared between neurodegenerative syndromes, and the diagnostic predictive value of binary reversals was assessed using logistic regression. RESULTS: Data were obtained for 83 patients (21 nfvPPA, 13 lvPPA, 22 svPPA, 27 bvFTD). Binary reversals occurred in all patients with nfvPPA, but significantly less frequently and later in lvPPA (54%), svPPA (9%) and bvFTD (44%). Patients with bvFTD with binary reversals had significantly more severe language (but not general executive or behavioural) deficits than those without reversals. Controlling for potentially confounding variables, binary reversals strongly predicted a diagnosis of nfvPPA over other syndromes. CONCLUSIONS: Binary reversals are a sensitive (though not specific) neurolinguistic feature of nfvPPA, and should suggest this diagnosis if present as a prominent early symptom.

Symptom-led staging for semantic and non-fluent/agrammatic variants of primary progressive aphasia.

INTRODUCTION: Here we set out to create a symptom-led staging system for the canonical semantic and non-fluent/agrammatic variants of primary progressive aphasia (PPA), which present unique diagnostic and management challenges not well captured by functional scales developed for Alzheimer's disease and other dementias. METHODS: An international PPA caregiver cohort was surveyed on symptom development under six provisional clinical stages and feedback was analyzed using a mixed-methods sequential explanatory design. RESULTS: Both PPA syndromes were characterized by initial communication dysfunction and non-verbal behavioral changes, with increasing syndromic convergence and functional dependency at later stages. Milestone symptoms were distilled to create a prototypical progression and severity scale of functional impairment: the PPA Progression Planning Aid ("PPA-Squared"). DISCUSSION: This work introduces a symptom-led staging scheme and functional scale for semantic and non-fluent/agrammatic variants of PPA. Our findings have implications for diagnostic and care pathway guidelines, trial design, and personalized prognosis and treatment for PPA. HIGHLIGHTS: We introduce new symptom-led perspectives on primary progressive aphasia (PPA). The focus is on non-fluent/agrammatic (nfvPPA) and semantic (svPPA) variants. Foregrounding of early and non-verbal features of PPA and clinical trajectories is featured. We introduce a symptom-led staging scheme for PPA. We propose a prototype for a functional impairment scale, the PPA Progression Planning Aid.

Primary progressive aphasia: six questions in search of an answer.

Here, we review recent progress in the diagnosis and management of primary progressive aphasia-the language-led dementias. We pose six key unanswered questions that challenge current assumptions and highlight the unresolved difficulties that surround these diseases. How many syndromes of primary progressive aphasia are there-and is syndromic diagnosis even useful? Are these truly 'language-led' dementias? How can we diagnose (and track) primary progressive aphasia better? Can brain pathology be predicted in these diseases? What is their core pathophysiology? In addition, how can primary progressive aphasia best be treated? We propose that pathophysiological mechanisms linking proteinopathies to phenotypes may help resolve the clinical complexity of primary progressive aphasia, and may suggest novel diagnostic tools and markers and guide the deployment of effective therapies.

Differential patterns of lysosomal dysfunction are seen in the clinicopathological forms of primary progressive aphasia.

Increasing evidence implicates endo-lysosomal dysfunction in frontotemporal dementia (FTD). 18 proteins were quantified using a mass spectrometry assay panel in the cerebrospinal fluid of 36 people with the language variant of FTD, primary progressive aphasia (PPA) (including 13 with non-fluent variant (nfvPPA), 11 with semantic variant (svPPA), and 12 with logopenic variant (lvPPA)) and 19 healthy controls. The concentrations of the cathepsins (B, D, F, L1, and Z) as well as AP-2 complex subunit beta, ganglioside GM2 activator, beta-hexosaminidase subunit beta, tissue alpha L-fucosidase, and ubiquitin were decreased in nfvPPA compared with controls. In contrast, the concentrations of amyloid beta A4 protein, cathepsin Z, and dipeptidyl peptidase 2 were decreased in svPPA compared with controls. No proteins were abnormal in lvPPA. These results indicate a differential alteration of lysosomal proteins in the PPA variants, suggesting those with non-Alzheimer's pathologies are more likely to show abnormal lysosomal function.

Identifying and Diagnosing TDP-43 Neurodegenerative Diseases in Psychiatry.

Neuropsychiatric symptoms (NPS) are common manifestations of neurodegenerative disorders and are often early signs of those diseases. Among those neurodegenerative diseases, TDP-43 proteinopathies are an increasingly recognized cause of early neuropsychiatric manifestations. TDP-43-related diseases include frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE). The majority of TDP-43-related diseases are sporadic, but a significant proportion is hereditary, with progranulin (GRN) mutations and C9orf72 repeat expansions as the most common genetic etiologies. Studies reveal that NPS can be the initial manifestation of those diseases or can complicate disease course, but there is a lack of awareness among clinicians about TDP-43-related diseases, which leads to common diagnostic mistakes or delays. There is also emerging evidence that TDP-43 accumulations could play a role in late-onset primary psychiatric disorders. In the absence of robust biomarkers for TDP-43, the diagnosis remains primarily based on clinical assessment and neuroimaging. Given the association with psychiatric symptoms, clinical psychiatrists have a key role in the early identification of patients with TDP-43-related diseases. This narrative review provides a comprehensive overview of the pathobiology of TDP-43, resulting clinical presentations, and associated neuropsychiatric manifestations to help guide clinical practice.

Altered plasma protein profiles in genetic FTD - a GENFI study.

BACKGROUND: Plasma biomarkers reflecting the pathology of frontotemporal dementia would add significant value to clinical practice, to the design and implementation of treatment trials as well as our understanding of disease mechanisms. The aim of this study was to explore the levels of multiple plasma proteins in individuals from families with genetic frontotemporal dementia. METHODS: Blood samples from 693 participants in the GENetic Frontotemporal Dementia Initiative study were analysed using a multiplexed antibody array targeting 158 proteins. RESULTS: We found 13 elevated proteins in symptomatic mutation carriers, when comparing plasma levels from people diagnosed with genetic FTD to healthy non-mutation controls and 10 proteins that were elevated compared to presymptomatic mutation carriers. CONCLUSION: We identified plasma proteins with altered levels in symptomatic mutation carriers compared to non-carrier controls as well as to presymptomatic mutation carriers. Further investigations are needed to elucidate their potential as fluid biomarkers of the disease process.

Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit.

A summit held March 2023 in Scottsdale, Arizona (USA) focused on the intronic hexanucleotide expansion in the C9ORF72 gene and its relevance in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS; C9ORF72-FTD/ALS). The goal of this summit was to connect basic scientists, clinical researchers, drug developers, and individuals affected by C9ORF72-FTD/ALS to evaluate how collaborative efforts across the FTD-ALS disease spectrum might break down existing disease silos. Presentations and discussions covered recent discoveries in C9ORF72-FTD/ALS disease mechanisms, availability of disease biomarkers and recent advances in therapeutic development, and clinical trial design for prevention and treatment for individuals affected by C9ORF72-FTD/ALS and asymptomatic pathological expansion carriers. The C9ORF72-associated hexanucleotide repeat expansion is an important locus for both ALS and FTD. C9ORF72-FTD/ALS may be characterized by loss of function of the C9ORF72 protein and toxic gain of functions caused by both dipeptide repeat (DPR) proteins and hexanucleotide repeat RNA. C9ORF72-FTD/ALS therapeutic strategies discussed at the summit included the use of antisense oligonucleotides, adeno-associated virus (AAV)-mediated gene silencing and gene delivery, and engineered small molecules targeting RNA structures associated with the C9ORF72 expansion. Neurofilament light chain, DPR proteins, and transactive response (TAR) DNA-binding protein 43 (TDP-43)-associated molecular changes were presented as biomarker candidates. Similarly, brain imaging modalities (i.e., magnetic resonance imaging [MRI] and positron emission tomography [PET]) measuring structural, functional, and metabolic changes were discussed as important tools to monitor individuals affected with C9ORF72-FTD/ALS, at both pre-symptomatic and symptomatic disease stages. Finally, summit attendees evaluated current clinical trial designs available for FTD or ALS patients and concluded that therapeutics relevant to FTD/ALS patients, such as those specifically targeting C9ORF72, may need to be tested with composite endpoints covering clinical symptoms of both FTD and ALS. The latter will require novel clinical trial designs to be inclusive of all patient subgroups spanning the FTD/ALS spectrum.

The C9ORF72 Summit was held in March 2023 in Scottsdale, Arizona (USA). Some people who have the disease frontotemporal dementia or the disease amyotrophic lateral sclerosis have a change in one of their genes; the name of the gene is C9ORF72. People who carry this genetic difference usually inherited it from a parent. Researchers are improving their understanding of how the change in the C9ORF72 gene affects people, and efforts are being made to use this knowledge to develop treatments for amyotrophic lateral sclerosis and frontotemporal dementia. In addition to studying the cellular and molecular mechanisms of how the C9ORF72 mutation leads to cellular dysfunction and frontotemporal dementia and amyotrophic lateral sclerosis clinical symptoms, a large effort of the research community is aimed at developing measurements, called biomarkers, that could enhance therapy development efforts in multiple ways. Examples include monitoring of disease activity, identifying those at risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, predicting which people might benefit from a particular treatment, and showing that a drug has had a biological effect. Markers that identify healthy people who are at risk of developing amyotrophic lateral sclerosis or frontotemporal dementia could be used to test treatments that would start before a person shows any symptoms and hopefully would delay or even prevent their onset.

microRNA-based predictor for diagnosis of frontotemporal dementia.

AIMS: This study aimed to explore the non-linear relationships between cell-free microRNAs (miRNAs) and their contribution to prediction of Frontotemporal dementia (FTD), an early onset dementia that is clinically heterogeneous, and too often suffers from delayed diagnosis. METHODS: We initially studied a training cohort of 219 subjects (135 FTD and 84 non-neurodegenerative controls) and then validated the results in a cohort of 74 subjects (33 FTD and 41 controls). RESULTS: On the basis of cell-free plasma miRNA profiling by next generation sequencing and machine learning approaches, we develop a non-linear prediction model that accurately distinguishes FTD from non-neurodegenerative controls in ~90% of cases. CONCLUSIONS: The fascinating potential of diagnostic miRNA biomarkers might enable early-stage detection and a cost-effective screening approach for clinical trials that can facilitate drug development.

Defining the presymptomatic phase of frontotemporal dementia.

PURPOSE OF REVIEW: Frontotemporal dementia (FTD) is a clinically, pathologically and genetically heterogeneous disorder. Whilst disease modifying therapy trials are mostly focused on the symptomatic phase, future studies will move earlier in the disease aiming to prevent symptom onset. This review summarizes the recent work to better understand this presymptomatic period. RECENT FINDINGS: The presymptomatic phase can be split into preclinical and prodromal stages. The onset of the preclinical phase is defined by the first presence of pathological inclusions of tau, TDP-43 or fused in sarcoma in the brain. Definitive biomarkers of these pathologies do not yet exist for FTD. The prodromal phase is defined by the onset of mild symptoms. Recent work has highlighted the wide phenotypic spectrum that occurs, with the concept of mild cognitive ± behavioural ± motor impairment (MCBMI) being put forward, and additions to scales such as the CDR plus NACC FTLD now incorporating neuropsychiatric and motor symptoms. SUMMARY: It will be important to better characterize the presymptomatic period moving forward and develop robust biomarkers that can be used both for stratification and outcome measures in prevention trials. The work of the FTD Prevention Initiative aims to facilitate this by bringing together data from natural history studies across the world.

Prodromal language impairment in genetic frontotemporal dementia within the GENFI cohort.

OBJECTIVE: To identify whether language impairment exists presymptomatically in genetic frontotemporal dementia (FTD), and if so, the key differences between the main genetic mutation groups. METHODS: 682 participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 290 asymptomatic and 82 prodromal mutation carriers (with C9orf72, GRN, and MAPT mutations) as well as 310 mutation-negative controls. Language was assessed using items from the Progressive Aphasia Severity Scale, as well as the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency task. Participants also underwent a 3 T volumetric T1-weighted MRI from which regional brain volumes within the language network were derived and compared between the groups. RESULTS: 3% of asymptomatic (4% C9orf72, 4% GRN, 2% MAPT) and 48% of prodromal (46% C9orf72, 42% GRN, 64% MAPT) mutation carriers had impairment in at least one language symptom compared with 13% of controls. In prodromal mutation carriers significantly impaired word retrieval was seen in all three genetic groups whilst significantly impaired grammar/syntax and decreased fluency was seen only in C9orf72 and GRN mutation carriers, and impaired articulation only in the C9orf72 group. Prodromal MAPT mutation carriers had significant impairment on the category fluency task and the BNT whilst prodromal C9orf72 mutation carriers were impaired on the category fluency task only. Atrophy in the dominant perisylvian language regions differed between groups, with earlier, more widespread volume loss in C9orf72, and later focal atrophy in the temporal lobe in MAPT mutation carriers. CONCLUSIONS: Language deficits exist in the prodromal but not asymptomatic stages of genetic FTD across all three genetic groups. Improved understanding of the language phenotype prior to phenoconversion to fully symptomatic FTD will help develop outcome measures for future presymptomatic trials.

Domain-agnostic segmentation of thalamic nuclei from joint structural and diffusion MRI.

The human thalamus is a highly connected subcortical grey-matter structure within the brain. It comprises dozens of nuclei with different function and connectivity, which are affected differently by disease. For this reason, there is growing interest in studying the thalamic nuclei in vivo with MRI. Tools are available to segment the thalamus from 1 mm T1 scans, but the contrast of the lateral and internal boundaries is too faint to produce reliable segmentations. Some tools have attempted to incorporate information from diffusion MRI in the segmentation to refine these boundaries, but do not generalise well across diffusion MRI acquisitions. Here we present the first CNN that can segment thalamic nuclei from T1 and diffusion data of any resolution without retraining or fine tuning. Our method builds on a public histological atlas of the thalamic nuclei and silver standard segmentations on high-quality diffusion data obtained with a recent Bayesian adaptive segmentation tool. We combine these with an approximate degradation model for fast domain randomisation during training. Our CNN produces a segmentation at 0.7 mm isotropic resolution, irrespective of the resolution of the input. Moreover, it uses a parsimonious model of the diffusion signal at each voxel (fractional anisotropy and principal eigenvector) that is compatible with virtually any set of directions and b-values, including huge amounts of legacy data. We show results of our proposed method on three heterogeneous datasets acquired on dozens of different scanners. An implementation of the method is publicly available at https://freesurfer.net/fswiki/ThalamicNucleiDTI.

Accurate Bayesian segmentation of thalamic nuclei using diffusion MRI and an improved histological atlas.

The human thalamus is a highly connected brain structure, which is key for the control of numerous functions and is involved in several neurological disorders. Recently, neuroimaging studies have increasingly focused on the volume and connectivity of the specific nuclei comprising this structure, rather than looking at the thalamus as a whole. However, accurate identification of cytoarchitectonically designed histological nuclei on standard in vivo structural MRI is hampered by the lack of image contrast that can be used to distinguish nuclei from each other and from surrounding white matter tracts. While diffusion MRI may offer such contrast, it has lower resolution and lacks some boundaries visible in structural imaging. In this work, we present a Bayesian segmentation algorithm for the thalamus. This algorithm combines prior information from a probabilistic atlas with likelihood models for both structural and diffusion MRI, allowing segmentation of 25 thalamic labels per hemisphere informed by both modalities. We present an improved probabilistic atlas, incorporating thalamic nuclei identified from histology and 45 white matter tracts surrounding the thalamus identified in ultra-high gradient strength diffusion imaging. We present a family of likelihood models for diffusion tensor imaging, ensuring compatibility with the vast majority of neuroimaging datasets that include diffusion MRI data. The use of these diffusion likelihood models greatly improves identification of nuclear groups versus segmentation based solely on structural MRI. Dice comparison of 5 manually identifiable groups of nuclei to ground truth segmentations show improvements of up to 10 percentage points. Additionally, our chosen model shows a high degree of reliability, with median test-retest Dice scores above 0.85 for four out of five nuclei groups, whilst also offering improved detection of differential thalamic involvement in Alzheimer's disease (AUROC 81.98%). The probabilistic atlas and segmentation tool will be made publicly available as part of the neuroimaging package FreeSurfer (https://freesurfer.net/fswiki/ThalamicNucleiDTI).