Right temporal variant frontotemporal dementia is pathologically heterogeneous: a case-series and a systematic review

Although the right temporal variant frontotemporal dementia (rtvFTD) is characterised by distinct clinical and radiological features, its underlying histopathology remains elusive. Being considered a right-sided variant of semantic variant primary progressive aphasia (svPPA), TDP-43 type C pathology has been linked to the syndrome, but this has not been studied in detail in large cohorts. In this case report and systematic review, we report the autopsy results of five subjects diagnosed with rtvFTD from our cohort and 44 single rtvFTD subjects from the literature. Macroscopic pathological evaluation of the combined results revealed that rtvFTD demonstrated either a frontotemporal or temporal evolution, even if the degeneration started in the right temporal lobe initially. FTLD-TDP type C was the most common underlying pathology in rtvFTD, however, in 64% of rtvFTD, other underlying pathologies than FTLD-TDP type C were present, such as Tau-MAPT and FTLD-TDP type A and B. Additionally, accompanying motor neuron or corticospinal tract degeneration was observed in 28% of rtvFTD patients. Our results show that in contrast to the general assumption, rtvFTD might not be a pure FTLD-TDP type C disorder, unlike its left temporal counterpart svPPA. Large sample size pathological studies are warranted to understand the diverse pathologies of the right and left temporal variants of frontotemporal dementia

Diagnostic Accuracy of the Frontotemporal Dementia Consensus Criteria in the Late-Onset Frontal Lobe Syndrome

BACKGROUND/AIMS: We aimed to prospectively assess the diagnostic accuracy of the revised criteria for behavioural variant frontotemporal dementia (bvFTD) among subjects presenting with a frontal lobe syndrome in middle-late adulthood. METHODS: Patients were included based on a predominant behavioural clinical presentation, a Frontal Behavioural Inventory (FBI) score of ≥11 and/or a Stereotypy Rating Inventory (SRI) score of ≥10. At baseline, the fulfilment of the international consensus criteria for behavioural variant FTD (FTDC) was systematically recorded. The 2-year follow-up consensus diagnosis was used as the gold standard to calculate sensitivity and specificity of the FTDC criteria for possible and probable bvFTD. RESULTS: Two-year follow-up data were available for 116 patients (85%). Two-year follow-up consensus diagnoses consisted of probable/definite bvFTD (n = 27), other dementia (n = 30), psychiatric disorders (n = 46) and other neurological disorders (n = 13). Sensitivity for possible bvFTD was 85% (95% CI 70-95%) at a specificity of 27% (95% CI 19-37%). Sensitivity for probable bvFTD was 85% (95% CI 69-95%), whereas their specificity was 82% (95% CI 73-89%). CONCLUSIONS: We found a good diagnostic accuracy for FTDC probable bvFTD. However, the specificity for FTDC possible bvFTD was low. Our results reflect the symptomatic overlap between bvFTD, other neurological conditions and psychiatric disorders, and the relevance of adding neuroimaging to the diagnostic process

Investigating the clinico-anatomical dissociation in the behavioral variant of Alzheimer disease

BACKGROUND: We previously found temporoparietal-predominant atrophy patterns in the behavioral variant of Alzheimer's disease (bvAD), with relative sparing of frontal regions. Here, we aimed to understand the clinico-anatomical dissociation in bvAD based on alternative neuroimaging markers. METHODS: We retrospectively included 150 participants, including 29 bvAD, 28 "typical" amnestic-predominant AD (tAD), 28 behavioral variant of frontotemporal dementia (bvFTD), and 65 cognitively normal participants. Patients with bvAD were compared with other diagnostic groups on glucose metabolism and metabolic connectivity measured by [18F]FDG-PET, and on subcortical gray matter and white matter hyperintensity (WMH) volumes measured by MRI. A receiver-operating-characteristic-analysis was performed to determine the neuroimaging measures with highest diagnostic accuracy. RESULTS: bvAD and tAD showed predominant temporoparietal hypometabolism compared to controls, and did not differ in direct contrasts. However, overlaying statistical maps from contrasts between patients and controls revealed broader frontoinsular hypometabolism in bvAD than tAD, partially overlapping with bvFTD. bvAD showed greater anterior default mode network (DMN) involvement than tAD, mimicking bvFTD, and reduced connectivity of the posterior cingulate cortex with prefrontal regions. Analyses of WMH and subcortical volume showed closer resemblance of bvAD to tAD than to bvFTD, and larger amygdalar volumes in bvAD than tAD respectively. The top-3 discriminators for bvAD vs. bvFTD were FDG posterior-DMN-ratios (bvADbvFTD, area under the curve [AUC] range 0.85-0.91, all p tAD), MRI anterior-DMN-ratios (bvAD<tAD), FDG anterior-DMN-ratios (bvAD<tAD, AUC range 0.71-0.84, all p < 0.05). CONCLUSIONS: Subtle frontoinsular hypometabolism and anterior DMN involvement may underlie the prominent behavioral phenotype in bvAD

Latent atrophy factors related to phenotypical variants of posterior cortical atrophy

OBJECTIVE: To determine whether atrophy relates to phenotypical variants of posterior cortical atrophy (PCA) recently proposed in clinical criteria; dorsal, ventral, dominant-parietal and caudal, we assessed associations between latent atrophy factors and cognition. METHODS: We employed a data-driven Bayesian modelling framework based on latent Dirichlet allocation to identify latent atrophy factors in a multi-center cohort of 119 individuals with PCA (age:64±7, 38% male, MMSE:21±5, 71% amyloid-β-positive, 29% amyloid-β status unknown). The model uses standardized gray matter density images as input (adjusted for age, sex, intracranial volume, field-strength and whole-brain gray matter volume) and provides voxelwise probabilistic maps for a predetermined number of atrophy factors, allowing every individual to express each factor to a degree without a-priori classification. Individual factor expressions were correlated to four PCA-specific cognitive domains (object-perception, space-perception, non-visual/parietal functions and primary visual processing) using general linear models. RESULTS: The model revealed four distinct yet partially overlapping atrophy factors; right-dorsal, right-ventral, left-ventral, and limbic. We found that object-perception and primary visual processing were associated with atrophy that predominantly reflects the right-ventral factor. Furthermore, space-perception was associated with atrophy that predominantly represents the right-dorsal and right-ventral factors. However, individual participant profiles revealed that the vast majority expressed multiple atrophy factors and had mixed clinical profiles with impairments across multiple domains, rather than displaying a discrete clinical-radiological phenotype. CONCLUSION: Our results indicate that particular brain-behavior networks are vulnerable in PCA, but most individuals display a constellation of affected brain-regions and symptoms, indicating that classification into four mutually exclusive variants is unlikely to be clinically useful

The natural history of primary progressive aphasia: beyond aphasia

Introduction: Primary progressive aphasia (PPA) is divided into three prototypical subtypes that are all characterized by their single core symptom of aphasia. Although later in their course, other cognitive, behavioral, and motor domains may become involved, little is known about the progression profile of each subtype relative to the other subtypes. Methods: In this longitudinal retrospective cohort study, based on the recent biomarker-supported diagnostic criteria, 24 subjects diagnosed with semantic variant (svPPA), 22 with non-fluent variant (nfvPPA), and 18 with logopenic variant (lvPPA) were collected and followed up for 1–6 years. Symptom distribution, cognitive test and neuropsychiatric inventory scores, and progression into another syndrome were assessed. Results: Over time, lvPPA progressed with broader language problems (PPA-extended) and nfvPPA progressed to mutism, whereas semantic impairment remained the major problem in svPPA. Apart from linguistic problems, svPPA developed pronounced behavioral disturbances, whereas lvPPA exhibited a greater cognitive decline. By contrast, in nfvPPA motor deficits were more common. Furthermore, within 5 years (IQR = 2.5) after clinical onset, 65.6% of the patients additionally fulfilled the clinical criteria for another neurodegenerative syndrome (PPA-plus). Fourteen out of 24 (58%) svPPA patients additionally met the diagnostic criteria of behavioral variant frontotemporal dementia (5.1 years, IQR = 1.1), whereas the clinical features of 15/18 (83%) lvPPA patients were consistent with Alzheimer disease dementia (4.5 years IQR = 3.4). Furthermore, 12/22 (54%) of the subjects with the nfvPPA progressed to meet the diagnostic criteria of corticobasal syndrome, progressive supranuclear palsy, or motor neuron disease (5.1 years IQR = 3.4). Discussion: Despite aphasia being the initial and unique hallmark of the syndrome, our longitudinal results showed that PPA is not a language limited disorder and progression differs widely for each subtype, both with respect to the nature of symptoms and disease duration

Differential patterns of gray matter volumes and associated gene expression profiles in cognitively-defined Alzheimer's disease subgroups

The clinical presentation of Alzheimer’s disease (AD) varies widely across individuals but the neurobiological mechanisms underlying this heterogeneity are largely unknown. Here, we compared regional gray matter (GM) volumes and associated gene expression profiles between cognitively-defined subgroups of amyloid-β positive individuals clinically diagnosed with AD dementia (age: 66 ± 7, 47% male, MMSE: 21 ± 5). All participants underwent neuropsychological assessment with tests covering memory, executive-functioning, language and visuospatial-functioning domains. Subgroup classification was achieved using a psychometric framework that assesses which cognitive domain shows substantial relative impairment compared to the intra-individual average across domains, which yielded the following subgroups in our sample; AD-Memory (n = 41), AD-Executive (n = 117), AD-Language (n = 33), AD-Visuospatial (n = 171). We performed voxel-wise contrasts of GM volumes derived from 3Tesla structural MRI between subgroups and controls (n = 127, age 58 ± 9, 42% male, MMSE 29 ± 1), and observed that differences in regional GM volumes compared to controls closely matched the respective cognitive profiles. Specifically, we detected lower medial temporal lobe GM volumes in AD-Memory, lower fronto-parietal GM volumes in AD-Executive, asymmetric GM volumes in the temporal lobe (left < right) in AD-Language, and lower GM volumes in posterior areas in AD-Visuospatial. In order to examine possible biological drivers of these differences in regional GM volumes, we correlated subgroup-specific regional GM volumes to brain-wide gene expression profiles based on a stereotactic characterization of the transcriptional architecture of the human brain as provided by the Allen human brain atlas. Gene-set enrichment analyses revealed that variations in regional expression of genes involved in processes like mitochondrial respiration and metabolism of proteins were associated with patterns of regional GM volume across multiple subgroups. Other gene expression vs GM volume-associations were only detected in particular subgroups, e.g., genes involved in the cell cycle for AD-Memory, specific sets of genes related to protein metabolism in AD-Language, and genes associated with modification of gene expression in AD-Visuospatial. We conclude that cognitively-defined AD subgroups show neurobiological differences, and distinct biological pathways may be involved in the emergence of these differences

Diagnostic Accuracy of MRI and Additional [F-18]FDG-PET for Behavioral Variant Frontotemporal Dementia in Patients with Late Onset Behavioral Changes

BACKGROUND: Neuroimaging has a reasonable accuracy to differentiate behavioral variant frontotemporal dementia (bvFTD) from other neurodegenerative disorders, its value for the differentiation of bvFTD among subjects with acquired behavioral disturbances is unknown. OBJECTIVE: To determine the diagnostic accuracy of MRI, additional [18F]FDG-PET, and their combination for bvFTD among subjects with late onset behavioral changes. METHODS: Patients with late onset behavioral changes referred to a memory clinic or psychiatric services were included. At baseline, 111 patients had a brain MRI scan and 74 patients received an additional [18F]FDG-PET when the MRI was inconclusive. The consensus diagnosis after two-year-follow-up was used as the gold standard to calculate sensitivity and specificity for baseline neuroimaging. RESULTS: 27 patients had probable/definite bvFTD and 84 patients had a non-bvFTD diagnosis (primary psychiatric diagnosis or other neurological disorders). MRI had a sensitivity of 70% (95% CI 52–85%) with a specificity of 93% (95% CI 86–97%). Additional [18F]FDG-PET had a sensitivity of 90% (95% CI 66–100%) with a specificity of 68% (95% CI 56–79%). The sensitivity of combined neuroimaging was 96% (95% CI 85–100%) with a specificity of 73% (95% CI 63–81%). In 66% of the genetic FTD cases, MRI lacked typical frontotemporal atrophy. 40% of cases with a false positive [18F]FDG-PET scan had a primary psychiatric diagnosis. CONCLUSION: A good diagnostic accuracy was found for MRI and additional [18F]FDG-PET for bvFTD in patients with late onset behavioral changes. Caution with the interpretation of neuroimaging results should especially be taken in cases with a genetic background and in cases with a primary psychiatric differential diagnosis where [18F]FDG-PET is the only abnormal investigation

[18F]Flortaucipir PET Across Various MAPT Mutations in Presymptomatic and Symptomatic Carriers

OBJECTIVE: To assess the [18F]flortaucipir binding distribution across MAPT mutations in presymptomatic and symptomatic carriers. METHODS: We compared regional [18F]flortaucipir binding potential(BPND) derived from a 130-minute dynamic [18F]flortaucipir PET scan, in nine (pre)symptomatic MAPT mutation carriers(4 with P301L[1 symptomatic], 2 with R406W[1 symptomatic]; 1 presymptomatic L315R, 1 presymptomatic S320F and 1 symptomatic G272V carrier) with 30 cognitively normal controls and 52 Alzheimer's disease patients. RESULTS: [18F]flortaucipir BPND images showed overall highest binding in the symptomatic carriers. This was most pronounced in the symptomatic R406W carrier in whom tau binding exceeded the normal control range in the anterior cingulate cortex, insula, amygdala, temporal, parietal and frontal lobe. Elevated medial temporal lobe BPND was observed in a presymptomatic R406W carrier. The single symptomatic and one of the three presymptomatic P301L carriers showed elevated [18F]flortaucipir BPND in the insula, parietal and frontal lobe compared to controls. The symptomatic G272V carrier exhibited a widespread elevated cortical BPND, with at neuropathological examination a combination of 3R pathology and encephalitis. The L315R presymptomatic mutation carrier showed higher frontal BPND compared to controls. The BPND values of the S320F presymptomatic mutation carrier fell within the range of controls. CONCLUSION: Presymptomatic MAPT mutation carriers already showed subtle elevated tau binding, whereas symptomatic MAPT mutation carriers showed a more marked increase in [18F]flortaucipir BPND. Tau deposition was most pronounced in R406W MAPT (pre)symptomatic mutation carriers, which is associated with both 3R and 4R tau accumulation. Thus, [18F]flortaucipir may serve as an early biomarker for MAPT mutation carriers in mutations that cause 3R/4R tauopathies

Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study

Neuroinflammation is emerging as an important pathological process in frontotemporal dementia (FTD), but biomarkers are lacking. We aimed to determine the value of complement proteins, which are key components of innate immunity, as biomarkers in cerebrospinal fluid (CSF) and plasma of presymptomatic and symptomatic genetic FTD mutation carriers.We measured the complement proteins C1q and C3b in CSF by ELISAs in 224 presymptomatic and symptomatic GRN, C9orf72 or MAPT mutation carriers and non-carriers participating in the Genetic Frontotemporal Dementia Initiative (GENFI), a multicentre cohort study. Next, we used multiplex immunoassays to measure a panel of 14 complement proteins in plasma of 431 GENFI participants. We correlated complement protein levels with corresponding clinical and neuroimaging data, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP).CSF C1q and C3b, as well as plasma C2 and C3, were elevated in symptomatic mutation carriers compared to presymptomatic carriers and non-carriers. In genetic subgroup analyses, these differences remained statistically significant for C9orf72 mutation carriers. In presymptomatic carriers, several complement proteins correlated negatively with grey matter volume of FTD-related regions and positively with NfL and GFAP. In symptomatic carriers, correlations were additionally observed with disease duration and with Mini Mental State Examination and Clinical Dementia Rating scale® plus NACC Frontotemporal lobar degeneration sum of boxes scores.Elevated levels of CSF C1q and C3b, as well as plasma C2 and C3, demonstrate the presence of complement activation in the symptomatic stage of genetic FTD. Intriguingly, correlations with several disease measures in presymptomatic carriers suggest that complement protein levels might increase before symptom onset. Although the overlap between groups precludes their use as diagnostic markers, further research is needed to determine their potential to monitor dysregulation of the complement system in FTD.© 2022. The Author(s)

A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia

Several CSF and blood biomarkers for genetic frontotemporal dementia (FTD) have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH)), synapse dysfunction (neuronal pentraxin 2 (NPTX2)), astrogliosis (glial fibrillary acidic protein (GFAP)), and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage FTD, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic FTD using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. 275 presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialised DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on prior diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF NfL, blood pNfH, blood GFAP, and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve (AUC) of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The AUC to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic FTD revealed that NPTX2 and NfL are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions