scholarly journals Redefining the multidimensional clinical phenotypes of frontotemporal lobar degeneration syndromes

Brain ◽  
2020 ◽  
Vol 143 (5) ◽  
pp. 1555-1571 ◽  
Author(s):  
Alexander G Murley ◽  
Ian Coyle-Gilchrist ◽  
Matthew A Rouse ◽  
P Simon Jones ◽  
Win Li ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Frontotemporal Dementia ◽  
Diagnostic Criteria ◽  
Clinical Features ◽  
Frontotemporal Lobar Degeneration ◽  
Clinical Phenotype ◽  
Principal Component ◽  
Corticobasal Syndrome ◽  
Diagnostic Features ◽  
Cross Sectional

Abstract The syndromes caused by frontotemporal lobar degeneration have highly heterogeneous and overlapping clinical features. There has been great progress in the refinement of clinical diagnostic criteria in the past decade, but we propose that a better understanding of aetiology, pathophysiology and symptomatic treatments can arise from a transdiagnostic approach to clinical phenotype and brain morphometry. In a cross-sectional epidemiological study, we examined 310 patients with a syndrome likely to be caused by frontotemporal lobar degeneration, including behavioural variant frontotemporal dementia, non-fluent, and semantic variants of primary progressive aphasia (PPA), progressive supranuclear palsy and corticobasal syndrome. We included patients with logopenic PPA and those who met criteria for PPA but not a specific subtype. To date, 49 patients have a neuropathological diagnosis. A principal component analysis identified symptom dimensions that broadly recapitulated the core features of the main clinical syndromes. However, the subject-specific scores on these dimensions showed considerable overlap across the diagnostic groups. Sixty-two per cent of participants had phenotypic features that met the diagnostic criteria for more than one syndrome. Behavioural disturbance was prevalent in all groups. Forty-four per cent of patients with corticobasal syndrome had progressive supranuclear palsy-like features and 30% of patients with progressive supranuclear palsy had corticobasal syndrome-like features. Many patients with progressive supranuclear palsy and corticobasal syndrome had language impairments consistent with non-fluent variant PPA while patients with behavioural variant frontotemporal dementia often had semantic impairments. Using multivariate source-based morphometry on a subset of patients (n = 133), we identified patterns of covarying brain atrophy that were represented across the diagnostic groups. Canonical correlation analysis of clinical and imaging components found three key brain-behaviour relationships, with a continuous spectrum across the cohort rather than discrete diagnostic entities. In the 46 patients with follow-up (mean 3.6 years) syndromic overlap increased with time. Together, these results show that syndromes associated with frontotemporal lobar degeneration do not form discrete mutually exclusive categories from their clinical features or structural brain changes, but instead exist in a multidimensional spectrum. Patients often manifest diagnostic features of multiple disorders while deficits in behaviour, movement and language domains are not confined to specific diagnostic groups. It is important to recognize individual differences in clinical phenotype, both for clinical management and to understand pathogenic mechanisms. We suggest that a transdiagnostic approach to the spectrum of frontotemporal lobar degeneration syndromes provides a useful framework with which to understand disease aetiology, progression, and heterogeneity and to target future treatments to a higher proportion of patients.

scholarly journals Redefining the multidimensional clinical phenotypes of frontotemporal lobar degeneration syndromes

2019 ◽  
Author(s):  
Alexander G. Murley ◽  
Ian Coyle-Gilchrist ◽  
Matthew Rouse ◽  
P Simon Jones ◽  
Win Li ◽  
...  
Keyword(s):  
Diagnostic Criteria ◽  
Clinical Features ◽  
Frontotemporal Lobar Degeneration ◽  
Clinical Phenotype ◽  
Principal Component ◽  
Primary Progressive Aphasia ◽  
Diagnostic Features ◽  
Cross Sectional ◽  
Progressive Aphasia ◽  
Primary Progressive

AbstractThe syndromes caused by frontotemporal lobar degeneration (FTLD) have highly heterogenous and overlapping clinical features. There has been great progress in the refinement of clinical diagnostic criteria in the last decade, but we propose that a better understanding of aetiology, pathophysiology and symptomatic treatments can arise from a transdiagnostic approach to clinical phenotype and brain morphometry. In a cross-sectional epidemiological study, we examined 310 patients with a syndrome likely to be caused by frontotemporal lobar degeneration, including behavioural variant frontotemporal dementia (bvFTD), the non-fluent (nfvPPA), semantic (svPPA) variants of primary progressive aphasia, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We also included patients with logopenic primary progressive aphasia (lvPPA) and those who met criteria for PPA but not one of the three subtypes. To date, forty-nine patients have a neuropathological diagnosis. A principal component analysis identified symptom dimensions that broadly recapitulated the core features of the main clinical syndromes. However, the subject-specific scores on these dimensions showed considerable overlap across the diagnostic groups. Sixty-two percent of participants had phenotypic features that met the diagnostic criteria for more than one syndrome. Behavioural disturbance was prevalent in all groups. Forty-four percent of patients with CBS had PSP-like features and thirty percent of patients with PSP had CBS-like features. Many patients with PSP and CBS had language impairments consistent with nfvPPA while patients with bvFTD often had semantic impairments. Using multivariate source-based morphometry on a subset of patients (n=133), we identified patterns of co-varying brain atrophy that were represented across the diagnostic groups. Canonical correlation analysis of clinical and imaging components found three key brain-behaviour relationships that revealed a continuous spectrum across the cohort rather than discrete diagnostic entities. In the forty-six patients with longitudinal follow up (mean 3.6 years) syndromic overlap increased with time. Together, these results show that syndromes associated with FTLD do not form discrete mutually exclusive categories from their clinical features or structural brain changes, but instead exist in a multidimensional spectrum. Patients often manifest diagnostic features of multiple disorders and deficits in behaviour, movement and language domains are not confined to specific diagnostic groups. It is important to recognise individual differences in clinical phenotype, both for clinical management and to understand pathogenic mechanisms. We suggest that the adoption of a transdiagnostic approach to the spectrum of FTLD syndromes provides a useful framework with which to understand disease progression, heterogeneity and treatment.

scholarly journals Behavioral variant frontotemporal dementia in patients with previous severe mental illness: a systematic and critical review

2019 ◽  
Vol 77 (9) ◽  
pp. 654-668 ◽  
Author(s):  
Leandro Boson Gambogi ◽  
Henrique Cerqueira Guimarães ◽  
Leonardo Cruz De Souza ◽  
Paulo Caramelli
Keyword(s):  
Mental Illness ◽  
Frontotemporal Dementia ◽  
Cognitive Performance ◽  
Frontotemporal Lobar Degeneration ◽  
English Language ◽  
Case Reports ◽  
Eligibility Criteria ◽  
Cross Sectional ◽  
Schizophrenic Patients ◽  
The Relationship

ABSTRACT Objectives: To explore the relationship between severe/serious mental illness (SMI) and the behavioral variant of frontotemporal dementia (bvFTD), as the patterns of symptoms and cognitive performance that characterize both disorders share similarities. Methods: We performed a systematic review investigating what has already been published regarding the relationship between bvFTD and SMI. Studies were selected from PubMed and LILACS databases, including those published up to February 12, 2018. The search strategy included the following terms: “frontotemporal dementia” plus “bipolar”, OR “frontotemporal dementia” plus “schizophrenia”, OR “frontotemporal dementia” plus “schizoaffective”. Publications without abstracts, case reports with absent genetic or histopathological confirmation, reviews and non-English language papers were excluded across the search process. Results: The search on PubMed retrieved 186 articles, of which 42 met eligibility criteria. On the LILACS database, none met the requirements. Generally, three major research aims were identified: 1) to look for frontotemporal lobar degeneration-associated genetic abnormalities in patients with prior SMI; 2) to compare the cognitive profile between patients affected by neurodegenerative disorders and schizophrenic patients; 3) to highlight the association between bvFTD and preceding psychiatric conditions and/or distinguish them both. The investigated mutations were found infrequently in the studied SMI samples. Cross-sectional studies comparing cognitive performance between bvFTD and psychiatric disorders mostly found no remarkable differences. There were only a few case reports identifying definite frontotemporal lobar degeneration in patients with previous psychiatric diagnoses. Conclusions: The available evidence demonstrates how fragile the current understanding is regarding the association between bvFTD and prior SMI.

Clinical and Genetic Aspects of Progressive Supranuclear Palsy

1998 ◽  
Vol 11 (2) ◽  
pp. 107-114 ◽  
Author(s):  
Irene Litvan ◽  
Michael Hutton
Keyword(s):  
Linkage Disequilibrium ◽  
Diagnostic Accuracy ◽  
Progressive Supranuclear Palsy ◽  
Frontotemporal Dementia ◽  
Clinical Features ◽  
Neuronal Degeneration ◽  
Chromosome 17 ◽  
Clinical Criteria ◽  
Degenerative Parkinsonism ◽  
Research Studies

Progressive supranuclear palsy (PSP) is, after Parkinson's disease, the most common form of degenerative parkinsonism. Several clinical features are used in the recognition of this disorder as well as in the differentiation from related disorders. Clinical criteria that could increase diagnostic accuracy in research studies are also emphasized. Due to a better understanding of the genetic aspects of PSP, recent studies have suggested that it is a recessive disorder in linkage disequilibrium with the tau (τ) gene, rather than a sporadic disorder. In addition, the recent identification of mutations in the τ gene associated with a similar neurodegenerative condition (frontotemporal dementia and parkinsonism linked to chromosome 17) has further strengthened the argument that τ dysfunction is somehow involved in the pathogenesis of PSP. Nongenetic factors that could trigger or perpetuate the cascade of events leading to neuronal degeneration in PSP are also reviewed.

Parkinsonism and Related Dementias

2021 ◽  
pp. 680-688
Author(s):  
Rodolfo Savica ◽  
Pierpaolo Turcano ◽  
Bradley F. Boeve
Keyword(s):  
Differential Diagnosis ◽  
Parkinson Disease ◽  
Progressive Supranuclear Palsy ◽  
Frontotemporal Dementia ◽  
Lewy Body ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Corticobasal Degeneration ◽  
Corticobasal Syndrome ◽  
Progressive Course

The differential diagnosis for dementia is wide. A slowly progressive course for parkinsonism suggests a degenerative cause and helps to narrow the differential diagnosis considerably. In patients with dementia in combination with parkinsonism (often collectively termed the parkinsonism-related dementias), the 4 most common neurodegenerative entities are 1) Lewy body dementias (which include dementia with Lewy bodies and Parkinson disease with dementia); 2) corticobasal syndrome or corticobasal degeneration; 3) Richardson syndrome or progressive supranuclear palsy; and 4) frontotemporal dementia with parkinsonism.

scholarly journals Neuropathological validation of the MDS-PSP criteria with PSP and other frontotemporal lobar degeneration

2019 ◽  
Author(s):  
Stefano Gazzina ◽  
Gesine Respondek ◽  
Yaroslau Compta ◽  
Kieren S.J. Allinson ◽  
Maria G. Spillantini ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Diagnostic Criteria ◽  
Sensitivity And Specificity ◽  
Frontotemporal Lobar Degeneration ◽  
Corticobasal Degeneration ◽  
Primary Progressive Aphasia ◽  
Clinical Diagnostic ◽  
Novel Therapeutic Strategies ◽  
Richardson’S Syndrome ◽  
Clinical Diagnostic Criteria

ABSTRACTBackgroundProgressive supranuclear palsy (PSP) is clinically heterogeneous. Clinical diagnostic criteria were revised in 2017, to increase sensitivity and operationalize the diagnosis of PSP Richardson’s syndrome (PSP-RS) and “variant” syndromes (vPSP).ObjectivesTo determine the (1) sensitivity and specificity of the 1996 NINDS-SPSP and 2017 MDS-PSP criteria; (2) false positive rates in frontotemporal dementia with frontotemporal lobar degeneration (FTLD); and (3) clinical evolution of variant PSP syndromes (vPSP).MethodsRetrospective multicenter review of 108 neuropathologically-confirmed PSP patients and 81 patients with other forms of FTLD: 38 behavioral variant frontotemporal dementia (bvFTD), 14 non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), and 29 corticobasal degeneration (CBD), Sensitivity and specificity of the MDS-PSP criteria were compared to the NINDS-SPSP criteria at baseline. In a subset of cases, the timing and frequency of clinical features were compared across groups over six years.ResultsSensitivity for recognition of probable and possible PSP pathology was higher by MDS-PSP criteria (72.2-100%) than NINDS-SPSP criteria (48.1-61.1%). Specificity was higher by NINDS-SPSP criteria (97.5-100%) than MDS-PSP criteria (53.1-95.1%). False positives by MDS-PSP criteria were few for bvFTD (10.5-18.4%) but common for CBD and nfvPPA (fulfilling “suggestive of’ PSP). Most vPSP cases developed PSP-RS-like features within six years, including falls and supranuclear gaze palsy, distinguishing frontal presentations of PSP from bvFTD, and speech/language presentations of PSP from nfvPPA.ConclusionsThe 2017 MDS-PSP criteria successfully identify PSP, including variant phenotypes. This independent validation of the revised clinical diagnostic criteria strengthens the case for novel therapeutic strategies against PSP to include variant presentations.

scholarly journals Midbrain Pons Ratio- A Diagnostic Tool for Progressive Supranuclear Palsy

2020 ◽  
Author(s):  
Mappilaveetil Sayed Jabir ◽  
Anjamparuthikal Aboobakar Haris
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Clinical Features ◽  
Corticobasal Degeneration ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
Course Of Illness ◽  
Medical College ◽  
Parkinsonian Syndromes ◽  
The Mean ◽  
Magnetic Resonance Imaging Mri

Introduction: Progressive Supranuclear Palsy (PSP) is a Parkinsonism plus syndrome. PSP has different clinical features, it is unresponsive to levodopa and have poor prognosis compared to classical Parkinson’s Disease (PD). However, in clinical practice accurate diagnosis of parkinsonian syndromes are difficult especially when the patient presents early during the course of illness. Diagnosis of each condition is important since it affects patient’s management, rehabilitation and prognosis. Magnetic Resonance Imaging (MRI) is especially useful tool in parkinsonian syndromes, since it identifies changes produced by the neurodegeneration. Rostral midbrain atrophy is seen in PSP. Midbrain pons ratio helps to identify the atrophy involving midbrain, thus helps in differentiating PSP from other causes of parkinsonism. Aim: To investigate the utility of midbrain diameter and midbrain pons ratio in mid-sagittal sections of MRI for differentiation of PSP from other neurodegenerative parkinsonism. Materials and Methods: This was a cross-sectional study conducted in Department of Neurology, Government Medical College, Kottayam, Kerala, India. Of all the patients who presented with clinical features of Parkinsonism, 124 patients who met the inclusion criteria were selected for the study. Comparison was made between the values obtained in clinically diagnosed patients with PSP (n=30), PD (n=30), Multiple System Atrophy (MSA) (n=30), Corticobasal Degeneration (CBD) (n=4) and normal Controls (n=30). These patients underwent MRI and the mid-sagittal T1 weighted MRI images were obtained; the diameter of midbrain and pontine base as well as midbrain-to-pons ratio was calculated. Quantitative analysis of five groups were done using Analysis of Variance (ANOVA) with post-hoc Tukey correction. Results: Mean age of patients in PSP was 59.47±3.86 years. The mean midbrain diameter was found to be lower in PSP, measuring 7.8±0.83 mm (p<0.001) with reduction of the midbrain-to-pons ratio. The mean midbrain pons ratio was found to be lower in PSP, measuring 0.45±0.03 in comparison with the other parkinsonian syndromes (p<0.001). Conclusion: Midbrain pons ratio and midbrain diameter in MRI is a simple measurement for differentiating PSP from other degenerative parkinsonian syndromes.

scholarly journals DAPHNE: A New Tool for the Assessment of the Behavioral Variant of Frontotemporal Dementia

2015 ◽  
Vol 5 (3) ◽  
pp. 503-516 ◽  
Author(s):  
Claire Boutoleau-Bretonnière ◽  
Christelle Evrard ◽  
Jean Benoît Hardouin ◽  
Laëtitia Rocher ◽  
Tiphaine Charriau ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Bipolar Disorder ◽  
Progressive Supranuclear Palsy ◽  
Frontotemporal Dementia ◽  
Clinical Features ◽  
External Validity ◽  
Diagnostic Performance ◽  
Validity And Reliability ◽  
Clinical Tools ◽  
Behavioral Scale

Background: The diagnosis of behavioral variant of frontotemporal dementia (bvFTD) relies primarily on clinical features and remains challenging. The specificity of the recently revised criteria can be disappointing, justifying development of new clinical tools. Objective: We produced a behavioral inventory named DAPHNE. This scale (adapted from Rascovsky's criteria) explores six domains: disinhibition, apathy, perseverations, hyperorality, personal neglect and loss of empathy. It is composed of ten items (five answer categories). The aim was (1) to assess the validity and reliability of DAPHNE and (2) to evaluate its contribution in differentiating patients. Methods: Two scores were computed: DAPHNE-6 (screening) from the six domains and DAPHNE-40 (diagnosis) from the ten items. Reliability and reproducibility were assessed. External validity was studied with the Frontal Behavioral Inventory (FBI) and the Frontotemporal Behavioral Scale (FBS). Finally, the diagnostic performance of DAPHNE was compared to revised criteria, FBI and FBS. Results: DAPHNE was administered to the caregivers of 89 patients, 36 with bvFTD, 22 with Alzheimer's disease, 15 with progressive supranuclear palsy and 16 with bipolar disorder. Reliability and reproducibility were excellent, as was external validity. DAPHNE-6 allowed bvFTD diagnosis (score ≥4) with a sensitivity of 92%, while DAPHNE-40 (score ≥15) had a specificity of 92%. Conclusion: We demonstrate excellent psychometric features for DAPHNE. This quick tool could help for both diagnosing and screening bvFTD.

scholarly journals White matter change with apathy and impulsivity in frontotemporal lobar degeneration syndromes

Neurology ◽  
2018 ◽  
Vol 90 (12) ◽  
pp. e1066-e1076 ◽  
Author(s):  
Claire J. Lansdall ◽  
Ian T.S. Coyle-Gilchrist ◽  
P. Simon Jones ◽  
Patricia Vázquez Rodríguez ◽  
Alicia Wilcox ◽  
...  
Keyword(s):  
White Matter ◽  
Progressive Supranuclear Palsy ◽  
Frontotemporal Lobar Degeneration ◽  
Diffusion Tensor ◽  
Challenging Behaviors ◽  
Mean Diffusivity ◽  
Principal Component ◽  
Corticospinal Tracts ◽  
Detailed Assessment ◽  
The Right

ObjectiveTo identify the white matter correlates of apathy and impulsivity in the major syndromes associated with frontotemporal lobar degeneration, using diffusion-weighted imaging and data from the PiPPIN (Pick's Disease and Progressive Supranuclear Palsy: Prevalence and Incidence) study. We included behavioral and language variants of frontotemporal dementia, corticobasal syndrome, and progressive supranuclear palsy.MethodsSeventy patients and 30 controls underwent diffusion tensor imaging at 3-tesla after detailed assessment of apathy and impulsivity. We used tract-based spatial statistics of fractional anisotropy and mean diffusivity, correlating with 8 orthogonal dimensions of apathy and impulsivity derived from a principal component analysis of neuropsychological, behavioral, and questionnaire measures.ResultsThree components were associated with significant white matter tract abnormalities. Carer-rated change in everyday skills, self-care, and motivation correlated with widespread changes in dorsal frontoparietal and corticospinal tracts, while carer observations of impulsive–apathetic and challenging behaviors revealed disruption in ventral frontotemporal tracts. Objective neuropsychological tests of cognitive control, reflection impulsivity, and reward responsiveness were associated with focal changes in the right frontal lobe and presupplementary motor area. These changes were observed across clinical diagnostic groups, and were not restricted to the disorders for which diagnostic criteria include apathy and impulsivity.ConclusionThe current study provides evidence of distinct structural network changes in white matter associated with different neurobehavioral components of apathy and impulsivity across the diverse spectrum of syndromes and pathologies associated with frontotemporal lobar degeneration.

scholarly journals GABA and glutamate deficits from frontotemporal lobar degeneration are associated with disinhibition

Brain ◽  
2020 ◽  
Vol 143 (11) ◽  
pp. 3449-3462
Author(s):  
Alexander G Murley ◽  
Matthew A Rouse ◽  
P Simon Jones ◽  
Rong Ye ◽  
Frank H Hezemans ◽  
...  
Keyword(s):  
Reaction Time ◽  
Progressive Supranuclear Palsy ◽  
Frontotemporal Dementia ◽  
Response Inhibition ◽  
Frontotemporal Lobar Degeneration ◽  
Inferior Frontal Gyrus ◽  
Stop Signal ◽  
Resonance Spectroscopy ◽  
Stop Signal Reaction Time ◽  
The Right

Abstract Behavioural disinhibition is a common feature of the syndromes associated with frontotemporal lobar degeneration (FTLD). It is associated with high morbidity and lacks proven symptomatic treatments. A potential therapeutic strategy is to correct the neurotransmitter deficits associated with FTLD, thereby improving behaviour. Reductions in the neurotransmitters glutamate and GABA correlate with impulsive behaviour in several neuropsychiatric diseases and there is post-mortem evidence of their deficit in FTLD. Here, we tested the hypothesis that prefrontal glutamate and GABA levels are reduced by FTLD in vivo, and that their deficit is associated with impaired response inhibition. Thirty-three participants with a syndrome associated with FTLD (15 patients with behavioural variant frontotemporal dementia and 18 with progressive supranuclear palsy, including both Richardson’s syndrome and progressive supranuclear palsy-frontal subtypes) and 20 healthy control subjects were included. Participants undertook ultra-high field (7 T) magnetic resonance spectroscopy and a stop-signal task of response inhibition. We measured glutamate and GABA levels using semi-LASER magnetic resonance spectroscopy in the right inferior frontal gyrus, because of its strong association with response inhibition, and in the primary visual cortex, as a control region. The stop-signal reaction time was calculated using an ex-Gaussian Bayesian model. Participants with frontotemporal dementia and progressive supranuclear palsy had impaired response inhibition, with longer stop-signal reaction times compared with controls. GABA concentration was reduced in patients versus controls in the right inferior frontal gyrus, but not the occipital lobe. There was no group-wise difference in partial volume corrected glutamate concentration between patients and controls. Both GABA and glutamate concentrations in the inferior frontal gyrus correlated inversely with stop-signal reaction time, indicating greater impulsivity in proportion to the loss of each neurotransmitter. We conclude that the glutamatergic and GABAergic deficits in the frontal lobe are potential targets for symptomatic drug treatment of frontotemporal dementia and progressive supranuclear palsy.

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