VentRa: distinguishing frontotemporal dementia from psychiatric disorders
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PROVIDER: S-EPMC10953623 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundEpidemiological and clinical studies have suggested comorbidity between frontotemporal dementia (FTD) and psychiatric disorders. FTD patients carrying specific mutations were at higher risk for some psychiatric disorders, and vice versa, implying potential shared genetic etiology, which is still less explored.MethodsWe examined the genetic correlation using summary statistics from genome-wide association studies and analyzed their genetic enrichment leveraging the conditional false discovery rate method. Furthermore, we explored the causal association between FTD and psychiatric disorders with Mendelian randomization (MR) analysis.ResultsWe identified a significant genetic correlation between FTD and schizophrenia at both genetic and transcriptomic levels. Meanwhile, robust genetic enrichment was observed between FTD and schizophrenia and alcohol use disorder. Seven shared genetic loci were identified, which were mainly involved in interleukin-induced signaling, synaptic vesicle, and brain-derived neurotrophic factor signaling pathways. By integrating cis-expression quantitative trait loci analysis, we identified MAPT and CADM2 as shared risk genes. MR analysis showed mutual causation between FTD and schizophrenia with nominal association.ConclusionsOur findings provide evidence of shared etiology between FTD and schizophrenia and indicate potential common molecular mechanisms contributing to the overlapping pathophysiological and clinical characteristics. Our results also demonstrate the essential role of autoimmunity in these diseases. These findings provide a better understanding of the pleiotropy between FTD and psychiatric disorders and have implications for therapeutic trials.
| S-EPMC9069762 | biostudies-literature
Project description:The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5-6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.
| S-EPMC7849953 | biostudies-literature
Project description:BackgroundBehavioural symptoms and frontotemporal hypometabolism overlap between behavioural variant of frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPD), hampering diagnostic distinction. Voxel-wise comparisons of brain metabolism might identify specific frontotemporal-(hypo)metabolic regions between bvFTD and PPD. We investigated brain metabolism in bvFTD and PPD and its relationship with behavioural symptoms, social cognition, severity of depressive symptoms and cognitive functioning.ResultsCompared to controls, bvFTD showed decreased metabolism in the dorsal anterior cingulate cortex (dACC) (p < 0.001), orbitofrontal cortex (OFC), temporal pole, dorsolateral prefrontal cortex (dlPFC) and caudate, whereas PPD showed no hypometabolism. Compared to PPD, bvFTD showed decreased metabolism in the dACC (p < 0.001, p < 0.05FWE), insula, Broca's area, caudate, thalamus, OFC and temporal cortex (p < 0.001), whereas PPD showed decreased metabolism in the motor cortex (p < 0.001). Across bvFTD and PPD, decreased metabolism in the temporal cortex (p < 0.001, p < 0.05FWE), dACC and frontal cortex was associated with worse social cognition. Decreased metabolism in the dlPFC was associated with compulsiveness (p < 0.001). Across bvFTD, PPD and controls, decreased metabolism in the PFC and motor cortex was associated with executive dysfunctioning (p < 0.001).ConclusionsOur findings indicate subtle but distinct metabolic patterns in bvFTD and PPD, most strongly in the dACC. The degree of frontotemporal and cingulate hypometabolism was related to impaired social cognition, compulsiveness and executive dysfunctioning. Our findings suggest that the dACC might be an important region to differentiate between bvFTD and PPD but needs further validation.
| S-EPMC10371967 | biostudies-literature
Project description:OBJECTIVE:The pathology of frontotemporal dementia, termed frontotemporal lobar degeneration (FTLD), is characterized by distinct molecular classes of aggregated proteins, the most common being TAR DNA-binding protein-43 (TDP-43), tau, and fused in sarcoma (FUS). With a few exceptions, it is currently not possible to predict the underlying pathology based on the clinical syndrome. In this study, we set out to investigate the relationship between pathological and clinical presentation at single symptom level, including neuropsychiatric features. METHODS:The presence or absence of symptoms from the current clinical guidelines, together with neuropsychiatric features, such as hallucinations and delusions, were scored and compared across pathological groups in a cohort of 150 brain donors. RESULTS:Our cohort consisted of 68.6% FTLD donors (35.3% TDP-43, 28% tau, and 5.3% FUS) and 31.3% non-FTLD donors with a clinical diagnosis of frontotemporal dementia and a different pathological substrate, such as Alzheimer's disease (23%). The presence of hyperorality points to FTLD rather than non-FTLD pathology (p < 0.001). Within the FTLD group, hallucinations in the initial years of the disease were related to TDP-43 pathology (p = 0.02), including but not limited to chromosome 9 open reading frame 72 (C9orf72) repeat expansion carriers. The presence of perseverative or compulsive behavior was more common in the TDP-B and TDP-C histotypes (p = 0.002). INTERPRETATION:Our findings indicate that neuropsychiatric features are common in FTLD and form an important indicator of underlying pathology. In order to allow better inclusion of patients in targeted molecular trials, the routine evaluation of patients with frontotemporal dementia should include the presence and nature of neuropsychiatric symptoms. ANN NEUROL 2020;87:950-961.
| S-EPMC7318614 | biostudies-literature
Project description:Distinguishing between Alzheimer's disease (AD) and frontotemporal dementia (FTD) presents a clinical challenge. Inexpensive and accessible techniques such as electroencephalography (EEG) are increasingly being used to address this challenge. In particular, the potential relevance between aperiodic components of EEG activity and these disorders has gained interest as our understanding evolves. This study aims to determine the differences in aperiodic activity between AD and FTD and evaluate its potential for distinguishing between the two disorders. A total of 88 participants, including 36 patients with AD, 23 patients with FTD, and 29 healthy controls (CN) underwent cognitive assessment and scalp EEG acquisition. Neuronal power spectra were parameterized to decompose the EEG spectrum, enabling comparison of group differences in different components. A support vector machine was employed to assess the impact of aperiodic parameters on the differential diagnosis. Compared with the CN group, both the AD and FTD groups showed varying degrees of increased alpha power (both periodic and raw power) and theta alpha power ratio. At the channel level, theta power (both periodic and raw power) in the frontal regions was higher in the AD group compared to the FTD group, and aperiodic parameters (both exponents and offsets) in the frontal, temporal, central, and parietal regions were higher in the AD group than in the FTD group. Importantly, the inclusion of aperiodic parameters led to improved performance in distinguishing between the two disorders. These findings highlight the significance of aperiodic components in discriminating dementia-related diseases.
| S-EPMC10828513 | biostudies-literature
Project description:The overlap of symptoms between neurodegenerative and psychiatric diseases has been reported. Neuropsychiatric alterations are commonly observed in dementia, especially in the behavioral variant of frontotemporal dementia (bvFTD), which is the most common clinical FTD subtype. At the same time, psychiatric disorders, like schizophrenia (SCZ), can display symptoms of dementia, including features of frontal dysfunction with relative sparing of memory. In the present review, we discuss common molecular features in these pathologies with a special focus on FTD. Molecules like Brain Derived Neurotrophic Factor (BDNF) and progranulin are linked to the pathophysiology of both neurodegenerative and psychiatric diseases. In these brain-associated illnesses, the presence of disease-associated variants in BDNF and progranulin (GRN) genes cause a reduction of circulating proteins levels, through alterations in proteins expression or secretion. For these reasons, we believe that prevention and therapy of psychiatric and neurological disorders could be achieved enhancing both BDNF and progranulin levels thanks to drug discovery efforts.
| S-EPMC4740789 | biostudies-literature
Project description:The behavioral variant of frontotemporal dementia (bvFTD) is a clinical syndrome resulting from various causes of neuronal demises associated with frontotemporal lobar degeneration. Symptoms include behavioral and personality changes, social cognitive impairment, and executive function deficits. There is a significant clinical overlap between this syndrome and various primary psychiatric disorders (PPD). Structural and functional neuroimaging are considered helpful to support the diagnosis of bvFTD, but their sensitivity and specificity remain imperfect. There is growing evidence concerning the potential of neurofilaments as biomarkers reflecting axonal and neuronal lesions. Ultrasensitive analytic platforms have recently enabled neurofilament light chains' (NfL) detection not only from cerebrospinal fluid but also from peripheral blood samples in FTD patients. In this short review, we present recent advances and perspectives for the use of NfL assessments as biomarkers of neuroaxonal damage to differentiate bvFTD from primary psychiatric disorders.
| S-EPMC8146697 | biostudies-literature
Project description:BackgroundDifferent dementia syndromes display different patterns of everyday functioning. This article explored different patterns of functioning at baseline and trajectories of change in behavioral variant frontotemporal dementia (bvFTD) and Alzheimer disease (AD).MethodsData from the Uniform Data Set of the National Alzheimer's Coordinating Centre were employed. The Functional Assessment Questionnaire assessed functioning at up to 7 follow-up visits. Independent t tests assessed variations in functioning between syndromes at baseline. Linear mixed-effect modeling explored longitudinal functional trajectories between syndromes.ResultsData from 3351 patients (306 bvFTD and 3,045AD) were analyzed. At baseline, patients with bvFTD performed all daily activities poorer than AD dementia. Linear mixed models showed a significant effect of syndrome and time on functioning, and evidence of interaction between syndrome and time, with bvFTD showing a steeper decline for using the stove and travel.ConclusionsFindings can help in the effective care planning of everyday functioning for bvFTD and AD dementia.
| S-EPMC7423644 | biostudies-literature
Project description:Recent studies have reported early cerebellar and subcortical impact in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72). However, the cerebello-subcortical circuitry in FTD has been understudied despite its essential role in cognition and behaviors related to FTD symptomatology. The present study aims to investigate the association between cerebellar and subcortical atrophy, and neuropsychiatric symptoms across genetic mutations. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative including mutation carriers and noncarrier first-degree relatives of known symptomatic carriers. Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed, and partial least squares analyses (PLS) were used to link morphometry and behavior. In presymptomatic C9orf72 expansion carriers, thalamic atrophy was found compared to noncarriers, suggesting the importance of this structure in FTD prodromes. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to neuropsychiatric symptoms, with significant overlap in brain/behavior patterns, but also specificity for each genetic mutation group. The largest differences were in the cerebellar atrophy (larger extent in C9orf72 expansion group) and more prominent amygdalar volume reduction in the MAPT group. Brain scores in the C9orf72 expansion carriers and MAPT carriers demonstrated covariation patterns concordant with atrophy patterns detectable up to 20 years before expected symptom onset. Overall, these results demonstrated the important role of the subcortical structures in genetic FTD symptom expression, particularly the cerebellum in C9orf72 and the amygdala in MAPT carriers.
| S-EPMC10089095 | biostudies-literature
Project description:ImportanceLittle is known about the specific timing and sequence of incident psychiatric comorbidities at different stages of dementia diagnosis.ObjectivesTo examine the temporal risk patterns of psychiatric disorders, including depression, anxiety, stress-related disorders, substance use disorders, sleep disorders, somatoform/conversion disorders, and psychotic disorders, among patients with dementia before, at the time of, and after receipt of a diagnosis.Design, setting, and participantsThis population-based, nationwide cohort study analyzed data from 796 505 participants obtained from 6 registers between January 1, 2000, and December 31, 2017, including the Swedish registry for cognitive/dementia disorders. Patients with dementia were matched on year of birth (±3 years), sex, and region of residence with up to 4 controls. Data were analyzed between March 1, 2023, and August 31, 2023.ExposuresAny cause of dementia and dementia subtypes.Main outcomes and measuresFlexible parametric survival models to determine the time-dependent risk of initial diagnosis of psychiatric disorders, from 7 years prior to dementia diagnosis to 10 years after diagnosis. Subgroup analysis was conducted for psychiatric drug use among persons receiving a diagnosis of dementia from January 1, 2011, to December 31, 2012.ResultsOf 796 505 patients included in the study (mean [SD] age at diagnosis, 80.2 [8.3] years; 448 869 (56.4%) female), 209 245 had dementia, whereas 587 260 did not, across 7 824 616 person-years. The relative risk of psychiatric disorders was consistently higher among patients with dementia compared with control participants and began to increase from 3 years before diagnosis (hazard ratio, [HR], 1.72; 95% CI, 1.67-1.76), peaked during the week after diagnosis (HR, 4.74; 95% CI, 4.21-5.34), and decreased rapidly thereafter. Decreased risk relative to controls was observed from 5 years after diagnosis (HR, 0.93; 95% CI, 0.87-0.98). The results were similar for Alzheimer disease, mixed dementia, vascular dementia and unspecified dementia. Among patients with dementia, markedly elevated use of psychiatric medications was observed in the year leading up to the dementia diagnosis and peaked 6 months after diagnosis. For example, antidepressant use was persistently higher among patients with dementia compared with controls, and the difference increased from 2 years before dementia diagnosis (15.9% vs 7.9%, P < .001), peaked approximately 6 months after dementia diagnosis (29.1% vs 9.7%, P < .001), and then decreased slowly from 3 years after diagnosis but remained higher than controls 5 years after diagnosis (16.4% vs 6.9%, P < .001).Conclusions and relevanceThe findings of this cohort study that patients with dementia had markedly increased risks of psychiatric disorders both before and after dementia diagnosis highlight the significance of incorporating psychiatric preventative and management interventions for individuals with dementia across various diagnostic stages.
| S-EPMC10582787 | biostudies-literature