RESUMO
Three subtypes of distinct pathological proteins accumulate throughout multiple brain regions and shape the heterogeneous clinical presentation of frontotemporal lobar degeneration (FTLD). Besides the main pathological subtypes, co-occurring pathologies are common in FTLD brain donors. The objective of this study was to investigate how the location and burden of (co-)pathology correlate to early psychiatric and behavioural symptoms of FTLD. Eighty-seven brain donors from The Netherlands Brain Bank cohort (2008-2017) diagnosed with FTLD were included: 46 FTLD-TAR DNA-binding protein 43 (FTLD-TDP), 34 FTLD-tau, and seven FTLD-fused-in-sarcoma (FTLD-FUS). Post-mortem brain tissue was dissected into 20 standard regions and stained for phosphorylated TDP-43, phosphorylated tau, FUS, amyloid-ß, and α-synuclein. The burden of each pathological protein in each brain region was assessed with a semi-quantitative score. Clinical records were reviewed for early psychiatric and behavioural symptoms. Whole-brain clinico-pathological partial correlations were calculated (local false discovery rate threshold = 0.01). Elaborating on the results, we validated one finding using a quantitative assessment of TDP-43 pathology in the granular layer of the hippocampus in FTLD-TDP brain donors with (n = 15) and without (n = 15) hallucinations. In subcortical regions, the presence of psychiatric symptoms showed positive correlations with increased hippocampal pathology burden: hallucinations with TDP-43 in the granular layer (R = 0.33), mania with TDP-43 in CA1 (R = 0.35), depression with TDP-43 in CA3 and with parahippocampal tau (R = 0.30 and R = 0.23), and delusions with CA3 tau (R = 0.26) and subicular amyloid-ß (R = 0.25). Behavioural disinhibition showed positive correlations with tau burden in the thalamus (R = 0.29) and with both TDP-43 and amyloid-ß burden in the subthalamus (R = 0.23 and R = 0.24). In the brainstem, the presence of α-synuclein co-pathology in the substantia nigra correlated with disinhibition (R = 0.24), tau pathology in the substantia nigra correlated with depression (R = 0.25) and in the locus coeruleus with both depression and perseverative/compulsive behaviour (R = 0.26 and R = 0.32). The quantitative assessment of TDP-43 in the granular layer validated the higher burden of TDP-43 pathology in brain donors with hallucinations compared to those without hallucinations (P = 0.007). Our results show that psychiatric symptoms of FTLD are linked to subcortical pathology burden in the hippocampus, and hallucinations are linked to a higher burden of TDP-43 in the granular layer. Co-occurring non-FTLD pathologies in subcortical regions could contribute to configuring the clinical phenotype of FTLD.
Assuntos
Demência Frontotemporal , Degeneração Lobar Frontotemporal , Doença de Pick , Humanos , Demência Frontotemporal/patologia , alfa-Sinucleína/metabolismo , Doença de Pick/patologia , Degeneração Lobar Frontotemporal/patologia , Encéfalo/patologia , Alucinações , Peptídeos beta-Amiloides/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas tau/metabolismoRESUMO
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.
Assuntos
Demência Frontotemporal/patologia , Demência Frontotemporal/psicologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/psicologia , Autopsia , Encéfalo/patologia , Estudos de Coortes , Proteínas de Ligação a DNA/sangue , Delusões/etiologia , Delusões/psicologia , Diagnóstico Diferencial , Feminino , Demência Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Alucinações/etiologia , Alucinações/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteína FUS de Ligação a RNA/sangueRESUMO
Frontotemporal lobar degeneration (FTLD) is pathologically subdivided based on the presence of particular pathological proteins that are identified in inclusion bodies observed post-mortem. The FTLD-FUS subgroup is defined by the presence of the fused in sarcoma protein (FUS) in pathological inclusions. FUS is a heterogeneous nuclear ribonucleoprotein (hnRNP) protein and a member of the FET (FUS, EWS, TAF15) protein family. It shuttles between the nucleus and cytoplasm, and has been implicated in many cellular functions including translation, splicing, and RNA transport. EWS, TAF15 and the nuclear import receptor transportin have been shown to co-accumulate with FUS in neuronal inclusions specifically in FTLD-FUS, with transportin-positive inclusions most frequently observed. Here, we report the identification of hnRNP R and hnRNP Q in neuronal cytoplasmic and intranuclear inclusions in the frontal cortex and hippocampus of FTLD-FUS patients, as frequently as transportin. hnRNP R and hnRNP Q were not found in the characteristic pathological inclusions observed in FTLD-TDP (subtypes A-C). Additionally, we studied the expression of hnRNP R in the frontal and temporal cortices from patients with FTLD and found significantly increased expression of the heterogeneous nuclear ribonucleoprotein R in several FTLD disease groups. Our identification of the frequent presence of hnRNP R and hnRNP Q in FTLD-FUS inclusions suggests a potential role for these hnRNPs in FTLD-FUS pathogenesis and supports the role of dysfunctional RNA metabolism in FTLD.
Assuntos
Degeneração Lobar Frontotemporal/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Hipocampo/patologia , Proteína FUS de Ligação a RNA/metabolismo , Lobo Temporal/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Degeneração Lobar Frontotemporal/patologia , Hipocampo/metabolismo , Humanos , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Corpos de Inclusão Intranuclear/metabolismo , Corpos de Inclusão Intranuclear/patologia , Masculino , Pessoa de Meia-Idade , Lobo Temporal/metabolismoRESUMO
In the majority of affected brain regions the pathological hallmarks of Alzheimer's disease (AD) are ß-amyloid (Aß) deposits in the form of diffuse and neuritic plaques, tau pathology in the form of neurofibrillary tangles, neuropil threads and plaque-associated abnormal neurites in combination with an inflammatory response. However, the anatomical area of the presubiculum, is characterised by the presence of a single large evenly distributed 'lake-like' Aß deposit with minimal tau deposition or accumulation of inflammatory markers. Post-mortem brain samples from sporadic AD (SAD) and familial AD (FAD) and two hereditary cerebral amyloid diseases, familial British dementia (FBD) and familial Danish dementia (FDD) were used to compare the morphology of the extracellular proteins deposited in the presubiculum compared to the entorhinal cortex. The level of tau pathology and the extent of microglial activation were quantitated in the two brain regions in SAD and FAD. Frozen tissue was used to investigate the Aß species and proteomic differences between the two regions. Consistent with our previous investigations of FBD and FDD cases we were able to establish that the 'lake-like' pre-amyloid deposits of the presubiculum were not a unique feature of AD but they also found two non-Aß amyloidosis. Comparing the presubiculum to the entorhinal cortex the number of neurofibrillary tangles and tau load were significantly reduced; there was a reduction in microglial activation; there were differences in the Aß profiles and the investigation of the whole proteome showed significant changes in different protein pathways. In summary, understanding why the presubiculum has a different morphological appearance, biochemical and proteomic makeup compared to surrounding brain regions severely affected by neurodegeneration could lead us to understanding protective mechanisms in neurodegenerative diseases.
Assuntos
Doença de Alzheimer/complicações , Córtex Entorrinal/metabolismo , Doenças Neurodegenerativas/etiologia , Giro Para-Hipocampal/metabolismo , Idoso , Idoso de 80 Anos ou mais , Anexina A1/metabolismo , Biologia Computacional , Citocinas/metabolismo , Feminino , Humanos , Microdissecção e Captura a Laser , Antígeno de Macrófago 1/metabolismo , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/patologiaRESUMO
Frontotemporal lobar degeneration with fused in sarcoma-positive inclusions (FTLD-FUS) is a disease with unknown cause. Transportin 1 is abundantly found in FUS-positive inclusions and responsible for the nuclear import of the FET proteins of which FUS is a member. The presence of all FET proteins in pathological inclusions suggests a disturbance of transportin 1-mediated nuclear import. FUS also belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) protein family. We investigated whether hnRNP proteins are associated with FUS pathology implicating dysfunctional nuclear export in the pathogenesis of FTLD-FUS. hnRNP proteins were investigated in affected brain regions in FTLD-FUS using immunohistochemistry, biochemical analysis, and the expression analysis. We demonstrated the presence of several hnRNP proteins in pathological inclusions including neuronal cytoplasmic inclusions and dystrophic neurites. The biochemical analysis revealed a shift in the location of hnRNP A1 from the nucleus to the cytoplasm. The expression analysis revealed an increase in several hnRNP proteins in FTLD-FUS. These results implicate a wider dysregulation of movement between intracellular compartments, than mechanisms only affecting the nuclear import of FUS proteins.