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1.
Acta Neuropathol ; 147(1): 56, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38478117

RESUMO

The stimulator of interferon genes (STING) pathway has been implicated in neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis (ALS). While prior studies have focused on STING within immune cells, little is known about STING within neurons. Here, we document neuronal activation of the STING pathway in human postmortem cortical and spinal motor neurons from individuals affected by familial or sporadic ALS. This process takes place selectively in the most vulnerable cortical and spinal motor neurons but not in neurons that are less affected by the disease. Concordant STING activation in layer V cortical motor neurons occurs in a mouse model of C9orf72 repeat-associated ALS and frontotemporal dementia (FTD). To establish that STING activation occurs in a neuron-autonomous manner, we demonstrate the integrity of the STING signaling pathway, including both upstream activators and downstream innate immune response effectors, in dissociated mouse cortical neurons and neurons derived from control human induced pluripotent stem cells (iPSCs). Human iPSC-derived neurons harboring different familial ALS-causing mutations exhibit increased STING signaling with DNA damage as a main driver. The elevated downstream inflammatory markers present in ALS iPSC-derived neurons can be suppressed with a STING inhibitor. Our results reveal an immunophenotype that consists of innate immune signaling driven by the STING pathway and occurs specifically within vulnerable neurons in ALS/FTD.


Assuntos
Esclerose Amiotrófica Lateral , Demência Frontotemporal , Células-Tronco Pluripotentes Induzidas , Doença de Pick , Animais , Humanos , Camundongos , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Proteína C9orf72/genética , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios Motores/metabolismo
2.
Acta Neuropathol ; 147(1): 58, 2024 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-38520489

RESUMO

Neurodegenerative pathologies such as Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and cerebrovascular disease (CVD) frequently coexist, but little is known about the exact contribution of each pathology to cognitive decline and dementia in subjects with mixed pathologies. We explored the relative cognitive impact of concurrent common and rare neurodegenerative pathologies employing multivariate logistic regression analysis adjusted for age, gender, and level of education. We analyzed a cohort of 6,262 subjects from the National Alzheimer's Coordinating Center database, ranging from 0 to 6 comorbid neuropathologic findings per individual, where 95.7% of individuals had at least 1 neurodegenerative finding at autopsy and 75.5% had at least 2 neurodegenerative findings. We identified which neuropathologic entities correlate most frequently with one another and demonstrated that the total number of pathologies per individual was directly correlated with cognitive performance as assessed by Clinical Dementia Rating (CDR®) and Mini-Mental State Examination (MMSE). We show that ADNC, LBD, LATE-NC, CVD, hippocampal sclerosis, Pick disease, and FTLD-TDP significantly impact overall cognition as independent variables. More specifically, ADNC significantly affected all assessed cognitive domains, LBD affected attention, processing speed, and language, LATE-NC primarily affected tests related to logical memory and language, while CVD and other less common pathologies (including Pick disease, progressive supranuclear palsy, and corticobasal degeneration) had more variable neurocognitive effects. Additionally, ADNC, LBD, and higher numbers of comorbid neuropathologies were associated with the presence of at least one APOE ε4 allele, and ADNC and higher numbers of neuropathologies were inversely correlated with APOE ε2 alleles. Understanding the mechanisms by which individual and concomitant neuropathologies affect cognition and the degree to which each contributes is an imperative step in the development of biomarkers and disease-modifying therapeutics, particularly as these medical interventions become more targeted and personalized.


Assuntos
Doença de Alzheimer , Doenças Cardiovasculares , Demência , Demência Frontotemporal , Doença por Corpos de Lewy , Doença de Pick , Proteinopatias TDP-43 , Humanos , Doença de Pick/patologia , Encéfalo/patologia , Doença de Alzheimer/patologia , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/patologia , Demência Frontotemporal/patologia , Cognição
3.
Acta Neuropathol Commun ; 12(1): 31, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38389095

RESUMO

Pick's disease (PiD) is a subtype of the tauopathy form of frontotemporal lobar degeneration (FTLD-tau) characterized by intraneuronal 3R-tau inclusions. PiD can underly various dementia syndromes, including primary progressive aphasia (PPA), characterized by an isolated and progressive impairment of language and left-predominant atrophy, and behavioral variant frontotemporal dementia (bvFTD), characterized by progressive dysfunction in personality and bilateral frontotemporal atrophy. In this study, we investigated the neocortical and hippocampal distributions of Pick bodies in bvFTD and PPA to establish clinicopathologic concordance between PiD and the salience of the aphasic versus behavioral phenotype. Eighteen right-handed cases with PiD as the primary pathologic diagnosis were identified from the Northwestern University Alzheimer's Disease Research Center brain bank (bvFTD, N = 9; PPA, N = 9). Paraffin-embedded sections were stained immunohistochemically with AT8 to visualize Pick bodies, and unbiased stereological analysis was performed in up to six regions bilaterally [middle frontal gyrus (MFG), superior temporal gyrus (STG), inferior parietal lobule (IPL), anterior temporal lobe (ATL), dentate gyrus (DG) and CA1 of the hippocampus], and unilateral occipital cortex (OCC). In bvFTD, peak neocortical densities of Pick bodies were in the MFG, while the ATL was the most affected in PPA. Both the IPL and STG had greater leftward pathology in PPA, with the latter reaching significance (p < 0.01). In bvFTD, Pick body densities were significantly right-asymmetric in the STG (p < 0.05). Hippocampal burden was not clinicopathologically concordant, as both bvFTD and PPA cases demonstrated significant hippocampal pathology compared to neocortical densities (p < 0.0001). Inclusion-to-neuron analyses in a subset of PPA cases confirmed that neurons in the DG are disproportionately burdened with inclusions compared to neocortical areas. Overall, stereological quantitation suggests that the distribution of neocortical Pick body pathology is concordant with salient clinical features unique to PPA vs. bvFTD while raising intriguing questions about the selective vulnerability of the hippocampus to 3R-tauopathies.


Assuntos
Doença de Alzheimer , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Doença de Pick , Tauopatias , Humanos , Doença de Pick/patologia , Demência Frontotemporal/patologia , Doença de Alzheimer/patologia , Encéfalo/patologia , Degeneração Lobar Frontotemporal/patologia , Atrofia/patologia , Tauopatias/patologia
4.
J Neuroinflammation ; 21(1): 47, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38347588

RESUMO

BACKGROUND: Progranulin (PGRN) haploinsufficiency due to progranulin gene (GRN) variants can cause frontotemporal dementia (FTD) with aberrant TAR DNA-binding protein 43 (TDP-43) accumulation. Despite microglial burden with TDP-43-related pathophysiology, direct microglial TDP-43 pathology has not been clarified yet, only emphasized in neuronal pathology. Thus, the objective of this study was to investigate TDP-43 pathology in microglia of patients with PGRN haploinsufficiency. METHODS: To design a human microglial cell model with PGRN haploinsufficiency, monocyte-derived microglia (iMGs) were generated from FTD-GRN patients carrying pathogenic or likely pathogenic variants (p.M1? and p.W147*) and three healthy controls. RESULTS: iMGs from FTD-GRN patients with PGRN deficiency exhibited severe neuroinflammation phenotype and failure to maintain their homeostatic molecular signatures, along with impaired phagocytosis. In FTD-GRN patients-derived iMGs, significant cytoplasmic TDP-43 aggregation and accumulation of lipid droplets with profound lysosomal abnormalities were observed. These pathomechanisms were mediated by complement C1q activation and upregulation of pro-inflammatory cytokines. CONCLUSIONS: Our study provides considerable cellular and molecular evidence that loss-of-function variants of GRN in human microglia can cause microglial dysfunction with abnormal TDP-43 aggregation induced by inflammatory milieu as well as the impaired lysosome. Elucidating the role of microglial TDP-43 pathology in intensifying neuroinflammation in individuals with FTD due to PGRN deficiency and examining consequential effects on microglial dysfunction might yield novel insights into the mechanisms underlying FTD and neurodegenerative disorders.


Assuntos
Demência Frontotemporal , Doença de Pick , Humanos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Demência Frontotemporal/genética , Haploinsuficiência , Lisossomos/metabolismo , Microglia/patologia , Doenças Neuroinflamatórias , Doença de Pick/metabolismo , Progranulinas/genética , Progranulinas/metabolismo
5.
Neurobiol Aging ; 137: 47-54, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38422798

RESUMO

Late-onset primary psychiatric disease (PPD) and behavioral frontotemporal dementia (bvFTD) present with a similar frontal lobe syndrome. We compare brain glucose metabolism in bvFTD and late-onset PPD and investigate the metabolic correlates of cognitive and behavioral disturbances through FDG-PET/MRI. We studied 37 bvFTD and 20 late-onset PPD with a mean clinical follow-up of three years. At baseline evaluation, metabolism of the dorsolateral, ventrolateral, orbitofrontal regions and caudate could classify the patients with a diagnostic accuracy of 91% (95% CI: 0.81-0.98%). 45% of PPD showed low-grade hypometabolism in the anterior cingulate and/or parietal regions. Frontal lobe metabolism was normal in 32% of genetic bvFTD and bvFTD with motor neuron signs. Hypometabolism of the frontal and caudate regions could help in distinguishing bvFTD from PPD, except in cases with motor neuron signs and/or genetic bvFTD for which brain metabolism may be less informative.


Assuntos
Demência Frontotemporal , Doença de Pick , Humanos , Demência Frontotemporal/psicologia , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Lobo Frontal/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Testes Neuropsicológicos
6.
J Neuropathol Exp Neurol ; 83(4): 238-244, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38412343

RESUMO

The pathobiology of tau is of great importance for understanding the mechanisms of neurodegeneration in aging and age-associated disorders such as Alzheimer disease (AD) and frontotemporal dementias. It is critical to identify neuronal populations and brain regions that are vulnerable or resistant to tau pathological changes. Pick disease (PiD) is a three-repeat (3R) tauopathy that belongs to the group of frontotemporal lobar degenerations. The neuropathologic changes of PiD are characterized by globular tau-positive neuronal intracytoplasmic inclusions, called Pick bodies, in the granule cells of the dentate gyrus and frontal and temporal neocortices, and ballooned neurons, named Pick neurons, in the neocortex. In the present study, we examined 13 autopsy-confirmed cases of PiD. Using immunohistochemistry for phospho-tau (AT8) and 3R tau isoform, all PiD cases demonstrated extensive lesions involving the hippocampus and neocortex. However, the lateral geniculate body (LGB) is spared of significant tau lesions in contrast to the neighboring hippocampus and other thalamic nuclei. Only 1 PiD case (7.7%) had tau-positive neurons, and 4 cases had tau-positive neurites (31%) in the LGB. By contrast, the LGB does consistently harbor tau lesions in other tauopathies including progressive supranuclear palsy, corticobasal degeneration, and AD.


Assuntos
Doença de Alzheimer , Neocórtex , Doença de Pick , Tauopatias , Humanos , Doença de Pick/patologia , Proteínas tau/metabolismo , Corpos Geniculados/metabolismo , Corpos Geniculados/patologia , Tauopatias/patologia , Neocórtex/patologia
8.
Int J Mol Sci ; 25(2)2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38256197

RESUMO

The accumulation of protein aggregates defines distinct, yet overlapping pathologies such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). In this study, we investigated ATG5, UBQLN2, ULK1, and LC3 concentrations in 66 brain specimens and 120 plasma samples from AD, DLB, FTD, and control subjects (CTRL). Protein concentration was measured with ELISA kits in temporal, frontal, and occipital cortex specimens of 32 AD, 10 DLB, 10 FTD, and 14 CTRL, and in plasma samples of 30 AD, 30 DLB, 30 FTD, and 30 CTRL. We found alterations in ATG5, UBQLN2, ULK1, and LC3 levels in patients; ATG5 and UBQLN2 levels were decreased in both brain specimens and plasma samples of patients compared to those of the CTRL, while LC3 levels were increased in the frontal cortex of DLB and FTD patients. In this study, we demonstrate alterations in different steps related to ATG5, UBQLN2, and LC3 autophagy pathways in DLB and FTD patients. Molecular alterations in the autophagic processes could play a role in a shared pathway involved in the pathogenesis of neurodegeneration, supporting the hypothesis of a common molecular mechanism underlying major neurodegenerative dementias and suggesting different potential therapeutic targets in the autophagy pathway for these disorders.


Assuntos
Doença de Alzheimer , Demência Frontotemporal , Doença por Corpos de Lewy , Doença de Pick , Humanos , Autofagia , Proteínas Relacionadas à Autofagia , Proteínas Adaptadoras de Transdução de Sinal
9.
Acta Neuropathol ; 147(1): 9, 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38175301

RESUMO

Nuclear clearance and cytoplasmic accumulations of the RNA-binding protein TDP-43 are pathological hallmarks in almost all patients with amyotrophic lateral sclerosis (ALS) and up to 50% of patients with frontotemporal dementia (FTD) and Alzheimer's disease. In Alzheimer's disease, TDP-43 pathology is predominantly observed in the limbic system and correlates with cognitive decline and reduced hippocampal volume. Disruption of nuclear TDP-43 function leads to abnormal RNA splicing and incorporation of erroneous cryptic exons in numerous transcripts including Stathmin-2 (STMN2, also known as SCG10) and UNC13A, recently reported in tissues from patients with ALS and FTD. Here, we identify both STMN2 and UNC13A cryptic exons in Alzheimer's disease patients, that correlate with TDP-43 pathology burden, but not with amyloid-ß or tau deposits. We also demonstrate that processing of the STMN2 pre-mRNA is more sensitive to TDP-43 loss of function than UNC13A. In addition, full-length RNAs encoding STMN2 and UNC13A are suppressed in large RNA-seq datasets generated from Alzheimer's disease post-mortem brain tissue. Collectively, these results open exciting new avenues to use STMN2 and UNC13A as potential therapeutic targets in a broad range of neurodegenerative conditions with TDP-43 proteinopathy including Alzheimer's disease.


Assuntos
Doença de Alzheimer , Esclerose Amiotrófica Lateral , Demência Frontotemporal , Doença de Pick , Humanos , Doença de Alzheimer/genética , Proteínas de Ligação a DNA/genética , Splicing de RNA , RNA Mensageiro/genética , Estatmina/genética
10.
Neurobiol Aging ; 134: 28-39, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37979250

RESUMO

Current genome-wide association studies of frontotemporal dementia (FTD) are underpowered due to limited samples. Further, common genetic etiologies between FTD and amyotrophic lateral sclerosis (ALS) remain unknown. Using the largest summary statistics of FTD (3526 cases and 9402 controls) and ALS (27,205 cases and 110,881 controls), we found a significant genetic correlation between them (rˆg = 0.637, P = 0.032) and identified 190 FTD-related variants within 5 loci (3p22.1, 5q35.1, 9p21.2, 19p13.11, and 20q13.13). Among these, ALS and FTD had causal variants in 9p21.2 and 19p13.11. Moreover, MOBP (3p22.1), C9orf72 (9p21.2), MOB3B (9p21.2), UNC13A (19p13.11), SLC9A8 (20q13.13), SNAI1 (20q13.13), and SPATA2 (20q13.13) were discovered by both SNP- and gene-level analyses, which together discovered 15 FTD-associated genes, with 10 not detected before (IFNK, RNF114, SLC9A8, SPATA2, SNAI1, SCFD1, POLDIP2, TMEM97, G2E3, and PIGW). Functional analyses showed these genes were enriched in heart left ventricle, kidney cortex, and some brain regions. Overall, this study provides insights into genetic determinants of FTD and shared genetic etiology underlying FTD and ALS.


Assuntos
Esclerose Amiotrófica Lateral , Demência Frontotemporal , Doença de Pick , Humanos , Demência Frontotemporal/genética , Esclerose Amiotrófica Lateral/genética , Estudo de Associação Genômica Ampla , Mutação , Proteínas/genética , Proteínas Nucleares/genética
11.
Artigo em Inglês | MEDLINE | ID: mdl-37855109

RESUMO

OBJECTIVE: The prevalence of behavior impairment (27.38%) in the Chinese amyotrophic lateral sclerosis (ALS) cohort is lower. We hypothesize that the screening scales used among studies might not be appropriate to diagnose behavioral disorders in ALS patients. So, we urgently need to find a behavior scale with a high detection rate designed specifically for ALS. This study aims to verify the Chinese translation of the Beaumont Behavioral Inventory (BBI) as an effective assessment in a Chinese ALS cohort. METHODS: Ninety-eighty ALS patients and ninety-three healthy controls were included in this cross-sectional study. All participants took emotional state, overall cognitive, sleep quality and gastroenteric function, and behavioral evaluation. RESULTS: The BBI scores showed a strong association with the amyotrophic lateral sclerosis-Frontotemporal Dementia-Questionnaire (ALS-FTD-Q) (rs = 0.71, p < 0.001) as well as a moderate correlation with the Frontal Behavioral Inventory (FBI) (rs = 0.55, p < 0.001). High internal consistency was demonstrated in patients using BBI-after items (Cronbach's a = 0.89). When tested against clinical diagnoses, the optimal cutoff of total BBI score was identified at 5.5 (AUC = 0.95; SE = 0.02; 95% CI [0.91, 0.99]), the BBI reached optimal sensitivity and specificity values (91.5% and 87.2%). The BBI turned out to be more precise than the FBI (AUC = 0.76; SE = 0.05; 95% CI [0.66, 0.86]) and the ALS-FTD-Q (AUC = 0.84; SE = 0.04; 95% CI [0.77, 0.92]). CONCLUSION: The Chinese version of BBI is a quicker and more efficient instrument for assessing behavioral impairment in the ALS population in China.


Assuntos
Esclerose Amiotrófica Lateral , Demência Frontotemporal , Doença de Pick , Humanos , Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/epidemiologia , Esclerose Amiotrófica Lateral/complicações , Demência Frontotemporal/diagnóstico , Estudos Transversais , Sensibilidade e Especificidade , Testes Neuropsicológicos
12.
Brain ; 147(1): 109-121, 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-37639327

RESUMO

We have recently identified the aberrant nuclear accumulation of the ESCRT-III protein CHMP7 as an initiating event that leads to a significant injury to the nuclear pore complex (NPC) characterized by the reduction of specific nucleoporins from the neuronal NPC in sporadic amyotrophic lateral sclerosis (sALS) and C9orf72 ALS/frontotemporal dementia (FTD)-induced pluripotent stem cell-derived neurons (iPSNs), a phenomenon also observed in post-mortem patient tissues. Importantly, this NPC injury is sufficient to contribute to TDP-43 dysfunction and mislocalization, a common pathological hallmark of neurodegenerative diseases. However, the molecular mechanisms and events that give rise to increased nuclear translocation and/or retention of CHMP7 to initiate this pathophysiological cascade remain largely unknown. Here, using an iPSN model of sALS, we demonstrate that impaired NPC permeability barrier integrity and interactions with the LINC complex protein SUN1 facilitate CHMP7 nuclear localization and the subsequent 'activation' of NPC injury cascades. Collectively, our data provide mechanistic insights in the pathophysiological underpinnings of ALS/FTD and highlight SUN1 as a potent contributor to and modifier of CHMP7-mediated toxicity in sALS pathogenesis.


Assuntos
Esclerose Amiotrófica Lateral , Demência Frontotemporal , Doença de Pick , Humanos , Esclerose Amiotrófica Lateral/metabolismo , Demência Frontotemporal/patologia , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Neurônios/metabolismo , Proteínas de Membrana , Proteínas Associadas aos Microtúbulos , Proteínas Nucleares , Complexos Endossomais de Distribuição Requeridos para Transporte
13.
Brain ; 147(2): 590-606, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37703311

RESUMO

Frontotemporal lobar degeneration with tau (FTLD-tau) is a group of tauopathies that underlie ∼50% of FTLD cases. Identification of genetic risk variants related to innate/adaptive immunity have highlighted a role for neuroinflammation and neuroimmune interactions in FTLD. Studies have shown microglial and astrocyte activation together with T cell infiltration in the brain of THY-Tau22 tauopathy mice. However, this remains to be confirmed in FTLD-tau patients. We conducted a detailed post-mortem study of FTLD-tau cases including 45 progressive supranuclear palsy with clinical frontotemporal dementia, 33 Pick's disease, 12 FTLD-MAPT and 52 control brains to characterize the link between phosphorylated tau (pTau) epitopes and the innate and adaptive immunity. Tau pathology was assessed in the cerebral cortex using antibodies directed against: Tau-2 (phosphorylated and unphosphorylated tau), AT8 (pSer202/pThr205), AT100 (pThr212/pSer214), CP13 (pSer202), PHF1 (pSer396/pSer404), pThr181 and pSer356. The immunophenotypes of microglia and astrocytes were assessed with phenotypic markers (Iba1, CD68, HLA-DR, CD64, CD32a, CD16 for microglia and GFAP, EAAT2, glutamine synthetase and ALDH1L1 for astrocytes). The adaptive immune response was explored via CD4+ and CD8+ T cell quantification and the neuroinflammatory environment was investigated via the expression of 30 inflammatory-related proteins using V-Plex Meso Scale Discovery. As expected, all pTau markers were increased in FTLD-tau cases compared to controls. pSer356 expression was greatest in FTLD-MAPT cases versus controls (P < 0.0001), whereas the expression of other markers was highest in Pick's disease. Progressive supranuclear palsy with frontotemporal dementia consistently had a lower pTau protein load compared to Pick's disease across tau epitopes. The only microglial marker increased in FTLD-tau was CD16 (P = 0.0292) and specifically in FTLD-MAPT cases (P = 0.0150). However, several associations were detected between pTau epitopes and microglia, supporting an interplay between them. GFAP expression was increased in FTLD-tau (P = 0.0345) with the highest expression in Pick's disease (P = 0.0019), while ALDH1L1 was unchanged. Markers of astrocyte glutamate cycling function were reduced in FTLD-tau (P = 0.0075; Pick's disease: P < 0.0400) implying astrocyte reactivity associated with a decreased glutamate cycling activity, which was further associated with pTau expression. Of the inflammatory proteins assessed in the brain, five chemokines were upregulated in Pick's disease cases (P < 0.0400), consistent with the recruitment of CD4+ (P = 0.0109) and CD8+ (P = 0.0014) T cells. Of note, the CD8+ T cell infiltration was associated with pTau epitopes and microglial and astrocytic markers. Our results highlight that FTLD-tau is associated with astrocyte reactivity, remarkably little activation of microglia, but involvement of adaptive immunity in the form of chemokine-driven recruitment of T lymphocytes.


Assuntos
Demência Frontotemporal , Degeneração Lobar Frontotemporal , Doença de Pick , Paralisia Supranuclear Progressiva , Tauopatias , Humanos , Epitopos , Demência Frontotemporal/patologia , Degeneração Lobar Frontotemporal/patologia , Glutamatos , Doença de Pick/patologia , Paralisia Supranuclear Progressiva/patologia , Proteínas tau/metabolismo , Tauopatias/patologia
14.
Artigo em Inglês | MEDLINE | ID: mdl-37779364

RESUMO

OBJECTIVE: Sporadic and familial amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that results in loss of motor neurons and, in some patients, associates with frontotemporal dementia (FTD). Apart from the accumulation of proteinaceous deposits, emerging literature indicates that aberrant mitochondrial bioenergetics may contribute to the onset and progression of ALS/FTD. Here we sought to investigate the pathophysiological signatures of mitochondrial dysfunction associated with ALS/FTD. METHODS: By means of label-free mass spectrometry (MS) and mRNA sequencing (mRNA-seq), we report pre-symptomatic changes in the cortices of TDP-43 and FUS mutant mouse models. Using tissues from transgenic mouse models of mitochondrial diseases as a reference, we performed comparative analyses and extracted unique and common mitochondrial signatures that revealed neuroprotective compensatory mechanisms in response to early damage. RESULTS: In this regard, upregulation of both Acyl-CoA Synthetase Long-Chain Family Member 3 (ACSL3) and mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) were the most representative change in pre-symptomatic ALS/FTD tissues, suggesting that fatty acid beta-oxidation and mitochondrial protein translation are mechanisms of adaptation in response to ALS/FTD pathology. CONCLUSIONS: Together, our unbiased integrative analyses unveil novel molecular components that may influence mitochondrial homeostasis in the earliest phase of ALS.


Assuntos
Esclerose Amiotrófica Lateral , Demência Frontotemporal , Doenças Mitocondriais , Doenças Neurodegenerativas , Doença de Pick , Camundongos , Animais , Humanos , Demência Frontotemporal/metabolismo , Esclerose Amiotrófica Lateral/patologia , Proteômica , Camundongos Transgênicos , Perfilação da Expressão Gênica , RNA Mensageiro
16.
Psychogeriatrics ; 24(2): 272-280, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38131520

RESUMO

BACKGROUND: Here, we aimed to investigate the roles of long-term potentiation-like (LTP-like) plasticity using intermittent theta burst (iTBS) protocol and resting motor threshold (rMT) in the differential diagnosis of Alzheimer's disease (AD), diffuse dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). METHOD: We enrolled 21 subjects with AD, 28 subjects with DLB, 14 subjects with FTD, and 33 elderly subjects with normal cognitive functions into the study. We recorded rMT and percentage amplitude change of motor evoked potentials (MEPs) after the iTBS protocol in each group. RESULTS: In patients with AD and DLB, the percentage amplitude change of MEPs, and rMTs were significantly lower than in healthy subjects. However, no significant difference was observed in individuals with FTD. CONCLUSION: Our findings showed that transcranial magnetic stimulation measures, particularly rMTs and LTP-like plasticity, may be potential biomarkers to distinguish between different dementia subtypes. Impaired motor cortical excitability and synaptic plasticity were more prominent in AD and DLB than in FTD. This aligns with the evidence that cortical motor networks are usually spared in FTDs in early-to-middle stages.


Assuntos
Doença de Alzheimer , Excitabilidade Cortical , Demência Frontotemporal , Doença por Corpos de Lewy , Doença de Pick , Idoso , Humanos , Demência Frontotemporal/diagnóstico , Doença de Alzheimer/diagnóstico , Doença por Corpos de Lewy/diagnóstico , Estimulação Magnética Transcraniana
17.
Psychogeriatrics ; 24(2): 281-294, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38152057

RESUMO

BACKGROUND: We aimed to validate the Clinical Dementia Rating (CDR®) dementia staging instrument plus the National Alzheimer's Coordinating Centre Behaviour and Language Domains (CDR® plus NACC FTLD) for use in clinical settings in Japan and in the Japanese language. METHODS: This prospective observational study enrolled 29 patients with frontotemporal dementia (FTD) and 21 patients with Alzheimer's disease (AD) dementia from the Departments of Psychiatry at Osaka University Hospital and Asakayama General Hospital and the Brain Function Centre at Nippon Life Hospital. CDR® plus NACC FTLD, CDR®, Mini-Mental State Examination (MMSE), Western Aphasia Battery (WAB), Neuropsychiatric Inventory-plus (NPI-plus), Stereotypy Rating Inventory (SRI), and frontal behavioural symptom scores obtained from items of NPI-plus and SRI, were conducted to assess inter- and intra-rater reliability, validity, and responsiveness. We performed receiver operating characteristic (ROC) curve analysis to evaluate the discriminating power of the Behaviour/Comportment/Personality (BEHAV) and Language (LANG) domains of the CDR® plus NACC FTLD and the MEMORY domain of the CDR® in patients AD dementia and FTD. RESULTS: The CDR® plus NACC FTLD showed good inter- and intra-rater reliabilities. In patients with FTD, the BEHAV domain of the CDR® plus NACC FTLD was significantly correlated with all clinical measures except for the SRI total score, while the LANG domain of the CDR® plus NACC FTLD was significantly correlated with the MMSE and the WAB-Aphasia quotient. In addition, the CDR® plus NACC FTLD sum of boxes significantly changed after 6 months and after 1 year. ROC curve analysis showed that the BEHAV and LANG domains of the CDR® plus NACC FTLD distinguished between patients with AD dementia and FTD better than the MEMORY domain of the CDR®. CONCLUSIONS: This study validated the Japanese version of the CDR® plus NACC FTLD with good reliability, validity, and responsiveness.


Assuntos
Doença de Alzheimer , Afasia , Demência Frontotemporal , Doença de Pick , Humanos , Demência Frontotemporal/diagnóstico , Doença de Alzheimer/diagnóstico , Japão , Reprodutibilidade dos Testes , Testes de Estado Mental e Demência , Idioma
18.
Med Sci (Basel) ; 11(4)2023 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-37987326

RESUMO

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by progressive impairments in behavior, executive function, and language, primarily affecting individuals under the age of 65. This disorder is associated with expressive and receptive anomia, word comprehension deficits, and behavioral symptoms such as apathy, loss of empathy, and disinhibition, all of which closely correlate with functional impairment in daily activities. Despite substantial efforts, research on occupational therapy (OT) interventions has yet to demonstrate clear benefits in managing the disease. The aim of this study is to investigate OT interventions and assess their efficacy, with a specific focus on individuals suffering from FTD. We systematically conducted searches on two databases, namely Medline and Science Direct, spanning a ten-year period from 2003 to 2023, in accordance with the PRISMA guidelines. Eleven studies met the inclusion criteria. OT interventions targeted both patients and caregivers and yielded significant positive improvements in their lives. A key focus of these interventions was to teach acceptable alternatives to the behaviors exhibited by FTD patients, as these behaviors are strongly influenced by the disease itself. OT contributes positively to enhancing the quality of life of FTD patients and alleviating the caregiving burden experienced by those providing long-term care to these patients.


Assuntos
Demência Frontotemporal , Terapia Ocupacional , Doença de Pick , Humanos , Demência Frontotemporal/terapia , Qualidade de Vida , Cuidadores
19.
Acta Neuropathol Commun ; 11(1): 168, 2023 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-37864255

RESUMO

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comprise a spectrum of neurodegenerative diseases linked to TDP-43 proteinopathy, which at the cellular level, is characterized by loss of nuclear TDP-43 and accumulation of cytoplasmic TDP-43 inclusions that ultimately cause RNA processing defects including dysregulation of splicing, mRNA transport and translation. Complementing our previous work in motor neurons, here we report a novel model of TDP-43 proteinopathy based on overexpression of TDP-43 in a subset of Drosophila Kenyon cells of the mushroom body (MB), a circuit with structural characteristics reminiscent of vertebrate cortical networks. This model recapitulates several aspects of dementia-relevant pathological features including age-dependent neuronal loss, nuclear depletion and cytoplasmic accumulation of TDP-43, and behavioral deficits in working memory and sleep that occur prior to axonal degeneration. RNA immunoprecipitations identify several candidate mRNA targets of TDP-43 in MBs, some of which are unique to the MB circuit and others that are shared with motor neurons. Among the latter is the glypican Dally-like-protein (Dlp), which exhibits significant TDP-43 associated reduction in expression during aging. Using genetic interactions we show that overexpression of Dlp in MBs mitigates TDP-43 dependent working memory deficits, conistent with Dlp acting as a mediator of TDP-43 toxicity. Substantiating our findings in the fly model, we find that the expression of GPC6 mRNA, a human ortholog of dlp, is specifically altered in neurons exhibiting the molecular signature of TDP-43 pathology in FTD patient brains. These findings suggest that circuit-specific Drosophila models provide a platform for uncovering shared or disease-specific molecular mechanisms and vulnerabilities across the spectrum of TDP-43 proteinopathies.


Assuntos
Esclerose Amiotrófica Lateral , Demência Frontotemporal , Doença de Pick , Proteinopatias TDP-43 , Animais , Humanos , Esclerose Amiotrófica Lateral/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Drosophila/metabolismo , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Neurônios Motores/metabolismo , Doença de Pick/patologia , RNA Mensageiro , Proteinopatias TDP-43/patologia
20.
Clin Neuropathol ; 42(6): 212-218, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37840526

RESUMO

Pick's disease (PiD) is a rare form of frontal temporal lobar degeneration. The pathognomonic feature is atrophy of the frontotemporal lobes and intraneuronal deposits of 3R-τ inclusions, the Pick body. Corticobasal syndrome (CBS) is an atypical parkinsonian syndrome with a heterogeneous spectrum of underlying pathologies. We report a case of clinically diagnosed CBS with a post-mortem diagnosis of PiD and conduct a clinicopathological review of the literature on this unusual presentation.


Assuntos
Degeneração Corticobasal , Doença de Pick , Humanos , Doença de Pick/patologia , Atrofia , Proteínas tau
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