FTD-PSP is an Unusual Clinical Phenotype in A Frontotemporal Dementia Patient with A Novel Progranulin Mutation

Deng, Bin; Zheng, Zhe; Zheng, Jialing; Yang, Wanlin; Huang, Yu; Luo, Yuqi; Jin, Dana; Shen, Lu; Jin, Kunlin; Wang, Qing

doi:10.14336/ad.2021.0309

Cited by 8 publications

(3 citation statements)

References 94 publications

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“…Individuals with GRN mutations and Parkinsonism could show reduced DOPA metabolism in bilateral corpus striatum by 18 F-DOPA PET ( 59 ) or reduced tracer uptake in left putamen by 123 I-ioflupane SPECT ( 61 ). Parkinsonism is not uncommon in GRN mutation carriers and sporadic patients with FTLD.…”

Section: Discussionmentioning

confidence: 99%

Molecular imaging biomarkers in familial frontotemporal lobar degeneration: Progress and prospects

et al. 2022

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Familial frontotemporal lobar degeneration (FTLD) is a pathologically heterogeneous group of neurodegenerative diseases with diverse genotypes and clinical phenotypes. Three major mutations were reported in patients with familial FTLD, namely, progranulin (GRN), microtubule-associated protein tau (MAPT), and the chromosome 9 open reading frame 72 (C9orf72) repeat expansion, which could cause neurodegenerative pathological changes years before symptom onset. Noninvasive quantitative molecular imaging with PET or single-photon emission CT (SPECT) allows for selective visualization of the molecular targets in vivo to investigate brain metabolism, perfusion, neuroinflammation, and pathophysiological changes. There was increasing evidence that several molecular imaging biomarkers tend to serve as biomarkers to reveal the early brain abnormalities in familial FTLD. Tau-PET with 18F-flortaucipir and 11C-PBB3 demonstrated the elevated tau position in patients with FTLD and also showed the ability to differentiate patterns among the different subtypes of the mutations in familial FTLD. Furthermore, dopamine transporter imaging with the 11C-DOPA and 11C-CFT in PET and the 123I-FP-CIT in SPECT revealed the loss of dopaminergic neurons in the asymptomatic and symptomatic patients of familial FTLD. In addition, PET imaging with the 11C-MP4A has demonstrated reduced acetylcholinesterase (AChE) activity in patients with FTLD, while PET with the 11C-DAA1106 and 11C-PK11195 revealed an increased level of microglial activation associated with neuroinflammation even before the onset of symptoms in familial FTLD. 18F-fluorodeoxyglucose (FDG)-PET indicated hypometabolism in FTLD with different mutations preceded the atrophy on MRI. Identifying molecular imaging biomarkers for familial FTLD is important for the in-vivo assessment of underlying pathophysiological changes with disease progression and future disease-modifying therapy. We review the recent progress of molecular imaging in familial FTLD with focused on the possible implication of these techniques and their prospects in specific mutation types.

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Section: Discussionmentioning

confidence: 99%

Molecular imaging biomarkers in familial frontotemporal lobar degeneration: Progress and prospects

et al. 2022

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“…Furthermore, accumulative evidence from studies in patients and experimental models suggests involvement of neuroinflammatory pathways [6][7][8][9][10]. Most PD cases have complex etiologies [11,12]. Several monogenic forms of PD have been linked to genes including α-synuclein (α-syn), Leucine-rich repeat kinase 2 (LRRK2), PTEN-induced kinase 1 (PINK1), Parkin, DJ-1, Glucosylceramidase beta, and Coiled-coil-helix-coiled-coil-helix domain containing 2 [13].…”

Section: Introductionmentioning

confidence: 99%

The role of tyrosine hydroxylase–dopamine pathway in Parkinson’s disease pathogenesis

Zhou

Saw

et al. 2022

Cell. Mol. Life Sci.

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Background Parkinson’s disease (PD) is characterized by selective and progressive dopamine (DA) neuron loss in the substantia nigra and other brain regions, with the presence of Lewy body formation. Most PD cases are sporadic, whereas monogenic forms of PD have been linked to multiple genes, including Leucine kinase repeat 2 (LRRK2) and PTEN-induced kinase 1 (PINK1), two protein kinase genes involved in multiple signaling pathways. There is increasing evidence to suggest that endogenous DA and DA-dependent neurodegeneration have a pathophysiologic role in sporadic and familial PD. Methods We generated patient-derived dopaminergic neurons and human midbrain-like organoids (hMLOs), transgenic (TG) mouse and Drosophila models, expressing both mutant and wild-type (WT) LRRK2 and PINK1. Using these models, we examined the effect of LRRK2 and PINK1 on tyrosine hydroxylase (TH)–DA pathway. Results We demonstrated that PD-linked LRRK2 mutations were able to modulate TH–DA pathway, resulting in up-regulation of DA early in the disease which subsequently led to neurodegeneration. The LRRK2-induced DA toxicity and degeneration were abrogated by wild-type (WT) PINK1 (but not PINK1 mutations), and early treatment with a clinical-grade drug, α-methyl-L-tyrosine (α-MT), a TH inhibitor, was able to reverse the pathologies in human neurons and TG Drosophila models. We also identified opposing effects between LRRK2 and PINK1 on TH expression, suggesting that functional balance between these two genes may regulate the TH–DA pathway. Conclusions Our findings highlight the vital role of the TH–DA pathway in PD pathogenesis. LRRK2 and PINK1 have opposing effects on the TH–DA pathway, and its balance affects DA neuron survival. LRRK2 or PINK1 mutations can disrupt this balance, promoting DA neuron demise. Our findings provide support for potential clinical trials using TH–DA pathway inhibitors in early or prodromic PD.

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“…Vascular cognitive impairment (VCI) is not only a common concomitant symptom in stroke patients but also an initial symptom in patients with cerebral small vessel disease (CSVD). Long-term and progressive cognitive impairment will develop into vascular dementia, which has become the type of dementia second only to Alzheimer's disease (AD) in worldwide prevalence (Wang T. et al, 2020;Deng et al, 2021;Zhu et al, 2021a). The pathophysiological mechanisms underlying VCI are complex.…”

Section: Introductionmentioning

confidence: 99%

Erythrocytes Are an Independent Protective Factor for Vascular Cognitive Impairment in Patients With Severe White Matter Hyperintensities

Zhou

et al. 2022

Front. Aging Neurosci.

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Background and Purpose: Hemoglobin is one of the main proteins in erythrocytes. There are significant correlations between low hemoglobin and white matter hyperintensities (WMH) and cognitive impairment. This study explored whether erythrocytopenia has predictive value for vascular cognitive impairment (VCI) in patients with WMH.Method: We conducted a cross-sectional study of 302 patients, including 62 with cerebral small vessel disease and 240 with stroke. Basic demographic data and fasting blood were collected. First, all patients were divided into normal cognition (NC), mild VCI (mVCI), and severe VCI (sVCI) groups (subgroups later) based on cognitive behavior scores. Second, all patients were divided into mild WMH (mWMH) and severe WMH (sWMH) groups based on Fazekas scores. The differences in blood markers between different groups or subgroups with different cognitive levels were analyzed by univariate analysis. Then, binary logistic regression was used to analyze the diagnostic value of erythrocyte counts for VCI in the sWMH group, and ordinal logistic regression was used to analyze the predictive value of multiple variables for different cognitive levels.Results: Univariate analysis showed that erythrocytes, hemoglobin, high-sensitivity C-reactive protein, retinol binding protein and prealbumin were potential blood markers for different cognitive levels in sWMH patients. Among them, erythrocytopenia has good predictive value for the diagnosis of mVCI (AUC = 0.685, P = 0.008) or sVCI (AUC = 0.699, P = 0.003) in patients with sWMH. Multivariate joint analysis showed that erythrocytes were an independent protective factor reducing the occurrence of VCI in patients with sWMH (OR = 0.633, P = 0.045). Even after adjusting for age, there was still a significant difference (P = 0.047).Conclusion: Erythrocytes are an independent protective factor for VCI in patients with sWMH. Promoting hematopoietic function may have potential value for prevention of cognitive decline in patients with cerebrovascular disease.

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FTD-PSP is an Unusual Clinical Phenotype in A Frontotemporal Dementia Patient with A Novel Progranulin Mutation

Cited by 8 publications

References 94 publications

Molecular imaging biomarkers in familial frontotemporal lobar degeneration: Progress and prospects

Molecular imaging biomarkers in familial frontotemporal lobar degeneration: Progress and prospects

The role of tyrosine hydroxylase–dopamine pathway in Parkinson’s disease pathogenesis

Erythrocytes Are an Independent Protective Factor for Vascular Cognitive Impairment in Patients With Severe White Matter Hyperintensities

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