Neurotransmitter deficits from frontotemporal lobar degeneration

Murley, Alexander G; Rowe, James B.

doi:10.1093/brain/awx327

Cited by 144 publications

(153 citation statements)

References 251 publications

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“…We have recently reported a high frequency of autoantibodies recognizing the GluA3 subunit of AMPARs in patients with FTD , corroborating the role of glutamate neurotransmission in this disorder (Murley and Rowe, 2018). Furthermore, in both rat hippocampal neuronal primary cultures and in human neurons derived from iPSCs, we demonstrated that anti-GluA3 antibodies were detrimental for neurons and for AMPA function .…”

supporting

confidence: 75%

Anti-GluA3 antibodies in frontotemporal dementia: effects on glutamatergic neurotransmission and synaptic failure

Palese

Bonomi

Nuzzo

et al. 2020

Neurobiology of Aging

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A number of evidences has put forward new players in the pathogenesis of Frontotemporal Dementia (FTD) claiming for a role of autoimmunity and altered glutamate neurotransmission in triggering disease onset. We reported the presence of autoantibodies recognizing the GluA3 subunit of AMPA receptors in about 25% of FTD cases. Here we evaluated the mechanisms involved in anti-GluA3 autoimmunity in FTD, through molecular/neurochemical analyses conducted on patients' brain specimens, corroborated by Transcranial Magnetic Stimulation (TMS) and analysis of glutamate, D-serine and L-serine levels in the CSF. We observed that GluA3 autoantibodies affect glutamatergic neurotransmission, decreasing glutamate release and altering GluA3-containing AMPA receptor levels. These alterations were accompanied by changes of scaffolding proteins involved in receptor synaptic retention/internalization. The above results were confirmed by TMS, suggesting a significant impairment of indirect measures of glutamate neurotransmission in FTD patients as compared to controls, with further add-on harmful effect in those FTD patients with anti-GluA3 antibodies. Finally, FTD patients showed a significant increase of glutamate, D-serine and L-serine levels in the CSF.

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supporting

confidence: 75%

Anti-GluA3 antibodies in frontotemporal dementia: effects on glutamatergic neurotransmission and synaptic failure

Palese

Bonomi

Nuzzo

et al. 2020

Neurobiology of Aging

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“…These changes seem to reflect the pharmacological abnormalities which are now clearly associated with FTLD, particularly in serotonin, dopamine, GABA and glutamate, possibly reflecting the underlying pathological process [30,31]. In particular, we observed a significant impairment in SICI and LICI, which indirectly and partially depend on GABA A and GABA B ergic transmission, respectively, and an impairment in ICF, which partly relies on glutamatergic circuits, in all FTD phenotypes.…”

Section: Discussionsupporting

confidence: 52%

TMS for staging and predicting functional decline in frontotemporal dementia

et al. 2020

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a b s t r a c tObjective: To evaluate if transcranial magnetic stimulation (TMS) measures correlate with disease severity and predict functional decline in frontotemporal dementia (FTD) phenotypes. Methods: Paired-pulse TMS was used to investigate the activity of different intracortical circuits in 171 FTD patients (122 bvFTD, 31 avPPA, 18 svPPA) and 74 healthy controls. Pearson's correlations were used to analyze the association between TMS measures and disease severity, while multiple regression analysis was used to identify the best clinical or neurophysiological measure to predict functional decline at 12 months. Results: We observed significant strong correlations between TMS measures [short interval intracortical inhibition-facilitation (SICI-ICF) and long interval intracortical inhibition (LICI)], and disease severity (evaluated with the FTLD-CDR) (all r > 0.5, p < 0.005). SICI-ICF, short interval intracortical facilitation (SICF) and LICI were also significant predictors of functional decline, evaluated as the change in FTLD-CDR scores at 12 months (all p < 0.005), while at the stepwise multiple regression analysis, SICI was the best predictor of disease progression, accounting for 72.5% of the variation in FTLD-CDR scores at 12 months (adjusted R 2 ¼ 0.72, p < 0.001). Conclusions:The present study has shown that the dysfunction of inhibitory and facilitatory intracortical circuits, evaluated with TMS, correlates with disease severity and progression, accurately predicting functional decline at 12 months, better than any other investigated marker.

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“…As SICI and LICI are considered to reflect short‐lasting postsynaptic inhibition mediated through the GABA A and GABA B receptors at the level of local interneurons, and ICF is thought to represent a net facilitation most likely mediated by glutamatergic N‐methyl‐D‐aspartate receptors, the impairment observed in FTD suggests a deficit of GABAergic and glutamatergic interneurons . On the other hand, Aβ peptides have been shown to impair acetylcholine synthesis and release, and to induce cholinergic cell toxicity, which could reflect the impairment of SAI observed in AD .…”

Section: Discussionmentioning

confidence: 99%

“…As SICI and LICI are considered to reflect short-lasting postsynaptic inhibition mediated through the GABA A and GABA B receptors at the level of local interneurons, 36,37 and ICF is thought to represent a net facilitation most likely mediated by glutamatergic N-methyl-D-aspartate receptors, 11,37 the impairment observed in FTD suggests a deficit of GABAergic and glutamatergic interneurons. [49][50][51] On the other hand, Aβ peptides have been shown to impair acetylcholine synthesis and release, and to induce cholinergic cell toxicity, 52 which could reflect the impairment of SAI observed in AD. [12][13][14][15][16][17][18][19][20][21] In the same view, the well-recognized cholinergic deficit and the documented impairment of GABAergic and glutamatergic neurotransmission in DLB might explain the impairment of both SAI and SICI-ICF in these patients.…”

Section: Discussionmentioning

confidence: 99%

Classification Accuracy of Transcranial Magnetic Stimulation for the Diagnosis of Neurodegenerative Dementias

Benussi

Grassi

Palluzzi

et al. 2020

Annals of Neurology

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Objective Transcranial magnetic stimulation (TMS) has been suggested as a reliable, noninvasive, and inexpensive tool for the diagnosis of neurodegenerative dementias. In this study, we assessed the classification performance of TMS parameters in the differential diagnosis of common neurodegenerative disorders, including Alzheimer disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Methods We performed a multicenter study enrolling patients referred to 4 dementia centers in Italy, in accordance with the Standards for Reporting of Diagnostic Accuracy. All patients underwent TMS assessment at recruitment (index test), with application of reference clinical criteria, to predict different neurodegenerative disorders. The investigators who performed the index test were masked to the results of the reference test and all other investigations. We trained and tested a random forest classifier using 5‐fold cross‐validation. The primary outcome measures were the classification accuracy, precision, recall, and F1 score of TMS in differentiating each neurodegenerative disorder. Results A total of 694 participants were included, namely 273 patients diagnosed as AD, 67 as DLB, and 207 as FTD, and 147 healthy controls (HC). A series of 3 binary classifiers was employed, and the prediction model exhibited high classification accuracy (ranging from 0.89 to 0.92), high precision (0.86–0.92), high recall (0.93–0.98), and high F1 scores (0.89–0.95) in differentiating each neurodegenerative disorder. Interpretation TMS is a noninvasive procedure that reliably and selectively distinguishes AD, DLB, FTD, and HC, representing a useful additional screening tool to be used in clinical practice. Ann Neurol 2020;87:394–404

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Neurotransmitter deficits from frontotemporal lobar degeneration

Cited by 144 publications

References 251 publications

Anti-GluA3 antibodies in frontotemporal dementia: effects on glutamatergic neurotransmission and synaptic failure

Anti-GluA3 antibodies in frontotemporal dementia: effects on glutamatergic neurotransmission and synaptic failure

TMS for staging and predicting functional decline in frontotemporal dementia

Classification Accuracy of Transcranial Magnetic Stimulation for the Diagnosis of Neurodegenerative Dementias

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