Pathologic Evaluation of the Supraoptic and Paraventricular Nuclei in Dementia

Abstract

Frontotemporal dementia (FTD) is a neurodegenerative disorder featuring striking changes in personality including emotional blunting, increased self-centered behaviour, and poor judgment [1][2][3] . At the cognitive level, patients with frontotemporal dementia have deficits in emotional processing including loss of empathy 4,5 , decreased emotion recognition [6][7][8] , and deficits in theory of mind 9,10 . Recent work in humans has demonstrated that the neuropeptide oxytocin may facilitate emotional and social cognition in each of these domains in healthy adults. Oxytocin is produced in the supraoptic (SON) and paraventricular (PVN) nuclei in the hypothalamus 11 . Despite the important role of oxytocin in many aspects of social cognition impaired in patients with FTD, little empirical data concerning the integrity of these nuclei in patients with frontotemporal dementia has been reported.Oxytocin produced in the hypothalamus and released via the pituitary into the systemic circulation has previously been most strongly associated with uterine contractions and milk ejection ABSTRACT: Background: The neuropeptide oxytocin, produced in the supraoptic (SON) and paraventricular nuclei (PVN) of the hypothalamus, is now understood to function as a neurotransmitter critical for various aspects of social cognition and pro-social behaviour. While patients with Frontotemporal dementia (FTD) display prominent and progressive deficits in such social behaviours, the integrity of these nuclei in FTD is not known. Methods: We conducted a quantitative neuropathologic examination of the SON and PVN from patients with FTLD with TDP-43 proteinopathy, Alzheimer's disease, Lewy body disease and controls to determine whether significant pathologic changes or neuronal loss may contribute to the striking behavioural symptoms of FTD. Results: Contrary to predictions, we found both nuclei to be free of significant pathologic change (TDP-43) in FTLD. In contrast, tau related pathology was found in the PVN in Alzheimer's disease, and alpha-synuclein pathology in the SON in patients with Lewy body dementia. Conclusions: These results indicate that the SON and PVN are resistant to FTLD TDP-43 pathology. They also support prior suggestions that the SON is resistant to Alzheimer's disease (AD) related pathology, and extend this to demonstrate SON susceptibility to alpha-synuclein pathology in patients with Lewy body dementia.RÉSUMÉ: Évaluation anatomopathologique des noyaux supraoptiques et paraventriculaires dans la démence. Contexte : On sait maintenant que l'ocytocine, un neuropeptide produit dans les noyaux supraoptiques (NSO) et paraventriculaires (NPV) de l'hypothalamus, agit comme un neurotransmetteur dont la fonction est importante pour différents aspects de la cognition sociale et du comportement prosocial. Les patients qui présentent une démence fronto-temporale (DFT) ont des déficits importants et progressifs de ces comportements sociaux. Cependant l'intégrité de ces noyaux dans la DFT n'a pas été étudiée. Méthode : Nous avons effect...

Oxytocin for frontotemporal dementia

“…How oxytocin may increase empathy and improve corresponding social behaviors in patients with FTD has yet to be determined. The integrity of oxytocinproducing neurons in the hypothalamic nuclei is preserved in patients with TDP-43 (TAR DNA-binding protein 43) frontotemporal lobar degeneration, 23 suggesting that disease pathology at the sites of afferent projections including the amygdala, orbitofrontal cortex, and insula may disrupt oxytocinergic systems, and that increased oxytocin receptor-dependent signaling to these regions may partially overcome deficits due to neuronal loss or dysfunction. In support of this hypothesis, intranasal oxytocin administration to mice increases levels of oxytocin in the amygdala and hippocampus after 30 minutes.…”

Adaptive crossover designs for assessment of symptomatic treatments targeting behaviour in neurodegenerative disease: a phase 2 clinical trial of intranasal oxytocin for frontotemporal dementia (FOXY)

“…Randomisation for stages 1 and 2 will be stratified across the treatment groups listed above according to sex and disease severity (mild vs. moderate) because oxytocin is known to have differential behavioural effects based on sex [ 29 ], and pilot data suggest that efficacy may differ as a function of disease severity and the integrity of remaining oxytocin receptor-positive neurons [ 19 , 30 ]. The FTLD-CDR allows severity assessment and stratification across the different FTD phenotypes included in the trial.…”

A Call for Drug Therapies for the Treatment of Social Behavior Disorders in Dementia: Systematic Review of Evidence and State of the Art

“…Oxytocin is produced in the supraoptic and paraventricular nuclei of the hypothalamus and released into circulation by the posterior pituitary. Both hypothalamic nuclei have been proved to be preserved in patients with TDP-43 (TAR DNA-binding protein 43) proteinopathy [ 78 ], suggesting possible differential responses to oxytocin treatments according to the underlying molecular pathologies. Oxytocin is also delivered directly to brain regions with afferent projections and paracrine signaling of oxytocin receptors, which are directly involved in emotion and reward processing [ 79 , 80 ].…”