Anxiety in synucleinopathies: neuronal circuitry, underlying pathomechanisms and current therapeutic strategies

Abstract

Synucleinopathies are neurodegenerative disorders characterized by alpha-synuclein (αSyn) accumulation in neurons or glial cells, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). αSyn-related pathology plays a critical role in the pathogenesis of synucleinopathies leading to the progressive loss of neuronal populations in specific brain regions and the development of motor and non-motor symptoms. Anxiety is among the most frequent non-motor symptoms in patients with PD, but it remains underrecognized and undertreated, which significantly reduces the quality of life for patients. Anxiety is defined as a neuropsychiatric complication with characteristics such as nervousness, loss of concentration, and sweating due to the anticipation of impending danger. In patients with PD, neuropathology in the amygdala, a central region in the anxiety and fear circuitry, may contribute to the high prevalence of anxiety. Studies in animal models reported αSyn pathology in the amygdala together with alteration of anxiety or fear learning response. Therefore, understanding the progression, extent, and specifics of pathology in the anxiety and fear circuitry in synucleinopathies will suggest novel approaches to the diagnosis and treatment of neuropsychiatric symptoms. Here, we provide an overview of studies that address neuropsychiatric symptoms in synucleinopathies. We offer insights into anxiety and fear circuitry in animal models and the current implications for therapeutic intervention. In summary, it is apparent that anxiety is not a bystander symptom in these disorders but reflects early pathogenic mechanisms in the cortico-limbic system which may even contribute as a driver to disease progression.

Sex-specific biphasic alpha-synuclein response and alterations of interneurons in a COVID-19 hamster model

“… 63 Similarly, the amygdala is suggested as being affected early in PD by aSyn pathology. 60 , 64 The recent compelling hypothesis of a dichotomy in PD pathogenesis in brain first vs gut first may well be supported by our results. 65 If virus indirectly causes aSyn accumulation in highly connected hub regions, such regions may develop aSyn aggregation which could spread across the brain to connected regions in a prion like fashion, as has been demonstrated in animal models of aSyn preformed fibril inoculation.…”

“…Interestingly, the brain regions mostly affected by this biphasic response were the BLA and the Cpu, both highly connected brain regions related to early PD pathogenesis. 59 , 60 , 61 The Cpu represents the main input region from the dopamine neurons of the SNc, and dopamine loss in response to dopamine neurodegeneration is causing the hallmark motor symptoms of PD. 62 It has long been suggested that pathology may, at least in some cases, start at the dopaminergic terminals followed by cell loss.…”

“…Interestingly, the decrease of GABAergic interneurons in the BLA could result in disinhibition of the fear circuitry and increased fear and anxiety, as observed in patients with PD and respective animal models. 41 , 60 …”

Alpha Synuclein Toxicity and Non-motor Parkinson’s

“…Anxiety has a relative high prevalence (22.2%-66.7%) in PD patients with female being at higher risk than male patients [127][128][129]. Several kinds of anxiety are described in PD, including generalized anxiety, panic attacks, social phobia, agoraphobia, and obsessive-compulsive disorder.…”

“…Likewise, injection of αSyn preformed fibrils into the bilateral olfactory bulb of A53T transgenic mice spreads into connected regions provoking severe pathology in the hippocampus, bed nucleus of the stria terminalis and central nucleus of the amygdala. Animals exhibited hyposmia, anxiety-like behavior, and memory impairment, consequence of atrophy, neuronal loss and gliosis [131]Increase in hippocampal aSyn expression has been detected in rats with high levels of innate anxiety, suggesting that anxiety can cause aSyn accumulation, besides being a contributor of synuclein progression [129].…”