Clinical correlates of selective pathology in the amygdala of patients with Parkinson’s disease. Brain

Prince of Wales Medical Research Institute and University of New South Wales, Sydney, NSW, Australia.
Brain (Impact Factor: 9.2). 11/2002; 125(Pt 11):2431-45.
Source: PubMed

ABSTRACT The amygdala exhibits significant pathological changes in Parkinson's disease, including atrophy and Lewy body (LB) formation. Amygdala pathology has been suggested to contribute to some clinical features of Parkinson's disease, including deficits of olfaction and facial expression. The degree of neuronal loss in amygdala subnuclei and the relationship with LB formation in non-demented Parkinson's disease cases have not been examined previously. Using stereological methods, the volume of neurones and the number of neurones in amygdala subdivisions were estimated in 18 prospectively studied, non-demented patients with Parkinson's disease and 16 age- and sex-matched controls. Careful exclusion (all cortical disease) and inclusion (non-demented, levodopa-responsive, idiopathic Parkinson's disease or controls) criteria were applied. Seven Parkinson's disease cases experienced well-formed visual hallucinations many years after disease onset, while nine Parkinson's disease cases and three controls were treated for depression. Anatomically, the amygdala was subdivided into the lateral nucleus, the basal (basolateral and basomedial) nuclei and the corticomedial (central, medial and cortical nuclei) complex. LB and Lewy neurites were identified by immunohistochemistry for alpha-synuclein and ubiquitin and were assessed semiquantitatively. LB were found throughout the amygdala in Parkinson's disease, being present in approximately 4% of neurones. Total amygdala volume was reduced by 20% in Parkinson's disease (P = 0.02) and LB concentrated in the cortical and basolateral nuclei. Lewy neurites were present in most cases but did not correlate with any structural or functional variable. Amygdala volume loss was largely due to a 30% reduction in volume (P = 0.01) and the total estimated number of neurones (P = 0.007) in the corticomedial complex. The degree of neurone loss and the proportion of LB-containing neurones in the cortical nucleus within this complex were constant across Parkinson's disease cases and neither variable was related to disease duration (R(2 )< 0.03; P > 0.5). The cortical nucleus has major olfactory connections and its degeneration is likely to contribute to the early selective anosmia common in Parkinson's disease. There was a small reduction in neuronal density in the basolateral nucleus in all Parkinson's disease cases, but no consistent volume or cell loss within this region. However, the proportion of LB-containing neurones in the basolateral nucleus was nearly doubled in cases that exhibited visual hallucinations, suggesting that neuronal dysfunction in this nucleus contributes to this late clinical feature. Detailed quantitation of the other amygdala subdivisions failed to reveal any other substantial anomalies or any associations with depression. Thus, the impact of Parkinson's disease on the amygdala is highly selective and correlates with both early and late clinical features.

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    • "Dopaminergic medications, cognitive dysfunction, depression, sleep disturbances, long duration of PD have been described as risk factors for the emergence of VH in PD [10]. Though autopsy studies in PD patients with VH have reported increased Lewy body (LB) deposition in the limbic regions, the pathogenesis is still unclear [11]. However in vivo imaging by advanced techniques has been utilized to detect structural, functional and metabolic changes in PD patients with and without VH. "
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    ABSTRACT: Patients with Parkinson's disease (PD) may develop various non-motor symptoms (NMS) during the course of the illness and psychosis is one of the common NMS of PD. Visual hallucinations (VH) are the most common manifestation of psychosis in PD. The exact pathogenesis of VH in patients with PD is not clearly understood. Presence of VH has been described to be associated with rapid cognitive decline and increased nursing home placements in PD patients. A large number of structural and functional neuroimaging studies have been conducted to understand the cerebral basis of VH in PD. Structural imaging studies (Voxel Based Morphometry) have reported grey matter atrophy in multiple regions of the brain such as primary visual cortex, visual association cortex, limbic regions, cholinergic structures such as pedunculopontine nucleus and substantia innominata, which conclude possible alterations of brain regions associated with functions such as visuospatial-perception, attention control and memory. Most functional neuroimaging studies (functional MRI, positron emission tomography and single photon emission computerized tomography) have reported altered activation, blood flow, or reduced metabolism in both dorsal and ventral visual pathways, which probably indicates an alteration in the normal bottom-top visual processing and the presence of an aberrant top-down visual processing. This review critically analyzes the published studies on the structural and functional neuroimaging in PD patients with VH. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Parkinsonism & Related Disorders 04/2015; 21(7). DOI:10.1016/j.parkreldis.2015.04.005 · 3.97 Impact Factor
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    • "The amygdala is one of the key regions in the limbic system of the brain and has been thought to have an important role in the emotional memory such as fear. Amygdala has three distinct subgroups: central nucleus, corticomedial nucleus, and basolateral nucleus [7]. The basolateral nucleus is the largest among these three and has been strongly implicated as key sites for stress and fear/anxiety functions [8,9]. "
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    ABSTRACT: Background Post-traumatic stress disorder (PTSD) is an anxious disorder associated with low levels of corticosterone and enhanced negative feedback of the hypothalamic–pituitary–adrenal (HPA) axis. Previous studies showed that the amygdala not only has an excitatory effect on the HPA axis but also plays a key role in fear-related behaviors. Coticosterone exert actions through binding to the mineralocorticoid (MR) and glucocorticoid receptor (GR), which are abundant in the amygdala. In our previous study, down-regulation of MR and GR in the hippocampus of PTSD rats was found. But the roles of MR and GR in the amygdala of PTSD rats is incompletely understood. Results wistar rats were divided into 1 d, 7 d, 14 d groups after single prolonged stress (SPS) and control group. SPS is a reliable animal model of PTSD. Open field test (OF) and elevated plus maze tests (EPM) were performed to examine fear-related behaviors. Morphological changes of the ultrastructure of the amygdala neurons were assessed by transmission electron microscopy (TEM). Dual-immunofluorescence histochemistry was used to determined subcellular distribution and colocalization of MR- and GR-ir. Protein and mRNA of MR and GR was examined by western blotting and RT-PCR. OF and EPM showed enhanced fear in SPS rats. Abnormal neuronal morphology was discovered in the amygdala of SPS rats. The expression of MR- and GR-ir intensity, mRNA and protein within the amygdala decreased after SPS at 1 day, and then gradually recovered by 14 days, although the degree of decrease and recovery were different amongst techniques. We found no change in the MR/GR ratio at 3 levels of the amygdala. But more cytoplasmic distribution and decreased colocalization of MR- and GR-ir were observed in the amygdala after 7 days of SPS. Conclusion These data suggest that change of MR and GR in the amygdala are involved in the mechanisms of fear in PTSD.
    BMC Neuroscience 06/2014; 15(1):77. DOI:10.1186/1471-2202-15-77 · 2.67 Impact Factor
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    • "However, a subsequent fMRI study utilising the presentation of more complex visual stimuli failed to find any evidence to support this " top-down " compensatory process [Meppelink et al., 2009]. In addition to the results of these neuroimaging studies, a strong clinicopathological correlation has been found between VH and Lewy body (LB) pathology within temporal cortical structures, such as the amygdala and parahippocampal gyrus [Harding et al., 2002], suggesting that VH in PD relate to a disruption across diverse yet related neural circuitry. These findings have led to several separate proposals suggesting that hallucinations in PD are related to deficits in perception and attention [Bronnick et al., 2005; Collerton et al., 2005; Diederich et al., 2005; Gallagher et al., 2011; Pieri et al., 2000; Price et al., 1992] being modulated by both neurotransmitter disturbances [Goetz et al., 1982, 1998] and specific subcortical and cortical pathology [Harding et al., 2002; Ram ırez-Ruiz et al., 2007; Sanchez-Castenada et al., 2010; Janzen et al., 2012]. "
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    ABSTRACT: Visual misperceptions and hallucinations represent a problematic symptom of Parkinson's disease. The pathophysiological mechanisms underlying these symptoms remain poorly understood, however, a recent hypothesis has suggested that visual misperceptions and hallucinations may arise from disrupted processing across attentional networks. To test the specific predictions of this hypothesis, 22 patients with Parkinson's disease underwent 3T fMRI while performing the Bistable Percept Paradigm, a task that has previously been shown to identify patients with hallucinations. Subjects are required to study a battery of randomly assigned "monostable" and "bistable" monochromatic images for the presence or absence of a bistable percept. Those patients who scored a high percentage of misperceptions and missed images on the task were less able to activate frontal and parietal hubs of the putative Dorsal Attention Network. Furthermore, poor performance on the task was significantly correlated with the degree of decreased activation in a number of these hubs. At the group level, the difference between processing a bistable versus a monostable cue was associated with increased recruitment of the anterior insula. In addition, those patients with impaired performance on the paradigm displayed decreased resting state functional connectivity between hubs of the Ventral and Dorsal Attention Networks. These same patients had significantly decreased gray matter in the insula bilaterally. In addition, a combined analysis of the separate neuroimaging approaches revealed significant relationships across the impaired networks. These findings are consistent with specific predictions from a recently proposed hypothesis that implicates dysfunction within attentional networks in Parkinsonian hallucinations. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.
    Human Brain Mapping 05/2014; 35(5). DOI:10.1002/hbm.22321 · 5.97 Impact Factor
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