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(a) A locus coeruleus is shown with a mild reduction in neurons and mild gliosis. (b) An enlarged image of the central part of (a). LB is seen in the neuron. (c) There is a Lewy body stained by α-synuclein staining in the neuron in the LC. (d) The immunoreactivity of the locus coeruleus is decreased in a case with Lewy body disease compared with that in the control case shown in (e). (a), (b) H&E staining. (c) α-synuclein staining. (d), (e) Norepinephrine-transporter-staining. Scale bar: (a), (d), (e) 100 μm, (b), (c) 10 μm.
Source publication
Aim:
The association between psychiatric symptoms in Lewy body disease (LBD) and the noradrenergic and serotonergic systems is still controversial. This study investigated the quantitative relationships of depression and delusion with these systems.
Methods:
We studied 24 postmortem tissues from individuals with a pathological diagnosis of LBD w...
Context in source publication
Context 1
... of TPH-positive cells, measured the area, and calculated the density of neuronal cells in the DRN from every case (Fig. 1). Next, we counted the number of LBs and determined their prevalence in the DRN using H&E staining and α-synuclein staining, respectively. We counted the number of nucleoli of neural cells and LBs in the LC by H&E staining (Fig. 2). We did not measure the area of the LC in any cases because severe neuronal cell loss made it difficult to recognize the LC border in most ...
Citations
... This eventually leads to neurodegeneration which progresses into chronic conditions such as LBD and PD. Additionally, the major deficit of serotonin (Zande et al. 2020) along with defects in the noradrenergic system (Mizutani et al. 2022) contributes directly to LBD and its most disturbing symptom of depression (Londos 2018). ...
The conventional method of one drug being used for one target has not yielded therapeutic solutions for Lewy body dementia (LBD), which is a leading progressive neurological disorder characterized by significant loss of neurons. The age-related disease is marked by memory loss, hallucinations, sleep disorder, mental health deterioration, palsy, and cognitive impairment, all of which have no known effective cure. The present study deploys a network medicine pipeline to repurpose drugs having considerable effect on the genes and proteins related to the diseases of interest. We utilized the novel SAveRUNNER algorithm to quantify the proximity of all drugs obtained from DrugBank with the disease associated gene dataset obtained from Phenopedia and targets in the human interactome. We found that most of the 154 FDA-approved drugs predicted by SAveRUNNER were used to treat nervous system disorders, but some off-label drugs like quinapril and selegiline were interestingly used to treat hypertension and Parkinson’s disease (PD), respectively. Additionally, we performed gene set enrichment analysis using Connectivity Map (CMap) and pathway enrichment analysis using EnrichR to validate the efficacy of the drug candidates obtained from the pipeline approach. The investigation enabled us to identify the significant role of the synaptic vesicle pathway in our disease and accordingly finalize 8 suitable antidepressant drugs from the 154 drugs initially predicted by SAveRUNNER. These potential anti-LBD drugs are either selective or non-selective inhibitors of serotonin, dopamine, and norepinephrine transporters. The validated selective serotonin and norepinephrine inhibitors like milnacipran, protriptyline, and venlafaxine are predicted to manage LBD along with the affecting symptomatic issues.
... In contrast to dopaminergic changes, serotonergic involvement in depression in DLB was limited, comparable with similar studies 42,72 . Whilst the dorsal raphe nucleus (DRN) shows LB pathology in DLB and PD, studies of neurone loss are variable with reduction 73 or no change in DRN neurones in PD or PDD 72,74 . ...
... In contrast to dopaminergic changes, serotonergic involvement in depression in DLB was limited, comparable with similar studies 42,72 . Whilst the dorsal raphe nucleus (DRN) shows LB pathology in DLB and PD, studies of neurone loss are variable with reduction 73 or no change in DRN neurones in PD or PDD 72,74 . In one report in DLB, neuronal loss is present within both the DRN and median raphe 75 . ...
In addition to the core clinical features of fluctuating cognition, visual hallucinations, and parkinsonism, individuals with dementia with Lewy bodies (DLB) frequently experience chronic and debilitating major depression. Treatment of depression in DLB is hampered by a lack of available effective therapies and standard serotonergic medication for major depressive disorder (MDD) is typically ineffective. Dysfunction of dopaminergic neurotransmission contributing to anhedonia and loss of motivation has been described in MDD. The subgenual anterior cingulate cortex (sgACC) is important in mood regulation and in the symptomatic expression of depression, displaying structural, functional and metabolic abnormalities in MDD. To assess dopaminergic and serotonergic synaptic changes in DLB, post mortem sgACC tissue from DLB donors with and without depression was investigated using high-resolution stimulated emission depletion (STED) microscopy, as well as Western and dot blotting techniques. STED imaging demonstrated the presence of α-synuclein within individual dopaminergic terminals in the sgACC, α-synuclein presence showing a significant positive correlation with increased SNAP25 volumes in depressed DLB cases. A reduction in dopaminergic innervation in the sgACC was observed in DLB cases with depression, along with reduced levels of multiple dopaminergic markers and receptors. Limited alterations were observed in serotonergic markers. Our work demonstrates a role for dopaminergic neurotransmission in the aetiology of depression in DLB. Careful and selective targeting of dopaminergic systems may be a therapeutic option for treatment of depression in DLB.
... In contrast to dopaminergic changes, we found limited evidence for serotonergic involvement in depression in DLB, comparable with similar studies (Mizutani et al. 2022;Wilson et al. 2013). Serotonergic neurotransmission has been suggested to be severely impaired in DLB compared to AD patients with depression, with reduced 5HT and 5HT-metabolite concentrations in the prefrontal cortex, temporal lobe, limbic regions, occipital cortex and hippocampus (Vermeiren et al. 2015). ...
... The dorsal raphe shows LB pathology in DLB and PD, with a suggested loss of serotonergic innervation to the forebrain (Ballard et al. 2013). Studies have however shown variable cell loss with some studies showing reduction (Seidel et al. 2015), or no change (Cheshire et al. 2015;Mizutani et al. 2022;Halliday et al. 1990) within the dorsal raphe in PD or PDD. In one report in DLB, neuronal loss is present within both the dorsal and median raphe (Benarroch et al. 2007). ...
... In the current study, due to the complexity of the dorsal raphe anatomy, tissue sampling strategy, and differences in dorsal raphe projection sites (Ren et al., 2018), dorsal raphe neurone numbers were not assessed. We however found no change in sgACC serotonergic fibre density in DLB indicating neuronal loss in DLB, similar to the findings of unaltered fibre density in the amygdala and dorsal prefrontal cortex in LBD donors with and without depression (Mizutani et al. 2022). We did however find α-synuclein associated with 5HTT positive synapses and, as with dopaminergic synapses, a positive correlation between SNAP-25 volume and α-synuclein volume. ...
In addition to the core clinical features of fluctuating cognition, visual hallucinations, and parkinsonism, individuals with dementia with Lewy bodies (DLB) frequently experience chronic and debilitating major depression. Treatment of depression in DLB is hampered by a lack of available effective therapies and standard serotonergic medication for major depressive disorder (MDD) is typically ineffective. Dysfunction of dopaminergic neurotransmission contributing to anhedonia and loss of motivation has been described in MDD. The subgenual anterior cingulate (sgACC) is important in mood regulation and in the symptomatic expression of depression, displaying structural, functional and metabolic abnormalities in MDD. To assess dopaminergic and serotonergic synaptic changes in DLB, post mortem sgACC tissue from DLB donors with and without depression was investigated using high-resolution stimulated emission depletion (STED) microscopy, as well as Western and dot blotting techniques. STED imaging demonstrated the presence of α-synuclein within individual dopaminergic terminals in the sgACC, α-synuclein presence showing a significant positive correlation with increased SNAP25 volumes in depressed DLB cases. A reduction in dopaminergic innervation in the sgACC was observed in DLB cases with depression, along with reduced levels of multiple dopaminergic markers and receptors. Limited alterations were observed in serotonergic markers. Our work demonstrates a role for dopaminergic neurotransmission in the aetiology of depression in DLB. Careful and selective targeting of dopaminergic systems may be a therapeutic option for treatment of depression in DLB.
... It is interesting to note that for patients with Parkinson's Disease, first-line antidepressants are shown to be efficacious [129], but this positive effect may not extend to Lewy Body Dementia [130] and contrasts with AD [39]. Monoaminergic deficits and increased degeneration of locus coeruleus and substantia nigra cells have been reported more consistently in Lewy Body disease with depression [131][132][133][134] or when the source of cognitive impairment is not specified [100,135,136] than in AD [137,138], which has more conflicting results. It is possible that when depression is caused solely by Lewy Bodies, such as in Parkinson's Disease, more typical antidepressant strategies are helpful, but when depression is influenced by other processes, as in most dementias, these same strategies are less efficacious. ...
Depression is a common and devastating neuropsychiatric symptom in the elderly and in patients with dementia. In particular, nearly 80% of patients with Alzheimer’s Disease dementia experience depression during disease development and progression. However, it is unknown whether the depression in patients with dementia shares the same molecular mechanisms as depression presenting as primary psychiatric disease or occurs and persists through alternative mechanisms. In this review, we discuss how the clinical presentation and treatment differ between depression in dementia and as a primary psychiatric disease, with a focus on major depressive disorder. Then, we hypothesize several molecular mechanisms that may be unique to depression in dementia such as neuropathological changes, inflammation, and vascular events. Finally, we discuss existing issues and future directions for investigation and treatment of depression in dementia.
... Indeed, it is estimated that one in three cases of DLB is missed [15]. In the prodromal stages of DLB, a variety of symptoms including Rapid Eye Movements sleep behavioral disorder (RBD) [16], olfactory impairment [17], and mood disturbances [18], could precede the onset of cognitive symptoms [19]. Interestingly, all these alterations have been linked to LC-NA system impairment [18,[20][21][22]. ...
... In the prodromal stages of DLB, a variety of symptoms including Rapid Eye Movements sleep behavioral disorder (RBD) [16], olfactory impairment [17], and mood disturbances [18], could precede the onset of cognitive symptoms [19]. Interestingly, all these alterations have been linked to LC-NA system impairment [18,[20][21][22]. ...
... These patients often suffer from RBD, which might also precede by years the clinical onset of DLB [16]; LC disruption is known to play a key role in RBD pathogenesis [74], and, in line with this, its integrity has been already explored by LC-MRI, and the occurrence of a significant alteration of the nucleus has been shown in patients suffering both from idiopathic RBD [22] and RBD associated to PD [21]. Furthermore, LC degeneration has been linked to behavioral and psychiatric symptoms that very often appear in the prodromal stages of DLB, in neuropathological studies [18,75,76]. ...
Background:
the integrity of Locus Coeruleus can be evaluated in vivo using specific Magnetic Resonance Imaging sequences. While this nucleus has been shown to be degenerated both in post-mortem and in vivo studies in Alzheimer's Disease, for other neurodegenerative dementias such as Dementia with Lewy Bodies this has only been shown ex-vivo.
Objective:
to evaluate the integrity of the Locus Coeruleus through Magnetic Resonance Imaging in patients suffering from Dementia with Lewy Bodies and explore the possible differences with the Locus Coeruleus alterations occurring in Alzheimer's Dementia.
Methods:
eleven patients with Dementia with Lewy Bodies and 35 with Alzheimer's Dementia were recruited and underwent Locus Coeruleus Magnetic Resonance Imaging, along with 52 cognitively intact, age-matched controls. Images were analyzed applying an already developed template-based approach; Locus Coeruleus signal was expressed through the Locus Coeruleus Contrast Ratio parameter, and a locoregional analysis was performed.
Results:
both groups of patients showed significantly lower values of Locus Coeruleus Contrast Ratio when compared to controls. A different pattern of spatial involvement was found; patients affected by Dementia with Lewy bodies showed global and bilateral involvement of the Locus Coeruleus, whereas the alterations in Alzheimer's Dementia patients were more likely to be localized in the rostral part of the left nucleus.
Conclusions:
Magnetic Resonance Imaging successfully detects widespread Locus Coeruleus degeneration in patients suffering from Dementia with Lewy Bodies. Further studies, in larger cohorts and in earlier stages of the disease, are needed to better disclose the potential diagnostic and prognostic role of this neuroradiological tool.
... Furthermore, in DLB patients with co-morbid depression ante mortem the substantia nigra compacta (SNc) dopaminergic neuron density was markedly lower than in non-depressed ones, although there were no differences in cognition, motor disease severity and disease duration (Saari et al. 2021). The DLB group with depressive mood had also a significantly smaller number of neurons in the noradrenergic locus ceruleus (LC) (Fischer et al. 2021;Frisina et al. 2009;Mizutani et al. 2022). LC degeneration also occurred in prodromal DLB, LC being earlier affected by degeneration than the dopaminergicergic SN which is impaired later in the disease course (Hansen 2021), whereas others found no significant correlation between depression in DLB and LB count in SN and LC, thus suggesting that depressive symptoms in DLB do not appear to be correlated to the severity of cortical and subcortical LB load (Samuels et al. 2004). ...
... Brains of DLB patients with depression had a significantly smaller number of neurons in the LC (Del Tredici and Braak 2013;Mizutani et al. 2022), which is a major component of the noradrenergic system (Foote et al. 1983). Previous studies suggested a relationship between depression and degenerative changes in the LC which implies that dysfunction of the noradrenergic system may be a cause of depression in DLB (Fischer et al. 2021;Frisina et al. 2009). ...
... Because the DRN has projection fibers to the cerebral cortex, a relationship between this nucleus and depression has been suggested, although there is still limited evidence to support this connection (Boldrini et al. 2005;Michelsen et al. 2007;Muzerelle et al. 2016). Recent histochemical studies of the DRN indicated that depression in DLB is more likely associated with abnormalities in the noradrenergic than in the serotonergic system (Mizutani et al. 2022). Major depression in DLB was associated with a significant preservation of 5-HT transporter re-uptake in the parietal neocortex (Ballard et al. 2002), and increased serotonin 1A receptor level was associated with depression in DLB (Sharp et al. 2008). ...
Depression with an estimated prevalence of 35% is a frequent manifestation of dementia with Lewy bodies (DLB), having negative effects on cognitive performance and life expectancy, yet the underlying neurobiology is poorly understood and most likely heterogeneous. Depressive symptoms in DLB can occur during the clinical course and, together with apathy, is a common prodromal neuropsychiatric symptom of this neurocognitive disorder in the group of Lewy body synucleinopathies. There are no essential differences in the frequency of depression in DLB and Parkinson disease-dementia (PDD), while its severity is up to twice as high as in Alzheimer disease (AD). Depression in DLB that is frequently underdiagnosed and undertreated, has been related to a variety of pathogenic mechanisms associated with the basic neurodegenerative process, in particular dysfunctions of neurotransmitter systems (decreased monoaminergic/serotonergic, noradrenergic and dopaminergic metabolism), α-synuclein pathology, synaptic zinc dysregulation, proteasome inhibition, gray matter volume loss in prefrontal and temporal areas as well as dysfunction of neuronal circuits with decreased functional connectivity of specific brain networks. Pharmacotherapy should avoid tricyclic antidepressants (anticholinergic adverse effects), second-generation antidepressants being a better choice, while modified electroconvulsive therapy, transcranial magnetic stimulation therapy and deep brain stimulation may be effective for pharmacotherapy-resistant cases. Since compared to depression in other dementias like Alzheimer disease and other parkinsonian syndromes, our knowledge of its molecular basis is limited, and further studies to elucidate the heterogeneous pathogenesis of depression in DLB are warranted.
... Given that both serotonergic and noradrenergic neurons projects to SN 27,28 , decreased serotonergic or noradrenergic neurons projecting to the substantia nigra may contribute to lower SN-zSBR. This explanation is also consistent with previous findings that intraneuronal α-synuclein burden in locus coeruleus precedes than SN 29 , and decreased SERT or NET is associated with symptoms and severity of LBD 26,[30][31][32] . Taken together, decreased SN-zSBR could be an early biomarker for DLB, attributed to the degeneration of dopaminergic, serotonergic, and noradrenergic neurons. ...
Nigrostriatal dopaminergic degeneration is a pathological hallmark of dementia with Lewy bodies (DLB). To identify the subregional dopamine transporter (DAT) uptake patterns that improve the diagnostic accuracy of DLB, we analyzed N-(3-[18F] fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl)-nortropane (FP-CIT) PET in 51 patients with DLB, in 36 patients with mild cognitive impairment with Lewy body (MCI-LB), and in 40 healthy controls (HCs). In addition to a high affinity for DAT, FP-CIT show a modest affinity to serotonin or norepinephrine transporters. Specific binding ratios (SBRs) of the nigrostriatal subregions were transformed to age-adjusted z-scores (zSBR) based on HCs. The diagnostic accuracy of subregional zSBRs were tested using receiver operating characteristic (ROC) curve analyses separately for MCI-LB and DLB versus HCs. Then, the effect of subregional zSBRs on the presence of clinical features and gray matter (GM) density were evaluated in all patients with MCI-LB or DLB as a group. ROC curve analyses showed that the diagnostic accuracy of DLB based on the zSBR of substantia nigra (area under the curve [AUC], 0.90) or those for MCI-LB (AUC, 0.87) were significantly higher than that based on the zSBR of posterior putamen for DLB (AUC, 0.72) or MCI-LB (AUC, 0.65). Lower zSBRs in nigrostriatal regions were associated with visual hallucination, severe parkinsonism, and cognitive dysfunction, while lower zSBR of substantia nigra was associated with widespread GM atrophy in DLB and MCI-LB patients. Taken together, our results suggest that evaluation of nigral DAT uptake may increase the diagnostic accuracy of DLB and MCI-LB than other striatal regions.
Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) are often associated with depressive symptoms from the prodromal stage. The aim of the present study was to investigate the neuroanatomical correlates of depression in prodromal to mild DLB patients compared with AD patients. Eighty-three DLB patients, 37 AD patients, and 18 healthy volunteers were enrolled in this study. Depression was evaluated with the Mini International Neuropsychiatric Interview (MINI), French version 5.0.0. T1-weighted three-dimensional anatomical images were acquired for all participants. Regression and comparison analyses were conducted using a whole-brain voxel-based morphometry (VBM) approach on the grey matter volume (GMV). DLB patients presented a significantly higher mean MINI score than AD patients (p = 0.004), 30.1% of DLB patients had clinical depression, and 56.6% had a history of depression, while 0% of AD patients had clinical depression and 29.7% had a history of depression. VBM regression analyses revealed negative correlations between the MINI score and the GMV of right prefrontal regions in DLB patients (p < 0.001, uncorrected). Comparison analyses between DLB patients taking and those not taking an antidepressant mainly highlighted a decreased GMV in the bilateral middle/inferior temporal gyrus (p < 0.001, uncorrected) in treated DLB patients. In line with the literature, our behavioral analyses revealed higher depression scores in DLB patients than in AD patients. We also showed that depressive symptoms in DLB are associated with decreased GMV in right prefrontal regions. Treated DLB patients with long-standing depression would be more likely to experience GMV loss in the bilateral middle/inferior temporal cortex. These findings should be taken into account when managing DLB patients.
Introduction: A number of prescribed medicines have been reported in cases of drug-induced delusion, such as dopaminergic agents or psychostimulants. But to this day, most studies are based on a limited number of cases and focus on a few drug classes, so a clear overview of this topic remains difficult. To address this issue, we provide in this article a comprehensive analysis of drug-induced delusion, based on the World Health Organization (WHO) pharmacovigilance database.
Methods: We performed a disproportionality analysis of this database using the information component (IC). The IC compares observed and expected values to find associations between drugs and delusion, using disproportionate Bayesian reporting. An IC0.25 (lower end of the IC 95% credibility interval) > 0 is considered statistically significant.
Results: Here we present an analysis of 4559 suspected drug-induced delusion reports in the WHO pharmacovigilance database. These results identified 66 molecules statistically associated with delusion and an extensive analysis of confounding factors and coprescriptions was performed, using full database as background with an IC0.25 > 0. The main drug classes involved were antidepressants, antiepileptics, dopaminergic agents, opioids, antiinfective agents, benzodiazepines, anti-dementia drugs and psychostimulants.
Conclusion: These results will help clinicians identify potential suspected drugs associated with delusion and decide which drug to discontinue and eventually lead to a re-evaluation of drug labels for some molecules.
