E.M.J. Foncke

Depressive symptoms in Parkinson's disease are related to reduced [123I]FP-CIT binding in the caudate nucleus.

Background Depression is a common neuropsychiatric symptom in Parkinsons disease (PD). In previous research, PD-related depression was associated with striatal dopaminergic deficits, presumably due to degeneration of brainstem dopaminergic projections. Segregated areas of the striatum are crucially involved in various parallelly arranged cortical-striatal-thalamocortical circuits and serve functions in, among others, motor control or emotion. This suggests regional specificity of dopaminergic deficits in the striatum in motor and depressive symptoms in PD. Methods In this cross-sectional retrospective study, we correlated severity scores of depressive and motor symptoms in 100 non-demented PD patients (median Hoehn & Yahr stage: 2) with dopamine loss in specific regions of the striatum as measured by [123I]FP-CIT SPECT tracer binding to the dopamine transporter (DaT). Results Depressive symptoms were related to lower DaT binding in the right caudate nucleus, while motor symptoms were associated with decreased DaT binding in the right putamen. This double dissociation was most pronounced in early-stage PD patients. Conclusions These results suggest that depressive symptoms in PD are associated with dopamine loss in the caudate nucleus, possibly related to degeneration of dopaminergic projections from the ventral tegmental area, while motor symptoms are associated with low dopamine signalling to the putamen and loss of nigrostriatal projections. This is consistent with the neuroanatomy of partially segregated cortical-striatal-thalamocortical circuits and supports the role of dysfunctional associative and motivational circuits in PD-related depression.

Depressive symptoms in Parkinson's disease are related to decreased hippocampus and amygdala volume

Depression and anxiety are common in Parkinsons disease (PD), and are among the non‐motor symptoms that interfere with quality of life dramatically. Motor, cognitive, and affective features overlap in PD, hampering diagnosis. To shed more light on the contribution of structural brain changes to the presence of PD‐related depressive symptoms, we conducted a Voxel‐Based Morphometry (VBM) study. We hypothesized that depressive symptoms in PD are related to regional gray matter (GM) volume loss within the limbic circuit. We analyzed the T1‐weigthed magnetic resonance imaging (MRI) images of 67 PD patients with a mean disease duration of 2.95 (±3.39) years. Scores on the Beck Depression Inventory (BDI) and GM probability maps were analyzed by regression analysis to study the association between GM volume and severity of depressive symptoms. Results are reported at both the uncorrected and the family‐wise error (FWE) corrected level for multiple comparisons. The BDI scores correlated negatively with bilateral hippocampus and right amygdala volume and positively with the volume of the anterior cingulate cortex. These findings confirm the hypothesized involvement of the limbic circuit in PD‐related depressive symptoms. We speculate that non‐dopaminergic changes are essential in the pathophysiology of depressive symptoms in PD, because our findings suggest the involvement of extra‐striatal brain regions.

Reduced dopamine transporter binding predates impulse control disorders in Parkinson's disease

Impulse control disorders (ICD) are relatively common in Parkinsons disease (PD) and generally are regarded as adverse effects of dopamine replacement therapy, although certain demographic and clinical risk factors are also involved. Previous single‐photon emission computed tomography (SPECT) studies showed reduced ventral striatal dopamine transporter binding in Parkinson patients with ICD compared with patients without. Nevertheless, these studies were performed in patients with preexisting impulse control impairments, which impedes clear‐cut interpretation of these findings. We retrospectively procured follow‐up data from 31 medication‐naïve PD patients who underwent dopamine transporter SPECT imaging at baseline and were subsequently treated with dopamine replacement therapy. We used questionnaires and a telephone interview to assess medication status and ICD symptom development during the follow‐up period (31.5 ± 12.0 months). Eleven patients developed ICD symptoms during the follow‐up period, eight of which were taking dopamine agonists. The PD patients with ICD symptoms at follow‐up had higher baseline depressive scores and lower baseline dopamine transporter availability in the right ventral striatum, anterior‐dorsal striatum, and posterior putamen compared with PD patients without ICD symptoms. No baseline between‐group differences in age and disease stage or duration were found. The ICD symptom severity correlated negatively with baseline dopamine transporter availability in the right ventral and anterior‐dorsal striatum. The results of this preliminary study show that reduced striatal dopamine transporter availability predates the development of ICD symptoms after dopamine replacement therapy and may constitute a neurobiological risk factor related to a lower premorbid dopamine transporter availability or a more pronounced dopamine denervation in PD patients susceptible to ICD.

Patterns of alpha-synuclein pathology in incidental cases and clinical subtypes of Parkinson's disease

Parkinsons disease (PD) is characterized by a gradual accumulation of neuropathology that may begin many years before a clinical diagnosis can be made using currently accepted criteria. Here, we first review the prevalence of α-synuclein neuropathology in elderly and discuss its clinical relevance in Parkinson patients. Subsequently, the results of a retrospective study focussing on the distribution of neuropathology in Parkinson patients with a tremor-dominant (TD), non-tremordominant (NTD) or rapid disease progression (RDP) subtype are presented. The study population recruited by the Netherlands Brain bank consisted of 149 non-neurological donors, 26 donors with incidental Lewy body disease (iLBD) and 111 Parkinson patients. In total, 89% of these cases could be classified in accordance with the Braak staging when taking into account the severity of α-synuclein pathology and adding an amygdala-predominant category of synucleinopathy. The pathological progression seemed to be non-linear. Interestingly, a strong correlation between neuronal loss and α-synuclein pathology was observed in the substantia nigra in Braak stages 3-6 (P < 0.01). However, there was no correlation between Hoehn & Yahr and Braak stages. Neuropathological progression may, however, vary between subtypes as cortical Lewy body load and Braak stages were higher in patients with NTD compared to TD and Alzheimer pathology was more prevalent in RDP patients. Recognition of clinical subtypes in neuropathological studies is essential to identify selective vulnerability to protein accumulation that may determine the clinical phenotype in PD.

Pedunculopontine cholinergic cell loss in hallucinating Parkinson disease patients but not in dementia with Lewy bodies patients

There is a cholinergic deficit in Parkinson disease (PD) and in dementia with Lewy bodies (DLB) that plays a role in a variety of clinical symptoms, including visual hallucinations (VH). The aim of this study was to assess cholinergic neuronal loss and PD and Alzheimer disease pathology in the pedunculopontine nucleus pars compacta (PPNc) of PD and DLB patients with VH. Postmortem brainstem tissue samples of 9 clinically diagnosed and pathologically confirmed PD patients with VH, 9 DLB patients with VH, and 9 age- and sex-matched nondemented controls were obtained from the Netherlands Brain Bank. Using a morphometric approach, we estimated the density of cholinergic neurons in the PPNc and determined the local load of α-synuclein-immunoreactive Lewy pathology, neurofibrillary tangles, and β-amyloid plaques. Cholinergic cell density in the PPNc was significantly lower in PD compared with DLB patients with VH (-39%, p < 0.001) and controls (-41%, p < 0.001). Alpha-synuclein load was higher in PD, whereas β-amyloid plaque pathology was more pronounced in DLB patients. The mean cell density in DLB patients was not significantly reduced compared with that in controls. These results may indicate different patterns of degeneration of cholinergic output structures in PD and DLB.

Novelty processing and memory formation in Parkinson's disease

BACKGROUND Parkinsons disease (PD) is characterized by a degeneration of nigrostriatal dopaminergic cells, resulting in dopamine depletion. This depletion is counteracted through dopamine replacement therapy (DRT). Dopamine has been suggested to affect novelty processing and memory, which suggests that these processes are also implicated in PD and that DRT could affect them. OBJECTIVE To investigate word learning and novelty processing in patients with PD as indexed by the P2 and P3 event-related potential components, and the role of DRT in these processes. METHODS 21 patients with PD and 21 matched healthy controls were included. Patients with PD were tested on and off DRT in two sessions in a counterbalanced design, and healthy controls were tested twice without intervention. Electroencephalogram (EEG) was measured while participants performed a word learning Von Restorff task. RESULTS Healthy controls showed the typical Von Restorff effect, with better memory for words that were presented in novel fonts, than for words presented in standard font. Surprisingly, this effect was reversed in the patients with PD. In line with the behavioral findings, the P3 was larger for novel than for standard font words in healthy controls, but not in patients with PD. For both groups the P2 and P3 event-related components were larger for recalled versus forgotten words. DRT did not affect these processes. CONCLUSIONS Learning of novel information is compromised in patients with PD. Likewise, the P2 and P3 components that predict successful memory encoding are reduced in PD patients. This was true both on and off DRT, suggesting that these findings reflect abnormalities in learning and memory in PD that are not resolved by dopaminergic medication.

Damaged fiber tracts of the nucleus basalis of Meynert in Parkinson’s disease patients with visual hallucinations

Damage to fiber tracts connecting the nucleus basalis of Meynert (NBM) to the cerebral cortex may underlie the development of visual hallucinations (VH) in Parkinson’s disease (PD), possibly due to a loss of cholinergic innervation. This was investigated by comparing structural connectivity of the NBM using diffusion tensor imaging in 15 PD patients with VH (PD + VH), 40 PD patients without VH (PD − VH), and 15 age- and gender-matched controls. Fractional anisotropy (FA) and mean diffusivity (MD) of pathways connecting the NBM to the whole cerebral cortex and of regional NBM fiber tracts were compared between groups. In PD + VH patients, compared to controls, higher MD values were observed in the pathways connecting the NBM to the cerebral cortex, while FA values were normal. Regional analysis demonstrated a higher MD of parietal (p = 0.011) and occipital tracts (p = 0.027) in PD + VH, compared to PD − VH patients. We suggest that loss of structural connectivity between the NBM and posterior brain regions may contribute to the etiology of VH in PD. Future studies are needed to determine whether these findings could represent a sensitive marker for the hypothesized cholinergic deficit in PD + VH patients.

Loss of Functional Connectivity in Patients with Parkinson Disease and Visual Hallucinations

Purpose To gain more insight into the pathophysiological mechanisms of visual hallucinations (VHs) in patients with Parkinson disease (PD) by analyzing whole-brain resting-state functional connectivity in PD patients with VH (hereafter, referred to as PD + VH patients) and without VH (hereafter, referred to as PD - VH patients) and control participants. Materials and Methods For this retrospective study, 15 PD + VH patients, 40 PD - VH patients, and 15 control participants from a prospective cohort study were included, which was approved by the local ethics board and written informed consent was obtained from all participants. Functional connectivity was calculated between 47 regions of interests, of which whole-brain and region-specific means were compared by using a general linear model with false discovery rate control for multiple comparisons. Results Whole-brain mean functional connectivity was significantly lower in PD patients compared with control participants, with regional decreases involving paracentral and occipital regions in both PD + VH and PD - VH patients (mean whole-brain functional connectivity in PD + VH vs PD - VH, 0.12 ± 0.01 [standard deviation] vs 0.14 ± 0.03, respectively; control participants, 0.15 ± 0.04; P < .05, corrected). In PD + VH patients, nine additional frontal, temporal, occipital, and striatal regions showed decreased functional connectivity compared with control participants (mean of these nine regions in PD + VH, PD - VH, and control participants: 0.12 ± 0.02, 0.14 ± 0.03, and 0.16 ± 0.04, respectively; P < .05, corrected). Resting-state functional connectivity was unrelated to motor performance (r = 0.182; P = .184) and related to cognitive deficits such as attention and perception (ρ, -0.555 and -0.558, respectively; P < .05). Conclusion The findings show a PD-related effect on resting-state functional connectivity of posterior and paracentral brain regions, whereas the presence of VH is associated with a more global loss of connectivity, related to attention and perception. These findings suggest that the pathophysiological mechanisms of VH in PD may include a global loss of network efficiency, which could drive disturbed attentional and visual processing.