Alexandru Hanganu

Mild cognitive impairment is linked with faster rate of cortical thinning in patients with Parkinson’s disease longitudinally

Previous studies have shown greater atrophy in grey and white matter of various brain regions in patients with Parkinsons disease with mild cognitive impairment than in those without. These anatomical differences likely account for the distinct clinical profiles observed between those groups, but do not account for the evolution of regional brain degradation observed as the disease evolves. Although we have shown recently that cortical thinning correlates significantly more with disease duration in Parkinsons patients with mild cognitive impairment than in those without, to the best of our knowledge no study to date has explored this longitudinally. The present study investigated the longitudinal changes of the cortical and subcortical grey matter in patients with Parkinsons disease with and without mild cognitive impairment. Additionally, these two groups were compared with healthy controls. We found a higher rate of cortical thinning in the temporal, occipital, parietal and supplementary motor area, in patients with Parkinsons disease with mild cognitive impairment compared with both cognitively stable patients and healthy controls. On the other hand cognitively stable patients had only one lateral occipital and one fusiform cluster with increased rate of thinning compared with healthy individuals. Correlating the rate of change of cortical thickness with the results of Montreal Cognitive Assessment scores revealed significant thinning associated with cognitive decline in the group of all patients, in similar regions including temporal and medial occipital lobe. Finally, a significant decrease in the volume of the amygdala and nucleus accumbens was observed specifically in patients with Parkinsons disease with mild cognitive impairment. These results indicate that the early presence of mild cognitive impairment in patients with Parkinsons disease is associated with a faster rate of grey matter thinning in various cortical regions as well as a significant diminishment of limbic subcortical structures. This specific pattern of brain degradation associated with the early presence of mild cognitive impairment might serve as a marker of development toward dementia.

Mild cognitive impairment in patients with Parkinson's disease is associated with increased cortical degeneration

Mild cognitive impairment (MCI) can occur early in the course of Parkinsons disease (PD), and its presence increases the risk of developing dementia. Determining the cortical changes associated with MCI in PD, thus, may be useful in predicting the future development of dementia. To address this objective, 37 patients with PD, divided into 2 groups according to the presence or absence MCI (18 with and 19 without) and 16 matched controls, underwent anatomic magnetic resonance imaging. Corticometry analyses were performed to measure the changes in cortical thickness and surface area as well as their correlation with disease duration. Compared with healthy controls, the PD‐MCI group exhibited increased atrophy and changes of local surface area in the bilateral occipital, left temporal, and frontal cortices; whereas the PD non‐MCI group exhibited only unilateral thinning and decreased surface area in the occipital lobe and in the frontal cortex. In addition, a comparison between the PD‐MCI and PD non‐MCI groups revealed increased local surface area in the occipital lobe, temporal lobe, and postcentral gyrus for the cognitively impaired patients. It is noteworthy that, in the PD‐MCI group, cortical thickness had a significant negative correlation with disease duration in the precentral, supramarginal, occipital, and superior temporal cortices; whereas, in the PD non‐MCI group, such a correlation was absent. The findings from this study reveal that, at the same stage of PD evolution, the presence of MCI is associated with a higher level of cortical changes, suggesting that cortical degeneration is increased in patients with PD because of the presence of MCI.

Markers of cognitive decline in PD: The case for heterogeneity.

Cognitive impairment is highly prevalent and has a severe negative effect on health related and perceived quality of life in Parkinsons disease (PD). It is now established that 20-40% of persons with PD will develop cognitive deficits early in the disease. Moreover, the risk of developing dementia is six times higher in PD patients than in age-matched controls and it is estimated that 80% of patients will develop dementia after 20 years of the disease. In order to address these symptoms properly it is crucial to identify very early in the disease the patients who are most likely to develop dementia rapidly. Persons who meet criteria for mild cognitive impairment (MCI) exhibit measurable cognitive deficits but those deficits are not severe enough to interfere significantly with daily life. While the presence of MCI in PD increases the chance of developing dementia, various studies suggest that PD-MCI might consist of distinct subtypes with different pathophysiologies and prognoses. In this paper we comment on various biomarkers associated with cognitive decline in PD, specifically clinical, neuropathological, genetic and neuroimaging ones. We also discuss disrupted functional connectivity in PD-MCI and reveal preliminary results from our own group. We propose that the current studies looking at different types of biomarkers provide support for different causes being associated with cognitive decline in PD. Large-scale multi-disciplinary and multi-modal longitudinal studies are required to identify more specifically the different phenotypes associated with different cognitive profiles and evolution in PD.

Common Effects of Amnestic Mild Cognitive Impairment on Resting-State Connectivity Across Four Independent Studies.

Resting-state functional connectivity is a promising biomarker for Alzheimers disease. However, previous resting-state functional magnetic resonance imaging studies in Alzheimers disease and amnestic mild cognitive impairment (aMCI) have shown limited reproducibility as they have had small sample sizes and substantial variation in study protocol. We sought to identify functional brain networks and connections that could consistently discriminate normal aging from aMCI despite variations in scanner manufacturer, imaging protocol, and diagnostic procedure. We therefore combined four datasets collected independently, including 112 healthy controls and 143 patients with aMCI. We systematically tested multiple brain connections for associations with aMCI using a weighted average routinely used in meta-analyses. The largest effects involved the superior medial frontal cortex (including the anterior cingulate), dorsomedial prefrontal cortex, striatum, and middle temporal lobe. Compared with controls, patients with aMCI exhibited significantly decreased connectivity between default mode network nodes and between regions of the cortico-striatal-thalamic loop. Despite the heterogeneity of methods among the four datasets, we identified common aMCI-related connectivity changes with small to medium effect sizes and sample size estimates recommending a minimum of 140 to upwards of 600 total subjects to achieve adequate statistical power in the context of a multisite study with 5–10 scanning sites and about 10 subjects per group and per site. If our findings can be replicated and associated with other established biomarkers of Alzheimers disease (e.g., amyloid and tau quantification), then these functional connections may be promising candidate biomarkers for Alzheimers disease.

Neuroimaging studies of the striatum in cognition Part I: healthy individuals.

The striatum has traditionally mainly been associated with playing a key role in the modulation of motor functions. Indeed, lesion studies in animals and studies of some neurological conditions in humans have brought further evidence to this idea. However, better methods of investigation have raised concerns about this notion, and it was proposed that the striatum could also be involved in different types of functions including cognitive ones. Although the notion was originally a matter of debate, it is now well-accepted that the caudate nucleus contributes to cognition, while the putamen could be involved in motor functions, and to some extent in cognitive functions as well. With the arrival of modern neuroimaging techniques in the early 1990, knowledge supporting the cognitive aspect of the striatum has greatly increased, and a substantial number of scientific papers were published studying the role of the striatum in healthy individuals. For the first time, it was possible to assess the contribution of specific areas of the brain during the execution of a cognitive task. Neuroanatomical studies have described functional loops involving the striatum and the prefrontal cortex suggesting a specific interaction between these two structures. This review examines the data up to date and provides strong evidence for a specific contribution of the fronto-striatal regions in different cognitive processes, such as set-shifting, self-initiated responses, rule learning, action-contingency, and planning. Finally, a new two-level functional model involving the prefrontal cortex and the dorsal striatum is proposed suggesting an essential role of the dorsal striatum in selecting between competing potential responses or actions, and in resolving a high level of ambiguity.

Depressive symptoms in Parkinson’s disease correlate with cortical atrophy over time

Introduction Depressive symptoms are very common in patients with Parkinson’s disease (PD) and have a significant impact on the quality of life. Methods The present study analyzed the correlations between over‐time changes in depressive symptoms and gray matter parameters of cortical thickness and subcortical volumes in non‐demented PD patients. Results A significant correlation was observed, between increased scores for depression over time and lower cortical thickness over time in the right temporo‐parietal junction, right occipital medial region, right dorsolateral prefrontal cortex, right posterior cingulate region, left middle temporal as well as left supplementary motor area. Furthermore, the presence of depressive symptoms at baseline predicted increased cortical thinning over time in the left middle temporal, left anterior cingulate, right posterior cingulate and right parahippocampal cortices. Finally, a statistically significant negative correlation has been revealed between the thalamus’ volume changes over time and the change in depressive symptoms scores. All other analyzed subcortical structures didn’t reveal any significant correlations. Conclusion These results suggest that depressive symptoms in PD patients are associated with gray matter cortical thinning and thalamus volume shrinkage over time and higher scores of depressive symptoms at baseline correlate with a higher rate of cortical thinning longitudinally. The present study highlights the importance of addressing depressive symptoms in PD patients early in the disease. HighlightsEarly presence of depressive symptoms in PD is a marker of faster neurodegeneration.Depressive symptoms in PD correlate with a higher neurodegeneration rate over time.These preliminary results indicate that even mild depressive symptoms should be treated early in PD.

Patterns of Longitudinal Neural Activity Linked to Different Cognitive Profiles in Parkinson's Disease

Mild cognitive impairment in Parkinsons disease (PD) has been linked with functional brain changes. Previously, using functional magnetic resonance imaging (fMRI), we reported reduced cortico-striatal activity in patients with PD who also had mild cognitive impairment (MCI) vs. those who did not (non-MCI). We followed up these patients to investigate the longitudinal effect on the neural activity. Twenty-four non-demented patients with Parkinsons disease (non-MCI: 12, MCI: 12) were included in the study. Each participant underwent two fMRIs while performing the Wisconsin Card Sorting Task 20 months apart. The non-MCI patients recruited the usual cognitive corticostriatal loop at the first and second sessions (Time 1 and Time 2, respectively). However, decreased activity was observed in the cerebellum and occipital area and increased activity was observed in the medial prefrontal cortex and parietal lobe during planning set-shift at Time 2. Increased activity in the precuneus was also demonstrated while executing set-shifts at Time 2. The MCI patients revealed more activity in the frontal, parietal and occipital lobes during planning set-shifts, and in the parietal and occipital lobes, precuneus, and cerebellum, during executing set-shift at Time 2. Analysis regrouping of both groups of PD patients revealed that hippocampal and thalamic activity at Time 1 was associated with less cognitive decline over time. Our results reveal that functional alteration along the time-points differed between the non-MCI and MCI patients. They also underline the importance of preserving thalamic and hippocampal function with respect to cognitive decline over time.

Structural Neuroimaging Markers of Cognitive Decline in Parkinson's Disease

Cognitive impairment in patients with Parkinsons disease is a major challenge since it has been established that 25 to 40% of patients will develop cognitive impairment early in the disease. Furthermore, it has been reported that up to 80% of Parkinsonian patients will eventually develop dementia. Thus, it is important to improve the diagnosing procedures in order to detect cognitive impairment at early stages of development and to delay as much as possible the developing of dementia. One major challenge is that patients with mild cognitive impairment exhibit measurable cognitive deficits according to recently established criteria, yet those deficits are not severe enough to interfere with daily living, hence being avoided by patients, and might be overseen by clinicians. Recent advances in neuroimaging brain analysis allowed the establishment of several anatomical markers that have the potential to be considered for early detection of cognitive impairment in Parkinsonian patients. This review aims to outline the neuroimaging possibilities in diagnosing cognitive impairment in patients with Parkinsons disease and to take into consideration the near-future possibilities of their implementation into clinical practice.

Reply: Is nucleus accumbens atrophy correlated with cognitive symptoms of Parkinson's disease?

Sir, We thank Dr Mavridis for this very thoughtful comment about nucleus accumbens atrophy in patients with Parkinson’s disease from a neurosurgical point of view. Indeed it had been previously reported that dopamine loss also occurs in the nucleus accumbens of patients with Parkinson’s disease especially at the advanced stages (Farley et al. , 1977). Different groups, including our own have shown that patients with Parkinson’s disease are affected differently on functions relying on the ventral versus the dorsal striatum …

Influence of Depressive Symptoms on Dopaminergic Treatment of Parkinson’s Disease

Introduction: Depressive symptoms are very common in patients with Parkinson’s disease (PD) and have a significant impact on the quality of life. Dopaminergic medication has been shown to have an influence on the development of depressive symptoms. Materials and methods: The present study analyzed two groups of non-demented patients with PD, with and without depressive symptoms, and reported the correlations between antiparkinsonian medication [specifically levodopa (l-DOPA) and dopaminergic agonists] with depressive symptoms. Results: A strong statistically significant positive correlation between l-DOPA dosages and the level of depressive symptoms has been revealed, suggesting that higher l-DOPA dosages correlate with a worsening of depressive status. No significant correlation was found with dopamine agonists. Discussion: The results of this study show that in patients with PD, higher l-DOPA dosages correlate with worse depressive symptoms. From this point of view, PD patients need to be better diagnosed with respect to depressive symptoms and need additional treatment adjustment when clinical manifestations of depression are present. Clinicians must be aware that dopaminergic drugs are not sufficient to alleviate depressive symptoms.