Aims

Parkinson’s Disease (PD) is associated with altered brain structure as assessed by volumetric MRI and diffusion tensor imaging (DTI). We performed voxelwise analyses of longitudinal changes in tissue density, diffusivity and the fraction of bound versus free water in PD patients.

Methods

In the Parkinson’s Progression Markers Initiative (PPMI), we identified 86 de-novo PD patients with MRI at baseline and two-year follow up. T1-weighted images were segmented by tissue class and normalized to a population-specific template using SPM12 DARTEL. DTI were registered to b=0, co-registered to 3DT1, and normalized to template space. Whole-brain free water (FW) maps and FW-corrected maps of fractional anisotropy (FA) and mean diffusivity (MD) were derived by fitting a bi-tensor model of signal attenuations from bound and free water. Whole-brain maps were entered into SPM12 GLM analysis. Change in DaTscan was calculated using minimum putamen SBR.

Results

PD patients demonstrated significant grey-matter volume loss, increased diffusivity, reduced anisotropy, and increased FW in a distributed set of brain regions. Following FWE-correction for multiple comparisons, atrophy was observed in striatum, thalamus, cingulate, parietal, temporal and frontal regions, with disrupted white-matter integrity in corpus callosum, cingulum, and thalamic radiations. Increased FW was widespread and apparent in both grey and white matter. A correlation between supplementary motor area atrophy and delta SBR survived multiple comparisons correction (R^2 = 0.44).

Conclusions

PD involves marked disruption to tissue volumes, tract integrity and free water fraction throughout the brain. MRI-based biomarkers can serve as robust indicators of disease progression in clinical trials.

Aims

The aim of this study was to investigate disease propagation in Parkinson’s disease (PD) using stepwise functional connectivity (SFC) analyses.

Methods

146 PD patients performed clinical-cognitive evaluations and resting-state functional MRI (rs-fMRI) at baseline. Cluster analysis using data on demographic information, motor symptoms and signs, cognitive and behavioural testing and non-motor manifestations identified PD subtypes: 86 were classified as “mild” and 60 as “moderate-to-severe”. 60 controls were enrolled. SFC analysis aims to characterize regions that connect to specific seed brain areas (medulla, known to be a pathological epicenter in PD) at different levels of link-step distances. Whole-brain two-sample t-test comparisons between each group were performed.

Results

Starting from medulla, we found direct functional connections to the insular cortex, pericalcarine, lingual and parahippocampal gyri in controls. With subsequent steps, medulla was connected to parietal-occipital-temporal lobes and the isthmus cingulate gyrus. In mild PD patients, we found an involvement of direct and indirect connections from the medulla to the sensorimotor network , cuneus, lateral and medial parietal regions and lateral temporal gyri. At a one-link step distance, moderate-to-severe PD patients showed decreased connectivity in the lateral occipital and inferior parietal gyri, and cuneus. Across 2-4 link-steps, we detected also a reduced functional connectivity within parietal, temporal, frontal and limbic lobes. Interestingly, SFC analysis highlighted a greater extent of damage in moderate-to-severe PD than in mild group.

Conclusions

SFC approach might help to predict a network-spread model of Parkinson-related pathology from 'a priori’ epicenter regions in PD. Funding:Ministry of Education and Science Republic of Serbia (Grant#175090).

Aims

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by motor and non-motor deficits. Studies found alterations in the topological organization of functional networks in PD, built by methods that assume simultaneous and undirected interregional activation. However, PD associated changes may result in specific modification of directed activity patterns. Here, we propose a novel method, the “anti-symmetric correlations”, to assess resting-state, whole-brain, directed functional networks in patients with PD.

Methods

We obtain lagged correlation adjacency matrix by calculating lagged correlations between all pairs of brain regions. The anti-symmetric correlation network can be derived as the anti-symmetric part of this lagged correlation adjacency matrix (Fig.1). To test this method, we compared 95 PD patients and 15 controls with functional MRI scans from the Parkinson's Progression Markers Initiative (PPMI) [https://www.ppmi-info.org/].

Results

Undirected analyses found no significant differences between the two groups. Conversely, directed functional networks in PD patients showed significant increases in global efficiency, local efficiency, clustering, transitivity, and decreases in modularity. Local topology changes were observed in precuneus, thalamus, fusiform and superior frontal gyrus. All global measures were significantly associated with the UPDRS-III and Letter-Number sequencing test scores. Nodal measures correlated with memory, olfactory and semantic fluency deficits.

Conclusions

Directed networks revealed widespread functional connectivity changes in PD, not identifiable by conventional undirected methods. These measures were associated with motor, executive and memory deficits, suggesting they are sensitive to clinical impairment in PD. Altogether, our findings suggest that the directional flow in brain activation could be used as an indicator of PD-related neuronal changes.

Aims

Elucidating compensatory mechanisms underpinning phonemic fluency may help to minimize its decline due to normal aging or neurodegenerative diseases. Previous studies have found that compensation in phonemic fluency was facilitated by a better performance in semantic and executive-visuospatial abilities. However, further research is needed to elucidate whether semantic and executive-visuospatial cortical networks are involved in compensation of phonemic fluency. We investigated cortical brain networks potentially underpinning compensation of performance in phonemic fluency in normal aging.

Methods

Using graph theory, we constructed networks from measures of thickness for phonemic fluency, semantic, and executive-visuospatial cortical networks. A total of 267 cognitively healthy individuals were divided into younger (YA, 38-58 years) and older age (OA, 59-79 years) groups, and low (LP) and high (HP) performance groups.

Results

The same pattern of reduced efficiency and increased transitivity was associated with both high performance (compensation) and older age (aberrant network organization) in the phonemic fluency and semantic cortical networks. The OA-HP group had a higher phonemic fluency performance than the OA-LP group. Our findings suggest that higher phonemic fluency performance in the OA-HP group was associated with: a more segregated phonemic fluency and semantic cortical networks; greater participation of frontal nodes; and stronger correlations within the phonemic fluency cortical network.

Conclusions

More segregated cortical networks with strong involvement of frontal areas allowed older adults to maintain their high performance in phonemic fluency. Nodal analyses and measures of average strength were helpful to disentangle compensation from the aberrant network organization associated with older age.

Aims

Neural compensatory mechanisms associated with broad cognitive abilities have been studied although those associated with specific cognitive subdomains (e.g. verbal fluency) remain to be investigated in healthy aging. Here, we delineate: (a) neural substrates of verbal (phonemic) fluency (PF), and (b) potential compensatory mechanisms mediating the association between these neural substrates and PF.

Methods

We included resting-state functional magnetic resonance imaging from 147 right-handed, cognitively normal individuals who underwent the Controlled Oral Word Association Test (COWAT) to record their PF. We evaluated functional connectivity in an established language network comprised of Wernicke, Broca, thalamic and anti-correlated modules. (a) Voxel-wise multiple linear regression model identified the brain areas associated with phonemic fluency with multiple comparisons corrections (family wise error; FWE). (b) Mediation effects of cognitive reserve, measured by the Wechsler Adult Intelligence Scale – Information test, upon the association between functional connectivity and PF tested for compensation.

Results

In this cohort (age=61.7±9.5 [40 82] years; 69 females), we observed PF of 35.8±13.03 [9, 72] words. We found that: (a) functional connectivity associated with the Wernicke module (peak at right cuneus, R²=0.138, p<0.0001) was associated with the PF (Figure 1), (b) cognitive reserve partially mediates the association between functional connectivity of the Wernicke module and PF (p<0.05).

Conclusions

Functional connectivity associated with the Wernicke module may be most indicative of PF, which can be disproportionately impaired and particularly indicative of preclinical cognitive decline in elderly. Moreover, compensation mediated by high cognitive reserve along with preserved connectivity associated with Wernicke areas could maintain PF during aging.

Aims

Dopaminergic dysfunction is an early pathophysiological event of Alzheimer’s disease (AD). This was demonstrated in animal models as well as in cross-sectional studies on AD patients. Using resting-state functional MRI (RS-fMRI), we aimed here at assessing, longitudinally, whether disconnection of the ventral tegmental area (VTA) contributes to a faster conversion from mild cognitive impairment (MCI) to AD.

Methods

We recruited 35 patients with amnestic-MCI due to AD who underwent an extensive neuropsychological assessment and MRI scanning at 3T at baseline and 24-months follow-up. At follow-up patients were reclassified in those who converted to AD (MCI-converters) and those who did not (MCI-non-Converters). MRI acquisitions included a T1-weighted volume and RS-fMRI, which was processed to quantify for each participant at each time-point, connectivity between VTA and the rest of the brain. VTA-driven connectivity was compared between MCI-converters and MCI-non-converters.

Results

Sixteen out of 35 patients converted to AD during follow-up. At baseline, MCI-converters and MCI-non-converters did not differ for demographic or neuropsychological characteristics. RS-fMRI data analysis revealed a significant reduction of VTA-driven connectivity in MCI-Converters that involved the posterior cingulate cortex and precentral gyrus. This between-group difference remained unchanged at follow-up.

Conclusions

This study indicates that a more extensive VTA disconnection precedes and predicts the occurrence of dementia in short time. The pattern of disconnection involves the posterior cingulate cortex (i.e., a key node of the default-mode-network), which was previously interpreted as exclusively due to hippocampal atrophy. These findings have relevant prognostic implications and support new opportunities for therapeutic interventions to slowdown the disease progression.

Aims

to assess the pontine noradrenergic nucleus Locus Coeruleus (LC) by 3T MRI neuromelanin (NM)-sensitive sequence in cognitive intact subjects (HC) and in patients suffering from Amnestic Mild Cognitive Impairment (aMCI), Alzheimer’s Disease Dementia (ADD), Lewy Body Dementia/Parkinson’s Disease Dementia (LBD/PDD) and Frontotemporal Dementia (FTD).

Methods

We submitted 234 subjects (HC=60; MCI=80; ADD=40; LBD/PDD=36; FTD=18) to a 3T Brain MR scan, which included a NM-sensitive T1-weighted sequence for LC assessment. MRI scans were then processed profiting of an in-house developed semi-automatic software, which was run by blinded operators. Results were expressed using two parameters: VOX, which is the total number of voxels recognized as belonging to LC; AVG, which is the average intensity of selected voxels.

Results

We found that ADD patients showed a significantly lower value of VOX, when compared to HC and FTD. No significant differences were observed between aMCI and HC, even if the former had lower values of VOX compared to the latter. DLB/PDD showed the lowest values of VOX, significantly different from HC, FTD, and even ADD. Interestingly, in early-onset ADD patients (<65 yy), we observed a reduction of VOX as marked as the one we found in DLB/PDD.

Conclusions

We observed a marked reduction of LC in patients suffering from ADD; even though we did not find a statistically significant involvement of LC in aMCI patients, these showed lower values compared to HC. These findings are in line with neuropathological findings, which showed an early and dramatic degeneration of LC in AD pathogenesis.

Funding: Italian Ministry of Health, PE-2013-02359574-(P.I.: FSG).

Aims

An Alzheimer’s disease (AD) subtype with no significant atrophy was noted in neuroimaging studies, later dubbed “minimal atrophy” (Persson 2017). Our goal was to examine differences amongst neuropathologically defined AD subtypes; including a Braak-IV AD group to act as a neuropathologic surrogate of the neuroimaging-defined reported minimal atrophy subtype.

Methods

The Florida Autopsied Multi-Ethnic (FLAME) cohort was queried for AD cases with a total of 1413 identified. Thioflavin-S stains were used to quantify tangle pathology and incorporated into a neuropathologic algorithm to classify subtypes. Demographic, clinical, and postmortem findings were collected.

Results

The age at onset of symptoms for Braak-IV AD was comparable to limbic predominant AD (p<0.001). There was a low proportion of Braak-IV AD cases with atypical clinical presentations, which was similar to typical AD (p<0.001). Braak-IV AD cases were cognitively impaired with an MMSE score between typical and limbic predominant AD (p=0.007), and longitudinal decline similar to typical AD (p<0.001). Compared to all three subtypes, Braak-IV AD cases were older at death, had higher brain weight, and less severe cerebrovascular disease (all p<0.001). Lewy body disease was most commonly observed in Braak-IV AD (p=0.002), which correlated with a greater frequency of clinically diagnosed Lewy body dementia (p=0.003).

Conclusions

As expected, the Braak-IV AD group demonstrated higher brain weight in keeping with observations of minimal atrophy from MRI studies. Although these individuals may be biomarker positive on amyloid-β PET and tau PET, the minimal atrophy may reflect Lewy body disease with co-existing AD pathology.