Marina Weiler

Differences and the Relationship in Default Mode Network Intrinsic Activity and Functional Connectivity in Mild Alzheimer's Disease and Amnestic Mild Cognitive Impairment

There is evidence that the default mode network (DMN) functional connectivity is impaired in Alzheimers disease (AD) and few studies also reported a decrease in DMN intrinsic activity, measured by the amplitude of low-frequency fluctuations (ALFFs). In this study, we analyzed the relationship between DMN intrinsic activity and functional connectivity, as well as their possible implications on cognition in patients with mild AD and amnestic mild cognitive impairment (aMCI) and healthy controls. In addition, we evaluated the differences both in connectivity and ALFF values between these groups. We recruited 29 controls, 20 aMCI, and 32 mild AD patients. To identify the DMN, functional connectivity was calculated by placing a seed in the posterior cingulate cortex (PCC). Within the DMN mask obtained, we calculated regional average ALFFs. Compared with controls, aMCI patients showed decreased ALFFs in the temporal region; compared with AD, aMCI showed higher values in the PCC but lower in the temporal area. The mild AD group had lower ALFFs in the PCC compared with controls. There was no difference between the connectivity in the aMCI group compared with the other groups, but AD patients showed decreased connectivity in the frontal, parietal, and PCC. Also, PCC ALFFs correlated to functional connectivity in nearly all subregions. Cognitive tests correlated to connectivity values but not to ALFFs. In conclusion, we found that DMN connectivity and ALFFs are correlated in these groups. Decreased PCC ALFFs disrupt the DMN functional organization, leading to cognitive problems in the AD spectrum.

Propagation of Pathology through Brain Networks in Neurodegenerative Diseases: From Molecules to Clinical Phenotypes

The cellular mechanisms underlying the stereotypical progression of pathology in neurodegenerative diseases are incompletely understood, but increasing evidence indicates that misfolded protein aggregates can spread by a self‐perpetuating neuron‐to‐neuron transmission. Novel neuroimaging techniques can help elucidating how these disorders spread across brain networks. Recent knowledge from structural and functional connectivity studies suggests that the relation between neurodegenerative diseases and distinct brain networks is likely to be a strict consequence of diffuse network dynamics. Diffusion tensor magnetic resonance imaging also showed that measurement of white matter tract involvement can be a valid surrogate to assess the in vivo spreading of pathological proteins in these conditions. This review will introduce briefly the main molecular and pathological substrates of the most frequent neurodegenerative diseases and provide a comprehensive overview of neuroimaging findings that support the “network‐based neurodegeneration” hypothesis in these disorders. Characterizing network breakdown in neurodegenerative diseases will help anticipate and perhaps prevent the devastating impact of these conditions.

Volumetric brain changes in thalamus, corpus callosum and medial temporal structures: mild Alzheimer's disease compared with amnestic mild cognitive impairment.

Background: It is widely known that atrophy of medial temporal structures is present in the mild stage of Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI). However, structures such as the thalamus and corpus callosum are much less studied. Methods: We compared the volumes of the entorhinal cortex, hippocampus, thalamus and the corpus callosum in 14 controls, 14 patients with mild AD and 15 with aMCI and correlated these volumes with neuropsychological data. MRI was obtained at 2 T followed by manual segmentation. Results: We found atrophy in hippocampi and thalami of MCI patients compared to controls, and in the bilateral entorhinal cortex of aMCI compared to AD patients. All the structures showed atrophy in AD patients compared to controls, including the corpus callosum. Conclusions: Our study confirms that thalamic areas are atrophied in aMCI, and the corpus callosum might represent a good structural marker for mild AD. Those areas were associated with cognitive functions already described in the literature.

Default Mode, Executive Function, and Language Functional Connectivity Networks are Compromised in Mild Alzheimer´s Disease

Alzheimers disease (AD) is characterized by mental and cognitive problems, particularly with memory, language, visuospatial skills (VS), and executive functions (EF). Advances in the neuroimaging of AD have highlighted dysfunctions in functional connectivity networks (FCNs), especially in the memory related default mode network (DMN). However, little is known about the integrity and clinical significance of FNCs that process other cognitive functions than memory. We evaluated 22 patients with mild AD and 26 healthy controls through a resting state functional MRI scan. We aimed to identify different FCNs: the DMN, language, EF, and VS. Seed-based functional connectivity was calculated by placing a seed in the DMN (posterior cingulate cortex), language (Brocas and Wernickes areas), EF (right and left dorsolateral prefrontal cortex), and VS networks (right and left associative visual cortex). We also performed regression analyses between individual connectivity maps for the different FCNs and the scores on cognitive tests. We found areas with significant decreases in functional connectivity in patients with mild AD in the DMN and Wernickes area compared with controls. Increased connectivity in patients was observed in the EF network. Regarding multiple linear regression analyses, a significant correlation was only observed between the connectivity of the DMN and episodic memory (delayed recall) scores. In conclusion, functional connectivity alterations in mild AD are not restricted to the DMN. Other FCNs related to language and EF may be altered. However, we only found significant correlations between cognition and functional connectivity in the DMN and episodic memory performance.

Structural connectivity of the default mode network and cognition in Alzheimer׳s disease

Disconnectivity between the Default Mode Network (DMN) nodes can cause clinical symptoms and cognitive deficits in Alzheimer׳s disease (AD). We aimed to examine the structural connectivity between DMN nodes, to verify the extent in which white matter disconnection affects cognitive performance. MRI data of 76 subjects (25 mild AD, 21 amnestic Mild Cognitive Impairment subjects and 30 controls) were acquired on a 3.0T scanner. ExploreDTI software (fractional Anisotropy threshold=0.25 and the angular threshold=60°) calculated axial, radial, and mean diffusivities, fractional anisotropy and streamline count. AD patients showed lower fractional anisotropy (P=0.01) and streamline count (P=0.029), and higher radial diffusivity (P=0.014) than controls in the cingulum. After correction for white matter atrophy, only fractional anisotropy and radial diffusivity remained significantly lower in AD compared to controls (P=0.003 and P=0.05). In the parahippocampal bundle, AD patients had lower mean and radial diffusivities (P=0.048 and P=0.013) compared to controls, from which only radial diffusivity survived for white matter adjustment (P=0.05). Regression models revealed that cognitive performance is also accounted for by white matter microstructural values. Structural connectivity within the DMN is important to the execution of high-complexity tasks, probably due to its relevant role in the integration of the network.

Carotid Stenting versus Endarterectomy Cognitive Outcomes

BACKGROUND The objectives are to analyze the impact of carotid revascularization on cognitive performance after a 3-month period in patients, who have undergone carotid artery stenting (CAS) or carotid endarterectomy (CEA), and to compare the cognitive outcomes between these 2 groups of patients. This a nonrandomized and prospective single-center experience. METHODS This study was performed in the University of Campinas Hospital from January 2010 to January 2012 and included 30 patients with carotid stenosis who received carotid interventions. Nineteen patients received CEA and 11 patients received CAS. Neuropsychologic evaluation included general cognitive, language, visuospatial, attentional, executive function, and memory tests. RESULTS After the follow-up period, there was improvement in episodic memory, encoding subitem (P = 0.02), and delayed recall (P = 0.02) for the CEA group. The CAS group improved in episodic memory, encoding subitem (P = 0.009), working memory (P = 0.04), and executive functions (P = 0.02). Comparing the techniques, the CAS group showed higher scores only in executive functions (P = 0.02). CONCLUSIONS Both groups had a similar performance in cognitive tests, comparing preoperative and postoperative results. However, patients who underwent CAS tended to achieve higher scores in executive function and operational memory/attention tests.

Self, cortical midline structures and the resting state: Implications for Alzheimer's disease.

Different aspects of the self have been reported to be affected in many neurological or psychiatric diseases such as Alzheimers disease (AD), including mainly higher-level cognitive self-unawareness. This higher sense of self-awareness is most likely related to and dependent on episodic memory, due to the proper integration of ourselves in time, with a permanent conservation of ourselves (i.e., sense of continuity across time). Reviewing studies in this field, our objective is thus to raise possible explanations, especially with the help of neuroimaging studies, for where such self-awareness deficits originate in AD patients. We describe not only episodic (and autobiographical memory) impairment in patients, but also the important role of cortical midline structures, the Default Mode Network, and the resting state (intrinsic brain activity) for the processing of self-related information.

Following the Spreading of Brain Structural Changes in Alzheimer's Disease: A Longitudinal, Multimodal MRI Study

BACKGROUND Longitudinal MRI studies in Alzheimers disease (AD) are one of the most reliable way to track brain changes along the course of the disease. OBJECTIVE To investigate the evolution of grey matter (GM) atrophy and white matter (WM) damage in AD patients, and to assess the relationships of MRI changes with baseline clinical and cognitive variables and their evolution over time. METHODS Clinical, neuropsychological, and MRI assessments (T1-weighted and diffusion tensor [DT]-MRI) were obtained from 14 patients with AD at baseline and after a 16 ± 3 month period. Lumbar puncture was obtained at study entry. At baseline, AD patients were compared to 37 controls. GM atrophy progression was assessed with tensor-based morphometry and GM volumes of interest, and WM damage progression using tract-based spatial statistics and tractography. RESULTS At baseline, patients showed cortical atrophy in the medial temporal and parietal regions and a widespread pattern of WM damage involving the corpus callosum, cingulum, and temporo-occipital, parietal, and frontal WM tracts. During follow up, AD patients showed total GM atrophy, while total WM volume did not change. GM tissue loss was found in frontal, temporal, and parietal regions. In addition, AD patients showed a progression of WM microstructural damage to the corpus callosum, cingulum, fronto-parietal and temporo-occipital connections bilaterally. Patients with higher baseline cerebrospinal fluid total tau showed greater WM integrity loss at follow up. GM and WM changes over time did not correlate with each other nor with cognitive evolution. CONCLUSION In AD, GM atrophy and WM tract damage are likely to progress, at least partially, independently. This study suggests that a multimodal imaging approach, which includes both T1-weighted and DT MR imaging, may provide additional markers to monitor disease progression.

Intranetwork and internetwork connectivity in patients with Alzheimer disease and the association with cerebrospinal fluid biomarker levels

Background In the last decade, many studies have reported abnormal connectivity within the default mode network (DMN) in patients with Alzheimer disease. Few studies, however, have investigated other networks and their association with pathophysiological proteins obtained from cerebrospinal fluid (CSF). Methods We performed 3 T imaging in patients with mild Alzheimer disease, patients with amnestic mild cognitive impairment (aMCI) and healthy controls, and we collected CSF samples from the patients with aMCI and mild Alzheimer disease. We analyzed 57 regions from 8 networks. Additionally, we performed correlation tests to investigate possible associations between the networks’ functional connectivity and the protein levels obtained from the CSF of patients with aMCI and Alzheimer disease. Results Our sample included 41 patients with Alzheimer disease, 35 with aMCI and 48 controls. We found that the main connectivity abnormalities in those with Alzheimer disease occurred between the DMN and task-positive networks: these patients presented not only a decreased anticorrelation between some regions, but also an inversion of the correlation signal (positive correlation instead of anti-correlation). Those with aMCI did not present statistically different connectivity from patients with Alzheimer disease or controls. Abnormal levels of CSF proteins were associated with functional disconnectivity between several regions in both the aMCI and mild Alzheimer disease groups, extending well beyond the DMN or temporal areas. Limitations The presented data are cross-sectional in nature, and our findings are dependent on the choice of seed regions used. Conclusion We found that the main functional connectivity abnormalities occur between the DMN and task-positive networks and that the pathological levels of CSF biomarkers correlate with functional connectivity disruption in patients with Alzheimer disease.

Systemic Inflammation and Multimodal Biomarkers in Amnestic Mild Cognitive Impairment and Alzheimer's Disease

There is increasing evidence suggesting that one of the most relevant pathophysiological features of Alzheimer’s disease (AD) is neuroinflammation, which plays an important role in the production and regulation of AD-related proteins (amyloid beta (Aβ) and Tau) and exacerbates AD pathology. Neuroinflammation can also be induced by systemic influences (factors from outside the central nervous system). However, the role of systemic inflammation in AD pathophysiology is much less understood. Thus, our main objective in this study was to verify whether the presence of serum cytokines (IL-1β, IL-6, IL-10, IL-12, and TNF-α) affects different AD biomarkers: Aβ1–42 and Tau protein levels, hippocampal volumes (HV), and default mode network functional connectivity (DMN FC) in healthy elderly controls, amnestic mild cognitive impairment (aMCI) patients due to AD, and mild AD patients. To accomplish this, we acquired 3-T MRI, blood, and cerebrospinal fluid (CSF) samples from 42 healthy controls, 55 aMCI patients due to AD, and 33 mild AD patients. Comparing the groups, we found that the mild AD patients presented smaller HV, disrupted DMN FC, and proportionally less IL-1β than the controls. The aMCI patients only differed from the controls in DMN FC. In intra-group comparison, aMCI and mild AD with detectable levels of cytokines (TNF-α, IL-1β, IL-10, and IL-12) had decreased DMN FC. On the other hand, patients with detectable levels of IL-10 and IL-12 presented a more favorable AD biomarkers profile (larger HV, more CSF Aβ1–42, and less p-Tau), indicating a possible protective role of these ILs. Our findings indicate a possible relationship between systemic inflammation with DMN FC disruption, hippocampal atrophy, and CSF protein levels in the subjects with mild AD and aMCI.