Transcranial magnetic stimulation (TMS) is among a growing family of noninvasive brain stimulation techniques being developed to treat multiple neurocognitive disorders, including Alzheimer's disease (AD). Although small clinical trials in AD have reported positive effects on cognitive outcome measures, significant knowledge gaps remain, and little attention has been directed at examining the potential influence of TMS on AD pathogenesis. Our review briefly outlines some of the proposed neurobiological mechanisms of TMS benefits in AD, with particular emphasis on the modulatory effects on excitatory/inhibitory balance. On the basis of converging evidence from multiple fields, we caution that TMS therapeutic protocols established in young adults may have unexpected detrimental effects in older individuals or in the brain compromised by AD pathology. Our review surveys clinical studies of TMS in AD alongside basic research as a guide for moving this important area of work forward toward effective treatment development.

Alzheimer's 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 (Broca's and Wernicke's 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 Wernicke's 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.

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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.

Depression and anxiety symptoms are common after stroke and associated to reduction in quality of life and poor physical and social outcomes. The Default Mode Network (DMN) plays an important role in the emotional processing. We investigated whether these symptoms are associated to a disruption of DMN functional connectivity in the first month after stroke. Thirty-four subacute ischemic stroke patients were submitted to: 1) behavioral assessment through Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) and Structured Clinical Interview for DSM Disorders; 2) neuropsychological assessment using Mini Mental State Examination and Montreal Cognitive Assessment; 3) resting state functional magnetic resonance imaging acquisition using a 3 T scanner (Philips Achieva). Patients with depression and/or anxiety symptoms showed an increased DMN functional connectivity in left inferior parietal gyrus and left basal nuclei, when compared to stroke controls. Specific correlation between BDI/BAI scores and DMN functional connectivity indicated that depression symptoms are correlated with increased functional connectivity in left inferior parietal gyrus, while anxiety symptoms are correlated with increased functional connectivity in cerebellum, brainstem and right middle frontal gyrus. Our study provides new insights into the underlying mechanisms of post stroke depression and anxiety, suggesting an alternate explanation other than regional structural damage following ischemic event, that these psychiatric symptoms are related to brain network dysfunction.

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: Aβ 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 Aβ, 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.

There is evidence that the default mode network (DMN) functional connectivity is impaired in Alzheimer's 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.

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.