Differential effects of Down's syndrome and Alzheimer's neuropathology on default mode connectivity

Down's syndrome is a chromosomal disorder that invariably results in both intellectual disability and Alzheimer's disease neuropathology. However, only a limited number of studies to date have investigated intrinsic brain network organisation in people with Down's syndrome, none of which addressed the links between functional connectivity and Alzheimer's disease. In this cross‐sectional study, we employed ¹¹C‐Pittsburgh Compound‐B (PiB) positron emission tomography in order to group participants with Down's syndrome based on the presence of fibrillar beta‐amyloid neuropathology. We also acquired resting state functional magnetic resonance imaging data to interrogate the connectivity of the default mode network; a large‐scale system with demonstrated links to Alzheimer's disease. The results revealed widespread positive connectivity of the default mode network in people with Down's syndrome (n = 34, ages 30–55, median age = 43.5) and a stark lack of anti‐correlation. However, in contrast to typically developing controls (n = 20, ages 30–55, median age = 43.5), the Down's syndrome group also showed significantly weaker connections in localised frontal and posterior brain regions. Notably, while a comparison of the PiB‐negative Down's syndrome group (n = 19, ages 30–48, median age = 41.0) to controls suggested that alterations in default mode connectivity to frontal brain regions are related to atypical development, a comparison of the PiB‐positive (n = 15, ages 39–55, median age = 48.0) and PiB‐negative Down's syndrome groups indicated that aberrant connectivity in posterior cortices is associated with the presence of Alzheimer's disease neuropathology. Such distinct profiles of altered connectivity not only further our understanding of the brain physiology that underlies these two inherently linked conditions but may also potentially provide a biomarker for future studies of neurodegeneration in people with Down's syndrome.     

Neuropsychiatric symptoms in Alzheimer's disease are related to functional connectivity alterations in the salience network

Neuropsychiatric syndromes are highly prevalent in Alzheimer's disease (AD), but their neurobiology is not completely understood. New methods in functional magnetic resonance imaging, such as intrinsic functional connectivity or “resting‐state” analysis, may help to clarify this issue. Using such approaches, alterations in the default‐mode and salience networks (SNs) have been described in Alzheimer's, although their relationship with specific symptoms remains unclear. We therefore carried out resting‐state functional connectivity analysis with 20 patients with mild to moderate AD, and correlated their scores on neuropsychiatric inventory syndromes (apathy, hyperactivity, affective syndrome, and psychosis) with maps of connectivity in the default mode network and SN. In addition, we compared network connectivity in these patients with that in 17 healthy elderly control subjects. All analyses were controlled for gray matter density and other potential confounds. Alzheimer's patients showed increased functional connectivity within the SN compared with controls (right anterior cingulate cortex and left medial frontal gyrus), along with reduced functional connectivity in the default‐mode network (bilateral precuneus). A correlation between increased connectivity in anterior cingulate cortex and right insula areas of the SN and hyperactivity syndrome (agitation, irritability, aberrant motor behavior, euphoria, and disinhibition) was found. These findings demonstrate an association between specific network changes in AD and particular neuropsychiatric symptom types. This underlines the potential clinical significance of resting state alterations in future diagnosis and therapy. Hum Brain Mapp 35:1237–1246, 2014. © 2013 Wiley Periodicals, Inc.     

Insight in Alzheimer's disease

Increasing interest in insight and anosognosia in neuropsychiatric illness has been accompanied by growing academic study of such awareness phenomena in Alzheimer's disease. This article reviews the current status of knowledge of this topic and makes the case that insight and anosognosia are concepts with direct clinical relevance to Alzheimer's disease. The associated symptomatology, and implications for patient management, are emphasized. Such relevance should form the basis for future research.     

Functional connectome hierarchy dysfunction in Alzheimer's disease and its relationship with cognition and gene expression profiling

Numerous researches have shown that the human brain organizes as a continuum axis crossing from sensory motor to transmodal cortex. Functional network alterations were commonly found in Alzheimer's disease (AD). Whether the hierarchy of AD brain networks has changed and how these changes related to gene expression profiling and cognition is unclear. Using resting-state functional magnetic resonance imaging data from 233 subjects (185 AD patients and 48 healthy controls), we studied the changes in the functional network gradients in AD. Moreover, we investigated the relationships between gradient alterations and cognition, and gene expression profiling, respectively. We found that the second gradient organizes as a continuum axis crossing from the sensory motor to the transmodal cortex. Compared to the healthy controls, the secondary gradient scores of the visual and somatomotor network (SOM) increased significantly in AD, and the secondary gradient scores of default mode and frontoparietal network decreased significantly in AD. The secondary gradient scores of SOM and salience network (SAL) significantly positively correlated with memory function in AD. The secondary gradient in SAL also significantly positively correlated with language function. The AD-related second gradient alterations were spatially associated with the gene expression and the relevant genes enriched in neurobiology-related pathways, specially expressed in various tissues, cell types, and developmental stages. These findings suggested the changes in the functional network gradients in AD and deepened our understanding of the correlation between macroscopic gradient structure and microscopic gene expression profiling in AD.     

Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease

IntroductionThe longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood.MethodsIn a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years.ResultsWidespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross-sectional differences, however, apolipoprotein E ε4 (APOE ε4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status.DiscussionFor the first time, we demonstrated that the pleiotropic biological effect of the APOE ε4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions.     

Model-free group analysis shows altered BOLD FMRI networks in dementia

FMRI research in Alzheimer's disease (AD) and mild cognitive impairment (MCI) typically is aimed at determining regional changes in brain function, most commonly by creating a model of the expected BOLD-response and estimating its magnitude using a general linear model (GLM) analysis. This crucially depends on the suitability of the temporal assumptions of the model and on assumptions about normality of group distributions. Exploratory data analysis techniques such as independent component analysis (ICA) do not depend on these assumptions and are able to detect unknown, yet structured spatiotemporal processes in neuroimaging data. Tensorial probabilistic ICA (T-PICA) is a model free technique that can be used for analyzing multiple subjects and groups, extracting signals of interest (components) in the spatial, temporal, and also subject domain of FMRI data. We applied T-PICA and model-based GLM to study FMRI signal during face encoding in 18 AD, 28 MCI patients, and 41 healthy elderly controls. T-PICA showed activation in regions associated with motor, visual, and cognitive processing, and deactivation in the default mode network. Six networks showed a significantly decreased response in patients. For two networks the T-PICA technique was significantly more sensitive to detect group differences than the standard model-based technique. We conclude that T-PICA is a promising tool to identify and detect differences in (de)activated brain networks in elderly controls and dementia patients. The technique is more sensitive than the commonly applied model-based method. Consistent with other research, we show that networks of activation and deactivation show decreased reactivity in dementia.     

A prospective longitudinal study of apathy in Alzheimer's disease

BACKGROUND: Apathy and depression are the most frequent behavioural and psychiatric disorders in Alzheimer's disease, and may both have a negative impact on the progression of the illness. OBJECTIVES: To examine the clinical correlates of apathy in Alzheimer's disease (AD), and to determine whether apathy is a significant predictor of more rapid cognitive, functional and emotional decline. METHODS: Using a structured psychiatric evaluation, we examined a consecutive series of 354 subjects meeting clinical criteria for AD. Apathy was assessed by the Apathy Scale, and diagnosed using standardised criteria. Additional measurements included scales for depression, functional impairment, and global cognitive functions. A follow up evaluation was carried out in 247 patients (70% of the total sample) between 1 and 4 years after the baseline evaluation. RESULTS: Apathy was significantly associated with older age (p = 0.009), and a higher frequency of minor and major depression (p < 0.0001). Apathy at baseline was a significant predictor of depression at follow up (p = 0.01), and was associated with a faster cognitive (p = 0.0007) and functional decline (p = 0.006). CONCLUSIONS: Apathy in AD is a behavioural marker of a more aggressive dementia, characterised by a faster progression of cognitive, functional, and emotional impairment.     

Further evidence of preserved memory function in Alzheimer's disease

Memory performance of elderly patients in the early stages of Alzheimer's disease (DAT) was compared with that of elderly control subjects. In explicit tests of recognition memory, which involve conscious recollection, the DAT patients were grossly impaired. In implicit tests of anagram solution and wordstem completion, which do not require conscious recollection, the DAT patients were not impaired. These findings further support the idea that a separate memory system, episodic memory, underlies conscious recollection, that it is this system which is most commonly damaged in amnesia, and that memory systems not involving conscious recollection may be spared in the early stages of Alzheimer's disease.     

Toward systems neuroscience in mild cognitive impairment and Alzheimer's disease: A meta‐analysis of 75 fMRI studies

Most of the previous task functional magnetic resonance imaging (fMRI) studies found abnormalities in distributed brain regions in mild cognitive impairment (MCI) and Alzheimer's disease (AD), and few studies investigated the brain network dysfunction from the system level. In this meta‐analysis, we aimed to examine brain network dysfunction in MCI and AD. We systematically searched task‐based fMRI studies in MCI and AD published between January 1990 and January 2014. Activation likelihood estimation meta‐analyses were conducted to compare the significant group differences in brain activation, the significant voxels were overlaid onto seven referenced neuronal cortical networks derived from the resting‐state fMRI data of 1,000 healthy participants. Thirty‐nine task‐based fMRI studies (697 MCI patients and 628 healthy controls) were included in MCI‐related meta‐analysis while 36 task‐based fMRI studies (421 AD patients and 512 healthy controls) were included in AD‐related meta‐analysis. The meta‐analytic results revealed that MCI and AD showed abnormal regional brain activation as well as large‐scale brain networks. MCI patients showed hypoactivation in default, frontoparietal, and visual networks relative to healthy controls, whereas AD‐related hypoactivation mainly located in visual, default, and ventral attention networks relative to healthy controls. Both MCI‐related and AD‐related hyperactivation fell in frontoparietal, ventral attention, default, and somatomotor networks relative to healthy controls. MCI and AD presented different pathological while shared similar compensatory large‐scale networks in fulfilling the cognitive tasks. These system‐level findings are helpful to link the fundamental declines of cognitive tasks to brain networks in MCI and AD. Hum Brain Mapp 36:1217–1232, 2015. © 2014 Wiley Periodicals, Inc.     

Anosognosia in patients with Alzheimer's disease: current perspectives

Alzheimer?s disease (AD) is a neurodegenerative disease characterised by neurocognitive impairments, especially memory impairment, as core symptoms linked to reductions in activities of daily life. As marginal symptoms, neuropsychiatric symptoms (NPSs) appear during the progressive course of the disease. A lack of self‐awareness (anosognosia) of cognitive and functional impairments is often seen in patients with AD, and associations between anosognosia and other NPSs have been previously reported. To account for anosognosia pathogenesis neurocognitively, the cognitive awareness model (CAM) has been helpful for explaining the stream of events from sensory input to behavioural/affective and metacognitive outputs. According to CAM, there are three types of anosognosia: (i) primary anosognosia, (ii) executive anosognosia, and (iii) mnemonic anosognosia. These types of anosognosia are generated from different neurocognitive modulations leading to metacognitive outputs or behavioural/affective regulations. Primary anosognosia is considered to be caused by deficits in the metacognitive awareness system (MAS). While preserved MAS function is associated with milder depression and anxiety in AD, a severer depressive mood in patients with mild AD can inversely cause self‐underestimation. The modulation of executive anosognosia is thought to be associated with dangerous/disinhibition behaviours and apathy among NPS sub‐symptoms, via impairments of comparator mechanism (Cm) within the central executive system. Other neurobehavioral reactions linked to self‐awareness include ‘denying’ and ‘confabulation’, and each of these reactions is thought to be affected by the MAS and a Cm. Denial of one?s own memory impairments appears as a defensive reaction to protect against dysphoric feelings, and the confabulatory comment is instantly reaction constructed by fabrications according to misinterpretations of memory information about oneself. Similarly, the innovative development of a theoretical model (CAM) has contributed to explaining the mechanism of anosognosia and some neurobehavioral outputs from a neurocognitive perspective.     

Parietal memory network and default mode network in first‐episode drug‐naïve schizophrenia: Associations with auditory hallucination

Atypical spontaneous activities in resting‐state networks may play a role in auditory hallucinations (AHs), but networks relevant to AHs are not apparent. Given the debating role of the default mode network (DMN) in AHs, a parietal memory network (PMN) may better echo cognitive theories of AHs in schizophrenia, because PMN is spatially adjacent to the DMN and more relevant to memory processing or information integration. To examine whether PMN is more relevant to AHs than DMN, we characterized these intrinsic networks in AHs with 59 first‐episode, drug‐naïve schizophrenics (26 AH+ and 33 AH?) and 60 healthy participants in resting‐state fMRI. We separated the PMN, DMN, and auditory network (AN) using independent component analysis, and compared their functional connectivity across the three groups. We found that only AH+ patients displayed dysconnectivity in PMN, both AH+ and AH? patients exhibited dysfunctions of AN, but neither patient group showed abnormal connectivity within DMN. The connectivity of PMN significantly correlated with memory performance of the patients. Further region‐of‐interest analyses confirmed that the connectivity between the core regions of PMN, the left posterior cingulate gyrus and the left precuneus, was significantly lower only in the AH+ group. In exploratory correlation analysis, this functional connectivity metric significantly correlated with the severity of AH symptoms. The results implicate that compared to the DMN, the PMN is more relevant to the AH symptoms in schizophrenia, and further provides a more precise potential brain modulation target for the intervention of AH symptoms.     

Similarities and differences in the default mode network across rest,retrieval, and future imagining

The default mode network (DMN) has been identified reliably during rest, as well as during the performance of tasks such as episodic retrieval and future imagining. It remains unclear why this network is engaged across these seemingly distinct conditions, though many hypotheses have been proposed to account for these effects. Prior to generating hypotheses explaining common DMN involvement, the degree of commonality in the DMN across these conditions, within individuals, must be statistically determined to test whether or not the DMN is truly a unitary network, equally engaged across rest, retrieval and future imagining. To provide such a test, we used comparable paradigms (self‐directed, uninterrupted thought of equal duration) across the three conditions (rest, retrieval, and future imagining) in a within‐participant design. We found lower than expected pattern similarity in DMN functional connectivity across the three conditions. Similarity in connectivity accounted for only 40–50% of the total variance. Partial Least Squares (PLS) analyses revealed the medial temporal regions of the DMN were preferentially coupled with one another during episodic retrieval and future imagining, whereas the non‐medial temporal regions of the DMN (e.g., medial prefrontal cortex, lateral temporal cortex, and temporal pole) were preferentially coupled during rest. These results suggest that DMN connectivity may be more flexible than previously considered. Our findings are in line with emerging evidence that the DMN is not a static network engaged commonly across distinct cognitive processes, but is instead a dynamic system, topographically changing in relation to ongoing cognitive demands. Hum Brain Mapp 38:1155–1171, 2017. © 2016 Wiley Periodicals, Inc.