Article

Impaired default network functional connectivity in autosomal dominant Alzheimer disease

Authors:
  • Massachusetts General Hospital - Harvard Medical School - Martinos Center
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Abstract

To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network. Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO). We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO. Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease.

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... indicating that better scores on tests measuring these faculties were correlated with stronger connectivity between the DMN and the right thalamus. Language score also cor- Down's syndrome group was reminiscent of that which has been shown to occur in sporadic and familial Alzheimer's disease (Chhatwal et al., 2013;Gili et al., 2011;Greicius et al., 2004;He et al., 2007;Yi et al., 2015;Zhou et al., 2010). That is, the alterations in DMN connectivity seen in this study encompassed regions including the posterior cingulate cortex and precuneus, a part of the brain that also shows altered metabolic function in people with Alzheimer's disease and is a key site of Aβ deposition (Buckner et al., 2005;Buckner et al., 2009). ...
... Alterations in the DMN connectivity of the posterior cingulate cortex and precuneus have also been seen in an asymptomatic population at high risk for Alzheimer's disease compared to asymptomatic individuals with no increased risk (Chhatwal et al., 2013). This is particularly interesting given the largely preclinical nature of the cohort involved in the present study, and taken together these findings may corroborate the notion that disrupted functional connectivity of the DMN is an early biomarker of Alzheimer's disease neuropathology. ...
... However, this finding was not replicated in a subsequent study that included slightly younger asymptomatic populations at risk of sporadic Alzheimer's disease due to the presence of the risk allele APOE ε4 (Thomas et al., 2014). Yet it must be noted that in the case of the study of a familial autosomal dominant Alzheimer's disease cohort by Chhatwal et al. (2013), and in the case of people with Down's syndrome as in the present study, the onset of Alzheimer's disease neuropathology is a near certainty provided that the required mutation or additional copy of APP is present, and therefore may represent a qualitatively different population to those with other risk factors such as APOE ε4 alleles, which are not determinant but greatly increase risk. ...
Article
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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.
... Functional brain connectivity is captured based on the assessment of temporal correlations between different brain regions of interest (ROIs) using functional magnetic resonance imaging (fMRI). There has been growing evidence that a number of functional connectivity networks are disrupted at each stage of the full clinical Alzheimer's disease (AD) spectrum [2][3][4]. Particularly, such neural differences are also detectable in cognitive normal (CN) carrying mutations of AD risk genes, suggesting a substantial relationship between genetics and AD-altered functional brain networks [5]. However, direct genetic effect on functional connectivity networks has not been measured [5,6]. ...
... Suppose we observe n 1 i.i.d. random samples {X (1) 1 , ..., X (1) n 1 } from X (1) and n 2 i.i.d samples random samples {X (2) 1 , ..., X (2) n 2 } from X (2) , and the two samples are independent. The goal is to estimate the differential correlation matrix D = R 1 − R 2 , under the assumption that D is sparse. ...
... Suppose we observe n 1 i.i.d. random samples {X (1) 1 , ..., X (1) n 1 } from X (1) and n 2 i.i.d samples random samples {X (2) 1 , ..., X (2) n 2 } from X (2) , and the two samples are independent. The goal is to estimate the differential correlation matrix D = R 1 − R 2 , under the assumption that D is sparse. ...
Article
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Background There is growing evidence indicating that a number of functional connectivity networks are disrupted at each stage of the full clinical Alzheimer’s disease spectrum. Such differences are also detectable in cognitive normal (CN) carrying mutations of AD risk genes, suggesting a substantial relationship between genetics and AD-altered functional brain networks. However, direct genetic effect on functional connectivity networks has not been measured. Methods Leveraging existing AD functional connectivity studies collected in NeuroSynth, we performed a meta-analysis to identify two sets of brain regions: ones with altered functional connectivity in resting state network and ones without. Then with the brain-wide gene expression data in the Allen Human Brain Atlas, we applied a new biclustering method to identify a set of genes with differential co-expression patterns between these two set of brain regions. Results Differential co-expression analysis using biclustering method led to a subset of 38 genes which showed distinctive co-expression patterns between AD-related and non AD-related brain regions in default mode network. More specifically, we observed 4 sub-clusters with noticeable co-expression difference, where the difference in correlations is above 0.5 on average. Conclusions This work applies a new biclustering method to search for a subset of genes with altered co-expression patterns in AD-related default mode network regions. Compared with traditional differential expression analysis, differential co-expression analysis yielded many more significant hits with extra insights into the wiring mechanism between genes. Particularly, the differential co-expression pattern was observed between two sets of genes, suggesting potential upstream genetic regulators in AD development.
... Alteration of DMN connectivity is associated with a genetic mutation in AD. In particular, autosomal-dominant mutation carriers (PSEN1, PSEN2, or APP), who were young and asymptomatic, presented with altered DMN connectivity [145][146][147]. Regarding the Apo ε4 allele, various studies have reported diminished DMN connectivity in carriers of at least one Apo ε4 allele in all age ranges [144,[146][147][148][149][150][151]. ...
... In particular, autosomal-dominant mutation carriers (PSEN1, PSEN2, or APP), who were young and asymptomatic, presented with altered DMN connectivity [145][146][147]. Regarding the Apo ε4 allele, various studies have reported diminished DMN connectivity in carriers of at least one Apo ε4 allele in all age ranges [144,[146][147][148][149][150][151]. These results suggest some potential for the use of DMN connectivity for early identification of AD in young adults who carry relevant genetic mutations. ...
... Decreased in DMN functional connectivity [112,118,123,[126][127][128]131] Dissociation within DMN network; -decreased posterior DMN functional connectivity -elevation anterior DMN functional connectivity [134,135] DMN networks had longer distances with the loss of edges [138,141,142] Altered DMN functional connectivity was associated with decline of cognition [143,158,160] Altered DMN functional connectivity was associated with genetic mutation [146,149,152,154,157,163] Abbreviations: DMN, default mode network. ...
Article
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Alzheimer’s disease (AD) is the most common type of dementia, and depression is a risk factor for developing AD. Epidemiological studies provide a clinical correlation between late-life depression (LLD) and AD. Depression patients generally remit with no residual symptoms, but LLD patients demonstrate residual cognitive impairment. Due to the lack of effective treatments, understanding how risk factors affect the course of AD is essential to manage AD. Advances in neuroimaging, including resting-state functional MRI (fMRI), have been used to address neural systems that contribute to clinical symptoms and functional changes across various psychiatric disorders. Resting-state fMRI studies have contributed to understanding each of the two diseases, but the link between LLD and AD has not been fully elucidated. This review focuses on three crucial and well-established networks in AD and LLD and discusses the impacts on cognitive decline, clinical symptoms, and prognosis. Three networks are the (1) default mode network, (2) executive control network, and (3) salience network. The multiple properties emphasized here, relevant for the hypothesis of the linkage between LLD and AD, will be further developed by ongoing future studies.
... Individuals with known pathogenic gene mutations showed declined functional connectivity of brain areas within the DMN in the symptomatic stage of ADAD. The connectivity decreased in frontal lobe and primarily in the precuneus/posterior cingulate and parietal cortices, which was accompanied by increased Clinical Dementia Rating (CDR) scores [19,20]. Disruption of DMN was not consistently present in presymptomatic mutation carriers (PMC). ...
... Disruption of DMN was not consistently present in presymptomatic mutation carriers (PMC). While some study showed no change of DMN connectivity [21], some studies showed a decrease in some areas and an increase in some other areas [19,20,22,23]. Specifically, PMC displayed lower intrinsic connectivity in precuneus or posterior cingulate cortex, and lower or higher connectivity in part of the frontal cortices [20,23]. ...
... The regions within the pDMN that showed disruption were similar to the results of previous studies of DMN in sporadic AD or ADAD [14,[17][18][19]. Specifically, precuneus was the brain area that consistently presented decreased connectivity in DMN. ...
Article
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Background: The default mode network (DMN) could be divided into subsystems, the functional connectivity of which are different across the Alzheimer's disease (AD) spectrum. However, the functional connectivity patterns within the subsystems are unknown in presymptomatic autosomal dominant AD (ADAD). Objective: To investigate functional connectivity patterns within the subsystems of the DMN in presymptomatic subjects carrying PSEN1, PSEN2, or APP gene mutations. Methods: Twenty-six presymptomatic mutation carriers (PMC) and twenty-nine cognitively normal non-carriers as normal controls (NC) from the same families underwent resting state functional MRI and structural MRI. Seed-based analyses were done to obtain functional connectivity of posterior and anterior DMN. For the regions that showed significant connectivity difference between PMC and NC, volumes were extracted and compared between the two groups. Connectivity measures were then correlated with cognitive tests scores. Results: The posterior DMN showed connectivity decrease in the PMC group as compared with the NC group, which was primarily the connectivity of left precuneus with right precuneus and superior frontal gyrus; the anterior DMN showed significant connectivity decrease in the PMC group, which was the connectivity of medial frontal gyrus with middle frontal gyrus. In the brain regions showing connectivity changes in the PMC group, there was no group difference in volume. A positive correlation was observed between the precuneus connectivity value and Mini-Mental State Examination total score. Conclusion: Functional connectivity within both posterior and anterior DMN were disrupted in the presymptomatic stage of ADAD. Connectivity disruption within the posterior DMN may be useful for early identification of general cognitive decline and a potential imaging biomarker for early diagnosis.
... To date, functional connectome changes in autosomal-dominant AD have been assessed with fMRI only. In one such fMRI study, Chhatwal et al. assessed DMN functional connectivity in asymptomatic autosomal-dominant AD mutation carriers (APP, PSEN1 and PSEN2) and non-carriers from the same families and found that the mutation carriers had a lower connectivity, particularly in the PCC/precuneus and right parietal cortex 167 . Of note, the disruption of DMN connectivity in mutation carriers worsened as the disease progressed. ...
... attention network and cingulo-opercular network (also referred to as the salience network) 168 . Consistent with the findings of Chhatwal et al. 167 , autosomal-dominant AD mutation carriers showed a lower functional connectivity in these multiple resting-state networks than non-carriers, slightly preceding their predicted age of symptom onset. The most recent of this series of fMRI connectivity studies, published in 2018, also reported specific effects of autosomal-dominant AD mutations on the degradation of the DMN and dorsal attention network in the preclinical stage of the disease 169 . ...
Article
The pathology of Alzheimer disease (AD) damages structural and functional brain networks, resulting in cognitive impairment. The results of recent connectomics studies have now linked changes in structural and functional network organization in AD to the patterns of amyloid-β and tau accumulation and spread, providing insights into the neurobiological mechanisms of the disease. In addition, the detection of gene-related connectome changes might aid in the early diagnosis of AD and facilitate the development of personalized therapeutic strategies that are effective at earlier stages of the disease spectrum. In this article, we review studies of the associations between connectome changes and amyloid-β and tau pathologies as well as molecular genetics in different subtypes and stages of AD. We also highlight the utility of connectome-derived computational models for replicating empirical findings and for tracking and predicting the progression of biomarker-indicated AD pathophysiology.
... Recently, a set of biomarker criteria has been proposed to stage late onset AD disease progression [11a]. This model describes the earliest changes involve amyloid accumulation (A), followed by tau (T) deposition, and eventually neurodegeneration (N) that lead to cognitive dysfunction [12][13][14][15][16][17][18][19]. Changes in amyloid biomarkers, such as cerebrospinal fluid (CSF) Aβ 1-42 and [11C] Pittsburgh compound B (PiB) amyloid positron emission tomography (PET), have been observed ~15-20 years before symptom onset in ADAD [8,18,20,21,22,23]. ...
... This model describes the earliest changes involve amyloid accumulation (A), followed by tau (T) deposition, and eventually neurodegeneration (N) that lead to cognitive dysfunction [12][13][14][15][16][17][18][19]. Changes in amyloid biomarkers, such as cerebrospinal fluid (CSF) Aβ 1-42 and [11C] Pittsburgh compound B (PiB) amyloid positron emission tomography (PET), have been observed ~15-20 years before symptom onset in ADAD [8,18,20,21,22,23]. Tau (T) biomarkers, such as CSF phosphorylated tau 181 (p-tau 181 ) [4], change ~10-15 years prior to symptom onset in ADAD. ...
Article
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Aim: Identify a global resting state functional connectivity (gFC) signature in mutation carriers (MC) from the Dominantly Inherited Alzheimer Network (DIAN). Assess the gFC with regards to amyloid (A), tau (T), and neurodegeneration (N) biomarkers and estimated years to symptom onset (EYO). Introduction: Cross-sectional measures were assessed in MC (n=171) and mutation non-carriers (NC) (n=70) participants. A FC matrix that encompassed multiple resting state networks (RSNs) was computed for each participant. Methods: A gFC was compiled as a single index indicating functional connectivity strength. Global FC signature was modeled as a non-linear function of EYO. gFC was linearly associated with other biomarkers used for assessing the AT(N) framework including: cerebrospinal fluid (CSF), positron emission tomography (PET) molecular biomarkers, and structural magnetic resonance imaging. Results: The gFC was reduced in MC compared to NC participants. When MC participants were differentiated by clinical dementia rating (CDR), the gFC was significantly decreased in MC CDR > 0 (demented) compared to either MC CDR 0 (cognitively normal) or NC participants. The gFC varied non-linearly with EYO and initially decreased at EYO = -24 years, followed by a stable period followed by a further decline near EYO =0 years. Irrespective of EYO, a lower gFC associated with values of amyloid PET, CSF Aβ1-42, CSF p-tau, CSF t-tau, FDG and hippocampal volume. Conclusions: The gFC correlated with biomarkers used for defining the AT(N) framework. A biphasic change in the gFC suggested early changes associated with CSF amyloid and later changes associated with hippocampal volume.
... Our results revealed an abnormal increase in mean diffusivity in the forceps major (which projects into the posterior parietal and occipital cortex) a decade before the onset of dementia symptoms, with the forceps minor (which projects into the medial and lateral frontal cortex) and long-ranging projection fibres such as the inferior fronto-occipital fasciculus all showing abnormal mean diffusivity several years before the expected onset of dementia symptoms. Anterior and posterior callosal fibres and fibres such as the inferior-fronto-occipital fasciculus provide major connections within the anterior and posterior components of the default mode network regions (van den Heuvel et al., 2009), a functional network showing reduced connectivity in early-stage Alzheimer's disease (Sorg et al., 2007;Chhatwal et al., 2013). Although any correlational data preclude a causative conclusion, our findings support the possibility that callosal white matter degeneration contribute to functional disruption of functional networks such as the default mode network (Chhatwal et al., 2013;Mueller and Weiner, 2017;Taylor et al., 2017). ...
... Anterior and posterior callosal fibres and fibres such as the inferior-fronto-occipital fasciculus provide major connections within the anterior and posterior components of the default mode network regions (van den Heuvel et al., 2009), a functional network showing reduced connectivity in early-stage Alzheimer's disease (Sorg et al., 2007;Chhatwal et al., 2013). Although any correlational data preclude a causative conclusion, our findings support the possibility that callosal white matter degeneration contribute to functional disruption of functional networks such as the default mode network (Chhatwal et al., 2013;Mueller and Weiner, 2017;Taylor et al., 2017). The hippocampal cingulum bundle showed alterations only after the expected onset of symptom. ...
Article
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White matter alterations are present in the majority of patients with Alzheimer's disease type dementia. However, the spatiotemporal pattern of white matter changes preceding dementia symptoms in Alzheimer's disease remains unclear, largely due to the inherent diagnostic uncertainty in the preclinical phase and increased risk of confounding age-related vascular disease and stroke in late-onset Alzheimer's disease. In early-onset autosomal-dominantly inherited Alzheimer's disease, participants are destined to develop dementia, which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease. Here, we assessed mean diffusivity alterations in the white matter in 64 mutation carriers compared to 45 non-carrier family non-carriers. Using tract-based spatial statistics, we mapped the interaction of mutation status by estimated years from symptom onset on mean diffusivity. For major atlas-derived fibre tracts, we determined the earliest time point at which abnormal mean diffusivity changes in the mutation carriers were detectable. Lastly, we assessed the association between mean diffusivity and cerebrospinal fluid biomarkers of amyloid, tau, phosphorylated-tau, and soluble TREM2, i.e. a marker of microglia activity. Results showed a significant interaction of mutations status by estimated years from symptom onset, i.e. a stronger increase of mean diffusivity, within the posterior parietal and medial frontal white matter in mutation carriers compared with non-carriers. The earliest increase of mean diffusivity was observed in the forceps major, forceps minor and long projecting fibres-many connecting default mode network regions-between 5 to 10 years before estimated symptom onset. Higher mean diffusivity in fibre tracts was associated with lower grey matter volume in the tracts' projection zones. Global mean diffusivity was correlated with lower cerebrospinal fluid levels of amyloid-β1-42 but higher levels of tau, phosphorylated-tau and soluble TREM2. Together, these results suggest that regionally selective white matter degeneration occurs years before the estimated symptom onset. Such white matter alterations are associated with primary Alzheimer's disease pathology and microglia activity in the brain.
... Evidence is also consistent when analysing ADAD reports. Even in PMC, volume loss (Fox et al., 2001), hypometabolism (Mosconi et al., 2006) and impaired functional connectivity (Chhatwal et al., 2013) in the PCC have been reported. As a core structure of the DMN, functional disruption of the PCC is evident in presymptomatic ADAD and continues worsening in more advanced stages of the disease (Chhatwal et al., 2013). ...
... Even in PMC, volume loss (Fox et al., 2001), hypometabolism (Mosconi et al., 2006) and impaired functional connectivity (Chhatwal et al., 2013) in the PCC have been reported. As a core structure of the DMN, functional disruption of the PCC is evident in presymptomatic ADAD and continues worsening in more advanced stages of the disease (Chhatwal et al., 2013). Notably, impaired DMN functional connectivity before clinical symptomatology onset traces a similar pattern in ADAD and sporadic AD. ...
Article
The hippocampus is regarded as the pivotal structure for episodic memory symptoms associated with Alzheimer’s disease (AD) pathophysiology. However, what is often overlooked is that the hippocampus is ‘only’ one part of a network of memory critical regions, the Papez circuit. Other Papez circuit regions are often regarded as less relevant for AD as they are thought to sit ‘downstream’ of the hippocampus. However, this notion is oversimplistic and increasing evidence suggest that other Papez regions might be affected before or concurrently with the hippocampus. In addition, AD research has mostly focused on episodic memory deficits, whereas spatial navigation processes are also subserved by the Papez circuit with increasing evidence supporting its valuable potential as a diagnostic measure of incipient AD pathophysiology. In the current review we take a step forward analysing recent evidence on the structural and functional integrity of the Papez circuit across AD disease stages. Specifically, we will review the integrity of specific Papez regions from at-genetic-risk (APOE4 carriers), to mild cognitive impairment (MCI), to dementia stage of sporadic AD, as well as autosomal dominant AD (ADAD). We related those changes to episodic memory and spatial navigation/orientation deficits in AD. Finally, we provide an overview of how the Papez circuit is affected in AD diseases and their specific symptomology contributions. This overview strengthened the need for moving away from a hippocampal-centric view to a network approach on how the whole Papez circuit is affected in AD and contributes to its symptomology, informing future research and clinical approaches.
... A cross-sectional functional MRI connectivity study of 83 mutation carriers from the DIAN cohort, harbouring either APP, PSEN1 or PSEN2 mutations, reported that the clinical diagnosis of AD can be preceded by many years by functional disruptions of the default mode network (DMN) in ADAD [157]. Similar changes in resting state network, though occurring later, are found in LOAD [157,158]. ...
... A cross-sectional functional MRI connectivity study of 83 mutation carriers from the DIAN cohort, harbouring either APP, PSEN1 or PSEN2 mutations, reported that the clinical diagnosis of AD can be preceded by many years by functional disruptions of the default mode network (DMN) in ADAD [157]. Similar changes in resting state network, though occurring later, are found in LOAD [157,158]. Altered default mode connectivity was also observed in adults with DS with detectable fibrillar Aβ as measured by positron emission tomography (PET) using PiB as the tracer [159]. There are different explanations for the functional changes described. ...
Article
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The purpose of this review is to compare and highlight the clinical and pathological aspects of genetic versus acquired Alzheimer’s disease: Down syndrome-associated Alzheimer’s disease in (DSAD) and Autosomal Dominant Alzheimer’s disease (ADAD) are compared with the late-onset form of the disease (LOAD). DSAD and ADAD present in a younger population and are more likely to manifest with non-amnestic (such as dysexecutive function features) in the prodromal phase or neurological features (such as seizures and paralysis) especially in ADAD. The very large variety of mutations associated with ADAD explains the wider range of phenotypes. In the LOAD, age-associated comorbidities explain many of the phenotypic differences.
... for early detection of AD have shown promising results and rsfMRI is discussed as a biomarker preceding Aβ biomarkers . In autosomal dominant AD, default-mode network (DMN) functional connectivity has been found to decrease with increasing CDR and to be lower in asymptomatic mutation carriers that noncarriers with prominent involvement of the posterior cingulate cortex (PCC) (Chhatwal et al., 2013), suggesting alterations in this functional network already at the preclinical stage. An earlier study using task-related fMRI showed that PCC activity during a sensorymotor processing task was decreased in individuals with mild AD compared to age-matched elderly controls (Greicius, Srivastava, Reiss, & Menon, 2004), ...
... Although rsfMRI provides promising measures in preclinical AD (Chhatwal et al., 2013;Greicius et al., 2004;Thomas et al., 2014) biomarker research possibly preceding Aβ biomarkers (Jagust & Mormino, 2011), it is not yet incorporated in AD biomarker change models (Counts et al., 2017;Jack et al., 2013) or in the proposed framework for stageing of the preclinical phase of AD by the NIA-AA working group . To date, only few studies have investigated rsfMRI in preclinical AD, and reliability and reproducibility are affected by pooling of data acquired by different scanners (Teipel et al., 2017), and variation in participant instruction Yan et al., 2009). ...
... Reduced connectivity within the default mode network (DMN) that connects the medial prefrontal ctx with the anterior/posterior cingulate, precuneus, parietal, and temporal cortices, is a putative biomarker of AD (Balthazar et al., 2014;Greicius et al., 2004;Hohenfeld et al., 2018;Jones et al., 2011), and occurs early in the progression of various forms of the disease (Chhatwal et al., 2013) (Celone et al., 2006;Greicius et al., 2004). Interestingly, asymptomatic male and female Ɛ4 carriers ages 20-35 show increased connectivity across the anterior/ posterior DMN as compared to controls (Filippini et al., 2009). ...
Article
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The APOE Ɛ4 genotype is the most prevalent genetic risk for Alzheimer's disease (AD). Women carriers of Ɛ4 have higher risk for an early onset of AD than men. Human imaging studies suggest apolipoprotein Ɛ4 may affect brain structures associated with cognitive decline in AD many years before disease onset. It was hypothesized that female APOE Ɛ4 carriers would present with decreased cognitive function and neuroradiological evidence of early changes in brain structure and function as compared to male carriers. Six-month old wild-type (WT) and human APOE Ɛ4 knock-in (TGRA8960), male and female Sprague Dawley rats were studied for changes in brain structure using voxel-based morphometry, alteration in white and gray matter microarchitecture using diffusion weighted imaging with indices of anisotropy, and functional coupling using resting state BOLD functional connectivity. Images from each modality were registered to, and analyzed, using a 3D MRI rat atlas providing site-specific data on over 168 different brain areas. Quantitative volumetric analysis revealed areas involved in memory and arousal were significantly different between Ɛ4 and wild-type (WT) females, with few differences between male genotypes. Diffusion weighted imaging showed few differences between WT and Ɛ4 females, while male genotypes showed significant different measures in fractional anisotropy and apparent diffusion coefficient. Resting state functional connectivity showed Ɛ4 females had greater connectivity between areas involved in cognition, emotion, and arousal compared to WT females, with male Ɛ4 showing few differences from controls. Interestingly, male Ɛ4 showed increased anxiety and decreased performance in spatial and episodic memory tasks compared to WT males, with female genotypes showing little difference across behavioral tests.
... Despite the consensus in the literature that AD-pathology is related to a breakdown in functional brain networks, its associations with functional connectivity are tenuous. The relationship between β-amyloid and decreased connectivity, mainly in the DMN, is well established for clinically manifest AD (Hedden et al., 2009;Sheline et al., 2010;Chhatwal et al., 2013;Wang et al., 2013). However, during aging and in the absence of cognitive disorder, both increased functional connectivity (Mormino et al., 2011;Lim et al., 2014), but also decreased network connectivity (Wang et al., 2013) has been observed to be associated with AD-pathology when assessing total β-amyloid load, and tau burden. ...
Article
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Background: Integrity of functional brain networks is closely associated with maintained cognitive performance at old age. Consistently, both carrier status of Apolipoprotein E ε4 allele (APOE4), and age-related aggregation of Alzheimer’s disease (AD) pathology result in altered brain network connectivity. The posterior cingulate and precuneus (PCP) is a node of particular interest due to its role in crucial memory processes. Moreover, the PCP is subject to the early aggregation of AD pathology. The current study aimed at characterizing brain network properties associated with unimpaired cognition in old aged adults. To determine the effects of age-related brain change and genetic risk for AD, pathological proteins β-amyloid and tau were measured by Positron-emission tomography (PET), PCP connectivity as a proxy of cognitive network integrity, and genetic risk by APOE4 carrier status. Methods: Fifty-seven cognitively unimpaired old-aged adults (MMSE = 29.20 ± 1.11; 73 ± 8.32 years) were administered 11C Pittsburgh Compound B and 18F Flutemetamol PET for assessing β-amyloid, and 18F AV-1451 PET for tau. Individual functional connectivity seed maps of the PCP were obtained by resting-state multiband BOLD functional MRI at 3-Tesla for increased temporal resolution. Voxelwise correlations between functional connectivity, β-amyloid- and tau-PET were explored by Biological Parametric Mapping (BPM). Results: Local β-amyloid was associated with increased connectivity in frontal and parietal regions of the brain. Tau was linked to increased connectivity in more spatially distributed clusters in frontal, parietal, occipital, temporal, and cerebellar regions. A positive interaction was observable for APOE4 carrier status and functional connectivity with brain regions characterized by increased local β-amyloid and tau tracer retention. Conclusions: Our data suggest an association between spatially differing connectivity systems and local β-amyloid, and tau aggregates in cognitively normal, old-aged adults, which is moderated by APOE4. Additional longitudinal studies may determine protective connectivity patterns associated with healthy aging trajectories of AD-pathology aggregation.
... Nonetheless, the decrease in FC between the anterior and posterior regions of the DMN and decreased within-network connectivity in the posterior DMN is more severe in MCI and AD compared to healthy subjects. Earlier studies also reported inconsistent results regarding anterior DMN and other frontal lobe connectivity, with some reporting increased FC and some reporting decreased FC. 37,38 More recent studies suggest that networks might undergo different phases of elevated or diminished connectivity over the course of normal aging or disease progression, with possibly initial compensatory hyperfunctioning of networks which, over time, progress to hypofunction. 39,40 This is also seen in MCI where the milder stage is associated with increased DMN connectivity, whereas the more severe phase is correlated with decreased DMN connectivity. ...
Article
Neurodegenerative disorders are a growing cause of morbidity and mortality worldwide. Onset is typically insidious and clinical symptoms of behavioral change, memory loss, or cognitive dysfunction may not be evident early in the disease process. Efforts have been made to discover biomarkers that allow for earlier diagnosis of neurodegenerative disorders, to initiate treatment that may slow the course of clinical deterioration. Neuronal dysfunction occurs earlier than clinical symptoms manifest. Thus, assessment of neuronal function using functional brain imaging has been examined as a potential biomarker. While most early studies used task-functional magnetic resonance imaging (fMRI), with the more recent technique of resting-state fMRI, "intrinsic" relationships between brain regions or brain networks have been studied in greater detail in neurodegenerative disorders. In Alzheimer's disease, the most common neurodegenerative disorder, and frontotemporal dementia, another of the common dementias, specific brain networks may be particularly susceptible to dysfunction. In this review, we highlight the major findings of functional connectivity assessed by resting state fMRI in Alzheimer's disease and frontotemporal dementia.
... The severe loss in strength of RSCd regions in dKI mice may therefore indicate an OP recall-dependent roadblock for the mPFC-MTL communication. Our results also corroborate those of human studies showing that mPFC and PCC/RSC regions are often disrupted when functional and structural connectivity are evaluated in aMCI patients, APOE e4 carriers and presymptomatic ADAD patients [12,16,85]. Reduced connectivity in the PCC/RSC may constitute a typical FC marker of preclinical AD [36]. ...
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A critical challenge in current research on Alzheimer’s disease (AD) is to clarify the relationship between network dysfunction and the emergence of subtle memory deficits in itspreclinical stage. The AppNL-F/MAPT double knock-in (dKI) model with humanized β-amyloid peptide (Aβ) and tau was used to investigate both memory and network dysfunctions at an early stage. Young male dKI mice (2 to 6 months) were tested in three tasks taxing different aspects of recognition memory affected in preclinical AD. An early deficit first appeared in the object-place association task at the age of 4 months, when increased levels of β-CTF and Aβ were detected in both the hippocampus and the medial temporal cortex, and tau pathology was found only in the medial temporal cortex. Object-place task-dependent c-Fos activation was then analyzed in 22 subregions across the medial prefrontal cortex, claustrum, retrosplenial cortex, and medial temporal lobe. Increased c-Fos activation was detected in the entorhinal cortex and the claustrum of dKI mice. During recall, network efficiency was reduced across cingulate regions with a major disruption of information flow through the retrosplenial cortex. Our findings suggest that early perirhinal-entorhinal pathology is associated with abnormal activity which may spread to downstream regions such as the claustrum, the medial prefrontal cortex and ultimately the key retrosplenial hub which relays information from frontal to temporal lobes. The similarity between our findings and those reported in preclinical stages of AD suggests that the AppNL-F/MAPT dKI model has a high potential for providing key insights into preclinical AD.
... The default mode network is a task-negative network engaged during wakeful rest (Raichle et al., 2001;Fox et al., 2005). Reduced functional connectivity with the DMN has been associated with cognitive impairment (Zhang et al., 2010;Chhatwal et al., 2013). In this study, we explored functional connectivity of the DMN by placing a seed in posterior cingulate cortex, a key node of the DMN (Fox et al., 2005). ...
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Single-sided deafness (SSD) or profound unilateral hearing loss is the condition where the transfer of acoustic information to the brain is restricted to one ear. SSD impairment is most evident under adverse acoustic environments with overlapping interference, which burdens cognitive resources. It is known that bilateral deafness induces cross-modal brain plasticity within visual cortical areas. Here we investigate whether similar cross-modal plasticity is observed in adult-onset SSD. In SSD patients (n = 29) and matched controls (n = 29) we estimated voxel level resting-state power and functional connectivity in the alpha band (8-12 Hz) from magnetoencephalography (MEG) data. We examined both global functional connectivity (mean functional connectivity of each voxel with the rest of the brain), and seeded functional connectivity of primary auditory cortices (A1), primary visual cortices (V1) and posterior cingulate cortex (PCC) of the default mode network (DMN). Power reduction was observed in left auditory cortex. Global functional connectivity showed reduction in frontal cortices and enhancement in visual cortex. Seeded functional connectivity of auditory cortices showed reduction in temporal, frontal and occipital regions, and enhancement in parietal cortex. Interestingly, seeded functional connectivity of visual cortices showed enhancement in visual cortices, inferior parietal lobe, post-central gyrus, and the precuneus, and reduction in auditory cortex. Seeded functional connectivity of PCC showed reduction in frontal cortical regions that are part of the DMN, attention, and working memory networks. Adult-onset SSD exhibited widespread cross-modal brain plasticity involving alterations in auditory, visual, attention, working memory and default mode networks.
... In addition to LOAD, decreased default network connectivity has also been well-described in early onset AD (EOAD; (M. Lehmann et al., 2013)) and geneticallydriven, autosomal dominant AD (ADAD; (Chhatwal et al., 2018b;J.P. 2013;Thomas et al., 2014). More recent studies that examine multiple networks in the same sample suggest that the degradation of the default network across the spectrum of AD is accompanied by decreased connectivity in a subset of other networks, particularly the salience, dorsal attention, and control networks (Chhatwal et al., 2018b;Thomas et al., 2014), and that the variation in clinical presentation in AD corresponds to variations in networks targeted by the disease process M. 2013;Ossenkoppele et al., 2015). ...
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Resting-state functional connectivity MRI (rs-fcMRI) is a non-invasive imaging technique that has come into increasing use to understand disrupted neural network function in neuropsychiatric disease. However, despite extensive study over the past 15 years, the development of rs-fcMRI as a biomarker has been impeded by a lack of reliable longitudinal rs-fcMRI measures. Here we focus on longitudinal change along the Alzheimer's disease (AD) trajectory and demonstrate the utility of Template Based Rotation (TBR) in detecting differential longitudinal rs-fcMRI change between higher and lower amyloid burden individuals with mildly impaired cognition. Specifically, we examine a small (N = 24), but densely sampled (~5 observations over ~3 years), cohort of symptomatic individuals with serial rs-fcMRI imaging and PiB-PET imaging for β-amyloid pathology. We observed longitudinal decline of the Default Mode and Salience network axis (DMN/SAL) among impaired individuals with high amyloid burden. No other networks showed differential change in high vs. low amyloid individuals over time. The standardized effect size of AD related DMN/SAL change is comparable to the standardized effect size of amyloid-related change on the mini-mental state exam (MMSE) and hippocampal volume (HV). Last, we show that the AD-related change in DMN/SAL connectivity is almost completely independent of change on MMSE or HV, suggesting that rs-fcMRI is sensitive to an aspect of AD progression that is not captured by these other measures. Together these analyses demonstrate that longitudinal rs-fcMRI using TBR can capture disease-relevant network disruption in a clinical population.
... Resting-state functional connectivity (rsFC), specifically within the default mode network (DMN), is vulnerable to the earliest stages of AD pathology, [7][8][9] which accumulates years before symptom onset, 10,11 suggesting the potential of rsFC as an early marker of synaptic and neuronal dysfunction in AD. Several studies also report that the APOE ε4 allele is associated with decreased DMN connectivity and function among cognitively normal older adults, [12][13][14] even in the absence of amyloid 15 and atrophy. ...
Article
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Introduction: Numerous neuroimaging studies demonstrated an association between the apolipoprotein E (APOE) ε4 allele and resting-state functional connectivity (rsFC) of regions within the default mode network (DMN), both in healthy populations and patients with AD. It remains unclear whether the APOE ε4 allele differentially affects the brain's functional network architecture across race/ethnicity. Methods: We investigated rsFC within DMN subsystems in 170 APOE ε4 carriers compared to 387 APOE ε4 non-carriers across three major racial/ethnic groups, including non-Hispanic Whites (n = 166), non-Hispanic Blacks (n = 185), and Hispanics (n = 206) from the Washington Heights-Inwood Columbia Aging Project. Results: Compared to APOE ε4 non-carriers, APOE ε4 carriers had lower rsFC in temporal DMN, but only in non-Hispanic Whites. Non-Hispanic Black and Hispanic APOE ε4 carriers had slightly higher or similar rsFC compared with non-Hispanic White APOE ε4 non-carriers. Discussion: These findings suggest that APOE ε4 modulates DMN rsFC differently in non-Hispanic Whites compared with non-Hispanic Blacks and Hispanics.
... The DMN regions, medial frontal, posterior cingulate and lateral parietal cortices are strongly connected to the medial temporal lobe memory system, including the hippocampus 2,3 . Assessment of functional connectivity with BOLD-fMRI has demonstrated abnormal activity in the DMN in AD patients 4 and subjects at high risk of developing AD 5,6 . Such changes may reflect early synaptic changes in neural networks. ...
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Sleep, in addition to its brain restorative processes, plays an important role in memory transfer from its temporary store in the hippocampus to the more permanent storage in the neocortex. Alzheimer’s disease (AD) affects memory and sleep. The aim of this study was to explore disturbances in global and local synchrony patterns between brain regions in the APP/PS1 mouse model of the AD during natural sleep. We used 8 male APPswe/PS1dE9 mice and 6 wild-type littermates, aged 5–6 months, with multiple electrode bundles implanted into cortical regions, thalamus and hippocampus. We measured video-EEG in freely moving animals and analyzed synchrony during NREM vs REM sleep. Global synchrony between medial frontal cortex and hippocampus measured with magnitude-squared coherence was slightly decreased in delta range during NREM stage of sleep in APP/PS1 mice. In contrast, local hippocampal synchrony measured with cross-frequency coupling remained intact. Ripple structure or frequency did not differ between the genotypes. However, the coupling of the spindle-band power peak in the medial prefrontal cortex to hippocampal ripples was significantly decreased compared to wild-type animals. The delicate timing of hippocampal ripples, frontal delta, and corticothalamic spindle oscillations may be the first sign of impaired memory in amyloid plaque-forming transgenic mice.
... 13 Neuroinflammation can also alter connectivity in the default mode network (DMN), a set of functionally connected brain regions identified by functional magnetic resonance imaging (fMRI). [15][16][17] Altered DMN connectivity has been observed in patients with AD, 15,17 delirium, 18 and POCD. 19 This study, Investigating Neuroinflammation Underlying Postoperative Brain Connectivity Changes, Postoperative Cognitive Dysfunction, Delirium in Older Adults (INTUIT), will further investigate the relationship between increases in CSF MCP-1 levels and monocyte numbers, and changes in DMN connectivity in patients with POCD and delirium ( Figure 1). ...
Article
BACKGROUND/OBJECTIVES Every year, up to 40% of the more than 16 million older Americans who undergo anesthesia/surgery develop postoperative cognitive dysfunction (POCD) or delirium. Each of these distinct syndromes is associated with decreased quality of life, increased mortality, and a possible increased risk of Alzheimer's disease. One pathologic process hypothesized to underlie both delirium and POCD is neuroinflammation. The INTUIT study described here will determine the extent to which postoperative increases in cerebrospinal fluid (CSF) monocyte chemoattractant protein 1 (MCP‐1) levels and monocyte numbers are associated with delirium and/or POCD and their underlying brain connectivity changes. DESIGN Observational prospective cohort. SETTING Duke University Medical Center, Duke Regional Hospital, and Duke Raleigh Hospital. PARTICIPANTS Patients 60 years of age or older (N = 200) undergoing noncardiac/nonneurologic surgery. MEASUREMENTS Participants will undergo cognitive testing before, 6 weeks, and 1 year after surgery. Delirium screening will be performed on postoperative days 1 to 5. Blood and CSF samples are obtained before surgery, and 24 hours, 6 weeks, and 1 year after surgery. CSF MCP‐1 levels are measured by enzyme‐linked immunosorbent assay, and CSF monocytes are assessed by flow cytometry. Half the patients will also undergo pre‐ and postoperative functional magnetic resonance imaging scans. 32‐channel intraoperative electroencephalogram (EEG) recordings will be performed to identify intraoperative EEG correlates of neuroinflammation and/or postoperative cognitive resilience. Eighty patients will also undergo home sleep apnea testing to determine the relationships between sleep apnea severity, neuroinflammation, and impaired postoperative cognition. Additional assessments will help evaluate relationships between delirium, POCD, and other geriatric syndromes. CONCLUSION INTUIT will use a transdisciplinary approach to study the role of neuroinflammation in postoperative delirium and cognitive dysfunction and their associated functional brain connectivity changes, and it may identify novel targets for treating and/or preventing delirium and POCD and their sequelae.
... In a second experiment, the effect of NB-360 treatment on long-range circuits within the mouse brain was investigated. In the brains of wild-type mice, there was a strong temporal correlation between the neuronal activity patterns of the various areas of the brain (occipital, somatosensory, motor, and frontal regions), reminiscent of the default network activity observed in humans (Busche et al., 2015;Chhatwal et al., 2013). In contrast, a highly asynchronous pattern was observed in the brains of 6-to 7-month-old APP23xPS45 mice, indicating a severe impairment of neuronal crosstalk because of Aβ deposition. ...
Article
Inhibition of Beta‐site‐ APP Cleaving Enzyme‐1 (BACE‐1) is a current approach to fight the β‐amyloid (Aβ) deposition in the brains of patients with Alzheimer's disease, and a number of BACE‐1 inhibitors are currently being tested in clinical trials. The BACE‐1 inhibitor NB‐360, although not a clinical compound, turned out as a valuable pharmacological tool to investigate the effects of BACE‐1 inhibition on the deposition of different Aβ species in APP transgenic mice. Furthermore, chronic animal studies with NB‐360 discovered relationships between BACE‐1 inhibition, Aβ deposition, and Aβ‐related downstream effects on neuroinflammation, neuronal function and markers of neurodegeneration. NB‐360 effects on the processing of physiological BACE‐1 substrates as well as on non‐enzymatic BACE‐1 functions have been investigated and complement studies performed with BACE‐1 knock‐out mice. Since NB‐360 is also an inhibitor for BACE‐2, non‐clinical studies in adult animals revealed physiological effects of BACE‐2 inhibition.
... Some variants appear to segregate into cell-specific functions (Raj et al., 2014), enriched in canonical (Karch and Goate, 2015) or data-driven pathway (Miller et al., 2013;Zhang et al., 2013). Other selected Alzheimer's dementia susceptibility variants show effects on brain structure (Sabuncu et al., 2012;Chauhan et al., 2015;Foley et al., 2017) or brain networks (Reiman et al., 2005;Filippini et al., 2009;Chhatwal et al., 2013;Zhang et al., 2015). At the same time, the biological significance of a portion of identified variants is unclear. ...
Article
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Alzheimer's dementia commonly impacts the health of older adults and lacks any preventative therapy. While Alzheimer's dementia risk has a substantial genetic component, the specific molecular mechanisms and neuropathologies triggered by most of the known genetic variants are unclear. Resultantly, they have shown limited influence on drug development portfolios to date. To facilitate our understanding of the consequences of Alzheimer's dementia susceptibility variants, we examined their relationship to a wide range of clinical, molecular and neuropathological features. Because the effect size of individual variants is typically small, we utilized a polygenic (overall) risk approach to identify the global impact of Alzheimer's dementia susceptibility variants. Under this approach, each individual has a polygenic risk score (PRS) that we related to clinical, molecular and neuropathological phenotypes. Applying this approach to 1,272 individuals who came to autopsy from one of two longitudinal aging cohorts, we observed that an individual's PRS was associated with cognitive decline and brain pathologies including beta-amyloid, tau-tangles, hippocampal sclerosis, and TDP-43, MIR132, four proteins including VGF, IGFBP5, and STX1A, and many chromosomal regions decorated with acetylation on histone H3 lysine 9 (H3K9Ac). While excluding the APOE/TOMM40 region (containing the single largest genetic risk factor for late-onset Alzheimer's dementia) in the calculation of the PRS resulted in a slightly weaker association with the molecular signatures, results remained significant. These PRS-associated brain pathologies and molecular signatures appear to mediate genetic risk, as they attenuated the association of the PRS with cognitive decline. Notably, the PRS induced changes in H3K9Ac throughout the genome, implicating it in large-scale chromatin changes. Thus, the PRS for Alzheimer's dementia (AD-PRS) showed effects on diverse clinical, molecular, and pathological systems, ranging from the epigenome to specific proteins. These convergent targets of a large number of genetic risk factors for Alzheimer's dementia will help define the experimental systems and models needed to test therapeutic targets, which are expected to be broadly effective in the aging population that carries diverse genetic risks for Alzheimer's dementia.
... Cross-sectional data from the Dominantly Inherited Alzheimer Network (DIAN) and other populations of autosomal dominant Alzheimer disease (ADAD) have identified a relatively consistent pattern of biomarker and clinical change spanning the decades before and after expected symptom onset. [1][2][3][4][5][6][7] Cross-sectional studies provide critical information to inform our understanding of the general pattern of biomarker changes relative to clinical symptoms [8][9][10][11] and provide support for proposed models in both ADAD and sporadic late-onset Alzheimer disease (LOAD). 12 The predictability of symptom onset in ADAD facilitates longitudinal studies of the presymptomatic period by enabling the study of rates of change and temporal ordering of biomarker changes relative to the onset of dementia. ...
Article
Objective: To assess the onset, sequence, and rate of progression of comprehensive biomarker and clinical measures across the spectrum of Alzheimer disease (AD) using the Dominantly Inherited Alzheimer Network (DIAN) study and compare these to cross-sectional estimates. Methods: We conducted longitudinal clinical, cognitive, CSF, and neuroimaging assessments (mean of 2.7 [±1.1] visits) in 217 DIAN participants. Linear mixed effects models were used to assess changes in each measure relative to individuals' estimated years to symptom onset and to compare mutation carriers and noncarriers. Results: Longitudinal β-amyloid measures changed first (starting 25 years before estimated symptom onset), followed by declines in measures of cortical metabolism (approximately 7-10 years later), then cognition and hippocampal atrophy (approximately 20 years later). There were significant differences in the estimates of CSF p-tau181 and tau, with elevations from cross-sectional estimates preceding longitudinal estimates by over 10 years; further, longitudinal estimates identified a significant decline in CSF p-tau181 near symptom onset as opposed to continued elevations. Conclusion: These longitudinal estimates clarify the sequence and temporal dynamics of presymptomatic pathologic changes in autosomal dominant AD, information critical to a better understanding of the disease. The pattern of biomarker changes identified here also suggests that once β-amyloidosis begins, additional pathologies may begin to develop less than 10 years later, but more than 15 years before symptom onset, an important consideration for interventions meant to alter the disease course.
... Neurodegeneration can be identified by structural (volumetrics) or functional (resting state functional connectivity [rs-fc] intranetwork) magnetic resonance imaging (MRI) changes. Hippocampal volume loss [10] and decreases in rs-fc intra-network strength have been observed during the conversion to symptomatic AD [11,12]. ...
Article
Background: Behavioral markers for Alzheimer's disease (AD) are not included within the widely used amyloid-tau-neurodegeneration framework. Objective: To determine when falls occur among cognitively normal (CN) individuals with and without preclinical AD. Methods: This cross-sectional study recorded falls among CN participants (n = 83) over a 1-year period. Tailored calendar journals recorded falls. Biomarkers including amyloid positron emission tomography (PET) and structural and functional magnetic resonance imaging were acquired within 2 years of fall evaluations. CN participants were dichotomized by amyloid PET (using standard cutoffs). Differences in amyloid accumulation, global resting state functional connectivity (rs-fc) intra-network signature, and hippocampal volume were compared between individuals who did and did not fall using Wilcoxon rank sum tests. Among preclinical AD participants (amyloid-positive), the partial correlation between amyloid accumulation and global rs-fc intra-network signature was compared for those who did and did not fall. Results: Participants who fell had smaller hippocampal volumes (p = 0.04). Among preclinical AD participants, those who fell had a negative correlation between amyloid uptake and global rs-fc intra-network signature (R = -0.75, p = 0.012). A trend level positive correlation was observed between amyloid uptake and global rs-fc intra-network signature (R = 0.70, p = 0.081) for preclinical AD participants who did not fall. Conclusion: Falls in CN older adults correlate with neurodegeneration biomarkers. Participants without falls had lower amyloid deposition and preserved global rs-fc intra-network signature. Falls most strongly correlated with presence of amyloid and loss of brain connectivity and occurred in later stages of preclinical AD.
... Así, estudios recientes han determinado que en la EA ocurre una desconexión o disrupción de la red neuronal a gran escala antes de la manifestación clínica 23 . La red afectada más precozmente es la DMN 14,24 , lo que se ha determinado no solo por técnicas de imagen sino también por la concentración de beta amiloide y proteína Tau en variantes autosómicas dominantes de la EA. Otro estudio respecto de la EA esporádica sostiene que las anormalidades de la MRI no solo se vinculan con la enfermedad, sino que también permiten predecir cuándo se manifestarían los síntomas. ...
Article
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Las crecientes cifras mundiales de prevalencia e incidencia de la Enfermedad de Alzheimer exigen el desarrollo de métodos diagnósticos cada vez más precoces. La enfermedad suele diagnosticarse cuando la patología ya está avanzada y poco se puede hacer terapéuticamente, conllevando una gran pérdida de años de vida y altos costos sociales y familiares. Considerando esta patología como una disrupción a gran escala de las redes neuronales del cerebro humano, distintos estudios han propuesto biomarcadores basados en resonancia magnética y tomografía por emisión de positrones. El presente artículo revisa sistemáticamente dichos estudios considerando un abordaje desde la ciencia de redes neuronales. The increased global prevalence and incidence of Alzheimer’s Disease demands the development of early diagnostic methods. This disease is usually diagnosed when the pathology is already advanced and therapeutically, there’s not much to do, leading to a great loss of years of life, high socials and family costs. Considering this pathology as a large-scale disruption of neural networks of the human brain, different studies have proposed biomarkers based on functional magnetic resonance imaging and positron emission tomography. This article systematically reviews these studies considering an approach of neural networks science.
... Concerning the neurophysiological mechanisms underlying the beneficial effects reported in the studies mentioned above, the chronic administration with the BACE-1 inhibitor restored the impaired synchronization of single neurons around amyloid plaques and in neuronal populations distributed in different brain regions [48,49]. It was speculated that the effects were due to an improvement in the neuronal crosstalk in several areas of the brain (occipital, somatosensory, motor, and frontal regions; [50]), reminiscent of the default network activity observed in humans [49,51]. In those encouraging previous experiments, the improvement in the neuronal function due to the BACE-1 inhibitor treatment could occur despite high amyloid plaque load, probably in relation to the lack of a significant brain neurodegeneration. ...
Article
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Objective: In this exploratory study, we tested whether electroencephalographic (EEG) rhythms may reflect the effects of a chronic administration (4 weeks) of an anti-amyloid β-site amyloid precursor protein (APP) cleaving enzyme 1 inhibitor (BACE-1; ER-901356; Eisai Co., Ltd., Tokyo, Japan) in TASTPM (double mutation in APP KM670/671NL and PSEN1 M146V) producing Alzheimer's disease (AD) amyloid neuropathology as compared to wild type (WT) mice. Methods: Ongoing EEG rhythms were recorded from a bipolar frontoparietal and two monopolar frontomedial (prelimbic) and hippocampal channels in 11 WT Vehicle, 10 WT BACE-1, 10 TASTPM Vehicle, and 11 TASTPM BACE-1 mice (males; aged 8/9 months old at the beginning of treatment). Normalized EEG power (density) was compared between the first day (Day 0) and after 4 weeks (Week 4) of the BACE-1 inhibitor (10 mg/Kg) or vehicle administration in the 4 mouse groups. Frequency and magnitude of individual EEG delta and theta frequency peaks (IDF and ITF) were considered during animal conditions of behaviorally passive and active wakefulness. Cognitive status was not tested. Results: Compared with the WT group, the TASTPM group generally showed a significantly lower reactivity in frontoparietal ITF power during the active over the passive condition (p < 0.05). Notably, there was no other statistically significant effect (e.g., additional electrodes, recording time, and BACE-1 inhibitor). Conclusions: The above EEG biomarkers reflected differences between the WT and TASTPM groups, but no BACE-1 inhibitor effect. The results suggest an enhanced experimental design with the use of younger mice, longer drug administrations, an effective control drug, and neuropathological amyloid markers.
... Amplitude of low-frequency fluctuation (ALFF) is a relatively stable indicator in fMRI sequences that can respond to the low-frequency electrical activity of local neurons in the resting state. Most studies using ALFF as a biomarker have focused on specific brain region findings and functional connectivity in patients with psychiatric and neurodegenerative disorders (17)(18)(19)(20)(21)(22)(23). ALFF has the potential to be a special tool in the study of psychiatric or neurological disorders to assess the electrical activity of neurons in the resting state early in the course of the disease (24,25). ...
Article
Background: Acute bilirubin encephalopathy or kernicterus is the worst consequence of brain damage caused by the elevation of total unbound serum bilirubin (TSB) in neonates. The present study aimed to visualize the characteristic brain regions of neonates with hyperbilirubinemia (HB) using functional magnetic resonance imaging (fMRI) and to measure the amplitude of low-frequency fluctuation (ALFF) values. Methods: This was a prospective cohort study, which included newborns with HB who were hospitalized at the Children's Hospital of Fudan University. The control group included neonates admitted with neonatal simple wet lung or pneumonia without neurological disease or brain injury. Newborns were divided into a severe hyperbilirubinemia group (SHB), moderate HB group, and control group based on TSB levels. The newborns completed routine MRI combined with fMRI scans and brainstem auditory evoked potentials (BAEPs) during their hospitalization. Results: A total of 251 newborns were included in this study. There were 45 patients in the SHB group, 65 in the HB group, and 141 in the control group. The average ALFF value in the basal ganglia region in the SHB group was the highest, which was greater than that in the HB and control groups (P<0.001). The ALFF increased with an increase in TSB concentration. Based on the results of the Bayley Scales of infant development assessment, we further found that the most significant difference in ALFF remained in the basal ganglia region between newborns with motor development scores above 70 (including 70) and below 70. Correlation analysis revealed a strong negative correlation between motor development scores and ALFF (r=-0.691, P<0.001). When ALFF alone was used to predict motor development, the sensitivity was 89%. When ALFF was combined with TSB and BEAP results, the area under the ROC curve was the largest (AUC =0.85). The sensitivity and specificity of the model were 67.86% and 90.77%, respectively. Conclusions: The ALFF value may be able to serve as an early imaging biomarker and has a greater sensitivity than TSB or BAEP results in predicting long-term motor development (18 m) in HB.
... Previous studies of ADAD in participants in DIAN have demonstrated that abnormal levels of amyloid were detected in the cortex of mutation carriers 15 years in advance of expected onset of clinical symptoms (11,19,20). Moreover, studies in the same population using resting-state functional MRI have demonstrated that functional disruption of the default mode network begins before clinically evident symptoms in mutation carriers and worsens with increasing impairment (23)(24)(25). Studies have demonstrated that white matter structural connectivity is affected by AD-related pathology, namely amyloid, and may mediate changes in other markers of AD (4,26,27). ...
Article
Background Pathologic evidence of Alzheimer disease (AD) is detectable years before onset of clinical symptoms. Imaging-based identification of structural changes of the brain in people at genetic risk for early-onset AD may provide insights into how genes influence the pathologic cascade that leads to dementia. Purpose To assess structural connectivity differences in cortical networks between cognitively normal autosomal dominant Alzheimer disease (ADAD) mutation carriers versus noncarriers and to determine the cross-sectional relationship of structural connectivity and cortical amyloid burden with estimated years to symptom onset (EYO) of dementia in carriers. Materials and Methods In this exploratory analysis of a prospective trial, all participants enrolled in the Dominantly Inherited Alzheimer Network between January 2009 and July 2014 who had normal cognition at baseline, T1-weighted MRI scans, and diffusion tensor imaging (DTI) were analyzed. Amyloid PET imaging using Pittsburgh compound B was also analyzed for mutation carriers. Areas of the cerebral cortex were parcellated into three cortical networks: the default mode network, frontoparietal control network, and ventral attention network. The structural connectivity of the three networks was calculated from DTI. General linear models were used to examine differences in structural connectivity between mutation carriers and noncarriers and the relationship between structural connectivity, amyloid burden, and EYO in mutation carriers. Correlation network analysis was performed to identify clusters of related clinical and imaging markers. Results There were 30 mutation carriers (mean age ± standard deviation, 34 years ± 10; 17 women) and 38 noncarriers (mean age, 37 years ± 10; 20 women). There was lower structural connectivity in the frontoparietal control network in mutation carriers compared with noncarriers (estimated effect of mutation-positive status, -0.0266; P = .04). Among mutation carriers, there was a correlation between EYO and white matter structural connectivity in the frontoparietal control network (estimated effect of EYO, -0.0015, P = .01). There was no significant relationship between cortical global amyloid burden and EYO among mutation carriers (P > .05). Conclusion White matter structural connectivity was lower in autosomal dominant Alzheimer disease mutation carriers compared with noncarriers and correlated with estimated years to symptom onset. Clinical trial registration no. NCT00869817 © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by McEvoy in this issue.
... Aggregation of amyloid beta (Aβ) peptides preferentially affects DMN regions , while impaired DMN connectivity is associated with AD clinical severity and memory abilities (Brier et al., 2012;Buckner et al., 2005;Petrella et al., 2011). Moreover, in asymptomatic carriers of pathogenic mutations for AD, DMN disruption occurs before clinically evident symptoms, suggesting that functional disconnection might serve as marker of brain changes among patients earlier in the AD clinical course (Chhatwal et al., 2013). Additionally, other networks are involved in AD pathology, including the LMB (Pini et al., 2020a;Gour et al., 2014). ...
Article
Alzheimer's disease (AD) is characterized by different clinical entities. Although AD phenotypes share a common molecular substrate (i.e., amyloid beta and tau accumulation), several clinicopathological differences exist. Brain functional networks might provide a macro-scale scaffolding to explain this heterogeneity. In this review, we summarize the evidence linking different large-scale functional network abnormalities to distinct AD phenotypes. Specifically, executive deficits in early-onset AD link with the dysfunction of networks that support sustained attention and executive functions. Posterior cortical atrophy relates to the breakdown of visual and dorsal attentional circuits, while the primary progressive aphasia variant of AD may be associated with the dysfunction of the left-lateralized language network. Additionally, network abnormalities might provide in vivo signatures for distinguishing proteinopathies that mimic AD, such as TAR DNA binding protein 43 related pathologies. These network differences vis-a-vis clinical syndromes are more evident in the earliest stage of AD. Finally, we discuss how these findings might pave the way for new tailored interventions targeting the most vulnerable brain circuit at the optimal time window to maximize clinical benefits.
... compared asymptomatic mutation carriers and non-carriers and suggested reduction in Default Mode Network functional connectivity among asymptomatic carriers 56 . This finding is concordant with literature on sAD suggesting that change in rs-fMRI is one of the earliest biomarkers of the disease 25,26 . ...
Article
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Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer’s disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of AD, as well as beta-amyloid (Aβ) pathology, can accelerate brain aging. Using data from 1340 cognitively unimpaired participants between 18–94 years of age from multiple sites, we showed that topological properties of graphs constructed from rs-fMRI can predict chronological age across the lifespan. Application of our predictive model to the context of pre-clinical AD revealed that the pre-symptomatic phase of autosomal dominant AD includes acceleration of functional brain aging. This association was stronger in individuals having significant Aβ pathology.
... The default network is intrinsically present in the absence of externally-oriented cognitive activity, and deactivated by tasks requiring sustained attention [59]. Impairments in default network connectivity are thought to develop early in AD pathology, and can be seen even in asymptomatic individuals at high risk of AD, including patients with autosomal dominant AD mutations or in healthy older adults with Aβ deposition [60,61]. In T2DM, aberrant functional connectivity in the default network is associated with both declines in executive function on a verbal fluency test and with increased insulin resistance [62]. ...
Article
Background: Alzheimer's disease (AD) and type 2 diabetes (T2DM) are common causes of cognitive decline among older adults and share strong epidemiological links. Distinct patterns of cortical atrophy are observed in with AD and T2DM, but robust comparisons between structure-function relationships across these two disease states are lacking. Objective: To compare how atrophy within distributed brain networks is related to cognition across a spectrum of cognitive aging. Methods: The relationship between structural MRI changes and cognition was studied in 22 mild-to-moderate AD, 28 T2DM, and 27 healthy participants. Cortical thickness measurements were obtained from networks of interest (NOIs) matching the limbic, default, and frontoparietal resting-state networks. Composite cognitive scores capturing domains of global cognition, memory, and executive function were created. Associations between cognitive scores and the NOIs were assessed using linear regression, with age as a covariate. Within-network General Linear Model (GLM) analysis was run in Freesurfer 6.0 to visualize differences in patterns of cortical atrophy related to cognitive function in each group. A secondary analysis examined hemispheric differences in each group. Results: Across all groups, cortical atrophy within the limbic NOI was significantly correlated with Global Cognition (p = 0.009) and Memory Composite (p = 0.002). Within-network GLM analysis and hemispheric analysis revealed qualitatively different patterns of atrophy contributing to cognitive dysfunction between AD and T2DM. Conclusion: Brain network atrophy is related to cognitive function across AD, T2DM, and healthy participants. Differences in cortical atrophy patterns were seen between AD and T2DM, highlighting neuropathological differences.
... The DMN is primarily implicated in episodic memory retrieval and deactivated during the processing of external stimuli in cognitively demanding tasks (59,60). Furthermore, the DMN system, especially the medial temporal lobe subsystem, is frequently disrupted in AD and correlates with disease severity (61,62). The brain regions comprising the DMN and areas with high Ab load also show considerable overlap, and subjects with positive 11 C Pittsburgh Compound B PET scans showed significantly lower resting-state FC in the DMN compared with subjects with negative 11 C Pittsburgh Compound B PET scans (63)(64)(65). ...
Article
Background Individualized and reliable biomarkers are crucial for diagnosing Alzheimer’s disease (AD). However, the lack of accessibility and neurobiological correlation are the main obstacles to their clinical application. Machine learning algorithms can effectively identify personalized biomarkers based on the prominent symptoms of AD. Methods The episodic memory-related magnetic resonance imaging (MRI) features of 143 amnesic mild cognitive impairment (aMCI) patients were identified using a multivariate relevance vector regression (RVR) algorithm. The support vector machine (SVM) classification model was constructed using these MRI features and verified in two independent datasets (N=994). The neurobiological basis was also investigated based on cognitive assessments, neuropathologic biomarkers of cerebrospinal fluid (CSF), and positron emission tomography (PET) images of amyloid-β plaques. Results The combination of gray matter volume and amplitude of low-frequency fluctuation MRI features accurately predicted episodic memory impairment in individual aMCI patients (correlation = 0.638) when measured using an episodic memory assessment panel. The MRI features that contributed to episodic memory prediction were primarily distributed across the default mode network and limbic network. The classification model based on these features distinguished patients with AD from normal controls (NCs) with more than 86% accuracy. Furthermore, most identified episodic memory-related regions showed significantly different amyloid-β PET measurements among the AD, MCI, and NC groups. Moreover, the classification outputs significantly correlated with cognitive assessment scores and CSF amyloid-β42 and total tau levels in the MCI and AD groups. Conclusions Neuroimaging features can reflect individual episodic memory function and serve as potential diagnostic biomarkers of AD.
... Looking to other neurodegenerative diseases, Alzheimer's studies have also demonstrated concurrent increases and decreases in functional connectivity in the early disease process but with more consistent widespread decreases in functional connectivity occurring with disease progression (Chhatwal et al. 2013;Badhwar et al. 2017;Demirtaş et al. 2017 ...
Conference Paper
Whilst there are currently no available disease modifying therapies for Huntington’s Disease (HD), recent progress in huntingtin-lowering strategies hold great promise. Initiating therapies early in the disease course will be important and a complete characterisation of the premanifest period will help inform when to initiate disease modifying therapies and the biomarkers that may be useful in such trials. Previous research has characterised the premanifest period up to approximately 15 years from predicted onset, but even at this early stage the disease process is already underway as evidenced by striatal and white matter atrophy, reductions in structural connectivity within brain networks, rising biofluid biomarkers of neuronal dysfunction, elevations in psychiatric symptoms and emerging subtle cognitive impairments. In order to understand how early neurodegeneration can be detected and which measures are most sensitive to the early disease processes, we need to look even earlier in the disease course. This thesis documents the recruitment and analysis of the HD Young Adult Study: a premanifest cohort further from predicted clinical onset than previously studied with an average of 24 years prior to predicted onset. Differences between gene carriers and controls were examined across a range of imaging, cognitive, neuropsychiatric and biofluid measures. The structural and functional brain connectivity in this cohort is then investigated in further detail. By providing a detailed characterisation of brain structure and function in the early premanifest period along with the most sensitive biomarkers at this stage, this work will inform future treatment strategies that may seek to delay the onset of functional impairments in HD.
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Dementia is a syndrome characterised by chronic, multi-domain, acquired cognitive impairment that causes significant functional limitations. MRI is the standard imaging study for these cases, since it enables detection of the atrophy patterns of the various neurodegenerative diseases (Alzheimer's disease, frontotemporal degeneration, Lewy body dementia), the vascular lesions associated with vascular dementia, and various potentially reversible diseases (for example, tumours, hydrocephaly) or diseases that require special management measures (for example, prion diseases). In certain cases other imaging methods can be used, such as CT, functional MRI, HMPAO SPECT or dopaminergic markers and FDG PET, amyloid markers or dopaminergic markers. The indications for these methods have not yet been clearly established, and therefore should be used in multidisciplinary dementia units.
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“Brain-predicted age” quantifies apparent brain age compared to normative neuroimaging trajectories. Advanced brain-predicted age has been well established in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior brain-predicted age studies have typically used structural MRI, but resting-state functional connectivity (FC) remains underexplored. Our model predicted age from FC in 391 cognitively normal, amyloid-negative controls (ages 18-89). We applied the trained model to 145 amyloid-negative, 151 preclinical AD, and 156 symptomatic AD participants to test group differences. The model accurately predicted age in the training set. FC-predicted brain age gaps (FC-BAG) were significantly older in symptomatic AD and significantly younger in preclinical AD compared to controls. There was minimal correspondence between networks predictive of age and AD. Elevated FC-BAG may reflect network disruption during symptomatic AD. Reduced FC-BAG in preclinical AD was opposite to the expected direction, and may reflect a biphasic response to preclinical AD pathology or may be driven by inconsistency between age-related vs. AD-related networks. Overall, FC-predicted brain age may be a sensitive AD biomarker.
Article
SIGNIFICANCE Amyloid-β and tau, hallmark pathologies of Alzheimer’s disease (AD), are hypothesized to spread through brain functional networks that are critical for neural communication. Using high-resolution network analyses and positron emission tomography, we showed that greater tau burden was related to functional dysconnectivity of regions associated with memory function and increased connectivity of structures that are important for integrating information in cognitively unimpaired Presenilin-1 E280A carriers, who will develop early-onset AD dementia. These findings enlighten how brain pathology relates to distinct patterns of functional connectivity in regions that are essential for memory and information processing. Elucidating how brain pathology alters functional connections before individuals experience cognitive impairment could help detect AD early and predict disease progression and dementia risk.
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Technologies for imaging the pathophysiology of Alzheimer disease (AD) now permit studies of the relationships between the two major proteins deposited in this disease - amyloid-β (Aβ) and tau - and their effects on measures of neurodegeneration and cognition in humans. Deposition of Aβ in the medial parietal cortex appears to be the first stage in the development of AD, although tau aggregates in the medial temporal lobe (MTL) precede Aβ deposition in cognitively healthy older people. Whether aggregation of tau in the MTL is the first stage in AD or a fairly benign phenomenon that may be transformed and spread in the presence of Aβ is a major unresolved question. Despite a strong link between Aβ and tau, the relationship between Aβ and neurodegeneration is weak; rather, it is tau that is associated with brain atrophy and hypometabolism, which, in turn, are related to cognition. Although there is support for an interaction between Aβ and tau resulting in neurodegeneration that leads to dementia, the unknown nature of this interaction, the strikingly different patterns of brain Aβ and tau deposition and the appearance of neurodegeneration in the absence of Aβ and tau are challenges to this model that ultimately must be explained.
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Objective: The amyloid cascade hypothesis of Alzheimer disease (AD) has been increasingly challenged. Here, we aim to refocus the amyloid cascade hypothesis on its original premise that the accumulation of amyloid beta (Aβ) peptide is the primary and earliest event in AD pathogenesis as based on current evidence, initiating several pathological events and ultimately leading to AD dementia. Background: An ongoing debate about the validity of the amyloid cascade hypothesis for AD has been triggered by clinical trials with investigational disease-modifying drugs targeting Aβ that have not demonstrated consistent clinically meaningful benefits. Updated hypothesis: It is an open question if monotherapy targeting Aβ pathology could be markedly beneficial at a stage when the brain has been irreversibly damaged by a cascade of pathological changes. Interventions in cognitively unimpaired individuals at risk for dementia, during amyloid-only and pre-amyloid stages, are more appropriate for proving or refuting the amyloid hypothesis. Our updated hypothesis states that anti-Aβ investigational therapies are likely to be most efficacious when initiated in the preclinical (asymptomatic) stages of AD and specifically when the disease is driven primarily by amyloid pathology. Given the young age at symptom onset and the deterministic nature of the mutations, autosomal dominant AD (ADAD) mutation carriers represent the ideal population to evaluate the efficacy of putative disease-modifying Aβ therapies. Major challenges for the hypothesis: Key challenges of the amyloid hypothesis include the recognition that disrupted Aβ homeostasis alone is insufficient to produce the AD pathophysiologic process, poor correlation of Aβ with cognitive impairment, and inconclusive data regarding clinical efficacy of therapies targeting Aβ. Challenges of conducting ADAD research include the rarity of the disease and uncertainty of the generalizability of ADAD findings for the far more common "sporadic" late-onset AD. Linkage to other major theories: The amyloid cascade hypothesis, modified here to pertain to the preclinical stage of AD, still needs to be integrated with the development and effects of tauopathy and other co-pathologies, including neuroinflammation, vascular insults, synucleinopathy, and many others.
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Alzheimer's disease (AD) begins several decades before the onset of clinical symptoms, at a time when women may still undergo reproductive cycling. Whether ovarian functions alter substrates of AD pathogenesis is unknown. Here we show that ovarian cycle stages significantly modulate AD-related alterations in neural network patterns, cognitive impairments, and pathogenic protein production in the hAPP-J20 mouse model of AD. Female hAPP mice spent more time in estrogen-dominant cycle stages and these ovarian stages worsened AD-related network dysfunction and cognitive impairments. In contrast, progesterone-dominant stages and gonadectomy attenuated these AD-related deficits. Further studies revealed a direct role for estradiol in stimulating neural network excitability and susceptibility to seizures in hAPP mice and increasing amyloid beta levels. Understanding dynamic effects of the ovarian cycle on the female nervous system in disease, including AD, is of critical importance and may differ from effects on a healthy brain. The pattern of ovarian cycle effects on disease-related networks, cognition, and pathogenic protein expression may be relevant to young women at risk for AD.
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Background: Down syndrome (DS) is associated with increased risk for Alzheimer's disease (AD). In neurotypical individuals, clinical AD is preceded by reduced resting state functional connectivity in the default mode network (DMN), but it is unknown whether changes in DMN connectivity predict clinical onset of AD in DS. Objective: Does lower DMN functional connectivity predict clinical onset of AD and cognitive decline in people with DS? Methods: Resting state functional MRI (rsfMRI), longitudinal neuropsychological, and clinical assessment data were collected on 15 nondemented people with DS (mean age = 51.66 years, SD = 5.34 years, range = 42-59 years) over four years, during which 4 transitioned to dementia. Amyloid-β (Aβ) PET data were acquired on 13 of the 15 participants. Resting state fMRI, neuropsychological, and clinical assessment data were also acquired on an independent, slightly younger unimpaired sample of 14 nondemented people with DS (mean age = 44.63 years, SD = 7.99 years, range = 38-61 years). Results: Lower functional connectivity between long-range but not short-range DMN regions predicts AD diagnosis and cognitive decline in people with DS. Aβ accumulation in the inferior parietal cortex is associated with lower regional DMN functional connectivity. Conclusion: Reduction of long-range DMN connectivity is a potential biomarker for AD in people with DS that precedes and predicts clinical conversion.
Article
Resting-state functional connectivity has been used to study Alzheimer's disease, revealing underlying differences between groups of individuals at different levels of cognitive impairment, or groupwise changes over time. Most of these studies have employed a single scanner and/or a single scan per subject. In this study, we used data collected from a substudy to two randomized clinical trials in patients with mild-to-moderate Alzheimer's Disease to investigate the robustness of functional connectivity in a multicenter, longitudinal setting. This substudy was not powered to detect drug treatment effects. With a basic imaging charter for inter-site acquisition standardization, we found no changes to functional connectivity over time in the placebo group, despite observable changes in clinical test scores and regional brain atrophy. We infer that functional connectivity, as implemented in our study, is not sensitive enough to detect disease progression in our patients. Using an 8-week interval between scans (in both treatment and placebo groups), we found that our test-retest reproducibility was comparable with other published results. We also found that the dominant source of measurement variability was within individuals over time, compared with variability between subjects and sites. Finally, we propose a simple method of visual inspection to identify scans that should be excluded from longitudinal analysis.
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Background: Changes in resting state functional connectivity (rs-fc) occur in Alzheimer's disease (AD), but few longitudinal rs-fc studies have been performed. Most studies focus on single networks and not a global measure of rs-fc. Although the amyloid tau neurodegeneration (AT(N)) framework is increasingly utilized by the AD community, few studies investigated when global rs-fc signature changes occur within this model. Objective: 1) Identify a global rs-fc signature that differentiates cognitively normal (CN) individuals from symptomatic AD. 2) Assess when longitudinal changes in rs-fc occur relative to conversion to symptomatic AD. 3) Compare rs-fc with amyloid, tau, and neurodegeneration biomarkers. Methods: A global rs-fc signature composed of intra-network connections was longitudinally evaluated in a cohort of cognitively normal participants at baseline (n = 335). Biomarkers, including cerebrospinal fluid (Aβ42 and tau), structural magnetic resonance imaging, and positron emission tomography were obtained. Results: Global rs-fc signature distinguished CN individuals from individuals who developed symptomatic AD. Changes occurred nearly four years before conversion to symptomatic AD. The global rs-fc signature most strongly correlated with markers of neurodegeneration. Conclusion: The global rs-fc signature changes near symptomatic onset and is likely a neurodegenerative biomarker. Rs-fc changes could serve as a biomarker for evaluating potential therapies for symptomatic conversion to AD.
Article
Background: Self-referential processing is associated with the progression of Alzheimer's disease (AD), and cerebrospinal fluid (CSF) proteins have become accepted biomarkers of AD. Objective: Our objective in this study was to focus on the relationships between the self-referential network (SRN) and CSF pathology in AD-spectrum patients. Methods: A total of 80 participants, including 20 cognitively normal, 20 early mild cognitive impairment (EMCI), 20 late MCI (LMCI), and 20 AD, were recruited for this study. Independent component analysis was used to explore the topological SRN patterns, and the abnormalities of this network were identified at different stages of AD. Finally, CSF pathological characteristics (i.e., CSF Aβ, t-tau, and p-tau) that affected the abnormalities of the SRN were further determined during the progression of AD. Results: Compared to cognitively normal subjects, AD-spectrum patients (i.e., EMCI, LMCI, and AD) showed a reversing trend toward an association between CSF pathological markers and the abnormal SRN occurring during the progression of AD. However, a certain disease state (i.e., the present LMCI) with a low concentration of CSF tau could evoke more hyperconnectivity of the SRN than other patients with progressively increasing concentrations of CSF tau (i.e., EMCI and AD), and this fluctuation of CSF tau was more sensitive to the hyperconnectivity of the SRN than the dynamic changes of CSF Aβ. Conclusion: The integrity of the SRN was closely associated with CSF pathological characteristics, and these findings support the view that the hyperconnectivity of the SRN will play an important role in monitoring the progression of the pre-dementia state to AD.
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There is growing recognition in the field of neurodegenerative diseases that mixed proteinopathies are occurring at greater frequency than originally thought. This is particularly true for three amyloid proteins defining most of these neurological disorders, amyloid-beta (Aβ), tau, and alpha-synuclein (αSyn). The co-existence and often co-localization of aggregated forms of these proteins has led to the emergence of concepts positing molecular interactions and cross-seeding between Aβ, tau, and αSyn aggregates. Amongst this trio, αSyn has received particular attention in this context during recent years due to its ability to modulate Aβ and tau aggregation in vivo, to interact at a molecular level with Aβ and tau in vivo and to cross-seed tau in mice. Here we provide a comprehensive, critical, and accessible review about the expression, role and nature of endogenous soluble αSyn oligomers because of recent developments in the understanding of αSyn multimerization, misfolding, aggregation, cross-talk, spreading and cross-seeding in neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Alzheimer's disease, and Huntington's disease. We will also discuss our current understanding about the relative toxicity of endogenous αSyn oligomers in vivo and in vitro, and introduce potential opportunities to counter their deleterious effects.
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Functional brain connectivity of the resting-state networks has gained recent attention as a possible biomarker of Alzheimer’s Disease (AD). In this paper, we review the literature of functional connectivity differences in young adults and middle-aged cognitively intact individuals with non-modifiable risk factors of AD (n = 17). We focus on three main intrinsic resting-state networks: The Default Mode network, Executive network, and the Salience network. Overall, the evidence from the literature indicated early vulnerability of functional connectivity across different at-risk groups, particularly in the Default Mode Network. While there was little consensus on the interpretation on directionality, the topography of the findings showed frequent overlap across studies, especially in regions that are characteristic of AD (i.e., precuneus, posterior cingulate cortex, and medial prefrontal cortex areas). We conclude that while resting-state functional connectivity markers have great potential to identify at-risk individuals, implementing more data-driven approaches, further longitudinal and cross-validation studies, and the analysis of greater sample sizes are likely to be necessary to fully establish the effectivity and utility of resting-state network-based analyses.
Chapter
Neuroimaging biomarkers for neurologic diseases are important tools, both for understanding pathology associated with cognitive and clinical symptoms and for differential diagnosis. This chapter explores neuroimaging measures, including structural and functional measures from magnetic resonance imaging (MRI) and molecular measures primarily from positron emission tomography (PET), in healthy aging adults and in a number of neurologic diseases. The spectrum covers neuroimaging measures from normal aging to a variety of dementias: late-onset Alzheimer's disease [AD; including mild cognitive impairment (MCI)], familial and nonfamilial early-onset AD, atypical AD syndromes, posterior cortical atrophy (PCA), logopenic aphasia (lvPPA), cerebral amyloid angiopathy (CAA), vascular dementia (VaD), sporadic and familial behavioral-variant frontotemporal dementia (bvFTD), semantic dementia (SD), progressive nonfluent aphasia (PNFA), frontotemporal dementia with motor neuron disease (FTD-MND), frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), Parkinson's disease (PD) with and without dementia, and multiple systems atrophy (MSA). We also include a discussion of the appropriate use criteria (AUC) for amyloid imaging and conclude with a discussion of differential diagnosis of neurologic dementia disorders in the context of neuroimaging.
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Background: The APOE Ɛ4 genotype is the most prevalent genetic risk for Alzheimer's disease (AD). Women carriers of Ɛ4 have higher risk for an early onset of AD than men. Human imaging studies suggest apolipoprotein E4 may affect brain structures associated with cognitive decline in AD many years before disease onset. It was hypothesized that female APOE Ɛ4 carriers would present with decreased cognitive function and neuroradiological evidence of early changes in brain structure and function as compared to male carriers. Methods: Six-month old wild-type (WT) and human APOE Ɛ4 knock-in (TGRA8960), male and female Sprague Dawley rats were studied for changes in brain structure using voxel-based morphometry, alteration in white and gray matter microarchitecture using diffusion weighted imaging with indices of anisotropy, and functional coupling using resting state BOLD functional connectivity. Images from each modality were registered to, and analyzed, using a 3D MRI rat atlas providing site-specific data on over 168 different brain areas. Results: Quantitative volumetric analysis revealed areas involved in memory and arousal were significantly different between Ɛ4 and wild-type (WT) females, with few differences between male genotypes. Diffusion weighted imaging showed few differences between WT and Ɛ4 females, while male genotypes showed significant different measures in fractional anisotropy and apparent diffusion coefficient. Resting state functional connectivity showed Ɛ4 females had greater connectivity between areas involved in cognition, emotion, and arousal compared to WT females, with male Ɛ4 showing few differences from controls. Interestingly, male Ɛ4 showed increased anxiety and decreased performance in spatial and episodic memory tasks compared to WT males, with female genotypes showing little difference across behavioral tests. Conclusion: The sex differences in behavior and diffusion weighted imaging suggest male carriers of the Ɛ4 allele may be more vulnerable to cognitive and emotional complications compared to female carriers early in life. Conversely, the data may also suggest that female carriers are more resilient to cognitive/emotional problems at this stage of life perhaps due to altered brain volumes and enhanced connectivity.
Article
Background: Cerebrospinal fluid t-tau (CSF t-tau) is a measure of neurodegeneration in Alzheimer's disease (AD) and has been increasingly demonstrated to be a non-specific biomarker within the AD continuum. Objective: We sought to test whether t-tau influences the longitudinal effects of amyloid-β (Aβ) and phospho-tau (p-tau) on memory and executive function (EF) in mild cognitive impairment (MCI). Methods: 319 MCI individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with baseline and 2-year CSF Aβ, p-tau, t-tau, and neuropsychological assessments were studied. Mediation and moderation analyses evaluated the role of t-tau in the effects of Aβ and p-tau on memory and EF over 2 years. Results: We found that high baseline p-tau but not Aβ was associated with higher t-tau and lower memory scores at 2 years follow-up. The association between p-tau and memory impairment was partially mediated by t-tau, whereby higher p-tau was indirectly associated with lower memory via higher t-tau. t-tau also moderated the association between p-tau and memory. When t-tau level was relatively lower, higher p-tau was associated with lower memory scores at 2 years. When t-tau level was higher, the memory scores were low regardless of the p-tau level. Conclusion: Tau-induced neurodegeneration is one key pathway by which AD pathology (p-tau) affects memory impairment. Furthermore, in individuals with lower levels of tau-induced neurodegeneration, higher levels of p-tau were required for memory impairment. Our findings suggest that t-tau plays a significant role in how early AD pathology affects cognitive outcomes.
Chapter
In this chapter, we review evidence from structural and functional neuroimaging in humans to consider the role of the cingulate cortex subregions (i.e., subgenual anterior cingulate cortex, pregenual anterior cingulate cortex, anterior midcingulate cortex, and dorsal posterior cingulate cortex) as major hubs anchoring multiple large-scale brain networks. We begin with a review of evidence from intrinsic functional connectivity and diffusion tensor imaging studies to show how connections within and between cingulate-centered networks contribute to processing and integrating signals related to autonomic, affective, executive, and memory functions. We then consider how variability in cingulate-centered networks could contribute to a range of aging outcomes, including typical aging and unusually successful aging (dubbed "superaging"), as well as early neurodegenerative dementias, including frontotemporal dementia and Alzheimer's disease.
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The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).
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Het concept ‘mild cognitive impairment’ (MCI) wordt gebruikt voor cognitieve stoornissen die niet zo ernstig zijn dat ze aan de criteria van dementie voldoen. MCI kan veroorzaakt worden door elke neurologische, somatische, of psychiatrische aandoening die het functioneren van de hersenen beïnvloedt. Het beloop van MCI is variabel en afhankelijk van de onderliggende oorzaak, de definitie van MCI, de setting waarin de patiënt gezien wordt en de leeftijd. De ziekte van Alzheimer is een belangrijke oorzaak van MCI bij oudere patiënten. De mogelijkheden voor de behandeling van MCI zijn vooralsnog beperkt.
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Recent progress in molecular imaging has provided new important knowledge for further understanding the time course of early pathological disease processes in Alzheimer's disease (AD). Positron emission tomography (PET) amyloid beta (Aβ) tracers such as Pittsburgh Compound B detect increasing deposition of fibrillar Aβ in the brain at the prodromal stages of AD, while the levels of fibrillar Aβ appear more stable at high levels in clinical AD. There is a need for PET ligands to visualize smaller forms of Aβ, oligomeric forms, in the brain and to understand how they interact with synaptic activity and neurodegeneration. The inflammatory markers presently under development might provide further insight into the disease mechanism as well as imaging tracers for tau. Biomarkers measuring functional changes in the brain such as regional cerebral glucose metabolism and neurotransmitter activity seem to strongly correlate with clinical symptoms of cognitive decline. Molecular imaging biomarkers will have a clinical implication in AD not only for early detection of AD but for selecting patients for certain drug therapies and to test disease-modifying drugs. PET fibrillar Aβ imaging together with cerebrospinal fluid biomarkers are promising as biomarkers for early recognition of subjects at risk for AD, for identifying patients for certain therapy and for quantifying anti-amyloid effects. Functional biomarkers such as regional cerebral glucose metabolism together with measurement of the brain volumes provide valuable information about disease progression and outcome of drug treatment.
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There is an urgent need to find effective presymptomatic Alzheimer's disease (AD) treatments that reduce the risk of AD symptoms or prevent them completely. It currently takes too many healthy people, too much money and too many years to evaluate the range of promising presymptomatic treatments using clinical endpoints. We have used brain imaging and other measurements to track some of the earliest changes associated with the predisposition to AD. We have proposed the Alzheimer's Prevention Initiative (API) to evaluate investigational amyloid-modifying treatments in healthy people who, based on their age and genetic background, are at the highest imminent risk of developing symptomatic AD using brain imaging, cerebrospinal fluid (CSF), and cognitive endpoints. In one trial, we propose to study AD-causing presenilin 1 [PS1] mutation carriers from the world's largest early-onset AD kindred in Antioquia, Colombia, close to their estimated average age at clinical onset. In another trial, we propose to study apolipoprotein E (APOE) ε4 homozygotes (and possibly heterozygotes) close to their estimated average age at clinical onset. The API has several goals: 1) to evaluate investigational AD-modifying treatments sooner than otherwise possible; 2) to determine the extent to which the treatment's brain imaging and other biomarker effects predict a clinical benefit-information needed to help qualify biomarker endpoints for use in pivotal prevention trials; 3) to provide a better test of the amyloid hypothesis than clinical trials in symptomatic patients, when these treatments may be too little too late to exert their most profound effect; 4) to establish AD prevention registries needed to support these and other presymptomatic AD trials; and 5) to give those individuals at highest imminent risk of AD symptoms access to the most promising investigational treatments in clinical trials.
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Information processing in the cerebral cortex involves interactions among distributed areas. Anatomical connectivity suggests that certain areas form local hierarchical relations such as within the visual system. Other connectivity patterns, particularly among association areas, suggest the presence of large-scale circuits without clear hierarchical relations. In this study the organization of networks in the human cerebrum was explored using resting-state functional connectivity MRI. Data from 1,000 subjects were registered using surface-based alignment. A clustering approach was employed to identify and replicate networks of functionally coupled regions across the cerebral cortex. The results revealed local networks confined to sensory and motor cortices as well as distributed networks of association regions. Within the sensory and motor cortices, functional connectivity followed topographic representations across adjacent areas. In association cortex, the connectivity patterns often showed abrupt transitions between network boundaries. Focused analyses were performed to better understand properties of network connectivity. A canonical sensory-motor pathway involving primary visual area, putative middle temporal area complex (MT+), lateral intraparietal area, and frontal eye field was analyzed to explore how interactions might arise within and between networks. Results showed that adjacent regions of the MT+ complex demonstrate differential connectivity consistent with a hierarchical pathway that spans networks. The functional connectivity of parietal and prefrontal association cortices was next explored. Distinct connectivity profiles of neighboring regions suggest they participate in distributed networks that, while showing evidence for interactions, are embedded within largely parallel, interdigitated circuits. We conclude by discussing the organization of these large-scale cerebral networks in relation to monkey anatomy and their potential evolutionary expansion in humans to support cognition.
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To examine default mode and salience network functional connectivity as a function of APOE ε4 status in a group of cognitively normal age-, sex-, and education-matched older adults. Case-control study. Fifty-six cognitively normal APOE ε4 carriers and 56 age-, sex- and education-matched cognitively normal APOE ε4 noncarriers. Alterations in in-phase default mode and salience network connectivity in APOE ε4 carriers compared with APOE ε4 noncarriers ranging from 63 to 91 years of age. A posterior cingulate seed revealed decreased in-phase connectivity in regions of the posterior default mode network that included the left inferior parietal lobe, left middle temporal gyrus, and bilateral anterior temporal lobes in the ε4 carriers relative to APOE ε4 noncarriers. An anterior cingulate seed showed greater in-phase connectivity in the salience network including the cingulate gyrus, medial prefrontal cortex, bilateral insular cortex, striatum, and thalamus in APOE ε4 carriers vs noncarriers. There were no groupwise differences in brain anatomy. The observation of functional alterations in default mode and salience network connectivity in the absence of structural changes between APOE ε4 carriers and noncarriers suggests that alterations in connectivity may have the potential to serve as an early biomarker.
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Although beta-amyloid (Aβ) deposition is a characteristic feature of Alzheimer's disease (AD), this pathology is commonly found in elderly normal controls (NC). The pattern of Aβ deposition as detected with Pittsburgh compound-B positron emission tomography (PIB-PET) imaging shows substantial spatial overlap with the default mode network (DMN), a group of brain regions that typically deactivates during externally driven cognitive tasks. In this study, we show that DMN functional connectivity (FC) during rest is altered with increasing levels of PIB uptake in NC. Specifically, FC decreases were identified in regions implicated in episodic memory (EM) processing (posteromedial cortex, ventral medial prefrontal cortex, and angular gyrus), whereas connectivity increases were detected in dorsal and anterior medial prefrontal and lateral temporal cortices. This pattern of decreases is consistent with previous studies that suggest heightened vulnerability of EM-related brain regions in AD, whereas the observed increases in FC may reflect a compensatory response.
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Autosomal-dominant Alzheimer's disease has provided significant understanding of the pathophysiology of Alzheimer's disease. The present review summarizes clinical, pathological, imaging, biochemical, and molecular studies of autosomal-dominant Alzheimer's disease, highlighting the similarities and differences between the dominantly inherited form of Alzheimer's disease and the more common sporadic form of Alzheimer's disease. Current developments in autosomal-dominant Alzheimer's disease are presented, including the international Dominantly Inherited Alzheimer Network and this network's initiative for clinical trials. Clinical trials in autosomal-dominant Alzheimer's disease may test the amyloid hypothesis, determine the timing of treatment, and lead the way to Alzheimer's disease prevention.
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Identifying high-risk populations is an important component of disease prevention strategies. One approach for identifying at-risk populations for Alzheimer's disease (AD) is examining neuroimaging parameters that differ between patients, including functional connections known to be disrupted within the default-mode network. We have previously shown these same disruptions in cognitively normal elderly who have amyloid-β (Aβ) plaques [detected using Pittsburgh Compound B (PIB) PET imaging], suggesting neuronal toxicity of plaques. Here we sought to determine if pathological effects of apolipoprotein E ε4 (APOE4) genotype could be seen independent of Aβ plaque toxicity by examining resting state fMRI functional connectivity (fcMRI) in participants without preclinical fibrillar amyloid deposition (PIB-). Cognitively normal participants enrolled in longitudinal studies (n = 100, mean age = 62) who were PIB- were categorized into those with and without an APOE4 allele and studied using fcMRI. APOE4 allele carriers (E4+) differed significantly from E4- in functional connectivity of the precuneus to several regions previously defined as having abnormal connectivity in a group of AD participants. These effects were observed before any manifestations of cognitive changes and in the absence of brain fibrillar Aβ plaque deposition, suggesting that early manifestations of a genetic effect can be detected using fcMRI and that these changes may antedate the pathological effects of fibrillar amyloid plaque toxicity.
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Amyloid-β (Aβ) plaque deposition can precede the clinical manifestations of dementia of the Alzheimer type (DAT) by many years and can be associated with changes in brain metabolism. Both the Aβ plaque deposition and the changes in metabolism appear to be concentrated in the brain's default-mode network. In contrast to prior studies of brain metabolism which viewed brain metabolism from a unitary perspective that equated glucose utilization with oxygen consumption, we here report on regional glucose use apart from that entering oxidative phosphorylation (so-called "aerobic glycolysis"). Using PET, we found that the spatial distribution of aerobic glycolysis in normal young adults correlates spatially with Aβ deposition in individuals with DAT and cognitively normal participants with elevated Aβ, suggesting a possible link between regional aerobic glycolysis in young adulthood and later development of Alzheimer pathology.
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Rare autosomal dominant mutations result in familial Alzheimer's disease (FAD) with a relatively consistent age of onset within families. This provides an estimate of years until disease onset (relative age) in mutation carriers. Increased AD risk has been associated with differences in functional magnetic resonance imaging (fMRI) activity during memory tasks, but most of these studies have focused on possession of apolipoprotein E allele 4 (APOE4), a risk factor, but not causative variant, of late-onset AD. Evaluation of fMRI activity in presymptomatic FAD mutation carriers versus noncarriers provides insight into preclinical changes in those who will certainly develop AD in a prescribed period of time. Adults from FAD mutation-carrying families (nine mutation carriers, eight noncarriers) underwent fMRI scanning while performing a memory task. We examined fMRI signal differences between carriers and noncarriers, and how signal related to fMRI task performance within mutation status group, controlling for relative age and education. Mutation noncarriers had greater retrieval period activity than carriers in several AD-relevant regions, including the left hippocampus. Better performing noncarriers showed greater encoding period activity including in the parahippocampal gyrus. Poorer performing carriers showed greater retrieval period signal, including in the frontal and temporal lobes, suggesting underlying pathological processes. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.
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During development, the healthy human brain constructs a host of large-scale, distributed, function-critical neural networks. Neurodegenerative diseases have been thought to target these systems, but this hypothesis has not been systematically tested in living humans. We used network-sensitive neuroimaging methods to show that five different neurodegenerative syndromes cause circumscribed atrophy within five distinct, healthy, human intrinsic functional connectivity networks. We further discovered a direct link between intrinsic connectivity and gray matter structure. Across healthy individuals, nodes within each functional network exhibited tightly correlated gray matter volumes. The findings suggest that human neural networks can be defined by synchronous baseline activity, a unified corticotrophic fate, and selective vulnerability to neurodegenerative illness. Future studies may clarify how these complex systems are assembled during development and undermined by disease.
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