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

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

Orientational changes of white matter fibers in Alzheimer's disease and amnestic mild cognitive impairment

White matter abnormalities represent early neuropathological events in neurodegenerative diseases such as Alzheimer''s disease (AD), investigating these white matter alterations would likely provide valuable insights into pathological changes over the course of AD. Using a novel mathematical framework called “Director Field Analysis” (DFA), we investigated the geometric microstructural properties (i.e., splay, bend, twist, and total distortion) in the orientation of white matter fibers in AD, amnestic mild cognitive impairment (aMCI), and cognitively normal (CN) individuals from the Alzheimer''s Disease Neuroimaging Initiative 2 database. Results revealed that AD patients had extensive orientational changes in the bilateral anterior thalamic radiation, corticospinal tract, inferior and superior longitudinal fasciculus, inferior fronto‐occipital fasciculus, and uncinate fasciculus in comparison with CN. We postulate that these orientational changes of white matter fibers may be partially caused by the expansion of lateral ventricle, white matter atrophy, and gray matter atrophy in AD. In contrast, aMCI individuals showed subtle orientational changes in the left inferior longitudinal fasciculus and right uncinate fasciculus, which showed a significant association with the cognitive performance, suggesting that these regions may be preferential vulnerable to breakdown by neurodegenerative brain disorders, thereby resulting in the patients'' cognitive impairment. To our knowledge, this article is the first to examine geometric microstructural changes in the orientation of white matter fibers in AD and aMCI. Our findings demonstrate that the orientational information of white matter fibers could provide novel insight into the underlying biological and pathological changes in AD and aMCI.     

Sensorimotor network rewiring in mild cognitive impairment and Alzheimer's disease

This study aimed at elucidating whether (a) brain areas associated with motor function show a change in functional magnetic resonance imaging (fMRI) signal in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD), (b) such change is linear over the course of the disease, and (c) fMRI changes in aMCI and AD are driven by hippocampal atrophy, or, conversely, reflect a nonspecific neuronal network rewiring generically associated to brain tissue damage. FMRI during the performance of a simple motor task with the dominant right‐hand, and structural MRI (i.e., dual‐echo, 3D T1‐weighted, and diffusion tensor [DT] MRI sequences) were acquired from 10 AD patients, 15 aMCI patients, and 11 healthy controls. During the simple‐motor task, aMCI patients had decreased recruitment of the left (L) inferior frontal gyrus compared to controls, while they showed increased recruitment of L postcentral gyrus and head of L caudate nucleus, and decreased activation of the cingulum compared with AD patients. Effective connectivity was altered between primary sensorimotor cortices (SMC) in aMCI patients vs. controls, and between L SMC, head of L caudate nucleus, and cingulum in AD vs. aMCI patients. Altered fMRI activations and connections were correlated with the hippocampal atrophy in aMCI and with the overall GM microstructural damage in AD. Motor‐associated functional cortical changes in aMCI and AD mirror fMRI changes of the cognitive network, suggesting the occurrence of a widespread brain rewiring with increasing structural damage rather than a specific response of cognitive network. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.     

Functional integrity of thalamocortical circuits differentiates normal aging from mild cognitive impairment

Resonance in thalamocortical networks is critically involved in sculpting oscillatory behavior in large ensembles of neocortical cells. Neocortical oscillations provide critical information about the integrity of thalamocortical circuits and functional connectivity of cortical networks, which seem to be significantly disrupted by the neuronal death and synapse loss characterizing Alzheimer's disease (AD). By applying a novel analysis methodology to overcome volume conduction effects between scalp electroencephalographic (EEG) measurements, we were able to estimate the temporal activation of EEG‐alpha sources in the thalamus and parieto‐occipital regions of the cortex. We found that synaptic flow underlying the lower alpha band (7.5–10 Hz) was abnormally facilitated in patients with mild cognitive impairment (MCI) as compared to healthy elderly individuals, particularly from thalamus to cortex (～38% higher). In addition, the thalamic generator of lower alpha oscillations was also abnormally activated in patients with MCI. Regarding the upper alpha subdivision (10.1–12.5 Hz), both controls and patients with MCI showed a bidirectional decrease of thalamocortical synaptic transmission, which was age‐dependent only in the control group. Altogether, our results suggest that functional dynamics of thalamocortical networks differentiate individuals at high risk of developing AD from healthy elderly subjects, supporting the hypothesis that neurodegeneration mechanisms are active years before the patient is clinically diagnosed with dementia. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

White matter tract integrity in aging and Alzheimer's disease

The pattern of degenerative changes in the brain white matter (WM) in aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD) has been under debate. Methods of image analysis are an important factor affecting the outcomes of various studies. Here we used diffusion tensor imaging (DTI) to obtain fractional anisotropy (FA) measures of the WM in healthy young (n = 8), healthy elderly (n = 22), MCI (n = 8), and AD patients (n = 16). We then applied "tract-based spatial statistics" (TBSS) to study the effects of aging, MCI, and AD on WM integrity. Our results show that changes in WM integrity (that is, decreases in FA) are different between healthy aging and AD: in healthy older subjects compared with healthy young subjects decreased FA was primarily observed in frontal, parietal, and subcortical areas whereas in AD, compared with healthy older subjects, decreased FA was only observed in the left anterior temporal lobe. This different pattern of decreased anatomical connectivity in normal aging and AD suggests that AD is not merely accelerated aging.     

Hippocampal atrophy patterns in mild cognitive impairment and Alzheimer's disease

Background:

Histopathological studies and animal models suggest that hippocampal subfields may be differently affected by aging, Alzheimer's disease (AD), and other diseases. High‐resolution images at 4 Tesla depict details of the internal structure of the hippocampus allowing for in vivo volumetry of different subfields. The aims of this study were as follows: (1) to determine patterns of volume loss in hippocampal subfields in normal aging, AD, and amnestic mild cognitive impairment (MCI). (2) To determine if measurements of hippocampal subfields provide advantages over total hippocampal volume for differentiation between groups.

Methods:

Ninety‐one subjects (53 controls (mean age: 69.3 ± 7.3), 20 MCI (mean age: 73.6 ± 7.1), and 18 AD (mean age: 69.1 ± 9.5) were studied with a high‐resolution T2 weighted imaging sequence aimed at the hippocampus. Entorhinal cortex (ERC), subiculum, CA1, CA1‐CA2 transition zone (CA1‐2), CA3 & dentate gyrus (CA3&DG) were manually marked in the anterior third of the hippocampal body. Hippocampal volume was obtained from the Freesurfer and manually edited.

Results:

Compared to controls, AD had smaller volumes of ERC, subiculum, CA1, CA1‐2, and total hippocampal volumes. MCI had smaller CA1‐2 volumes. Discriminant analysis and power analysis showed that CA1‐2 was superior to total hippocampal volume for distinction between controls and MCI.

Conclusion:

The patterns of subfield atrophy in AD and MCI were consistent with patterns of neuronal cell loss/reduced synaptic density described by histopathology. These preliminary findings suggest that hippocampal subfield volumetry might be a better measure for diagnosis of early AD and for detection of other disease effects than measurement of total hippocampus. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.

     

Biological heterogeneity in ADNI amnestic mild cognitive impairment

BackgroundPrevious work examining normal controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI) identified substantial biological heterogeneity. We hypothesized that ADNI mild cognitive impairment (MCI) subjects would also exhibit heterogeneity with possible clinical implications.MethodsADNI subjects diagnosed with amnestic MCI (n = 138) were clustered based on baseline magnetic resonance imaging, cerebrospinal fluid, and serum biomarkers. The clusters were compared with respect to longitudinal atrophy, cognitive trajectory, and time to conversion.ResultsFour clusters emerged with distinct biomarker patterns: The first cluster was biologically similar to normal controls and rarely converted to Alzheimer's disease (AD) during follow-up. The second cluster had characteristics of early Alzheimer's pathology. The third cluster showed the most severe atrophy but barely abnormal tau levels and a substantial proportion converted to clinical AD. The fourth cluster appeared to be pre-AD and nearly all converted to AD.ConclusionsSubjects with MCI who were clinically similar showed substantial heterogeneity in biomarkers.     

Distinct medial temporal contributions to different forms of recognition in amnestic mild cognitive impairment and Alzheimer's disease

The simplest expression of episodic memory is the experience of familiarity, the isolated recognition that something has been encountered previously. Brain structures of the medial temporal lobe (MTL) make essential contributions to episodic memory, but the distinct contributions from each MTL structure to familiarity are debatable. Here we used specialized tests to assess recognition impairments and their relationship to MTL integrity in people with amnestic mild cognitive impairment (aMCI, n=19), people with probable Alzheimer's disease (AD; n=10), and age-matched individuals without any neurological disorder (n=20). Recognition of previously presented silhouette objects was tested in two formats—forced-choice recognition with four concurrent choices (one target and three foils) and yes/no recognition with individually presented targets and foils. Every foil was extremely similar to a corresponding target, such that forced-choice recognition could be based on differential familiarity among the choices, whereas yes/no recognition necessitated additional memory and decision factors. Only yes/no recognition was impaired in the aMCI group, whereas both forced-choice and yes/no recognition were impaired in the AD group. Magnetic resonance imaging showed differential brain atrophy, as MTL volume was reduced in the AD group but not in the aMCI group. Pulsed arterial spin-labeled scans demonstrated that MTL blood flow was abnormally increased in aMCI, which could indicate physiological dysfunction prior to the emergence of significant atrophy. Regression analyses with data from all patients revealed that regional patterns of MTL integrity were differentially related to forced-choice and yes/no recognition. Smaller perirhinal cortex volume was associated with lower forced-choice recognition accuracy, but not with lower yes/no recognition accuracy. Instead, smaller hippocampal volumes were associated with lower yes/no recognition accuracy. In sum, familiarity memory can be specifically assessed using the forced-choice recognition test, it declines later than other MTL-dependent memory functions as AD progresses, and it has distinct anatomical substrates.     

Differential microstructural and morphological abnormalities in mild cognitive impairment and Alzheimer's disease: Evidence from cortical and deep gray matter

One aim of this study is to use non‐Gaussian diffusion kurtosis imaging (DKI) for capturing microstructural abnormalities in gray matter of Alzheimer's disease (AD). The other aim is to compare DKI metrics against thickness of cortical gray matter and volume of deep gray matter, respectively. A cohort of 18 patients with AD, 18 patients with amnestic mild cognitive impairment (MCI), and 18 normal controls underwent morphological and DKI MR imaging. Images were investigated using regions‐of‐interest‐based analyses for deep gray matter and vertex‐wise analyses for cortical gray matter. In deep gray matter, more regions showed DKI parametric abnormalities than atrophies at the early MCI stage. Mean kurtosis (MK) exhibited the largest number of significant abnormalities among all DKI metrics. At the later AD stage, diffusional abnormalities were observed in fewer regions than atrophies. In cortical gray matter, abnormalities in thickness were mainly in the medial and lateral temporal lobes, which fit the locations of known early pathological changes. Microstructural abnormalities were predominantly in the parietal and even frontal lobes, which fit the locations of known late pathological changes. In conclusion, MK can complement conventional diffusion metrics for detecting microstructural changes, especially in deep gray matter. This study also provides evidence supporting the notion that microstructural changes predate morphological changes. Hum Brain Mapp 38:2495–2508, 2017. © 2017 Wiley Periodicals, Inc.     

CERAD test performances in amnestic mild cognitive impairment and Alzheimer's disease

OBJECTIVES: The aim of the study was to examine the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test performances cross-sectionally in patients suffering from amnestic mild cognitive impairment (MCI) and mild Alzheimer's disease (AD). Moreover, we wanted to determine the sensitivity to amnestic MCI and mild AD, as well as the specificity of different CERAD subtests in our study groups. MATERIAL AND METHODS: Fifteen healthy elderly individuals, 15 amnestic MCI patients and 15 probable AD patients suffering from mild dementia were tested with the CERAD neurocognitive dementia screening test. RESULTS: Significant differences were found in all CERAD tests except Constructional praxis (copy) and Clock drawing between the controls and the AD group. The MCI group was differentiated from the controls only in the Wordlist learning test. In the language tests the sensitivity to MCI and AD was quite low and the specificity very high. In the savings scores the sensitivity to AD was high, but the specificity rather low. The Wordlist recognition test screened no false positives using the current cut-off score and the sensitivity to AD was 0.6, but only one MCI patient was detected using the current cut-off score. Raising the cut-off score also raised the sensitivity to MCI without dramatic loss of specificity. Cut-off scores for the Wordlist learning test and Wordlist delayed recall, which have been found to differentiate normal aging from dementia, are lacking in the Finnish CERAD. The current data indicates that the Wordlist learning test might be relatively sensitive to MCI. CONCLUSIONS: The results indicate that the Finnish CERAD test battery with its current cut-off scores has low sensitivity to MCI, and using it as a sole cognitive screening instrument for MCI and preclinical dementia might result in false negatives.     

A divergent breakdown of neurocognitive networks in Parkinson's Disease mild cognitive impairment

Cognitive decline is a major disabling feature in Parkinson's disease (PD). Multimodal imaging studies have shown functional disruption in neurocognitive networks related to cognitive impairment. However, it remains unknown whether these changes are related to gray matter loss, or whether they outline network vulnerability in the early stages of cognitive impairment. In this work, we intended to assess functional connectivity and graph theoretical measures and their relation to gray matter loss in Parkinson's disease with mild cognitive impairment (PD‐MCI). We recruited 53 Parkinson's disease patients and classified them for cognitive impairment using Level‐1 Movement Disorders Society‐Task Force Criteria. Voxel‐based morphometry, functional connectivity and graph theoretical measures were obtained on a 3‐Tesla MRI scanner. Loss of gray matter was observed in the default mode network (bilateral precuneus), without a corresponding disruption of functional or graph theoretical properties. However, functional and graph theoretical changes appeared in salience network nodes, without evidence of gray matter loss. Global cognition and executive scores showed a correlation with node degree in the right anterior insula. We also found a correlation between visuospatial scores and right supramarginal gyrus node degree. Our findings highlight the loss of functional connectivity and topological features without structural damage in salience network regions in PD‐MCI. They also underline the importance of multimodal hubs in the transition to mild cognitive impairment. This functional disruption in the absence of gray matter atrophy suggests that the salience network is a key vulnerable system at the onset of mild cognitive impairment in PD.     

Diagnostic power of resting‐state fMRI for detection of network connectivity in Alzheimer's disease and mild cognitive impairment: A systematic review

Resting‐state fMRI (rs‐fMRI) detects functional connectivity (FC) abnormalities that occur in the brains of patients with Alzheimer''s disease (AD) and mild cognitive impairment (MCI). FC of the default mode network (DMN) is commonly impaired in AD and MCI. We conducted a systematic review aimed at determining the diagnostic power of rs‐fMRI to identify FC abnormalities in the DMN of patients with AD or MCI compared with healthy controls (HCs) using machine learning (ML) methods. Multimodal support vector machine (SVM) algorithm was the commonest form of ML method utilized. Multiple kernel approach can be utilized to aid in the classification by incorporating various discriminating features, such as FC graphs based on “nodes” and “edges” together with structural MRI‐based regional cortical thickness and gray matter volume. Other multimodal features include neuropsychiatric testing scores, DTI features, and regional cerebral blood flow. Among AD patients, the posterior cingulate cortex (PCC)/Precuneus was noted to be a highly affected hub of the DMN that demonstrated overall reduced FC. Whereas reduced DMN FC between the PCC and anterior cingulate cortex (ACC) was observed in MCI patients. Evidence indicates that the nodes of the DMN can offer moderate to high diagnostic power to distinguish AD and MCI patients. Nevertheless, various concerns over the homogeneity of data based on patient selection, scanner effects, and the variable usage of classifiers and algorithms pose a challenge for ML‐based image interpretation of rs‐fMRI datasets to become a mainstream option for diagnosing AD and predicting the conversion of HC/MCI to AD.     

Altered resting state networks in mild cognitive impairment and mild Alzheimer's disease: an fMRI study

Activity and reactivity of the default mode network in the brain was studied using functional magnetic resonance imaging (fMRI) in 28 nondemented individuals with mild cognitive impairment (MCI), 18 patients with mild Alzheimer's disease (AD), and 41 healthy elderly controls (HC). The default mode network was interrogated by means of decreases in brain activity, termed deactivations, during a visual encoding task and during a nonspatial working memory task. Deactivation was found in the default mode network involving the anterior frontal, precuneus, and posterior cingulate cortex. MCI patients showed less deactivation than HC, but more than AD. The most pronounced differences between MCI, HC, and AD occurred in the very early phase of deactivation, reflecting the reactivity and adaptation of the network. The default mode network response in the anterior frontal cortex significantly distinguished MCI from both HC (in the medial frontal) and AD (in the anterior cingulate cortex). The response in the precuneus could only distinguish between patients and HC, not between MCI and AD. These findings may be consistent with the notion that MCI is a transitional state between healthy aging and dementia and with the proposed early changes in MCI in the posterior cingulate cortex and precuneus. These findings suggest that altered activity in the default mode network may act as an early marker for AD pathology.     

Subjective memory complaints in Chinese subjects with mild cognitive impairment and early Alzheimer's disease

BACKGROUND: Mild cognitive impairment (MCI) represents a transitional state between normal aging and dementia. However, there is inconsistent opinion as to the validity of subjective memory complaints as a criterion for diagnosis. OBJECTIVE: This study aimed to examine the potential significance of applying a short memory questionnaire in the assessment of Chinese subjects with MCI and early dementia. METHODS: Three hundred and six ambulatory Chinese subjects were recruited. Each participant completed a short memory questionnaire. They were also assessed with the Chinese versions of the mini-mental state examination (CMMSE), Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog), category verbal fluency test (CVFT) and span tests. Severity of cognitive impairment was evaluated using the Clinical Dementia Rating (CDR); subjects with CDR 0.5 were further classified into MCI not demented (MCIND) and MCI possible incipient dementia (MCIID) depending on the subscale scores of CDR. RESULTS: An increasing frequency of memory complaints with increasing CDR was observed (Kruskal Wallis test, chi square = 21.29, df 3, p < 0.001). With a cutoff of 3 or more memory complaints, the memory questionnaire demonstrated a sensitivity of 65.3% and 70.4% in identifying subjects with incipient and early dementia respectively. Significant associations between memory complaints and most cognitive test performance were found (Spearman's correlations, p < 0.01). Logistic regression analysis revealed that educational level, the memory questionnaire, ADAS-Cog total and delayed recall scores were significant predictors of MCIID status. CONCLUSIONS: The findings suggested that a short memory questionnaire is useful in the screening of MCI, particularly in subjects who already present with subtle functioning disturbances. Subjective memory complaints were significant correlated with objective performance of memory functions, reflecting the usefulness of memory complaints in the assessment of MCI.     

Assessment of white matter tract damage in mild cognitive impairment and Alzheimer's disease

Diffusion tensor MRI‐based tractography was used to investigate white matter (WM) changes in the major limbic (i.e., fornix and cingulum) and cortico‐cortical association pathways [i.e., the uncinate fasciculus, the inferior fronto‐occipital fasciculus, the inferior longitudinal fasciculus (ILF), the superior longitudinal fasciculus, and the corpus callosum] in 25 Alzheimer's disease (AD) patients, 19 amnestic mild cognitive impairment (aMCI) patients, and 15 healthy controls (HC). Mean diffusivity (MD), fractional anisotropy (FA), as well as axial (DA) and radial (DR) diffusivities were measured for each tract, using an atlas‐based tractography approach. The association of WM tract integrity with hippocampal volume was also assessed. MD values were significantly different among groups in all WM tracts (P values ranging from 0.002 to 0.03), except in the fornix (P = 0.06) and the inferior fronto‐occipital fasciculus (P = 0.09). Conversely, FA was significantly different among groups in the fornix only (P = 0.02). DA values were significantly different among groups in all WM tracts (P values ranging from 0.001 to 0.01), except in the fornix (P = 0.13) and the cingulum (P = 0.29). Significantly different DR values among groups were found in the fornix (P = 0.02) and the ILF (P = 0.01). In the fornix and cingulum, DR was significantly more increased than DA in both patient groups compared to HC. No difference in DA versus DR was found in cortico‐cortical WM tracts. DA values in the fornix were significantly correlated with the hippocampal volume. This study demonstrates a different pattern of WM involvement in the limbic and cortico‐cortical association pathways in aMCI and AD patients. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.