Functional network topology associated with apathy in Alzheimer's disease

Background: Apathy, a common neuropsychiatric (NPS) in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD), is associated with structural and metabolic brain changes. However, functional connectivity changes across the brain in association with apathy remain unclear. In this study, graph theoretical measures of integration and segregation from resting state functional connectivity in MCI and AD patients with low depression scores, and healthy controls. Methods: In MCI and AD patients with low depression scores, graph theoretical measures of integration and segregation were derived from resting state functional connectivity in patients, which were compared between those with apathy (NPS_A, n = 21) to those without NPS (NPS_None, n = 28) and those with NPS other than apathy (NPS_NA, n = 38). Additionally, the same measures were compared between AD patients and healthy controls (amyloid uptake below threshold levels). Results: Altered whole brain global efficiency and reduced local efficiency were found in NPS_A compared to NPS_None and NPS_NA. In similar contrasts, apathy was associated with increased participation coefficient in the frontoparietal and cingulo-opercular template-based networks. A study-specific network definition also showed similar results. In comparison, AD patients showed higher modularity compared to controls at the whole brain level and higher participation coefficient in the ventral attention network. Limitations: The severity and dimensions of apathy were not assessed. Conclusions: Loss of segregation in the frontoparietal and cingulo-opercular network, which are involved in the control of goal-directed behavior, was associated with apathy in MCI/AD. The results also suggest that network-level changes in AD patients may underlie specific NPS

Widespread white matter aberration is associated with the severity of apathy in amnestic Mild Cognitive Impairment:Tract-based spatial statistics analysis

Apathy is recognized as a prevalent behavioral symptom of amnestic Mild Cognitive Impairment (aMCI). In aMCI, apathy is associated with an increased risk and increases the risk of progression to Alzheimer's Disease (AD). Previous DTI study in aMCI showed that apathy has been associated with white matter alterations in the cingulum, middle and inferior longitudinal fasciculus, fornix, and uncinate fasciculus. However, the underlying white matter correlates associated with apathy in aMCI are still unclear. We investigated this relationship using whole-brain diffusion tensor imaging (DTI). Twenty-nine aMCI patients and 20 matched cognitively healthy controls were included. Apathy severity was assessed using the Apathy Evaluation Scale Clinician version. We applied the tract-based spatial statistics analyses to DTI parameters: fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity to investigate changes in white matter pathways associated with the severity of apathy. No significant difference was found in any of the DTI parameters between aMCI and the control group. In aMCI, higher severity of apathy was associated with lower FA in various white matter pathways including the left anterior part of inferior fronto-occipital fasciculus/uncinate fasciculus, genu and body of the corpus callosum, superior and anterior corona radiata, anterior thalamic radiation of both hemispheres and in the right superior longitudinal fasciculus/anterior segment of arcuate fasciculus (p < .05, TFCE-corrected) after controlling for age, gender and GDS non-apathy. A trend association was observed in the right posterior corona radiata and corticospinal tract/internal capsule, and bilateral forceps minor (p < .065, TFCE-corrected). In conclusion, in aMCI, severity of apathy is associated with aberrant white matter integrity in widely distributed pathways, within and between hemispheres

On the neural mechanisms of reduced behavior in people with cognitive decline

We denken niet altijd na over hoe we tot ons gedrag komen. Dit op het oog spontane gedrag komt onder druk te staan bij patiënten met verschillende stoornissen die problemen hebben in het produceren van vrijwillig gedrag. De studies beschreven in dit proefschrift onderzochten hersen mechanismen onderliggend aan een verstoring in het genereren van gedrag, apathie, in oudere personen met geheugenklachten. Hiervoor hebben we twee verschillende maten van hersenfunctie gebruikt. De eerste methode onderzocht biologische markers van hersenfunctie in gebieden die waarschijnlijk zijn aangedaan bij deze personen. De resultaten lieten zien dat wanneer er sprake is van meer apathie een neurotransmitter belangrijk voor leren en geheugen minder aanwezig is in de laterale pariëtaal kwab van het brein. De tweede methode onderzocht de hersenen als een netwerk, het op een gecoördineerde manier samenwerken van verschillende gebieden. We vonden dat apathie was geassocieerd met veranderingen in twee specifieke netwerken in het brein die belangrijk zijn voor het voorstellen van doelen en het uitvoeren van acties om de gestelde doelen te halen. Samengenomen laten deze studies twee mogelijk aanvullende mechanismen zien die betrokken zijn bij apathie in deze personen. Op moment wordt er nog niet een duidelijke rol toegekend aan hoe de laterale pariëtale gebieden betrokken zijn apathie. Wij suggereren dat veranderingen in dit gebied resulteren in een vermindering in het initiëren van vrijwillige acties, wat leidt tot verminderd gedrag. Samenvattend, dit proefschrift integreert bevindingen van neurobiologie, hersenfunctie en cognitieve wetenschap om mechanismen onderliggend aan apathie te begrijpen

"Average is good, extremes are bad" - Non-linear inverted U-shaped relationship between neural mechanisms and functionality of mental features

Traditionally, studies emphasize differences in neural measures between pathological and healthy groups, assuming a binary distinction between the groups, and a linear relationship between neural measures and symptoms. Here, we present four examples that show a continuous relation across the divide of normal and pathological states between neural measures and mental functions. This relation can be characterized by a nonlinear inverted-U shaped curve. Along this curve, mid-range or average expression of a neural measure is associated with optimal function of a mental feature (in healthy states), whereas extreme expression, either high or low, is associated with sub-optimal function, and occurs in different neural disorders. Neural expression between the optimal or intermediate and pathological or extreme values is associated with sub-optimal function and atrisk mental states. Thus, this model of neuro-mental relationship can be summarized as "average is good, extremes are bad". By focussing on neuro-mental relationships, this model can facilitate the transition of psychiatry from a categorical to a dimensional and individualized approach needed in the era of precision medicine

Magnetic resonance spectroscopy in mild cognitive impairment: Systematic review and meta-analysis

Research using proton magnetic resonance spectroscopy (MRS) can potentially elucidate metabolite changes representing early degeneration in Mild Cognitive Impairment (MCI), an early stage of dementia. We integrated the published literature using meta-analysis to identify patterns of metabolite changes in MCI. 29 MRS studies (with a total of 607 MCI patients and 862 healthy controls) were classified according to brain regions. Hedges' g was used as effect size in a random effects model. N-Acetyl Aspartate (NAA) measures were consistently reduced in posterior cingulate (PC), hippocampus, and the paratrigonal white matter (PWM). Creatine (Cr) concentration was reduced in the hippocampus and PWM. Choline (Cho) concentration was reduced in the hippocampus while Cho/Cr ratio was raised in the PC. Myo-inositol (mI) concentration was raised in the PC and mI/Cr ratio was raised in the hippocampus. NAA/mI ratio was reduced in the PC. NAA may be the most reliable marker of brain dysfunction in MCI though mI, Cho, and Cr may also contribute towards this. (C) 2013 Elsevier Ltd. All rights reserved

Rest-task modulation of fMRI-derived global signal topography is mediated by transient coactivation patterns.

Recent resting-state functional MRI (fMRI) studies have revealed that the global signal (GS) exhibits a nonuniform spatial distribution across the gray matter. Whether this topography is informative remains largely unknown. We therefore tested rest-task modulation of GS topography by analyzing static GS correlation and dynamic coactivation patterns in a large sample of an fMRI dataset (n = 837) from the Human Connectome Project. The GS topography in the resting state and in seven different tasks was first measured by correlating the GS with the local time series (GSCORR). In the resting state, high GSCORR was observed mainly in the primary sensory and motor regions, whereas low GSCORR was seen in the association brain areas. This pattern changed during the seven tasks, with mainly decreased GSCORR in sensorimotor cortex. Importantly, this rest-task modulation of GSCORR could be traced to transient coactivation patterns at the peak period of GS (GS-peak). By comparing the topography of GSCORR and respiration effects, we observed that the topography of respiration mimicked the topography of GS in the resting state, whereas both differed during the task states; because of such partial dissociation, we assume that GSCORR could not be equated with a respiration effect. Finally, rest-task modulation of GS topography could not be exclusively explained by other sources of physiological noise. Together, we here demonstrate the informative nature of GS topography by showing its rest-task modulation, the underlying dynamic coactivation patterns, and its partial dissociation from respiration effects during task states

Lower Choline and Myo-Inositol in Temporo-Parietal Cortex Is Associated With Apathy in Amnestic MCI

Apathy is a common symptom in patients with amnestic mild cognitive impairment (aMCI) and is associated with an increased risk of progression to Alzheimer’s disease (AD). The neural substrates underlying apathy in aMCI may involve multiple brain regions, including the anterior cingulate cortex and the temporo-parietal region. Here we investigated neurometabolites in brain regions that may underlie apathy in aMCI patients using proton magnetic resonance spectroscopy (1H-MRS). Twenty-eight aMCI patients with varying degrees of apathy and 20 matched controls underwent 1H-MRS. Spectra were acquired from single voxels in the posterior cingulate cortex (PCC), dorsal anterior cingulate cortex (DACC), right dorsolateral prefrontal cortex (DLPFC), and right temporo-parietal cortex (TPC). Apathy was measured with the Apathy Evaluation Scale (AES). Spearman partial correlations between metabolite concentrations in each region and severity of apathy were determined. Additionally, analyses of covariance (ANCOVA) were performed to determine whether metabolite changes differed between patients with or without clinically-diagnosed apathy. The degree of apathy was found to be negatively correlated with choline and myo-inositol (mI) in the TPC. Additional exploratory analyses suggested that N-acetylaspartate (NAA)/mI ratio was reduced in aMCI without clinical apathy but not in aMCI with clinical apathy. In the DACC, glutamate and glutamine (Glx) levels tended to be higher in the aMCI with apathy group compared to controls and reduced in association with depression scores. In conclusion, apathy in aMCI patients was associated with neurometabolite changes indicative of altered membranal integrity and glial function in the right TPC. Findings also indicated that in a clinically-diagnosed aMCI cohort, apathy symptoms may be suggestive of neural changes that are distinct from aMCI without apathy