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• What is the primary question addressed by this study? Are there specific anxiety symptoms associated with Alzheimer's disease pathologies, amyloid-β and tau, in cognitively unimpaired older adults? • What is the main finding of this study? Greater amyloid-β deposition was associated with higher levels of self-reported worry but not global anxiety, independent of subjective and objective cognition and depression. No associations were found between regional tau deposition and either worry or global anxiety. • What is the meaning of the finding? These findings implicate worry as an early, specific behavioral marker and possible therapeutic target in preclinical AD. Anxiety disorders and subsyndromal anxiety symptoms are highly prevalent in late life. Recent studies support that anxiety may be a neuropsychiatric symptom during preclinical Alzheimer's disease (AD) and that higher anxiety is associated with more rapid cognitive decline and progression to cognitive impairment. However, the associations of specific anxiety symptoms with AD pathologies and with co-occurring subjective and objective cognitive changes have not yet been established. Baseline data from the A4 and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration studies were analyzed. Older adult participants (n = 4,486) underwent assessments of anxiety (State-Trait Anxiety Inventory–6 item version [STAI]), and cerebral amyloid-beta (Aβ; 18F-florbetapir) PET and a subset underwent tau (18F-flortaucipir) PET. Linear regressions estimated associations of Aβ in a cortical composite and tau in the amygdala, entorhinal, and inferior temporal regions with STAI-Total and individual STAI item scores. Models adjusted for age, sex, education, marital status, depression, Apolipoprotein ε4 genotype, and subjective and objective cognition (Cognitive Function Index-participant; Preclinical Alzheimer Cognitive Composite). Greater Aβ deposition was significantly associated with higher STAI-Worry, adjusting for all covariates, but not with other STAI items or STAI-Total scores. In mediation analyses, the association of Aβ with STAI-Worry was partially mediated by subjective cognition with a stronger direct effect. No associations were found for regional tau deposition with STAI-Total or STAI-Worry score. Greater worry was associated with Aβ but not tau deposition, independent of subjective and objective cognition in cognitively unimpaired (CU) older adults. These findings implicate worry as an early, specific behavioral marker and a possible therapeutic target in preclinical AD. [ABSTRACT FROM AUTHOR]

Blood-brain barrier (BBB) leakage is considered an important underlying process in both cerebral small vessel disease (cSVD) and Alzheimer's disease (AD). The objective of this study was to examine associations between BBB leakage, cSVD, neurodegeneration, and cognitive performance across the spectrum from normal cognition to dementia. Leakage was measured with dynamic contrast-enhanced magnetic resonance imaging in 80 older participants (normal cognition, n = 32; mild cognitive impairment, n = 34; clinical AD-type dementia, n = 14). Associations between leakage and white matter hyperintensity (WMH) volume, hippocampal volume, and cognition (information processing speed and memory performance) were examined with multivariable linear regression and mediation analyses. Leakage within the gray and white matter was positively associated with WMH volume (gray matter, p = 0.03; white matter, p = 0.01). A negative association was found between white matter BBB leakage and information processing speed performance, which was mediated by WMH volume. Leakage was not associated with hippocampal volume. WMH pathology is suggested to form a link between leakage and decline of information processing speed in older individuals with and without cognitive impairment. • BBB leakage throughout the whole brain is positively related to cSVD severity. • BBB leakage forms an indirect process underlying processing speed deterioration. • This process is independent of clinical diagnosis. [ABSTRACT FROM AUTHOR]

Objective: Public health recommendations promote social engagement to reduce risk of cognitive decline and dementia. The objective of this study was to evaluate the longitudinal associations of social engagement and cognition in cognitively normal older adults with varying levels of neocortical amyloid-β, the Alzheimer's disease (AD) pathologic marker.Methods: Two hundred seventeen men and women, age 63-89 underwent assessments for social engagement and cognitive performance at baseline and 3 years later using the Community Healthy Activities Model Program for Seniors questionnaire and the Preclinical Alzheimer Cognitive Composite (PACC). Amyloid-β was measured using Pittsburgh compound B-PET. Multivariable regression models estimated main and interactive effects of baseline social engagement and amyloid-β on cognitive change. Reciprocal models estimated main and interactive effects of baseline cognitive performance and amyloid-β on change in social engagement.Results: Baseline social engagement was associated with PACC change as a modifier but not as a main effect. Lower baseline social engagement was associated with greater amyloid-β-related PACC decline, while higher baseline social engagement was associated with relative preservation of PACC scores (β = 0.05, p = 0.03). Reciprocally, lower baseline PACC score was associated with decline in social engagement score (β = 1.1, p = 0.02). This association was not modified by amyloid-β, and there was no direct association of amyloid-β with change in social engagement.Conclusions: Low social engagement may be a marker of neurocognitive vulnerability in older adults who are cognitively normal but have evidence of AD pathophysiologic change. Understanding changes in social engagement in older adults may lead to earlier diagnosis of AD and advances in evidence-based prevention and treatment. [ABSTRACT FROM AUTHOR]

The locus coeruleus (LC) plays a crucial role in modulating several higher order cognitive functions via its widespread projections to the entire brain. We set out to investigate the hypothesis that LC functional connectivity (FC) may fluctuate nonlinearly with age and explored its relation to memory function. To that end, 49 cognitively healthy individuals (19–74 years) underwent ultra high-resolution 7T resting-state functional magnetic resonance imaging and cognitive testing. FC patterns from the LC to regions of the isodendritic core network and cortical regions were examined using region of interest–to–region of interest analyses. Curvilinear patterns with age were observed for FC between the left LC and cortical regions and the nucleus basalis of Meynert. A linear negative association was observed between age and LC-FC and ventral tegmental area. Higher levels of FC between the LC and nucleus basalis of Meynert or ventral tegmental area were associated with lower memory performance from age of 40 years onward. Thus, different LC-FC patterns early in life can signal subtle memory deficits. Furthermore, these results highlight the importance of intact interactions between neurotransmitter systems for optimal cognitive aging. [ABSTRACT FROM AUTHOR]

The posterior cingulate cortex (PCC) is a key hub of the default mode network, a resting-state network involved in episodic memory, showing functional connectivity (FC) changes in Alzheimer's disease (AD). However, PCC is a cytoarchitectonically heterogeneous region. Specifically, the retrosplenial cortex (RSC), often subsumed under the PCC, is an area functionally and microanatomically distinct from PCC. To investigate FC patterns of RSC and PCC separately, we used resting-state functional magnetic resonance imaging in healthy aging participants, patients with subjective cognitive impairment, and prodromal AD. Compared to the other 2 groups, we found higher FC from RSC to frontal cortex in subjective cognitive impairment but higher FC to occipital cortex in prodromal AD. Conversely, FC from PCC to the lingual gyrus was higher in prodromal AD. Furthermore, data indicate that RSC and PCC are characterized by differential FC patterns represented by hub-specific interactions with memory and attentions scores in prodromal AD compared to cognitively normal individuals, possibly reflecting compensatory mechanisms for RSC and neurodegenerative processes for PCC. Data thus confirm and extend previous studies suggesting that the RSC is functionally distinct from PCC. [ABSTRACT FROM AUTHOR]

Direct vagus nerve stimulation (dVNS) is known to improve mood, epilepsy, and memory. Memory improvements have been observed in Alzheimer's disease patients after long-term stimulation. The potential of transcutaneous vagus nerve stimulation (tVNS), a noninvasive alternative to dVNS, to alter memory performance remains unknown. We aimed to investigate the effect of a single-session tVNS on associative memory performance in healthy older individuals. To investigate this, we performed a single-blind sham-controlled randomized crossover pilot study in healthy older individuals ( n = 30, 50% female). During the stimulation or sham condition, participants performed an associative face-name memory task. tVNS enhanced the number of hits of the memory task, compared with the sham condition. This effect was specific to the experimental task. Participants reported few side effects. We conclude that tVNS is a promising neuromodulatory technique to improve associative memory performance in older individuals, even after a single session. More research is necessary to investigate its underlying neural mechanisms, the impact of varying stimulation parameters, and its applicability in patients with cognitive decline. [ABSTRACT FROM AUTHOR]

Neuropathology suggests an important role for the locus coeruleus (LC) in Alzheimer's disease (AD) pathophysiology. Neuropathology and structural damage in the LC appears to be one of the earliest changes. We hypothesize that reduced functional integration of the LC reflected by lower brain functional connectivity contributes to early memory dysfunction. To test this, we examined resting-state functional connectivity from the LC in 18 healthy older individuals and 18 mildly cognitively impaired patients with possible AD. Connectivity measures were correlated with memory scores. The left LC showed strong connectivity to the left parahippocampal gyrus that correlated with memory performance in healthy persons. This connectivity was reduced in aMCI patients. Lateralization of connectivity-memory correlations was altered in less impaired aMCI patients: greater right LC-left parahippocampal gyrus connectivity was associated with better memory performance, in particular for encoding. Our results provide new evidence that the LC, in interaction with the parahippocampal gyrus, may contribute to episodic memory formation. They suggest functional impairment and the possibility that associated compensatory changes contribute to preserved memory functions in early AD. Structural and functional LC-related measures may provide early AD markers. [ABSTRACT FROM AUTHOR]

Highlights: [•] We compare findings of frontoparietal activation across four cognitive functions. [•] We argue that this activation partly reflects internal attention processes. [•] Task-specific frontoparietal activations are related to internal representations. [•] We develop a neural model of cognitive functions emerging from internal attention. [Copyright &y& Elsevier]

Highlights: [•] Current biomarkers lack sensitivity in the earliest stage of Alzheimer's disease. [•] The symptomatology of Alzheimer's disease is suggestive for neural network disruption. [•] Functional MRI has the potential to map whole-brain network alterations. [•] This meta-analysis showed robust network changes in two important neural hubs. [•] Compensation in precuneus and subcortical areas are evident before cognitive deficits. [Copyright &y& Elsevier]

Abstract: Atrophy of the medial temporal lobe, especially the hippocampus and the parahippocampal gyrus, is considered to be the most predictive structural brain biomarker for Alzheimer''s Dementia (AD). However, recent neuroimaging studies reported a possible mismatch between structural and metabolic findings, showing medial temporal lobe atrophy and medial parietal hypoperfusion as biomarkers for AD. The role of the parietal lobe in the development of AD is only recently beginning to attract attention. The current review discusses parietal lobe involvement in the early stages of AD, viz. mild cognitive impairment, as reported from structural, functional, perfusion and metabolic neuroimaging studies. The medial and posterior parts of the parietal lobe seem to be preferentially affected, compared to the other parietal lobe parts. On the basis of the reviewed literature we propose a model showing the relationship between the various pathological events, as measured by different neuroimaging techniques, in the development of AD. In this model myelin breakdown is a beginning of the chain of pathological events leading to AD pathology and an AD diagnosis. [Copyright &y& Elsevier]

Five decades ago, seminal studies positioned the brainstem locus coeruleus (LC) norepinephrine (NE) system as a key substrate for the regulation of wakefulness and sleep, and this picture has recently been elaborated thanks to methodological advances in the precise investigation and experimental modulation of LC structure and functions. This review presents and discusses findings that support the major role of the LC-NE system at different levels of sleep-wake organization, ranging from its involvement in the overall architecture of the sleep-wake cycle to its associations with sleep microstructure, while accounting for the intricate neuroanatomy surrounding the LC. Given the particular position held by the LC-NE system by being at the intersection of sleep-wake dysregulation and initial pathophysiological processes of Alzheimer's disease (AD), we conclude by examining emerging opportunities to investigate LC-NE mediated relationships between sleep-wake alteration and AD in human aging. We further propose several research perspectives that could support the LC-NE system as a promising target for the identification of at-risk individuals in the preclinical stages of AD, and for the development of novel preventive interventions. [ABSTRACT FROM AUTHOR]

Abstract: White matter hyperintensities (WMH) in Mild Cognitive Impairment (MCI) have been associated with impaired executive functioning, although contradictory findings have been reported. The aim of this study was to examine whether WMH location influenced the relation between WMH and executive functioning in MCI participants (55–90 years) in the European multicenter memory-clinic-based DESCRIPA study, who underwent MRI scanning at baseline (N = 337). Linear mixed model analysis was performed to test the association between WMH damage in three networks (frontal-parietal, frontal-subcortical and frontal-parietal-subcortical network) and change in executive functioning over a 3-year period. WMH in the frontal-parietal and in the frontal-parietal-subcortical network were associated with decline in executive functioning. However, the frontal-subcortical network was not associated with change in executive functioning. Our results suggest that parietal WMH are a significant contributor to executive decline in MCI and that investigation of WMH in the cerebral networks supporting cognitive functions provide a new way to differentiate stable from cognitive declining MCI individuals. [Copyright &y& Elsevier]

Abstract: The parietal cortex of the human brain plays a unique role in the coordination of movement and in the integration of signals from the other cortices. Because of its extensive connections and involvement in many higher-order cognitive functions, neurodegenerative changes in the parietal lobe are believed to be crucial in the early symptoms of Alzheimer''s disease (AD). Little is known about the transcriptome of this part of the human brain or how it is perturbed by the neurodegenerative process. To that end, we performed mRNA sequencing using the Illumina RNA-Seq technique on samples derived from normal and AD parietal lobes. Gene expression analysis evaluating alternatively spliced isoform expression and promoter usage revealed surprisingly elevated transcriptome activity in the AD condition. This phenomenon was particularly apparent in the alternative usage of transcriptional start sites. A Gene Ontology analysis of the differentially expressed genes revealed enrichment in the functional pathways related to lipid metabolism, thus highlighting the importance of astrocyte activity in the neurodegenerative process. We also identified an upregulation of the diazepam-binding inhibitor (DBI) gene in AD, as the result of a splicing switch toward shorter, intron-retaining isoforms driven by alternative promoters and was coupled with a simultaneous decrease in the abundance of protein-coding transcripts. These two DBI isoforms have not been described previously. [Copyright &y& Elsevier]

The vascular and neurodegenerative processes related to clinical dementia cause cell loss which induces, amongst others, an increase in interstitial fluid (ISF). We assessed microvascular, parenchymal integrity, and a proxy of ISF volume alterations with intravoxel incoherent motion imaging in 21 healthy controls and 53 memory clinic patients – mainly affected by neurodegeneration (mild cognitive impairment, Alzheimer's disease dementia), vascular pathology (vascular cognitive impairment), and presumed to be without significant pathology (subjective cognitive decline). The microstructural components were quantified with spectral analysis using a non-negative least squares method. Linear regression was employed to investigate associations of these components with hippocampal and white matter hyperintensity (WMH) volumes. In the normal appearing white matter, a large f int (a proxy of ISF volume) was associated with a large WMH volume and low hippocampal volume. Likewise, a large f int value was associated with a lower hippocampal volume in the hippocampi. Large ISF volume (f int) was shown to be a prominent factor associated with both WMHs and neurodegenerative abnormalities in memory clinic patients and is argued to play a potential role in impaired glymphatic functioning. [ABSTRACT FROM AUTHOR]

• No evidence of incipient neurodegeneration in subjective cognitive decline. • Subjective memory complaints are linked to greater amygdala gray matter density. • Subjective cognitive decline is associated with sub-clinical depression. The neural correlates of subjective cognitive decline (SCD; i.e., without objectifiable deficit) remain to be elucidated. Possible causes of SCD include early neurodegeneration related to Alzheimer's disease or functional and structural changes related to sub-clinical depression. We investigated the relationship between episodic memory performance or memory complaints and structural or functional magnetic resonance imaging (MRI) measures in participants with SCD (n =18) but without psychiatric disorders and healthy controls (n =31). In SCD, memory complaints were not associated with memory performance but with sub-clinical depression and executive functions. SCD-associated memory complaints correlated with higher amygdala and parahippocampal gyrus (specifically subiculum) gray matter density. In controls, but not in SCD, mesiotemporal gray matter density and superior frontal gyrus functional connectivity predicted memory performance. In contrast, in SCD, only a trend toward a correlation between memory performance and gray matter density in the parietooccipital lobes was observed. In our memory-clinic sample of SCD, we did not observe incipient neurodegeneration (limited to structural and functional MRI) but rather sub-clinical depression underlying subjective cognitive complaints. [ABSTRACT FROM AUTHOR]

• Noradrenaline turnover and cortical thickness are related at high biomarker levels. • This noradrenaline turnover and thickness relation occurs at subthreshold amyloid. • Locus coeruleus function may be an indicator of Alzheimer-related brain morphology. Advanced Alzheimer's disease (AD) is characterized by higher noradrenaline metabolite levels that may be associated with AD pathology. The locus coeruleus (LC) is the main site for cerebral noradrenaline synthesis and LC volume loss occurs as early as Braak stage 1. This study investigates the association between noradrenergic turnover and brain morphology, and the modifying effect of AD pathology. The study sample included 77 memory clinic patients (37 cognitively unimpaired and 40 cognitively impaired (mild cognitive impairment or AD dementia)). Cortical thickness and volumetric analyses were performed using FreeSurfer. Cerebrospinal fluid was analyzed for noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), Aβ42 and phosphorylated tau. Higher MHPG was associated with lower cortical thickness and hippocampal volume at lower, but subthreshold, levels of Aβ42 and at higher p-tau levels. These associations remained significant after adding APOE-E4 or cognitive status as covariates. Our results suggest that greater MHPG together with worse AD pathology contributes to neurodegeneration, possibly before significant amyloidosis. The noradrenergic system may play an important role in early detection of AD-related processes. [ABSTRACT FROM AUTHOR]

Previous studies have shown that arousal can influence hemispatial bias, suggesting that changes in arousal affect the neural networks involved in spatial attention control. The goal of the present study was to measure the effects of increased arousal on endogenous attentional orienting. We used a Spatial Orienting Paradigm to quantify attentional benefits and costs as measures of attentional orienting and re-orienting responses and exposed participants (N = 25; Experiment 1) to a bilateral feet Cold Pressor Test (CPT) to manipulate arousal. Increases in subjective distress ratings and blood pressure confirmed the effect of CPT on arousal. Although no overall effects of CPT on reaction times in the Spatial Orienting Paradigm were detected, an exploratory analysis of sex-specific effects revealed a left-lateralised decrease in benefits and increase in costs after CPT exposure in the male subsample (N = 11). To confirm these preliminary results, we repeated the experiment in a larger sample (N = 29, all male), but found no effect of CPT on orienting, with moderate to strong evidence in favour of a model excluding all (interaction) effects of CPT exposure (all BF Incl < 0.3). Instead, our replicated results indicate that voluntary orienting is unaffected by CPT-induced increases of arousal. In the light of previous studies, and keeping in mind the interpretative challenges of null results, we discuss how and why our findings may be specific to endogenous as opposed to exogenous orienting and how arousal could possibly lead to the previously established effects on visuospatial bias without simultaneously affecting orienting and the underlying attention control networks. • We investigated the effects of arousal on endogenous orienting of spatial attention. • A bilateral feet Cold Pressor Test (CPT) successfully manipulated arousal. • Exploratory analyses revealed left-lateralised effects that could not be replicated. • Bayesian analyses indicate that endogenous attention and arousal do not interact. [ABSTRACT FROM AUTHOR]

The APOE- ε4 genotype is a risk factor for late-onset Alzheimer's disease (AD) as well as vascular pathology. Given the increased risk of blood-brain barrier (BBB) dysfunction and inflammation among APOE- ε4 carriers, we aimed to examine whether BBB dysfunction and inflammation contribute to the relationship between APOE and AD key pathologies, as measured in the cerebrospinal fluid (CSF). We applied bootstrapped regression and path analyses involving Q-albumin CSF/plasma ratio (a BBB/blood-CSF barrier function marker), interleukins (IL-1β, IL-6, and IL-12p70; inflammation markers), and CSF p-Tau 181 and amyloid-β 1−42 (AD pathology markers) of 97 participants (aged 38–83 years) from a university memory clinic. Our results showed that relationship between BBB dysfunction and AD pathology is modulated by IL-6 and these associations appear to be driven by the APOE-ε4 genotype. This suggests that APOE-ε4-related vascular factors are also part of the pathway to AD pathology, in synergy with an elevated immune response, and could become targets for trials focused on delaying AD. • APOE- ε4 is a risk factor for late-onset Alzheimer's disease and vascular pathology. • Relation between blood-brain barrier dysfunction and Alzheimer's pathology. • Blood-brain/CSF barrier dysfunction and vascular are intertwined. • This relation appears to be driven by the APOE- ε4 status and modulated by IL-6. • APOE- ε4 and inflammation joined with vascular factors possible pathway to AD pathology. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairment is a common non-motor symptom in Parkinson's disease. So far, the underlying pathophysiology remains unclear. Several alterations in functional network connectivity have been described in Parkinson's disease patients with cognitive impairment which are probably the result of the heterogenous pathophysiology underlying this cognitive decline, including dopaminergic and cholinergic deficits. Accordingly, the reported resting-state connectivity patterns vary greatly among studies.Objective: To evaluate the localization and magnitude of functional connectivity patterns in resting-state brain networks in Parkinson's disease patients with cognitive impairment by pooling data from available studies.Methods: We searched PubMed, the Cochrane Library, MEDLINE, Embase and PsycINFO to identify functional MRI studies in Parkinson's disease patients with cognitive impairment. A voxel-based meta-analysis combined with quality statistics was performed, using the anisotropic effect-size version of the signed differential mapping method.Results: Seventeen studies with cognitively impaired Parkinson's disease patients were included consisting of 222 Parkinson's disease patients with mild cognitive impairment, 68 patients with Parkinson's disease dementia, 289 cognitively unimpaired Parkinson's disease patients and 353 healthy controls. Parkinson's disease patients with cognitive impairment predominantly showed a reduced connectivity in specific brain regions that are part of the default mode network.Conclusion: Cognitive impairment in Parkinson's disease is associated with reduced connectivity in networks relevant to cognition, most prominently the default mode network. Specific alterations in functional connectivity may contribute to cognitive decline in Parkinson patients and may be a promising future biomarker. [ABSTRACT FROM AUTHOR]

The underlying pathology of white matter signal abnormalities (WMSAs) is heterogeneous and may vary dependent on the magnetic resonance imaging contrast used to define them. We investigated differences in white matter diffusivity as an indicator for white matter integrity underlying WMSA based on T1-weighted and fluid-attenuated inversion recovery (FLAIR) imaging contrast. In addition, we investigated which white matter region of interest (ROI) could predict clinical diagnosis best using diffusion metrics. One hundred three older individuals with varying cognitive impairment levels were included and underwent neuroimaging. Diffusion metrics were extracted from WMSA areas based on T1 and FLAIR contrast and from their overlapping areas, the border surrounding the WMSA and the normal-appearing white matter (NAWM). Regional diffusivity differences were calculated with linear mixed effects models. Multinomial logistic regression determined which ROI diffusion values classified individuals best into clinically defined diagnostic groups. T1-based WMSA showed lower white matter integrity compared to FLAIR WMSA-defined regions. Diffusion values of NAWM predicted diagnostic group best compared to other ROI's. To conclude, T1- or FLAIR-defined WMSA provides distinct information on the underlying white matter integrity associated with cognitive decline. Importantly, not the “diseased” but the NAWM is a potentially sensitive indicator for cognitive brain health status. [ABSTRACT FROM AUTHOR]

Background Age-related memory decline has been well-documented; however, some individuals reach their 8th−10th decade while maintaining strong memory performance. Objective To determine which demographic and biomarker factors differentiated top memory performers (aged 75+, top 20% for memory) from their peers and whether top memory performance was maintained over 3 years. Methods Clinically normal adults (n=125, CDR=0; age: 79.5±3.57 years) from the Harvard Aging Brain Study underwent cognitive testing and neuroimaging (amyloid PET, MRI) at baseline and 3-year follow-up. Participants were grouped into Optimal (n=25) vs. Typical (n=100) performers using performance on 3 challenging memory measures. Non-parametric tests were used to compare groups. Results There were no differences in age, sex, or education between Optimal vs. Typical performers. The Optimal group performed better in Processing Speed (p=0.016) and Executive Functioning (p<0.001). Optimal performers had larger hippocampal volumes at baseline compared with Typical Performers (p=0.027) but no differences in amyloid burden (p=0.442). Twenty-three of the 25 Optimal performers had longitudinal data and16 maintained top memory performance while 7 declined. Non-Maintainers additionally declined in Executive Functioning but not Processing Speed. Longitudinally, there were no hippocampal volume differences between Maintainers and Non-Maintainers, however Non-Maintainers exhibited higher amyloid burden at baseline in contrast with Maintainers (p=0.008). Conclusions Excellent memory performance in late life does not guarantee protection against cognitive decline. Those who maintain an optimal memory into the 8th and 9th decades may have lower levels of AD pathology. [ABSTRACT FROM AUTHOR]

Primary prevention trials have shifted their focus to the earliest stages of Alzheimer's disease (AD). Autopsy data indicates that the neuromodulatory subcortical systems' (NSS) nuclei are specifically vulnerable to initial tau pathology, indicating that these nuclei hold great promise for early detection of AD in the context of the aging brain. The increasing availability of new imaging methods, ultra-high field scanners, new radioligands, and routine deep brain stimulation implants has led to a growing number of NSS neuroimaging studies on aging and neurodegeneration. Here, we review findings of current state-of-the-art imaging studies assessing the structure, function, and molecular changes of these nuclei during aging and AD. Furthermore, we identify the challenges associated with these imaging methods, important pathophysiologic gaps to fill for the AD NSS neuroimaging field, and provide future directions to improve our assessment, understanding, and clinical use of in vivo imaging of the NSS. • Structural and functional alterations of NSS predict AD-related phenotypes. • Multimodal examination of NSS provides complementary information on AD pathogenesis. • Post-mortem validation is crucial for accurate in vivo localization of NSS in humans. • In vivo NSS measurements are essential for early detection and treatment of AD. [ABSTRACT FROM AUTHOR]

In fact, only 7 studies included patients with PDD and those patient groups were separately analysed from PD-MCI in only 5 experiments. In addition, 11 studies that compared healthy controls (HC) with PD patients with cognitive impairment (PD-CI) have performed the fMRI while ON medication and 3 experiments carried out the fMRI while OFF medication. [Extracted from the article]