Understanding Alzheimer's disease as a disorder of consciousness

Huntley, Jonathan; Fleming, Stephen M.; Mograbi, Daniel C.; Bor, Daniel; Naçi, Lorina; Owen, Adrian M.; Howard, Robert

doi:10.1002/trc2.12203

Cited by 22 publications

(37 citation statements)

References 111 publications

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“…Moreover, the relationship between fNIRS and pupillometry data merits further investigation vis-à-vis arousal mechanisms. Arousal mechanisms have broad implications for the bedside neuromonitoring of disorders of consciousness [ 77 ], including Alzheimer’s disease [ 78 ], where monitoring of the neurovascular coupling [ 3 ] and pupil dilation [ 1 , 2 ] may be feasible. For bedside neuromonitoring, an important aspect is the neurometabolic state of the brain, which is partially regulated by tonic and phasic norepinephrine activity [ 79 ].…”

Section: Discussionmentioning

confidence: 99%

Human-in-the-Loop Optimization of Transcranial Electrical Stimulation at the Point of Care: A Computational Perspective

Arora

Dutta

2022

Brain Sciences

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Individual differences in the responsiveness of the brain to transcranial electrical stimulation (tES) are increasingly demonstrated by the large variability in the effects of tES. Anatomically detailed computational brain models have been developed to address this variability; however, static brain models are not “realistic” in accounting for the dynamic state of the brain. Therefore, human-in-the-loop optimization at the point of care is proposed in this perspective article based on systems analysis of the neurovascular effects of tES. First, modal analysis was conducted using a physiologically detailed neurovascular model that found stable modes in the 0 Hz to 0.05 Hz range for the pathway for vessel response through the smooth muscle cells, measured with functional near-infrared spectroscopy (fNIRS). During tES, the transient sensations can have arousal effects on the hemodynamics, so we present a healthy case series for black-box modeling of fNIRS–pupillometry of short-duration tDCS effects. The block exogeneity test rejected the claim that tDCS is not a one-step Granger cause of the fNIRS total hemoglobin changes (HbT) and pupil dilation changes (p < 0.05). Moreover, grey-box modeling using fNIRS of the tDCS effects in chronic stroke showed the HbT response to be significantly different (paired-samples t-test, p < 0.05) between the ipsilesional and contralesional hemispheres for primary motor cortex tDCS and cerebellar tDCS, which was subserved by the smooth muscle cells. Here, our opinion is that various physiological pathways subserving the effects of tES can lead to state–trait variability, which can be challenging for clinical translation. Therefore, we conducted a case study on human-in-the-loop optimization using our reduced-dimensions model and a stochastic, derivative-free covariance matrix adaptation evolution strategy. We conclude from our computational analysis that human-in-the-loop optimization of the effects of tES at the point of care merits investigation in future studies for reducing inter-subject and intra-subject variability in neuromodulation.

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Section: Discussionmentioning

confidence: 99%

Human-in-the-Loop Optimization of Transcranial Electrical Stimulation at the Point of Care: A Computational Perspective

Arora

Dutta

2022

Brain Sciences

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“…A self-experienced decline in cognitive capacity, especially in the memory domain, is an important clinical feature in Alzheimer’s disease (AD), amnestic mild cognitive impairment (aMCI), and subjective cognitive decline (SCD) ( Albert et al, 2011 ; Jessen’s et al, 2014 ). The capacity to accurately assess one’s cognitive states or memory state (metacognition or metamemory) can be impaired in AD and those deficits may become more pronounced as the disease progresses ( Starkstein, 2014 ; Castrillo et al, 2016 ; Steward et al, 2020 ; Huntley et al, 2021 ). Impaired metamemory capacity may portend a preclinical stage of progressive disease and reflect the first effects of AD pathology ( Jessen’s et al, 2014 ; Hanseeuw et al, 2020 ), such as amyloid-beta (Aβ) burden ( Vannini et al, 2017 ; Hanseeuw et al, 2020 ) and tauopathy ( Vannini et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…About 71–93% of patients with AD dementia were observed with metacognition impairment ( Starkstein, 2014 ; Castrillo et al, 2016 ; Steward et al, 2020 ; Huntley et al, 2021 ). Metamemory is described as lacking insight or awareness of their own cognitive and functional impairments in the memory domain ( Souchay, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

“…The deficit of metamemory in AD dementia may indicate damage to a personal database or memory storage with the recent information ( Stewart et al, 2010 ; Gagliardi and Vannini, 2022 ). Previous studies have generally demonstrated impaired metamemory capacity in MCI or mild AD, with patients tending to overestimate their episodic memory performance ( Stewart et al, 2010 ; Dodson et al, 2011 ; Huntley et al, 2021 ). Specifically, a general tendency was reported by Fragkiadaki et al (2016) demonstrating that the overestimation of neuropsychological performance was observed in individuals with aMCI, and underestimation of performance was observed in a group of healthy elderly.…”

Section: Introductionmentioning

confidence: 99%

“…The key regions of neural substrates in the brain associated with metacognition are located in the midline structures, such as the medial prefrontal cortex (mPFC) ( Lak et al, 2014 ; Steward et al, 2019b ; Hallam et al, 2020 ; Huntley et al, 2021 ), medial temporal lobe (MTL) regions ( Hu et al, 2017 ; Hallam et al, 2020 ; Huntley et al, 2021 ), anterior cingulate cortex (ACC), and posterior cingulate cortex (PCC) regions ( Fleming and Dolan, 2012 ; Steward et al, 2019b ; D’Oleire Uquillas et al, 2020 ; Hallam et al, 2020 ; Huntley et al, 2021 ), which correlated with the functional connection between self-related (i.e., the mPFC, orbitofrontal) and memory-related (i.e., MTL) networks. Previous studies have consistently demonstrated that decreased gray matter volume in the MTL, such as the hippocampus and parahippocampus ( Genon et al, 2016 ; Vannini et al, 2019 ), prefrontal cortex ( Bertrand et al, 2018 ), and ACC and PCC ( Guerrier et al, 2018 ; Vannini et al, 2019 ; Hallam et al, 2020 ) were associated with impaired metamemory performance in patients with AD dementia and MCI.…”

Section: Introductionmentioning

confidence: 99%

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Altered metamemory precedes cognitive impairment in subjective cognitive decline with positive amyloid-beta

Pan

Huang

et al. 2022

Front. Aging Neurosci.

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Subjective cognitive decline (SCD) as an indicator of preclinical Alzheimer’s disease (AD) may precede mild cognitive impairment (MCI) over several decades. Self-reported cognitive decline as a typical clinical manifestation is critical in preclinical AD. Metacognition represents a person’s ability to accurately assess cognition. Our study aimed to examine (1) the alternations of metamemory in a cohort across the Alzheimer’s continuum, (2) the association between metamemory and cognition, and (3) the relationship of cortical thickness in four regions of interest (ROI) with metamemory scores. Six hundred ninety-seven participants were classified as 79 AD dementia, 161 aMCI, 261 SCD, and 196 cognitively unimpaired (CU) individuals, in which 418 participants aged above 65, 131 participants with Aβ+ after receiving positron emission tomography, and 602 participants received sMRI. The degree of confidence (DOC) was measured by calculating discrepancies between judgments and memory performance. We assessed the relationships between DOC tertiles and cognition and analyzed the screening power, then investigated the partial correlation between DOC and ROIs, controlled by age, sex, and cognition. In the Aβ+ subgroup, SCD showed significantly higher DOC scores than the CU group. There was an increasing trend of overconfidence with the decline of cognition across the AD spectrum (P for trend < 0.001). After adjusting for age, sex, and education, the lower degree of confidence-long-term delay recall (DOC-LD) tertiles were associated with lower odds ratio in SCD, aMCI, and AD in the Aβ+ subgroup (all P for trend < 0.05). The area under the curves of DOC scores for screening SCD from CU in the Aβ+ subgroup was better than that in all participants and the age ≥65 subgroup. Partial correlation showed that in the Aβ+ subgroup, DOC-SD (degree of confidence-short-term delay recall) was negatively correlated with the anterior cingulate cortex; DOC-LD was negatively correlated with the cortices of parahippocampal, anterior cingulate, posterior cingulate, and medial orbitofrontal. In individuals with Aβ+, SCD exhibited a detectable metamemory alternation before objective cognitive impairment could be tested, indicated by the overestimation in the memory performance. The pattern of an increasing trend of overconfidence across SCD, aMCI, and AD dementia supports the view of a continuum in Alzheimer’s disease.

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Neural markers of reduced arousal and consciousness in mild cognitive impairment

Estarellas,

Huntley,

Bor

2024

Int J Geriat Psychiatry

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ObjectivesPeople with Alzheimer's Disease (AD) experience changes in their level and content of consciousness, but there is little research on biomarkers of consciousness in pre‐clinical AD and Mild Cognitive Impairment (MCI). This study investigated whether levels of consciousness are decreased in people with MCI.MethodsA multi‐site site magnetoencephalography (MEG) dataset, BIOFIND, comprising 83 people with MCI and 83 age matched controls, was analysed. Arousal (and drowsiness) was assessed by computing the theta‐alpha ratio (TAR). The Lempel‐Ziv algorithm (LZ) was used to quantify the information content of brain activity, with higher LZ values indicating greater complexity and potentially a higher level of consciousness.ResultsLZ was lower in the MCI group versus controls, indicating a reduced level of consciousness in MCI. TAR was higher in the MCI group versus controls, indicating a reduced level of arousal (i.e. increased drowsiness) in MCI. LZ was also found to be correlated with mini‐mental state examination (MMSE) scores, suggesting an association between cognitive impairment and level of consciousness in people with MCI.ConclusionsA decline in consciousness and arousal can be seen in MCI. As cognitive impairment worsens, measured by MMSE scores, levels of consciousness and arousal decrease. These findings highlight how monitoring consciousness using biomarkers could help understand and manage impairments found at the preclinical stages of AD. Further research is needed to explore markers of consciousness between people who progress from MCI to dementia and those who do not, and in people with moderate and severe AD, to promote person‐centred care.

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Understanding Alzheimer's disease as a disorder of consciousness

Cited by 22 publications

References 111 publications

Human-in-the-Loop Optimization of Transcranial Electrical Stimulation at the Point of Care: A Computational Perspective

Human-in-the-Loop Optimization of Transcranial Electrical Stimulation at the Point of Care: A Computational Perspective

Altered metamemory precedes cognitive impairment in subjective cognitive decline with positive amyloid-beta

Neural markers of reduced arousal and consciousness in mild cognitive impairment

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