Neuronal dysfunction and cognitive deterioration in Alzheimer's disease (AD) are likely caused by multiple pathophysiological factors. However, mechanistic evidence in humans remains scarce, ...requiring improved non-invasive techniques and integrative models. We introduce personalized AD computational models built on whole-brain Wilson-Cowan oscillators and incorporating resting-state functional MRI, amyloid-β (Aβ) and tau-PET from 132 individuals in the AD spectrum to evaluate the direct impact of toxic protein deposition on neuronal activity. This subject-specific approach uncovers key patho-mechanistic interactions, including synergistic Aβ and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP) and grey matter atrophy obtained through voxel-based morphometry. Furthermore, reconstructed EEG proxy quantities show the hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Aβ-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental activation phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions.
Neuropsychiatric symptoms (NPS) are increasingly recognized as early non-cognitive manifestations in the Alzheimer's disease (AD) continuum. However, the role of NPS as an early marker of ...pathophysiological progression in AD remains unclear. Dominantly inherited AD (DIAD) mutation carriers are young individuals who are destined to develop AD in future due to the full penetrance of the genetic mutation. Hence, the study of DIAD mutation carriers enables the evaluation of the associations between pure AD pathophysiology and metabolic correlates of NPS without the confounding effects of co-existing pathologies. In this longitudinal study, we aimed to identify regional brain metabolic dysfunctions associated with NPS in cognitively intact DIAD mutation carriers.
We stratified 221 cognitively intact participants from the Dominantly Inherited Alzheimer's Network according to their mutation carrier status. The interactions of NPS measured by the Neuropsychiatric Inventory-Questionnaire (NPI-Q), age, and estimated years to symptom onset (EYO) as a function of metabolism measured by
Fflurodeoxyglucose (
FFDG) positron emission tomography, were evaluated by the mixed-effects regression model with family-level random effects in DIAD mutation carriers and non-carriers. Exploratory factor analysis was performed to identify the neuropsychiatric subsyndromes in DIAD mutation carriers using the NPI-Q sub-components. Then the effects of interactions between specific neuropsychiatric subsyndromes and EYO on metabolism were evaluated with the mixed-effects regression model.
A total of 119 mutation carriers and 102 non-carriers were studied. The interaction of higher NPI-Q and shorter EYO was associated with more rapid declines of global and regional
FFDG uptake in the posterior cingulate and ventromedial prefrontal cortices, the bilateral parietal lobes and the right insula in DIAD mutation carriers. The neuropsychiatric subsyndromes of agitation, disinhibition, irritability and depression interacted with the EYO to drive the
FFDG uptake decline in the DIAD mutation carriers. The interaction of NPI and EYO was not associated with
FFDG uptake in DIAD mutation non-carriers.
The NPS in cognitively intact DIAD mutation carriers may be a clinical indicator of subsequent metabolic decline in brain networks vulnerable to AD, which supports the emerging conceptual framework that NPS represent early manifestations of neuronal injury in AD. Further studies using different methodological approaches to identify NPS in preclinical AD are needed to validate our findings.
Background: Among a rapidly aging population, there is increased need for neuroprotective interventions promoting healthy neurological aging. Mind-body interventions, such as Kundalini yoga, are ...actively being explored as accessible means to encourage healthy aging. However, little remains known about the neurobiological effects of Kundalini yoga. Aims: This pilot randomized-controlled trial (RCT) examined the potential neuroprotective effects of Kundalini yoga in older adults. Methods: We conducted an RCT with 11 healthy meditation-naïve older adults. Participants were randomized to a Kundalini yoga or psychoeducation intervention. Structural magnetic resonance imaging data were obtained at baseline and 12-week follow-up. The primary outcome measure was gray matter volume of the bilateral hippocampi and bilateral posterior cingulate cortex. Results: We found significant right hippocampal volume increases specific to the Kundalini yoga group (P = 0.034, ηp2 = 0.408). Conclusions: These findings provide initial neurobiological support for the neuroprotective effects of Kundalini yoga.
Associations between pathophysiological events and cognitive measures provide insights regarding brain networks affected during the clinical progression of Alzheimer's disease (AD). In this study, we ...assessed patients' scores in two delayed episodic memory tests, and investigated their associations with regional amyloid deposition and brain metabolism across the clinical spectrum of AD. We assessed the clinical, neuropsychological, structural, and positron emission tomography (PET) baseline measures of participants from the Alzheimer's Disease Neuroimaging Initiative. Subjects were classified as cognitively normal (CN), or with early (EMCI) or late (LMCI) mild cognitive impairment, or AD dementia. The memory outcome measures of interest were logical memory 30 min delayed recall (LM30) and Rey Auditory Verbal Learning Test 30 min delayed recall (RAVLT30). Voxel-based
Fflorbetapir and
FFDG uptake-ratio maps were constructed and correlations between PET images and cognitive scores were calculated. We found that EMCI individuals had LM30 scores negatively correlated with
Fflorbetapir uptake on the right parieto-occipital region. LMCI individuals had LM30 scores positively associated with left lateral temporal lobe
FFDG uptake, and RAVLT30 scores positively associated with
FFDG uptake in the left parietal lobe and in the right enthorhinal cortex. Additionally, LMCI individuals had LM30 scores negatively correlated with
Fflorbetapir uptake in the right frontal lobe. For the AD group,
FFDG uptake was positively correlated with LM30 in the left temporal lobe and with RAVLT30 in the right frontal lobe, and
Fflorbetapir uptake was negatively correlated with LM30 scores in the right parietal and left frontal lobes. The results show that the association between regional brain metabolism and the severity of episodic memory deficits is dependent on the clinical disease stage, suggesting a dynamic relationship between verbal episodic memory deficits, AD pathophysiology, and clinical disease stages.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Introduction
18FAZD4694 is an amyloid beta (Aβ) imaging agent used in several observational studies and clinical trials. However, no studies have yet published data on longitudinal Aβ ...accumulation measured with 18FAZD4694.
Methods
We assessed 146 individuals who were evaluated with 18FAZD4694 at baseline and 2‐year follow‐up. We calculated annual rates of 18FAZD4694 change for clinically defined and biomarker‐defined groups
Results
Cognitively unimpaired (CU) older adults displayed subtle 18FAZD4694 standardized uptake value ratio (SUVR) accumulation over the follow‐up period. In contrast, Aβ positive CU older adults displayed higher annual 18FAZD4694 SUVR increases. 18FAZD4694 SUVR accumulation in Aβ positive mild cognitive impairment (MCI) and dementia was modest across the neocortex
Discussion
Larger increases in 18FAZD4694 SUVR were observed in CU individuals who had abnormal amyloid positron emission tomography levels at baseline. 18FAZD4694 can be used to monitor Aβ levels in therapeutic trials as well as clinical settings, particularly prior to initiating anti‐amyloid therapies.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objective
To investigate the relationship between the topography of amyloid‐β plaques, tau neurofibrillary tangles, and the overlap between the two, with cognitive dysfunction in individuals without ...dementia.
Methods
We evaluated 154 individuals who were assessed with amyloid‐β PET with 18FAZD4694, tau‐PET with 18FMK6240, structural MRI, and neuropsychological testing. We also evaluated an independent cohort of 240 individuals who were assessed with amyloid‐β PET with 18FFlorbetapir, tau‐PET with 18FFlortaucipir, structural MRI, and neuropsychological testing. Using the VoxelStats toolbox, we conducted voxel‐wise linear regressions between amyloid‐PET, tau‐PET, and their interaction with cognitive function, correcting for age, sex, and years of education.
Results
In both cohorts, we observed that tau‐PET standardized uptake value ratio in medial temporal lobes was associated with clinical dementia rating Sum of Boxes (CDR‐SoB) scores independently of local amyloid‐PET uptake (FWE corrected at p < 0.001). We also observed in both cohorts that in regions of the neocortex, associations between neocortical tau‐PET and clinical function were dependent on local amyloid‐PET (FWE corrected at p < 0.001).
Interpretation
In medial temporal brain regions, characterized by the accumulation of tau pathology in the absence of amyloid‐β, tau had direct associations with cognitive dysfunction. In brain regions characterized by the accumulation of both amyloid‐β and tau pathologies such as the posterior cingulate and medial frontal cortices, tau’s relationship with cognitive dysfunction was dependent on local amyloid‐β concentrations. Our results provide evidence that amyloid‐β in Alzheimer’s disease influences cognition by potentiating the deleterious effects of tau pathology.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Introduction
Alzheimer's disease consensus recommends biomarker dichotomization, a practice with well‐described clinical strengths and methodological limitations. Although neuroimaging studies have ...explored alternative biomarker interpretation strategies, a formally defined three‐range approach and its prognostic impact remains under‐explored for cerebrospinal fluid (CSF) biomarkers .
Methods
With two‐graph receiver‐operating characteristics based on different reference schemes, we derived three‐range cut‐points for CSF Elecsys biomarkers. According to baseline CSF status, we assessed the prognostic utility of this in predicting risk of clinical progression and longitudinal trajectories of cognitive decline and amyloid–beta (Aβ) positron emission tomography (PET) accumulation in non‐demented individuals (Alzheimer's Disease Neuroimaging Initiative ADNI; n = 1246). In all analyses, we compared herein‐derived three‐range CSF cut‐points to previously described binary ones.
Results
In our main longitudinal analyses, we highlight CSF p‐tau181/Aβ1‐42 three‐range cut‐points derived based on the cognitively normal Aβ‐PET negative versus dementia Aβ‐PET positive reference scheme for best depicting a prognostically relevant biomarker abnormality range. Longitudinally, our approach revealed a divergent intermediate cognitive trajectory undetected by dichotomization and a clearly abnormal group at higher risk for cognitive decline, with power analyses suggesting the latter group as potential trial enrichment candidates. Furthermore, we demonstrate that individuals with intermediate‐range CSF status have similar rates of Aβ deposition to those in the clearly abnormal group.
Discussion
The proposed approach can refine clinico‐biological prognostic assessment and potentially enhance trial recruitment, as it captures faster biomarker‐related cognitive decline in comparison to binary cut‐points. Although this approach has implications for trial recruitment and observational studies, further discussion is needed regarding clinical practice applications.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
This scientific commentary refers to ‘Age-related and amyloid-beta-independent tau deposition and its downstream effects’ by Wuestefeld et al. (https://doi.org/10.1093/brain/awad135).
Introduction
Abnormal brain amyloid beta (Aβ) is typically assessed in vivo using global concentrations from cerebrospinal fluid and positron emission tomography (PET). However, it is unknown whether ...the assessment of the topographical distribution of Aβ pathology can provide additional information to identify, among global Aβ positive individuals, those destined for dementia.
Methods
We studied 260 amnestic mild cognitive impairment (MCI) subjects who were Aβ‐PET positive with 18Fflorbetapir. Using 18Fflorbetapir, we assessed the percentage of voxels sowing Aβ abnormality as well as the standardized uptake value ratio (SUVR) values across brain regions. Regressions tested the predictive effect of Aβ on progression to dementia over 2 years.
Results
Neither global nor regional 18Fflorbetapir SUVR concentrations predicted progression to dementia. In contrast, the spatial extent of Aβ pathology in regions comprising the default mode network was highly associated with the development of dementia over 2 years.
Discussion
These results highlight that the regional distribution of Aβ abnormality may provide important complementary information at an individual level regarding the likelihood of Aβ positive MCI to progress to dementia.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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