Predicting time to dementia using a quantitative template of disease progression

Bilgel, Murat; Jedynak, Bruno

doi:10.1016/j.dadm.2019.01.005

Cited by 33 publications

(41 citation statements)

References 42 publications

(68 reference statements)

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“…More than a decade after the first signs of memory dys- function, brain hypometabolism develops, accompanied by abnormal changes in total and phosphorylated tau proteins levels [ 62 ]. These conclusions are consistent with the study of predicting time to dementia in AD patients participating in the Neuroimaging Initiative that reported early changes in verbal memory, CSF Aβ1–42, and hippocampal volume [ 63 ]. Therefore, early diagnosis and treatment at the asymptomatic phase of AD seems to be vital and can be assisted by a personalised prediction of the AD progression timeline [ 64 ].…”

Section: Discussionsupporting

confidence: 91%

Nanotechnology Therapy for Alzheimer′s Disease Memory Impairment Attenuation

Ribarič

2021

IJMS

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Currently, there is no cure for Alzheimer’s disease (AD) in humans; treatment is symptomatic only. Aging of the population, together with an unhealthy diet and lifestyle, contribute to the steady, global increase of AD patients. This increase creates significant health, societal and economical challenges even for the most developed countries. AD progresses from an asymptomatic stage to a progressively worsening cognitive impairment. The AD cognitive impairment is underpinned by progressive memory impairment, an increasing inability to recall recent events, to execute recently planned actions, and to learn. These changes prevent the AD patient from leading an independent and fulfilling life. Nanotechnology (NT) enables a new, alternative pathway for development of AD treatment interventions. At present, the NT treatments for attenuation of AD memory impairment are at the animal model stage. Over the past four years, there has been a steady increase in publications of AD animal models with a wide variety of original NT treatment interventions, able to attenuate memory impairment. NT therapy development, in animal models of AD, is faced with the twin challenges of the nature of AD, a chronic impairment, unique to human, of the tau protein and A β peptides that regulate several key physiological brain processes, and the incomplete understanding of AD′s aetiology. This paper reviews the state-of-the-art in NT based treatments for AD memory impairment in animal models and discusses the future work for translation to the successful treatment of AD cognitive impairment in human.

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Section: Discussionsupporting

confidence: 91%

Nanotechnology Therapy for Alzheimer′s Disease Memory Impairment Attenuation

Ribarič

2021

IJMS

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“…This may imply a link between memory deficits and elevated amyloid deposition, a view that is supported by previous reports [2,[58][59][60][61]. The value of episodic memory tests, and associations of changes in the performance in delayed recall tasks and the clinical progression to ADem, has also been observed and discussed in previous studies [2,9,10,[62][63][64][65]. However, it should be noted that such markers may not be sufficient for the improvement of participant recruitment and endpoint choice in very early-stage prevention trials.…”

Section: Discussionmentioning

confidence: 57%

“…In the common form of sporadic AD, estimating the time required to reach a disease state is more challenging [8]. Techniques that have been employed for the prediction of the dynamics of biomarkers include the synchronisation of individual data based on a disease progression score, which can be a function of the individual's age [9,10], and the optimal alignment of individuals' biomarker trajectories with the estimated long-term population-level trajectory [11,12]. Time-dependent changes of potential biomarkers have also been characterised on different scales of disease progression based on the individual biomarker rate of change as estimated from the short-term longitudinal observations [2,[13][14][15].…”

Section: Introductionmentioning

confidence: 99%

The dynamics of biomarkers across the clinical spectrum of Alzheimer’s disease

et al. 2020

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Background: Quantifying changes in the levels of biological and cognitive markers prior to the clinical presentation of Alzheimer's disease (AD) will provide a template for understanding the underlying aetiology of the clinical syndrome and, concomitantly, for improving early diagnosis, clinical trial recruitment and treatment assessment. This study aims to characterise continuous changes of such markers and determine their rate of change and temporal order throughout the AD continuum. Methods: The methodology is founded on the development of stochastic models to estimate the expected time to reach different clinical disease states, for different risk groups, and synchronise short-term individual biomarker data onto a disease progression timeline. Twenty-seven markers are considered, including a range of cognitive scores, cerebrospinal (CSF) and plasma fluid proteins, and brain structural and molecular imaging measures. Data from 2014 participants in the Alzheimer's Disease Neuroimaging Initiative database is utilised. Results: The model suggests that detectable memory dysfunction could occur up to three decades prior to the onset of dementia due to AD (ADem). This is closely followed by changes in amyloid-β CSF levels and the first cognitive decline, as assessed by sensitive measures. Hippocampal atrophy could be observed as early as the initial amyloid-β accumulation. Brain hypometabolism starts later, about 14 years before onset, along with changes in the levels of total and phosphorylated tau proteins. Loss of functional abilities occurs rapidly around ADem onset. Neurofilament light is the only protein with notable early changes in plasma levels. The rate of change varies, with CSF, memory, amyloid PET and brain structural measures exhibiting the highest rate before the onset of ADem, followed by a decline. The probability of progressing to a more severe clinical state increases almost exponentially with age. In accordance with previous studies, the presence of apolipoprotein E4 alleles and amyloid-β accumulation can be associated with an increased risk of developing the disease, but their influence depends on age and clinical state. Conclusions: Despite the limited longitudinal data at the individual level and the high variability observed in such data, the study elucidates the link between the long asynchronous pathophysiological processes and the preclinical and clinical stages of AD.

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“…A recent review of mathematical models in neurodegenerative diseases reports several mathematical models involving some of the processes we addressed above, such as energy metabolism and synaptic plasticity (Lloret-Villas et al, 2017). A multivariate Bayesian model of biomarker measurements was used to estimate AD dementia onset age (Bilgel and Jedynak, 2019). Similarly, multivariate models have been used to relate image based morphological features to the risk of dementia (Gutierrez Becker et al, 2018; Cole et al, 2019).…”

Section: From Consequences To Causes: Academic and Preclinical Considmentioning

confidence: 99%

Re-thinking the Etiological Framework of Neurodegeneration

et al. 2019

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Castillo et al. Neurodegeneration Revisited cognitive impairment, dementia, and cerebrovascular events such as stroke. Second, we suggest that the persistence of senescent cells in neuronal circuits may favor, together with systemic metabolic diseases, neurodegeneration to occur. Third, we argue that neurodegeneration may start in response to altered body and brain trophic interactions established via the hardwire that connects peripheral targets with central neuronal structures or by means of extracellular vesicle (EV)-mediated communication. Lastly, we elaborate on how lifespan body dysbiosis may be linked to the origin of neurodegeneration. We highlight the existence of bacterial products that modulate the gut-brain axis causing neuroinflammation and neuronal dysfunction. As a concluding section, we end by recommending research avenues to investigate these etiological paths in the future. We think that this requires an integrated, interdisciplinary conceptual research approach based on the investigation of the multimodal aspects of physiology and pathophysiology. It involves utilizing proper conceptual models, experimental animal units, and identifying currently unused opportunities derived from human data. Overall, the proposed etiological paths and experimental recommendations will be important guidelines for future cross-discipline research to overcome the translational roadblock and to develop causative treatments for neurodegenerative diseases.

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Predicting time to dementia using a quantitative template of disease progression

Cited by 33 publications

References 42 publications

Nanotechnology Therapy for Alzheimer′s Disease Memory Impairment Attenuation

Nanotechnology Therapy for Alzheimer′s Disease Memory Impairment Attenuation

The dynamics of biomarkers across the clinical spectrum of Alzheimer’s disease

Re-thinking the Etiological Framework of Neurodegeneration

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