A Proposed Hypothesis on Dementia: Inflammation, Small Vessel Disease, and Hypoperfusion Is the Sequence That Links All Harmful Lifestyles to Cognitive Impairment

Hakim, Antoine M.

doi:10.3389/fnagi.2021.679837

Cited by 19 publications

(17 citation statements)

References 128 publications

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“…The multifaceted physiological consequences of depression described here conform to the already outlined pattern for other recognized risks for dementia such as obesity, sedentary lifestyle and inadequate sleep ( Hakim, 2021 ). The major difference between depression and the other cognitive risk factors is the possibility of offering various therapeutic modalities to the affected individuals.…”

Section: Discussionsupporting

confidence: 76%

“…The recognition that certain risk factors increase the risk for dementia provides the possibility of reducing this burden by intensifying efforts to reduce and control the risk factors. In a recent article ( Hakim, 2021 ), a hypothesis was presented that a sequence of physiological events links dementia risk factors to their cognitive outcomes. It was proposed that in the presence of a risk factor, the sequence that leads to dementia is triggered by inflammation which leads to cerebral small vessel disease.…”

Section: Introductionmentioning

confidence: 99%

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Perspectives on the complex links between depression and dementia

Hakim

2022

Front. Aging Neurosci.

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This review highlights that depression is a growing health problem for the individual, and because of its high frequency in most societies, a growing burden on health care budgets. The focus of the review is the physiological links between depression and dementia, specifically Alzheimer’s disease. It suggests that depression is a significant risk factor for cognitive decline and explores the pathways that may lead depressed individuals to suffer this outcome. This review shows that depression and a number of its precursors activate pro-inflammatory mediators. These lead to cerebral small vessel disease with the consequent reduction in cerebral blood flow, which is known to precede cognitive decline. Thus, the impact of depression on the physiological events that lead to dementia is identical to the impact of other dementia risk factors recently reviewed. Depression is distinct, however, in being a relatively treatable condition, but the impact of treating depression on later cognitive decline is not always positive, leading to the hypothesis that only the antidepressants that attenuate inflammation alleviate subsequent cognitive decline.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Perspectives on the complex links between depression and dementia

Hakim

2022

Front. Aging Neurosci.

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“…Lifestyle-related diseases, including diabetes mellitus, play a role in the development of dementia by activating chronic inflammatory processes associated with oxidative stress. These changes lead to small vessel diseases, resulting in a reduction in CBF ( 37 – 39 ). In addition, lifestyle-related diseases can also result in arteriosclerosis of large vessels, leading to a decrease in CBF.…”

Section: Discussionmentioning

confidence: 99%

Estimation of Human Cerebral Atrophy Based on Systemic Metabolic Status Using Machine Learning

Sakatani

Oyama

et al. 2022

Front. Neurol.

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BackgroundBased on the assumption that systemic metabolic disorders affect cognitive function, we have developed a deep neural network (DNN) model that can estimate cognitive function based on basic blood test data that do not contain dementia-specific biomarkers. In this study, we used the same DNN model to assess whether basic blood data can be used to estimate cerebral atrophy.MethodsWe used data from 1,310 subjects (58.32 ± 12.91years old) enrolled in the Brain Doc Bank. The average Mini Mental State Examination score was 28.6 ± 1.9. The degree of cerebral atrophy was determined using the MRI-based index (GM-BHQ). First, we evaluated the correlations between the subjects' age, blood data, and GM-BHQ. Next, we developed DNN models to assess the GM-BHQ: one used subjects' age and blood data, while the other used only blood data for input items.ResultsThere was a negative correlation between age and GM-BHQ scores (r = -0.71). The subjects' age was positively correlated with blood urea nitrogen (BUN) (r = 0.40), alkaline phosphatase (ALP) (r = 0.22), glucose (GLU) (r = 0.22), and negative correlations with red blood cell counts (RBC) (r = −0.29) and platelet counts (PLT) (r = −0.26). GM-BHQ correlated with BUN (r = −0.30), GLU (r = −0.26), PLT (r = 0.26), and ALP (r = 0.22). The GM-BHQ estimated by the DNN model with subject age exhibited a positive correlation with the ground truth GM-BHQ (r = 0.70). Furthermore, even if the DNN model without subject age was used, the estimated GM-BHQ showed a significant positive correlation with ground truth GM-BHQ (r = 0.58). Age was the most important variable for estimating GM-BHQ.DiscussionAging had the greatest effect on cerebral atrophy. Aging also affects various organs, such as the kidney, and causes changes in systemic metabolic status, which may contribute to cerebral atrophy and cognitive impairment. The DNN model may serve as a new screening test for dementia using basic blood tests for health examinations. Finally, the blood data reflect systemic metabolic disorders in each subject—this method may thus contribute to personalized care.

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“…Regarding DWML pathogenesis, decreased cerebral blood flow or a blood–brain barrier disruption induced by endothelial damage of cerebral deep small arteries have been reported 33–35 . Experimental studies have revealed that chronic cerebral hypoperfusion causes myelin sheath damage and neuronal death, 36,37 while endothelial cells of deep small arteries have been reported to be injured by chronic inflammatory response caused by hypertension, diabetes mellitus, dyslipidemia, smoking, and chronic kidney disease 38 . With respect to our study, no difference was observed in the incidence of hypertension and diabetes mellitus between the Cons[+] and Cons[−] groups, and the incidence of hyperlipidemia was rather lower in the Cons[+] group.…”

Section: Discussionmentioning

confidence: 99%

Impact of constipation on progression of Alzheimer's disease: A retrospective study

et al. 2022

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Background and Purpose In terms of the gut‐brain axis, constipation has been considered to be an important factor of neurodegenerative diseases, although the exact mechanism is still controversial. Herein, we aimed to investigate the contribution of constipation to the progression of dementia in a retrospective study. Methods Patients of Alzheimer's disease(AD) and amnestic mild cognitive impairment were consecutively screened between January 2015 and December 2020, and those of whom brain MRI and neuropsychological tests were performed twice were enrolled in this study. Participants were classified into with constipation (Cons[+], n = 20) and without constipation (Cons[−], n = 64) groups. Laboratory data at the first visit were used. Regression analysis was performed in MMSE, ADAS‐Cog, and the volumes of hippocampus on MRI‐MPRAGE images and deep white matter lesions (DWMLs) on MRI‐FLAIR images obtained at two different time points. Results The main finding was that the Cons[+] group showed 2.7 times faster decline in cognitive impairment compared with the Cons[−] group, that is, the liner coefficients of ADAS‐Cog were 2.3544 points/year in the Cons[+] and 0.8592 points/year in the Cons[−] groups. Ancillary, changes of DWMLs showed significant correlation with the time span (p < 0.01), and the liner coefficients of DWMLs were 24.48 ml/year in the Cons[+] and 14.83 ml/year in the Cons[−] group, although annual rate of hippocampal atrophy was not different between the two groups. Moreover, serum homocysteine level at baseline was significantly higher in the Cons[+] group than Cons[−] group (14.6 ± 6.4 and 11.5 ± 4.2 nmol/ml, respectively: p = 0.03). Conclusion There is a significant correlation between constipation and faster progression of AD symptoms along with expansion of DWMLs.

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A Proposed Hypothesis on Dementia: Inflammation, Small Vessel Disease, and Hypoperfusion Is the Sequence That Links All Harmful Lifestyles to Cognitive Impairment

Cited by 19 publications

References 128 publications

Perspectives on the complex links between depression and dementia

Perspectives on the complex links between depression and dementia

Estimation of Human Cerebral Atrophy Based on Systemic Metabolic Status Using Machine Learning

Impact of constipation on progression of Alzheimer's disease: A retrospective study

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