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Neuropsychological performance of young familial hypercholesterolemia patients
... On the physical front, hypercholesterolemia has been recognized for decades as a potential risk factor for cardiovascular disease development. Emerging evidence has also indicated a strong association between cholesterol dyshomeostasis and cognitive impairment [3]. In support of this view, many preclinical studies suggest that mechanisms that are involved in the expression of FH tend to disrupt the integrity of the blood-brain barrier. ...
... Another study from Spain explored cognitive status among young people with FH. This study appears to suggest that even a young FH population tends to exhibit cognitive decline [3]. Suárez Bagnasco [8] reviewed articles appearing in various medical and psychological search engines from 1980 until March 2017. ...
... While clinical and epidemiological surveys have been conducted among patients with FH in emerging economies, to date, there is a dearth of studies on the effects of the disease process on higher functioning. The diminution of higher functioning has been attributed to the effects of elevated levels of cholesterol and the lack or dysfunction of LDL receptors, contributing to the development of cognitive impairment among patients with FH [3]. ...
Citation: Chan, M.F.; Ganesh, A.; Mahadevan, S.; Shamli, S.A.; Al-Waili, K.; Al-Mukhaini, S.; Al-Rasadi, K.; Al-Adawi, S. A Comprehensive Neuropsychological Study of Familial Hypercholesterolemia and Its Relationship with Psychosocial Functioning: A Biopsychosocial Approach. Brain Sci. 2022, 12, 1127.
... On the physical front, hypercholesterolemia has been recognized for decades as a potential risk factor for cardiovascular disease development. Emerging evidence has also indicated a strong association between cholesterol dyshomeostasis and cognitive impairment [3]. In support of this view, many preclinical studies suggest that mechanisms that are involved in the expression of FH tend to disrupt the integrity of the blood-brain barrier. ...
... Another study from Spain explored cognitive status among young people with FH. This study appears to suggest that even a young FH population tends to exhibit cognitive decline [3]. Suárez Bagnasco [8] reviewed articles appearing in various medical and psychological search engines from 1980 until March 2017. ...
... It was not possible in the present ideographic approach to recruit a larger sample size as is often done in traditional nomothetic studies [35]. However, it is also worthwhile to note that the present sample size appears to echo the sample sizes that have been used to previously explore the neuropsychological status of people with FH [3,7,10]. The third limitation is regarding the specificity of the cognitive domains, a feature that is pervasive in neuropsychological studies. ...
BACKGROUND: Over the past few years, there has been an increasing interest to view the diagnosis of Familial hypercholesterolemia (FH) through the lens of the biopsychosocial model. However, other than a few epidemiological surveys, there is a dearth of studies from emerging economies that have examined FH using the biological, psychological and socio-environmental facets of the aforementioned model. AIM. The three aims of the current study were as follows: (i) to examine the psychosocial status among patients with genetically confirmed FH, (ii) to compare the intellectual capacity and cognitive outcomes with a reference group, and (iii) to examine the relationship between health literacy and cognitive functioning. METHOD: Consecutive FH patients referred to the lipid clinic at a tertiary care center for an expert opinion were recruited into this study, conducted from September 2019 to March 2020. Information regarding psychosocial functioning, health literacy, quality of life, and affective ranges were surveyed. Indices of current reasoning ability (attention and concentration, memory, and executive functioning) were compared with an age-matched reference group. The current hypothesis also explored the impact of FH on health literacy and cognition. RESULT: A total of 70 participants out of 106 (response rate: 66.0%) initially agreed to participate. However, 18 out of 70 dropped out of the study, yielding a final total of 52 FH patients. With 27 (51.9%) males and 25 (48.1%) females, the mean participant age stood at 37.2 years (SD=9.2), ranging from 21 to 52 years of age. In the psychosocial data, thirty-two percent (n=17) of them had anxiety (HADS≥ 8), and twenty-five percent (n=13) had depressive symptoms (HADS≥ 8). The performance of the FH patients was significantly impaired compared to the control group on the indices of current reasoning ability and all domains of cognitive functioning. In univariate analysis conducted to compare cognitive functioning with health literacy status, only indices of attention and concentration emerged as being significant. CONCLUSION: To date, there are only a few studies employing the biopsychosocial paradigm to investigate the FH population. The current study indicates that the FH population is marked by an impediment in almost all of the core features that are characteristically assessed by the biopsychosocial approach.
... A proportion of FH patients fall short of full compliance or follow regimens inconsistently. Understanding the factors likely to affect treatment adherence is paramount [70][71][72][73][74][75][76][77][78][79]. ...
... As well as in other chronic pathologies that require long-term treatment, psychological and cognitive issues can influence adherence to treatment [70][71][72][73][74][75][76][77][78][79]. ...
... Deficits in executive functioning and memory may affect medication adherence because taking medicines involves developing and implementing a plan to adhere and remembering the plan (for example: the plan may require time-based (e.g., at 8:00 p.m.) or event-based prospective remembering (e.g., with meals) and remembering what medicine take and whether the medicine was taken). Furthermore, executive functions may affect the achievement of lifestyle modifications and maintain healthy behavior over time included in FH management [70][71][72][73][74][75][76]. ...
Familial hypercholesterolemia is a genetic and metabolic disorder associated with an increased risk of morbidity and mortality. Two main types of familial hypercholesterolemia are distinguished: heterozygous familial hypercholesterolemia and homozygous familial hypercholesterolemia. Homozygous familial hypercholesterolemia progresses much more aggressively with higher levels of LDL-C and higher risk of cardiovascular disease at earlier ages. The prognosis of homozygous familial hypercholesterolemia largely depends on the LDL-C levels. Reducing the LDL-C level is one of the primary goals of treatment patients with familial hypercholesterolemia. Effective control of LDL-C significantly reduces the cardiovascular morbidity and mortality. Understanding the factors likely to affect treatment adherence is paramount. Adherence to treatment can be improve when a genetic etiology is confirmed. Positive genetic test result has beneficial effects on adherence to pharmacotherapy and in achieving LDL-C levels reduction.
... FH represents a unique opportunity to study the effects of cholesterol metabolism on cognition over time, because affected individuals are exposed to hypercholesterolemia from early in life and carry a dysfunction of LDLr [6,7]. One clinical study revealed that middle-aged individuals with FH were more likely to exhibit abnormal cognitive functions that meet the criteria for mild cognitive impairment (MCI) [6]. ...
... One clinical study revealed that middle-aged individuals with FH were more likely to exhibit abnormal cognitive functions that meet the criteria for mild cognitive impairment (MCI) [6]. Recent findings have reported neuropsychological deficits, including memory decline, in young FH individuals aged between 18 and 40 years old [7]. We and others corroborated these clinical observations when we showed that LDLr knockout (LDLr -/-) mice, an experimental FH mouse model, displayed cognitive impairment [8,9]. ...
... The natural history of FH patients involves the premature development of cardiovascular diseases associated with atherosclerosis [31]. In the last decade, it has been discovered that FH is also related to the emergence of cognitive impairment in adulthood [6,7]. In this context, we previously reported that three-month-old LDLr -/mice already displayed learning and memory deficits that seemed to be triggered by BBB dysfunction and neuroinflammation within the hippocampus [9,10]. ...
Evidence has revealed an association between familial hypercholesterolemia and cognitive impairment. In this regard, a connection between cognitive deficits and hippocampal blood-brain barrier (BBB) breakdown was found in low-density lipoprotein receptor knockout mice (LDLr-/-), a mouse model of familial hypercholesterolemia. We investigated the impact of a hypercholesterolemic diet on cognition and BBB function in C57BL/6 wild-type and LDLr–/– mice.
Animals were fed with normal or high cholesterol diets for 30 days. Thus, wild-type and LDLr–/– mice were submitted to memory paradigms. Additionally, BBB integrity was evaluated in the mice’s prefrontal cortices and hippocampi.
... Three manuscripts and two abstracts presented at international congresses explore cognitive function in FH patients (20)(21)(22)(23)(24). ...
... Authors reported deficits in executive functioning and memory (20)(21)(22). One study found that patients with long-term statin therapy had better episodic memory than controls (23). ...
... A paper reports that FH patients with long-term statin treatment had better episodic memory than controls (20). The results of this study suggest statins have beneficial effects on cognition. ...
A literature review about depression, anxiety, illness perception and neurocognitive impairment in adults with familial hypercholesterolemia (FH) was performed. Through PubMed and PsycINFO published studies from 1980 until March 2017 were searched. Two papers assessed depression and anxiety. Four papers explored illness perception. Five studies assessed cognitive impairment. Mean depression and anxiety scores were within normal range. From the reviewed research, it can be concluded that deficits in executive functioning and memory appear in FH patients between 18 and 40 years old, and mild cognitive impairment in older than 50. The research in the field of the present review is relatively recent: all the studies have been published in the current century. Further research should be done using complete standardized neuropsychological assessment and brain imaging techniques. Studies exploring the possible influence of cognitive deficits on adherence should be conducted also.
... Middle-aged individuals with FH are more likely to exhibit abnormal cognitive function and meet the criteria for mild cognitive impairment, which could be considered a prodromal stage of Alzheimer's disease (Zambón et al., 2010). It was also reported that those neuropsychological deficits, including memory decline, could be observed in young FH individuals aged between 18 and 40 years (Ariza et al., 2016). In line with these clinical data, experimental studies have shown that impaired cognitive performance can already be observed in young adult LDL receptor knockout (LDLr−/−) mice, an experimental model of FH (De Oliveira et al., 2011;Moreira et al., 2012). ...
... Clinical and experimental studies have demonstrated that FH impairs cognition (Ariza et al., 2016;De Oliveira et al., 2011;Moreira et al., 2012Moreira et al., , 2014Mulder et al., 2004;Zambón et al., 2010). In an attempt to better understand the mechanisms underlying this negative outcome of FH, preclinical data derived from studies using LDLr−/− mice have described that these animals show impaired adult hippocampal neurogenesis (Engel et al., 2019), neuronal apoptosis (de Oliveira, Engel, de Paula, Melo, et al., 2020), BBB dysfunction (de Oliveira, Engel, de Paula, Dos Santos, et al., 2020), and also increased glial cell density (de Oliveira, Engel, de Paula, Dos Santos, et al., 2020;Moreira et al., 2014;Thirumangalakudi et al., 2008) in brain areas involved in memory formation. ...
Familial hypercholesterolemia (FH) is caused by mutations in the gene that encodes the low-density lipoprotein (LDL) receptor, which leads to an excessive increase in plasma LDL cholesterol levels. Previous studies have shown that FH is associated with gliosis, blood-brain barrier (BBB) dysfunction, and memory impairment, but the mechanisms associated with these events are still not fully understood. Therefore, we aimed to investigate the role of microgliosis in the neurochemical and behavioral changes associated with FH using LDL receptor knockout (LDLr-/-) mice. We noticed that microgliosis was more severe in the hippocampus of middle-aged LDLr-/- mice, which was accompanied by microglial morphological changes and alterations in the immunocontent of synaptic protein markers. At 3 months of age, the LDLr-/- mice already showed increased microgliosis and decreased immunocontent of claudin-5 in the prefrontal cortex (PFC). Subsequently, 6-month-old male C57BL/6 wild-type and LDLr-/- mice were treated once daily for 30 days with minocycline (a pharmacological inhibitor of microglial cell reactivity) or vehicle (saline). Adult LDLr-/- mice displayed significant hippocampal memory impairment, which was ameliorated by minocycline treatment. Non-treated LDLr-/- mice showed increased microglial density in all hippocampal regions analyzed, a process that was not altered by minocycline treatment. Region-specific microglial morphological analysis revealed different effects of genotype or minocycline treatment on microglial morphology, depending on the hippocampal subregion analyzed. Moreover, 6-month-old LDLr-/- mice exhibited a slight but not significant increase in IBA-1 immunoreactivity in the PFC, which was reduced by minocycline treatment without altering microglial morphology. Minocycline treatment also reduced the presence of microglia within the perivascular area in both the PFC and hippocampus of LDLr-/- mice. However, no significant effects of either genotype or minocycline treatment were observed regarding the phagocytic activity of microglia in the PFC and hippocampus. Our results demonstrate that hippocampal microgliosis, microglial morphological changes, and the presence of these glial cells in the perivascular area, but not increased microglial phagocytic activity, are associated with cognitive deficits in a mouse model of FH.
... Esse conhecimento poderia ajudar a eliminar ou controlar a formação de subprodutos provenientes do metabolismo lipídico, e consequentemente, preservar a atividade cerebral, principalmente no que concerne a manutenção da composição das membranas, sinapses, neurogênese, sinalização celular, e neurotransmissão 4,10 . Fatores esses que são primordiais para manter a comunicação saudável entre as células e evitar a perda da memória 11 Além disso, esses estudos clínicos revelaram uma tendência maior de perda nas memórias episódica e verbal, indicando que a HF não induz uma perda lateralizada, e que pode estar atingindo regiões além do nível hipocampal, como áreas do córtex pré-frontal, por exemplo (Quadro 1) 14,15,18,19 . Outro ponto importante é que o uso precoce de estatinas não somente reduziu os níveis séricos de colesterol, como também desacelerou o processo de perda cognitiva [13][14][15] Logo, essa descoberta indica que a hiperativação da via apoptótica poderia justificar a perda da comunicação celular de forma precoce 19 . ...
... Fatores esses que são primordiais para manter a comunicação saudável entre as células e evitar a perda da memória 11 Além disso, esses estudos clínicos revelaram uma tendência maior de perda nas memórias episódica e verbal, indicando que a HF não induz uma perda lateralizada, e que pode estar atingindo regiões além do nível hipocampal, como áreas do córtex pré-frontal, por exemplo (Quadro 1) 14,15,18,19 . Outro ponto importante é que o uso precoce de estatinas não somente reduziu os níveis séricos de colesterol, como também desacelerou o processo de perda cognitiva [13][14][15] Logo, essa descoberta indica que a hiperativação da via apoptótica poderia justificar a perda da comunicação celular de forma precoce 19 . ...
A hipercolesterolemia familiar é uma doença genética que afeta o metabolismo de lipídios e que em longo prazo pode influenciar a atividade cerebral, resultando em perdas cognitivas. Nesse sentido, o objetivo do trabalho foi discutir como o controle nutricional pode conter a perda de cognição precoce em casos de hipercolesterolemia familiar. No entanto, a literatura sobre o tema é limitada, havendo apenas 8 artigos que relacionam hipercolesterolemia familiar e perda cognitiva. Sendo que, nenhum deles pesquisou sobre o efeito da intervenção nutricional ou da dietoterapia na perda cognitiva causada pela hipercolesterolemia familiar. Essa escassez de dados limita a compreensão não somente sobre o processo da doença, mas também sobre a dietoterapia que deva ser utilizada. Nesse contexto, o presente estudo propõe que o controle de colesterol, desde as fases iniciais da vida, seja uma forma de controlar a hipercolesterolemia familiar em curto prazo, e também de combater a perda cognitiva precoce em longo prazo. Uma vez que o consumo controlado de colesterol bom seria uma forma indireta de manter as células nervosas funcionando corretamente através da manutenção da composição lipídica da membrana.
... Notably, the metabolic diseases in early life are risk factors for dementia. The epidemiological studies have shown that obesity and hypercholesterolemia in adulthood or in middle age increase the risk of dementia in the future (Kivipelto et al., 2001(Kivipelto et al., , 2005Whitmer et al., 2005;Ariza et al., 2016). In the elderly, obesity and high plasma cholesterol levels are not correlated with a higher occurrence of dementia (Reitz et al., 2008;Anjum et al., 2018). ...
... Familial hypercholesterolemia is closely related to the development of atherosclerotic cardiovascular disease (Austin et al., 2004). Individuals suffering from familial hypercholesterolemia also display a high incidence of cognitive impairments (Zambon et al., 2010;Ariza et al., 2016). ...
The incidence of metabolic disorders, as well as of neurodegenerative diseases—mainly the sporadic forms of Alzheimer’s and Parkinson’s disease—are increasing worldwide. Notably, obesity, diabetes, and hypercholesterolemia have been indicated as early risk factors for sporadic forms of Alzheimer’s and Parkinson’s disease. These conditions share a range of molecular and cellular features, including protein aggregation, oxidative stress, neuroinflammation, and blood-brain barrier dysfunction, all of which contribute to neuronal death and cognitive impairment. Rodent models of obesity, diabetes, and hypercholesterolemia exhibit all the hallmarks of these degenerative diseases, and represent an interesting approach to the study of the phenotypic features and pathogenic mechanisms of neurodegenerative disorders. We review the main pathological aspects of Alzheimer’s and Parkinson’s disease as summarized in rodent models of obesity, diabetes, and hypercholesterolemia.
... Compared to individuals with the sporadic form, those with familial hypercholesterolemia (FH) present a higher incidence of mild cognitive impairment in later life [5]. Ariza and coworkers [6] reported that even young FH subjects already showed neuropsychological deficits. FH is caused by inherited genetic abnormalities, predominantly in the low-density lipoprotein (LDL) receptor (LDLr) gene, resulting in an ineffective metabolism of LDL particles. ...
... Notably, ablation of adult neurogenesis is well known to impair performance in behavioral tasks that require resolution of similar inputs, such as a subtle metric novelty [52]. The higher incidence of early cognitive deficits in FH patients, when compared to patients with sporadic hypercholesterolemia [5,6], draws attention to inherited factors, such as mutations in the LDLr gene. In the LDLr À/mice, high plasma cholesterol levels and the absence of LDLr might both have a role in impairing the neurogenic process. ...
Objective:
In familial hypercholesterolemia (FH), mutations in the low-density lipoprotein (LDL) receptor (LDLr) gene result in increased plasma LDL cholesterol. Clinical and preclinical studies have revealed an association between FH and hippocampus-related memory and mood impairment. We here asked whether hippocampal pathology in FH might be a consequence of compromised adult hippocampal neurogenesis.
Methods:
We evaluated hippocampus-dependent behavior and neurogenesis in adult C57BL/6JRj and LDLr-/- mice. We investigated the effects of elevated cholesterol and the function of LDLr in neural precursor cells (NPC) isolated from adult C57BL/6JRj mice in vitro.
Results:
Behavioral tests revealed that adult LDLr-/- mice showed reduced performance in a dentate gyrus (DG)-dependent metric change task. This phenotype was accompanied by a reduction in cell proliferation and adult neurogenesis in the DG of LDLr-/- mice, suggesting a potential direct impact of LDLr mutation on NPC. Exposure of NPC to LDL as well as LDLr gene knockdown reduced proliferation and disrupted transcriptional activity of genes involved in endogenous cholesterol synthesis and metabolism. The LDL treatment also induced an increase in intracellular lipid storage. Functional analysis of differentially expressed genes revealed parallel modulation of distinct regulatory networks upon LDL treatment and LDLr knockdown.
Conclusions:
Together, these results suggest that high LDL levels and a loss of LDLr function, which are characteristic to individuals with FH, might contribute to a disease-related impairment in adult hippocampal neurogenesis and, consequently, cognitive functions.
... Since plasma lipoproteins are unable to cross the blood brain barrier (BBB), cholesterol must be synthesized in the brain. Cholesterol is also responsible for the correct function of neurotransmitter, and an its impaired metabolism could cause brain dysfunction (39). On this basis, hypotheses concerning a possible relationship between autism and alterations of cholesterol metabolism have been advanced. ...
Autism spectrum disorder is a neurodevelopmental disorder characterized by social interactions and communication skills impairments that include intellectual disabilities, communication delays and self-injurious behaviors; often are present systemic comorbidities such as gastrointestinal disorders, obesity and cardiovascular disease. Moreover, in recent years has emerged a link between alterations in the intestinal microbiota and neurobehavioral symptoms in children with autism spectrum disorder. Recently, physical activity and exercise interventions are known to be beneficial for improving communication and social interaction and the composition of microbiota. In our review we intend to highlight how different types of sports can help to improve communication and social behaviors in children with autism and also show positive effects on gut microbiota composition.
... High total cholesterol levels have previously been associated with cognitive impairment and Alzheimer's disease [62], and low levels were found to predict improved cognitive functions in the cognitively impaired elderly [63]. In addition, a poorer performance in memory tasks [64] and executive functions [64,65] has been observed in patients with familial hypercholesterolemia, and attention and executive function deficits have been reported in patients with type-2 diabetes mellitus and poor cholesterol control [66]. ...
Background
Cognitive problems are frequent in patients with end-stage renal disease (ESRD) treated with hemodialysis. However, previous studies used only a single cognitive screening test or a small number of cognitive indices, which is inadequate for an exhaustive evaluation of cognitive deficits. This case-control study aimed to evaluate cognitive function in patients with ESRD before and after hemodialysis at centers in southern Spain, and included analysis of associations between cognitive function and duration of hemodialysis, biochemistry, body composition, and treatment variables.
Material/Methods
Cognitive performance was evaluated in 42 healthy participants (HPs) and in 43 ESRD patients, before and after hemodialysis. The tests measured verbal and visual memory, sustained/selective attention, and processing speed. The diagnostic criterion for ESRD was a glomerular filtration rate <15 mL/min/1.73 m². Correlation and multiple regression analyses were used to explore the relationships between cognitive and clinical variables, controlling for age, schooling, mood, and blood pressure.
Results
Scores for verbal memory, sustained/selective attention, and processing speed were lower in patients with ESRD treated with hemodialysis than in HPs, with no between-group differences in visual memory. No acute hemodialysis-specific effect on performance was observed. Several biochemistry variables were associated with performance, both negatively (eg total cholesterol, calcium, and total protein) and positively (eg sodium, phosphorus, and creatinine).
Conclusions
Patients with ESRD treated with hemodialysis showed cognitive deficits in verbal memory, sustained/selective attention, and processing speed. Performance was not significantly different between tests administered before and after hemodialysis. An adequate diet as well as physical exercise could be useful to improve cognitive performance in this population.
... Furthermore, a higher depression incidence was observed in hypercholesterolemic individuals [12][13][14][15]. Similar results were found in experimental models of familial hypercholesterolemia and diet-induced hypercholesterolemia. Hypercholesterolemic animals showed increased depressive-like behavior when compared to their respective healthy controls [16,17]. ...
Hypercholesterolemia has been linked to neurodegenerative disease development. Previously others and we demonstrated that high levels of plasma cholesterol-induced memory impairments and depressive-like behavior in mice. More recently, some evidence reported that a hypercholesterolemic diet led to motor alterations in rodents. Peripheral inflammation, blood-brain barrier (BBB) dysfunction, and neuroinflammation seem to be the connective factors between hypercholesterolemia and brain disorders. Herein, we aimed to investigate whether treatment with gold nanoparticles (GNPs) can prevent the inflammation, BBB disruption, and behavioral changes related to neurodegenerative diseases and depression, induced by hypercholesterolemic diet intake in mice. Adult Swiss mice were fed with a standard or high cholesterol diet for eight weeks and concomitantly treated with either vehicle or GNPs by the oral route. At the end of treatments, mice were subjected to behavioral tests. After that, the blood, liver, and brain structures were collected for biochemical analysis. The high cholesterol diet-induced an increase in the plasma cholesterol levels and body weight of mice, which were not modified by GNPs treatment. Hypercholesterolemia was associated with enhanced liver TNF-α, BBB dysfunction in the hippocampus and olfactory bulb, memory impairment, cataleptic posture, and depressive-like behavior. Notably, GNPs administration attenuated liver inflammation, BBB dysfunction, and improved behavioral and memory deficits in hypercholesterolemic mice. Also, GNPs increased mitochondrial complex I activity in the prefrontal cortex of mice. It is worth Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation
... A pioneering study has shown that individuals with high levels of cholesterol in middle age meet the criteria for mild cognitive impairment (MCI), a transitional state between normal aging and dementia in elderly [4]. More recently, a clinical study demonstrated that young individuals with FH make more errors in verbal memory and in executive performance in relation to healthy people [32]. These authors proposed that the early exposure to high cholesterol levels and/or the dysfunction of lipoprotein receptors, i.e. ...
Although the benefits of moderate intake of red wine in decreasing incidence of cardiovascular diseases associated to hypercholesterolemia are well recognized, there are still widespread misconceptions about its effects on the hypercholesterolemia-related cognitive impairments. Herein we investigated the putative benefits of regular red wine consumption on cognitive performance of low-density lipoprotein receptor knockout (LDLr−/−) mice, an animal model of familial hypercholesterolemia, which display cognitive impairments since early ages. The red wine was diluted into the drinking water to a final concentration of 6% ethanol and was available for 60 days for LDLr−/− mice fed a normal or high-cholesterol diet. The results indicated that moderate red wine consumption did not alter locomotor parameters and liver toxicity. Across multiple cognitive tasks evaluating spatial learning/reference memory and recognition/identification memory, hypercholesterolemic mice drinking red wine performed significantly better than water group, regardless of diet. Additionally, immunofluorescence assays indicated a reduction of astrocyte activation and lectin stain in the hippocampus of LDLr−/− mice under consumption of red wine. These findings demonstrate that the moderate consumption of red wine attenuates short- and long-term memory decline associated with hypercholesterolemia in mice and suggest that it could be through a neurovascular action.
... On the other hand, the pathogenic concept of LDL-induced atherosclerosis development, including foam cell formation 32) , inflammatory response, and endothelial dysfunction 33) , might be relevant to cerebral arteries as well as to coronary arteries. In fact, our imaging analysis revealed the prevalence of PVH to be significantly higher and that of DWMH to show an Advance Publication Journal of Atherosclerosis and Thrombosis Accepted for publication: January 29, 2019 Published online: March 15, 2019 patients had a higher incidence of mild cognitive impairment, which is considered to be a result of long-term hypercholesterolemia 37) , an observation made even in young patients 38) . Therefore, as an aspect of managing cognitive impairment, evaluation of cerebral SVD has become an important issue in FH. ...
Aim: It remains unclear whether elevated low-density lipoprotein cholesterol (LDL-C) is a risk factor for cerebral vascular disease. Familial hypercholesterolemia (FH) is the most appropriate model for understanding the effects of excess LDL-C because affected individuals have inherently high levels of circulating LDL-C. To clarify the effects of hypercholesterolemia on cerebral small vessel disease (SVD), we investigated cerebrovascular damage in detail due to elevated LDL-C using high resolution brain magnetic resonance imaging (MRI) in patients with FH.
Methods: Twenty-eight patients with FH and 35 healthy controls underwent 7T brain MRI. The prevalence of SVD and arterial structural changes were determined in each group.
Results: The prevalence of periventricular hyperintensity (PVH) was significantly higher (control, 0% vs. FH, 14.2%, p=0.021) and deep white matter intensity tended to be more frequent in FH patients than in controls. The prevalence of SVD in patients with forms of cerebral damage, such as lacunar infarction, PVH, deep white matter hyperintensities (DWMH), microbleeding, and brain atrophy, was significantly higher among FH patients (control, n=2, 5.7% vs. FH, n=7, 25.0%, p＜0.001, chi-square test). The tortuosity of major intracranial arteries and the signal intensity of lenticulostriate arteries were similar in the two groups. In FH patients, as the grade of PVH progressed, several atherosclerosis risk factors, such as body mass index, blood pressure, and triglyceride level, showed ever worsening values.
Conclusion: These results obtained from FH patients revealed that persistently elevated LDL-C leads to cerebral PVH. It is necessary in the management of FH to pay attention not only to the development of coronary heart disease but also to the presence of cerebral SVD.
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by a persistent impairment of social skills, including aspects of perception, interpretation, and response, combined with restricted and repetitive behavior. ASD is a complex and multifactorial condition, and its etiology could be attributed to genetic and environmental factors. Despite numerous clinical and experimental studies, no etiological factor, biomarker, and specific model of transmission have been consistently associated with ASD. However, an imbalance in cholesterol levels has been observed in many patients, more specifically, a condition of hypocholesterolemia, which seems to be shared between ASD and ASD-related genetic syndromes such as fragile X syndrome (FXS), Rett syndrome (RS), and Smith- Lemli-Opitz (SLO). Furthermore, it is known that alterations in cholesterol levels lead to neuroinflammation, oxidative stress, impaired myelination and synaptogenesis. Thus, the aim of this review is to discuss the cholesterol metabolic pathways in the ASD context, as well as in genetic syndromes related to ASD, through clinical observations and animal models. In fact, SLO, FXS, and RS patients display early behavioral markers of ASD followed by cholesterol disturbances. Several studies have demonstrated the role of cholesterol in psychiatric conditions and how its levels modulate brain neurodevelopment. This review suggests an important relationship between ASD pathology and cholesterol metabolism impairment; thus, some strategies could be raised - at clinical and pre-clinical levels - to explore whether cholesterol metabolism disturbance has a generally adverse effect in exacerbating the symptoms of ASD patients.
Familial hypercholesterolemia (FH) is a genetic disorder caused by dysfunction of low density lipoprotein receptors (LDLr), resulting in elevated plasma cholesterol levels. FH patients frequently exhibit cognitive impairment, a finding recapitulated in LDLr deficient mice (LDLr-/-), an animal model of FH. In addition, LDLr-/- mice are more vulnerable to the deleterious memory impact of amyloid-β (Aβ), a peptide linked to Alzheimer's disease. Here, we investigated whether the expression of proteins involved in Aβ metabolism are altered in the brains of adult or middle-aged LDLr-/- mice. After spatial memory assessment, Aβ levels and gene expression of LDLr related-protein 1, proteins involved in Aβ synthesis, and apoptosis-related proteins were evaluated in prefrontal cortex and hippocampus. Moreover, the location and cell-specificity of apoptosis signals were evaluated. LDLr-/- mice presented memory impairment, which was more severe in middle-aged animals. Memory deficit in LDLr-/- mice was not associated with altered expression of proteins involved in Aβ processing or changes in Aβ levels in either hippocampus or prefrontal cortex. We further found that the expression of Bcl-2 was reduced while the expression of Bax was increased in both prefrontal cortex and hippocampus in 3- and 14-month-old LDLr-/-mice Finally, LDLr-/- mice presented increased immunoreactivity for activated caspase-3 in the prefrontal cortex and hippocampus. The activation of caspase 3 was predominantly associated with neurons in LDLr-/- mice. Cognitive impairment in LDLr-/- mice is thus accompanied by an exacerbation of neuronal apoptosis in brain regions related to memory formation, but not by changes in Aβ processing or levels.
Obesity is a multifactorial disease caused by the interaction between genotype and environment, and it is considered to be a type of addictive alteration. The A1 allele of the DRD2/ANKK1-TaqIA gene has been associated with addictive disorders, with obesity and with the performance in executive functions. The 7 repeat allele of the DRD4 gene has likewise been associated with the performance in executive functions, as well as with addictive behaviors and impulsivity. Participants were included in the obesity group (N = 42) if their body mass index (BMI) was equal to or above 30, and in the lean group (N = 42) if their BMI was below 25. The DRD2/ANKK1-TaqIA and DRD4 VNTR polymorphisms were obtained. All subjects underwent neuropsychological assessment. Eating behavior traits were evaluated. The 'DRD2/ANKK1-TaqIA A1-allele status' had a significant effect on almost all the executive variables, but no significant 'DRD4 7R-allele status' effects were observed for any of the executive variables analyzed. There was a significant 'group' x 'DRD2/ANKK1-TaqIA A1-allele status' interaction effect on LN and 'group' x 'DRD4 7R-allele status' interaction effect on TMT B-A score. Being obese and a carrier of the A1 allele of DRD2/ANKK1-TaqIA or the 7R allele of DRD4 VNTR polymorphisms could confer a weakness as regards the performance of executive functions.
There is increasing evidence that hypercholesterolemia during midlife may represent a predictor of subsequent mild cognitive impairments and dementia decades later. However, the exact mechanism underlying this phenomenon remains unknown since plasmatic cholesterol is not able to cross the blood-brain barrier. In the present study, we evaluated the hypothesis that cognitive impairments triggered by hypercholesterolemia during aging may be related to brain oxidative stress and altered brain acetylcholinesterase (AChE) activity. We also performed a neuropathological investigation in order to analyze whether the cognitive impairments may be associated with stroke-related features. To address these questions we used three- and fourteen-month-old low-density lipoprotein receptor-deficient mice (LDLr-/-). The current findings provide new evidence that aged LDLr-/- mice, exposed to over three-fold cholesterol levels from early life, show working, spatial reference, and procedural memory impairments, without alterations in motor function. Antioxidant imbalance and oxidative damage were evidenced by a marked increase in lipid peroxidation (thiobarbituric acid reactive substances levels) and glutathione metabolism (increase in glutathione levels, glutathione reductase, and glutathione peroxidase activities) together with a significant increase in the AChE activity in the prefrontal cortex of aged hypercholesterolemic LDLr-/- mice. Notably, hypercholesterolemia was not related to brain infarcts and neurodegeneration in mice, independent of their age. These observations provide new evidence that hypercholesterolemia during aging triggers cognitive impairments on different types of learning and memory, accompanied by antioxidant imbalance, oxidative damage, and alterations of cholinergic signaling in brain areas associated with learning and memory processes, particularly in the prefrontal cortex.
Recent clinical findings support the notion that the progressive deterioration of cholesterol homeostasis is a central player in Alzheimer's disease (AD). Epidemiological studies suggest that high midlife plasma total cholesterol levels are associated with an increased risk of AD. This paper reports the plasma cholesterol concentrations, cognitive performance, locomotor activity and neuropathological signs in a murine model (transgenic mice expressing apoB100 but knockout for the LDL receptor [LDLR]) of human familial hypercholesterolaemia (FH). From birth, these animals have markedly elevated LDL-cholesterol and apolipoprotein B100 (apoB100) levels. These transgenic mice were confirmed to have higher plasma cholesterol concentrations than wild-type mice, an effect potentiated by aging. Further, 3-month-old transgenic mice showed cholesterol (total and fractions) concentrations considerably higher than those of 18-month-old wild-type mice. The hypercholesterolaemia of the transgenic mice was associated with a clear locomotor deficit (as determined by rotarod, grip strength and open field testing) and impairment of the episodic-like memory (determined by the integrated memory test). This decline in locomotor activity and cognitive status was associated with neuritic dystrophy and/or the disorganization of the neuronal microtubule network, plus an increase in astrogliosis and lipid peroxidation in the brain regions associated with AD, such as the motor and lateral entorhinal cortex, the amygdaloid basal nucleus, and the hippocampus. Aortic atherosclerotic lesions were positively correlated with age, although potentiated by the transgenic genotype, while cerebral β-amyloidosis was positively correlated with genetic background rather than with age. These findings confirm hypercholesterolaemia as a key biomarker for monitoring mild cognitive impairment, and shows these transgenic mice can be used as a model for cognitive and psycho-motor decline.
An abnormal production of reactive oxygen species (ROS) and the subsequent decrease in vascular bioavailability of nitric oxide (NO) have long been proposed to be the common pathogenetic mechanism of the endothelial dysfunction, resulting from diverse cardiovascular risk factors such as hypercholesterolaemia, diabetes mellitus, chronic smoking, metabolic syndrome, and hypertension. Superoxide produced by the nicotinamide dinucleotide phosphate (NADPH) oxidase, mitochondrial sources, or the xanthine oxidase may react with NO, thereby resulting in excessive formation of peroxynitrite, a reactive nitrogen species that has been demonstrated to accelerate the atherosclerotic process by causing direct structural damage and by causing further ROS production. Despite this sound biological rationale and a number of pre-clinical and clinical lines of evidence, studies testing the effects of classical antioxidants such as vitamin C, vitamin E, or folic acid in combination with vitamin E have been disappointing. Rather, substances such as statins, angiotensin-converting enzyme inhibitors, or AT1-receptor blockers, which possess indirect antioxidant properties mediated by the stimulation of NO production and simultaneous inhibition of superoxide production (e.g. from the NADPH oxidase), have been shown to improve vascular function in pre-clinical and clinical studies and to reduce the incidence of cardiovascular events in patients with cardiovascular disease. Today, oxidative stress remains an attractive target for cardiovascular prevention and therapy. However, a deeper understanding of its source, and of its role in vascular pathology, is necessary before new trials are attempted.
To examine the relation of midlife raised blood pressure and serum cholesterol concentrations to Alzheimer's disease in later life.
Prospective, population based study.
Populations of Kuopio and Joensuu, eastern Finland.
Participants were derived from random, population based samples previously studied in a survey carried out in 1972, 1977, 1982, or 1987. After an average of 21 years' follow up, a total of 1449 (73%) participants aged 65-79 took part in the re-examination in 1998.
Midlife blood pressure and cholesterol concentrations and development of Alzheimer's disease in later life.
People with raised systolic blood pressure (>/=160 mm Hg) or high serum cholesterol concentration (>/=6.5 mmol/l) in midlife had a significantly higher risk of Alzheimer's disease in later life, even after adjustment for age, body mass index, education, vascular events, smoking status, and alcohol consumption, than those with normal systolic blood pressure (odds ratio 2.3, 95% confidence interval 1.0 to 5.5) or serum cholesterol (odds ratio 2.1, 1.0 to 4.4). Participants with both of these risk factors in midlife had a significantly higher risk of developing Alzheimer's disease than those with either of the risk factors alone (odds ratio 3.5, 1.6 to 7.9). Diastolic blood pressure in midlife had no significant effect on the risk of Alzheimer's disease.
Raised systolic blood pressure and high serum cholesterol concentration, and in particular the combination of these risks, in midlife increase the risk of Alzheimer's disease in later life.
Cardiovascular risk factors, such as oxidative stress and elevated lipids, are linked to the development of cognitive impairment. A mediator common to both stressors is the apolipoprotein E (apoE). The objectives of this study are to determine the effects of apoE deficiency and diet-induced systemic oxidative stress in mice on vascular expression of inflammatory proteins and on cognitive function. Mice are placed on a diet enriched in homocysteine for fifteen weeks and then assessed for spatial learning using an eight-arm radial maze and for inflammatory protein expression by immunohistochemistry. Our results show that diet-induced oxidative stress does not affect cognitive function in normal mice. In contrast, apoE-/- mice on the homocysteine diet show significantly impaired (p<0. 001) maze performance. ApoE-/- mice also have high cholesterol levels. There is no expression of inflammatory proteins IL-6 and IL-8 in the vasculature of control mice on normal or homocysteine diet and little in apoE-/- mice on normal diet. In contrast, apoE-/- mice on homocysteine diet show pronounced vascular reactivity to IL-6 and IL-8 antibodies. These data show that systemic oxidative stress correlates with expression of inflammatory proteins in the cerebral vasculature and impaired cognitive function. These results are consistent with the hypothesis that an oxidative-inflammatory cycle in the cerebral vasculature could have deleterious consequences for cognition.
Hypercholesterolemia is an early risk factor for Alzheimer's disease. Low-density lipoprotein (LDL) receptors might be involved in this disorder. Our objective was to determine the risk of mild cognitive impairment in a population of patients with heterozygous familial hypercholesterolemia, a condition involving LDL receptor dysfunction and lifelong hypercholesterolemia.
By using a cohort study design, patients with familial hypercholesterolemia (N=47) meeting inclusion criteria and comparison patients without familial hypercholesterolemia (N=70) were consecutively selected from academic specialty and primary care clinics, respectively. All patients were older than 50 years. Those with disorders that could affect cognition, including history of stroke or transient ischemic attacks, were excluded from both groups. Thirteen standardized neuropsychologic tests were performed in all subjects. Mutational analysis was performed in patients with familial hypercholesterolemia, and brain imaging was obtained in those with familial hypercholesterolemia and mild cognitive impairment.
Patients with familial hypercholesterolemia showed a high incidence of mild cognitive impairment compared with those without familial hypercholesterolemia (21.3% vs 2.9%; P=.00). This diagnosis was unrelated to structural pathology or white matter disease. There were significant differences, independent of apolipoprotein E4 or E2 status, between those with familial hypercholesterolemia and those with no familial hypercholesterolemia in several cognitive measures, all in the direction of worse performance for those with familial hypercholesterolemia.
Because prior studies have shown that older patients with sporadic hypercholesterolemia do not show a higher incidence of mild cognitive impairment, the findings presented suggest that early exposure to elevated cholesterol or LDL receptor dysfunction may be risk factors for mild cognitive impairment.
A historical perspective on atherosclerosis allows us to reflect on the once controversial hypotheses in the field. Plaque formation was once thought to be dependent upon hypercholesterolemia alone, or solely in response to injury. More recently, inflammatory cascades were thought to be at the root of lesion development. A more realistic view may be that atherosclerosis is neither exclusively an inflammatory disease nor solely a lipid disorder: it is both.