Background
Many epidemiologic studies have found that patients with chronic kidney disease (CKD) are at risk of subsequent cognitive function impairment [
1,
2], particularly among the elderly [
3]. Furthermore, even in patients with established dementia, it has been shown that renal dysfunction is associated with episodic memory deficits, medial temporal lobe atrophy, and cortical thickness [
4]. Several potential mechanisms have been proposed to explain the linkage between CKD and cognitive function decline, including cerebrovascular pathologies, inflammation, alterations in amyloid homeostasis, and metabolic dysregulation [
2,
5].
In addition to kidney function, there has been considerable interest in elucidating the role of nutritional factors in impaired cognition and dementia risk among older people. Several studies have reported that low serum level of albumin is independently associated with poor cognitive performance in the elderly [
6,
7]. Furthermore, anemia or abnormal hemoglobin concentrations have been reported to be associated with an increased risk for dementia and rapid cognitive decline among the elderly [
7,
8].
Individuals aged 80 years and older, who are often termed the “oldest-old” in the literature, are the fastest growing age group in many parts of the world. The prevalence of dementia among the oldest-old population ranges from 18 to 38% [
9], and several factors have been proposed to be involved in the development of dementia, including aging, gender, race, education, genotype, diabetes, dyslipidemia, hypertension, and vascular disease [
10,
11]. It should be noted that these factors may have slightly different effects on risk of dementia in the very old compared with younger-old subjects. However, the relationship between CKD, nutritional status (biochemical and hematological parameters), and development and/or progression of dementia in the oldest-old is unclear.
In Taiwan, the prevalence of dementia is around 1.7 to 4.3% with the most common type being Alzheimer’s disease (AD) [
12]. In a nationwide survey, it was shown that the age-adjusted prevalence of dementia in the following age groups was 3.40% for 65–69 years, 3.46% for 70–74 years, 7.19% for 75–79 years, 13.03% for 80–84 years, 21.92% for 85–89 years, and 36.88% for ≥90 years [
12]. Because the oldest-old subpopulation has the highest rate of dementia, which involves a variety of social and financial burdens, provision of satisfactory care for this age group presents clinicians and public health policymakers with a considerable challenge [
12,
13]. At present, nearly 70,000 old people (mean age 84.7 years) are living in veterans’ residential communities in Taiwan and are provided with relatively poor psycho-socio-economic resources [
14]. Our previous prospective cohort study of the oldest-old with newly diagnosed AD living in a veterans’ home showed that comorbidity burden, as well as nutritional and physical functional status were important predictors of survival [
15]. To date, few studies on the factors related to dementia severity, particularly in the oldest-old population, such as kidney function and nutrition, have been conducted in Taiwan. To address this issue, we conducted a cross-sectional study to determine the effect of kidney function, serum albumin, and hemoglobin on dementia severity at the time of AD diagnosis among old people aged ≥80 years.
Discussion
In this cross-sectional study, we found that in the oldest old patients with AD, eGFR was significantly associated with dementia severity scores by CDR. In addition, serum albumin and hemoglobin were significantly associated with MMSE scores. These results suggest that renal, nutritional, and hematological status may play a role in disease progression in the oldest old patients with dementia.
The prevalence of CKD increases markedly with age. An analysis of the 30,528 participants in the NHANES 1988–1994 and 1999–2006 pooled cohort revealed that the highest prevalence of eGFR < 60 mL/min/1.73m
2 was among those ≥80 years of age, with a rate of nearly 51% [
23]. In our study, the percentage of oldest old with CKD was 50%, which was compatible with the aforementioned report. Several studies have shown that risk of cognitive decline or dementia is increased in older adults with reduced kidney function [
3]. However, only a few studies have investigated the association between the decrease in renal function and cognitive performance in the oldest old people. Three previous studies reported that eGFR was associated with cognitive impairment in individuals aged 80 years or older [
24‐
26]. Our results were in line with the aforementioned studies, and also found a significant association between impaired kidney function and cognitive decline in the oldest old people, although some other studies showed conflicting results [
27,
28]. The reason that eGFR was associated with CDR but not MMSE scores after adjustment for potential confounding variables is not clear. It has been reported that most domains of cognitive function are affected by impaired kidney function across all stages of CKD with the executive function being affected earlier than episodic memory and global ability, which may be assessed by CDR [
3]. In contrast, MMSE is limited in the assessment of all cognitive domains, with the notable absence of executive function and psychomotor speed [
29].
It was proposed that CKD in old people may often coexist with risk factors for cognitive impairment, such as diabetes, hyperlipidemia, and cardiovascular disease, and these in turn can contribute to the development of dementia [
27]. In addition, neuroimaging studies showed that kidney function is associated with hippocampal volume, white matter hyperintensity, and cognitive decline in oldest old patients with mild cognitive impairment and AD [
10,
30,
31]. Several pathological changes, such as hippocampal sclerosis, amyloid angiopathy, and microvascular injury in particular, have been found in the oldest old dementia patients, including Alzheimer’s disease [
32]. Because CKD is often associated with systemic endothelial injury, it may contribute to the development of dementia by interacting with neuronal pathologies [
33]. Finally, in renal insufficiency, amyloid homeostasis may be altered, which thus exacerbates neuronal damage [
34]. Overall, previous studies in the literature as well as the investigation presented herein indicate a relationship between kidney function and cognition decline in the oldest old individuals with dementia.
CKD in the older population has been associated with several CKD-related metabolic complications, such as anemia and hypoalbuminemia [
23]. In our study, after adjustment for kidney function, serum albumin and hemoglobin were both still associated with MMSE scores, suggesting their potential roles in the development of AD in the oldest old. This association of cognitive impairment with serum albumin and hemoglobin levels may be explained by certain pathophysiological mechanisms. Albumin is an antioxidant which may help prevent excessive oxidant stress induced by inflammation in the aging neuronal cell [
35]. As inflammatory mechanisms are involved in the pathogenesis of dementia, including Alzheimer’s disease [
36], low serum albumin levels may become a risk factor for cognitive decline in AD. Anemia can cause tissue oxygenation, and consequently reduce the reserve response of the brain to external insults, and promote neuronal degeneration [
37]. Thus, low hemoglobin levels may potentially predispose to dementia and poor cognitive performance. Also, both hypoalbuminemia and anemia may be a consequence of underlying comorbidities, and nutrient deficiency (e.g., folate and vitamin B12), which have been shown to have deleterious effects on cognitive functioning [
35,
38]. However, it should be noted that MMSE scores are influenced by several factors such as age, educational level, and premorbid intelligence of the patients [
20,
21]. Further longer studies are required to clarify the relationship between serum albumin, hemoglobin, and disease severity in the oldest old people with dementia. A variety of risk factors for cardiovascular disease are reported to have less obvious effects on cognition in the oldest old when compared with younger individuals [
39,
40]. In individuals over 75 years of age, it was reported that high systolic blood pressure (≥ 160 mmHg) was not associated with a greater risk of dementia [
41], and the risk of dementia even decreased with an increasing blood pressure level in subjects aged 85 years or older [
42]. In our study, we found that in the oldest old, those with a history of dementia and hypertension tended to exhibit less decline in cognition. This finding supports previous reports, although the optimal blood pressure with respect to dementia risk in this subpopulation requires further research. In this study, we also found that ADL scale was significantly associated with dementia severity scores by CDR. This finding was compatible with several previous reports that cognitive decline affects the performance of activities of daily living in patients with dementia [
43]. Executive dysfunction is a common manifestation of AD in all stages, and it has been shown in several studies that there is a link between executive dysfunction and impaired performance on ADL scales [
44]. The effect of cognitive functions on changes of daily functions is important because it will tell clinicians and families to provide appropriate interventions to improve or maintain daily performances for preparation of sufficient supporting resources in the care of older patients with dementia.
In a previous study in Taiwan, it was demonstrated that the risk of dementia increased with the number of medications used, possibly due to their adverse effects on the central nervous system [
45]. Besides, multiple comorbidities also exhibited a strong influence on dementia. Although, in our study, the numbers of comorbidities and medications were not related to dementia severity at the time of AD diagnosis, careful management of comorbidities and medications is necessary to prevent dementia. On the other hand, people with dementia often present with concomitant chronic medical conditions, that may worsen clinical course (i.e., by accelerating cognitive and functional decline) and complicate their pharmacological management for dementia [
46]. Thus, after the diagnosis of dementia, a comprehensive evaluation of associated diseases and all pharmacological treatments was required [
46].
A few demographic and social factors have been identified as risk factors for developing dementia in the oldest old, including the pre-dementia status of instrumental activities during daily living, mental stimulation, and levels of leisure activities [
47]. In our study, it was shown that moderate to severe dementia by CDR was present in 51.8% of the subjects who were newly admitted to the dementia care institute. Two previous reports have shown similar severity rates in residents at nursing homes [
48,
49], although some have reported less severe rates [
50,
51]. We speculate that our oldest old patients’ symptoms of dementia might not have been recognized early because their disability may have been attributed to comorbid diseases or other physiological complexities, rather than to dementia. In our patients, the majority (56.0%) had less than 6 years of education, and there was no significant association between education level and dementia severity by CRD or MMSE scoring at the diagnosis of AD. It has been reported that education is only a relevant variable for understanding cognitive performance in older age, as it is related to the rate of decline in aging [
52]. Moreover, some studies have found education to be a risk factor for vascular dementia, rather than Alzheimer’s disease [
53].
Our findings may have some clinical implications. A recent study reported that among frail elderly individuals’ severity of renal dysfunction was independently correlated with cognitive impairment [
26]. It was suggested that a combination of cognitive and renal function decline may more exacerbate the vulnerability of older persons, and resulted in adverse health-related outcomes. Altogether, our study findings as well as the previous report implicate future research focusing efforts on identifying renal impairment early in patients with dementia to prevent frailty progression and preserve the quality of life. Besides, some experimental and clinical studies have shown that through inhibiting the renin-angiotensin system in patients with dementia, not only is the progression of renal disease slowed down, but dementia incident risks can also be reduced [
54,
55]. Moreover, restoration of malnutrition and anemia has also been reported to improve cognition in older patients with dementia [
56,
57]. In caring for elderly patients with dementia, clinicians should not only recognize the severity of cognitive dysfunction, but should also examine the nutrition and hemoglobin before proposing treatment strategies to slow progression of cognition impairment.
There were several limitations in this study. First, it employed a cross-sectional design, and it lacked a control group. Thus, a causal relationship could not be established. Second, the study population was small, and more than half of the enrolled subjects were at a moderate or severe stage of cognition impairment. Based on the findings presented herein, it is not possible to establish whether the associations between renal and cognitive function would be found among oldest old patients in the early stage of their disease, and thus further investigation is required. Third, about 93% of the study subjects were male. Thus, the result may be hard to be representative of both genders. Because many studies have reported that women have a higher incidence rate of dementia than men especially at their oldest-old ages [
9]. Further research in the oldest-old female patients with dementia is necessary to establish a more definite conclusion. Fourth, using CKD-MDRD eGFR to represent renal function in oldest old individuals may not be accurate as no consensus has been reached regarding the best renal assessment method for this age subpopulation [
58]. Lastly, other potential risk factors for oldest old dementia, such as low level of physical activity, depression, delirium, inflammatory markers, genotyping, and drugs for AD treatment were not examined in the current study [
9‐
11]. Further larger and longitudinal analyses are required to determine whether decreased renal function, nutritional, and hematological status predict cognitive decline in the oldest old with dementia.
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