Journals | Policy | Permission

Journal of Clinical Medicine Research

Original Article

Volume 15, Number 4, April 2023, pages 216-224

Predictors of Conversion to Dementia in Patients With Mild Cognitive Impairment: The Role of Low Body Temperature

The prevalence of cognitive impairment in the general population increases with age [1]. As life expectancy continues to climb, so will the prevalence of cognitive impairment. Mild cognitive impairment (MCI) is a stage where individuals experience trouble recalling details, learning new information, and concentrating on tasks. This stage, which lies between normal cognitive decline related to aging and dementia, can remain undetected in older adults. Patients diagnosed with MCI often progress to dementia [1]. Dementia is a condition characterized by a progressive decline in cognitive function that can affect a patient’s day to day functioning. In addition, dementia is a heavy burden on caregivers and family members living with the patient. In fact, the total annual cost for managing individuals with cognitive impairment globally has reached nearly $244 billion [2].

Studies have been conducted to determine the factors that play a role in the conversion of MCI to dementia [2]. Multiple factors including age, educational level, physical activity, lifestyle behaviors, and chronic diseases have been associated with cognitive decline [3]. Radiological, brain function and cerebrospinal fluid (CSF) tests have been useful in determining those who are likely to convert from MCI to dementia. These radiological markers include entorhinal atrophy, hippocampal atrophy and white matter disease seen on computed tomography (CT) and magnetic resonance imaging (MRI). Additionally, decreased glucose metabolism in Lewy body dementia can be seen with positron emission tomography (PET) [4, 5]. Some studies have shown that biomarkers, such as amyloid-beta and tau proteins in CSF, predict conversion as well [6, 7]. Certain neuropsychological tests may also help to predict conversion [8]. In addition, some studies have shown that these markers in combination can be used to predict conversion to dementia [9]. While these markers may be useful for patients able to do more advanced testing, there are common medical factors that can be collected on history and physical exam in clinic that may also contribute to conversion.

Temperature regulation is a vital body function and can serve as a marker for other physiological changes that occur as part of the normal aging process in the elderly. The normal range of body temperature is 36 - 38 °C. Hypothermia is defined as a body temperature below 35 °C, and low body temperature is defined as below 36 °C. Low body temperature is commonly seen in geriatric patients [10]. The temperature ranges between 35 and 36 °C, which we have defined as subnormal low body temperature, has not been studied in the literature. Body temperature has been postulated to be a risk factor for Alzheimer’s disease (AD) and may also be implicated in the pathophysiology of dementia [11]. There is some evidence in the literature regarding the effect of hypothermia and heat stroke on cognitive decline, but research on low body temperature, especially subnormal low body temperature and its affect on cognition, is lacking [12].

In this study, we hypothesized that low and subnormal body temperature, along with other risk factors, play a role in the conversion of MCI to dementia. Orthostatic and postural hypotension (OH and PH) are disabling conditions that are associated with cognitive decline in geriatric patients [13]. Hearing impairment, depression, vascular risk factors, family history of dementia, low education, and living alone are other potential risk factors that have also been shown to be associated with dementia. Epidemiological studies have shown that about 15% of patients diagnosed with MCI progress to dementia annually [14]. Thus, patients with MCI represent a high-risk group for the development of dementia and would be ideal targets for interventions related to modifiable risk factors [15]. A better understanding of factors that influence conversion from MCI to dementia is needed to inform these interventions. Given the importance of behavioral health integration in physician practice, this study may shed light on these other less emphasized aspects of dementia management [16]. The objectives of this study are firstly to assess the prevalence of MCI, secondly to determine the proportion of patients that convert from MCI at baseline to dementia during the follow-up period of 5.5 years and lastly to determine demographic, social, lifestyle and clinical factors that were associated with conversion from MCI to dementia.

This study is based on a retrospective chart review of 1,330 patients aged 61 to 103 years at the Kaye Edmonton Senior’s Clinic in the University of Alberta Hospital. Information on onset of MCI, demographic, social, lifestyle and clinical risk factors, as well as current medications at baseline was collected from an electronic database with patient charts. The baseline period was defined as January 2015 to July 2018 and was considered the entry point of patients into our study. Patients with MCI were then followed until the end of our study in July 2021 to determine the developments of dementia. Ethics approval was obtained from the ethics committee at the University of Alberta Hospital. The study was conducted in compliance with the ethical standards of the responsible institution on human subjects as well as with the Helsinki Declaration.

Subjects who had been diagnosed with MCI at baseline were included in the study. MCI diagnoses were made based on medical history, physical and neurological examinations, cognitive testing, and brain imaging with CT by geriatricians who were familiar with MCI and dementia diagnostic criteria. Subjects with dementia and those without a cognitive assessment at the baseline were excluded.

The standards of practice which recognize the cognitive stages of MCI and dementia were based on Petersen’s/European Consortium Criteria and DSM IV or DSM V criteria. MCI is defined as the presence of subjective and objective cognitive impairment without functional decline, hence not meeting the criteria for dementia. The clinical diagnosis of MCI is very similar to that of dementia. MCI was diagnosed according to the European Consortium on Alzheimer’s disease criteria, which is the currently available standard test to diagnose MCI. The Consortium criteria include: 1) cognitive complaints coming from the patients or their families, 2) the reporting of a decline in cognitive functioning relative to previous abilities during the past year by the patient or informant, 3) cognitive disorders as evidenced by clinical evaluation (impairment in memory or in another cognitive domain, which in this study was assessed by Montreal cognitive assessment (MoCA) and mini-mental status exam (MMSE)), 4) absence of major repercussions on daily life, and 5) absence of dementia criteria [17, 18]. The Peterson’s criteria for MCI include: 1) impaired memory usually corroborated by an informant, 2) objective memory impairment for the patient’s age, and 3) intact functional activities. Petersen divided MCI into two categories: 1) amnestic MCI, where there is evidence of memory domain impairment only, and 2) non-amnestic MCI, where there is a single non-memory cognitive domain impairment [17, 18].

In this study, impairment in memory or in another cognitive domain was assessed by MoCA, and absence of major limitations on daily life was measured using Katz activities of daily living (ADL) and Lawton’s instrumental activities of daily living (IADL). Dementia was ruled out by using DSM IV or DSM V criteria.

The diagnosis of dementia, and screening for depression, was made according to DSM IV or DSM V criteria [19]. Functional information on daily activities was collected using Katz basic activities of daily living (BADL) and Lawton IADL questionnaires [20, 21]. Patients were followed for a period of 3 to 5.5 years, depending on when their baseline assessment was completed, for the development of dementia according to the diagnostic criteria described above.

Information on the presence of low body temperature, OH, hearing impairment, vascular risk factors and current medications was determined from geriatric assessments completed in the Kaye Edmonton Senior’s clinic at baseline, which we defined as the period from January 2015 to July 2018. Other demographic information was also obtained from the electronic charts, such as age, sex, and smoking status.

Blood pressures were measured in the supine and standing position after 3 min. These measurements were taken by trained clinical nurses during patient’s baseline geriatric assessments. OH was defined as a systolic blood pressure drop of greater than or equal to 20 mm Hg or a diastolic drop of greater than or equal to10 mm Hg [22].

Temperature was measured once between 8 am and 4 pm during the clinic hours. Among types of temperature measurement techniques, rectal temperature is the most accurate. Oral and tympanic temperatures are acceptable and often more practical in clinical settings [23]. Skin and axillary temperature measurements have some limitations [24]. In this study, tympanic temperatures were taken in all subjects. The normal range of body temperature is 36 to 38 °C [25]. We have defined low body temperature as less than 36 °C and subnormal body temperature as ≥ 35 °C and < 36 °C.

Standardized MMSE and MoCA scores were used to measure global cognitive function and clock drawing was used for executive function testing [26-28].

Baseline characteristics were compared between those who converted from MCI to dementia and those who did not to convert in the univariate analysis. The factors that were significant in the univariate analysis were then considered in the multivariable logistic regression to identify the factors individually associated with conversion to dementia. All analysis was performed using STATA. Statistical significance was set at P < 0.05 for all statistical tests.

After a search for patient encounters at the Kaye Edmonton Senior’s Clinic during the period of January 2015 to July 2018, we were able to retrieve 1,330 patient charts. Of these patients, 335 had a diagnosis of MCI at baseline, resulting in a prevalence of 25.6%. The mean age of patients with MCI at baseline was 76.5 years (standard deviation (SD): 7.2) with the range being 61 to 103 years. The proportion of females in this study was slightly greater than that for males (54.6% vs. 45.4%). The proportion of patients who converted to dementia from MCI was 42.7% (143/335) over the follow-up period of 5.5 years. Mean time to conversion in this study was 2.14 years (SD: 1.34) with the range being 0.15 to 5.3 years. The proportion of polypharmacy seen was 58.5% (196/ 335). The proportion of subjects with low body temperature (temperature less than 36 °C) was 13.5% (44/326) and the proportion of subjects with subnormal body temperature (≥ 35 °C and < 36 °C) was 12.6% (41/326). There were only three subjects with a temperature less than 35 °C.

Baseline characteristics of non-converters and converters from MCI to dementia are shown in Table 1. There were significant differences between non-converters and converters in mean age (P = 0.04), mean MoCA score (P = 0.001), and in the proportion of patients with a family history of dementia (P < 0.001), abnormal clock drawing (P = 0.004), polypharmacy (P = 0.003), overweight/obesity (P = 0.03), body mass index (BMI) (P = 0.001) and low body temperature (P < 0.001). Age, sex, smoking history, family history of dementia, IADL, MoCA, polypharmacy and low body temperatures were taken into consideration for the multivariable logistic regression analysis. Abnormal clock drawing was excluded from the multivariable logistic regression because of the high correlation with MoCA.

Click to view

Table 1. Baseline Characteristics of MCI Converter and MCI Non-Converter Groups

As shown in Table 2, factors that were significantly associated with conversion from MCI to dementia in the multivariable logistic regression were family history of dementia (odds ratio (OR): 2.78, 95% confidence interval (CI): 1.56 - 4.95, P = 0.001), MoCA score (OR: 0.91, 95% CI: 0.85 - 0.97, P = 0.01), and low body temperature (below 36 °C) (OR: 10.01, 95% CI: 3.59 - 27.88, P < 0.001). Although age, sex, smoking history, IADL, BMI and polypharmacy were not significant in the multivariable logistic regression, they were not removed from the multivariable regression as they were considered as potential confounders.

Click to view

Table 2. Risk Factors for Conversion of MCI to Dementia: Results From the Multiple Logistic Regression Analysis

A sensitivity analysis was conducted to determine characteristics that were significantly different between the patients with low and normal body temperature. Patients with low body temperature were taking fewer number of medications (45.5% vs. 61.4%, P = 0.05) and less likely to be overweight or obese (45.5% vs. 61.4%, P = 0.02).

MCI is the prodromal phase of dementia [27]. A study by Espinosa et al examined different risk factors that played a role in subsequent conversion to dementia [29]. In our study, low MoCA score, family history of dementia and low body temperature were the three risk factors that played a significant role in the conversion of MCI to dementia in the final multivariate analysis model.

MoCA is one of the screening tests to assess for MCI. It measures cognitive domains like abstraction and executive function which are not normally measured by MMSE. It has been shown to have excellent psychometric properties, such as internal consistency and test-retest reliability [26, 27]. In addition, the MoCA test is effective at discriminating between patients with normal cognition and MCI. The European Consortium Criteria diagnosis for MCI in elderly needs a detailed clinical history which is not available most of the time [17, 18]. This makes the MoCA score a quick and useful assessment in practice to determine if a patient is exhibiting some cognitive deficits.

In this study, low MoCA score at baseline was a predictor of conversion to dementia. As expected, subjects with higher global cognitive function as measured by MoCA were less likely to progress to dementia.

In practice, a detailed family history of dementia may have similar utility to blood-based biomarkers. However, tests to screen for these biomarkers are costly and invasive. A good understanding of family history can shed light on genetic risk and susceptibility for a dementia diagnosis. As seen in the literature, an individual’s risk of developing dementia increases with a positive family history [30, 31]. The lifetime risk for developing dementia when having a first degree relative with an AD diagnosis ranges from 25% to 40% [30, 31]. Additionally, previous research has shown that patients with a maternal history had a higher risk of progression to dementia [32]. Although our study confirmed the role that family history plays in conversion of MCI to dementia, it did not distinguish between paternal and maternal family history.

This study has shown that lower body temperature was associated with increased risk of conversion from MCI to dementia. Age-associated decrease in body temperature in the elderly is well documented in the literature [33]. Low body temperature in the elderly could be due to decreased production of heat by low basal metabolic rate, decreased blood flow due to changes in vasculature and increased heat loss due to thinner skin and less subcutaneous fat. Animal and human studies have shown that elderly body temperature can be lower than 37 °C [10, 34]. Core body temperature, or temperature of vital organs, including the brain, is not well understood and thermoregulation plays a major role in maintaining it. Thermoregulation is less efficient at regulating core body temperature in older adults [34, 35]. In spite of external temperature variations, body temperature is maintained in a tight range by homeostatic mechanisms. Neurohormonal control of body temperature plays a large part in thermoregulation, and in the elderly these mechanisms begin to deteriorate. The inability to regulate body temperature is known as poikilothermia. Other factors that can affect thermoregulation and cause low body temperature include cardiovascular, neurological, and endocrine conditions [34, 35]. Mental illness, alcohol and recreational drug use can also impact thermoregulation. As medications can also disrupt thermoregulation, our study accounted for this by adjusting for polypharmacy in statistical analyses. Impaired thermoregulation with aging increased the incidence of hypothermia, and this may be a risk factor for AD [34, 35]. Hypothermia may also be iatrogenic or secondary to medical conditions, such as diabetes or use of anesthesia [36, 37]. Hypothermia is commonly seen during surgery. In an animal study, intraoperative hypothermia caused hippocampal damage and led to postoperative cognitive dysfunction (POCD) [36]. An animal study using transgenic mice demonstrated that mice with low temperature have more abnormal tau proteins and a loss of synaptic proteins, both of which are pathological markers of AD [38]. Additionally, when environmental temperature was elevated by even 1 °C, there was a decrease in brain plaques and memory test results were comparable to normal mice. In another study, La Freche et al reported increased tau protein levels in the brain after anesthesia-induced hypothermia [39]. A different animal study showed that for each °C below normal body temperature, there was an 80% increase in tau protein phosphorylation [40].

Although our finding regarding low body temperature being a risk factor for conversion of MCI to dementia is novel, there are some studies that may explain this phenomenon. Holtzman et al have hypothesized that low body temperature over long periods may accelerate pathology and progression of AD [11]. This lower-than-normal body temperature may even be prodromal, as a case report has shown low body temperature can be seen several years prior to the onset of AD [42]. In a small human study, low nocturnal core body temperature seen in Lewy body dementia was shown to be a biomarker of neurodegeneration [42]. Additionally, Whittington et al suggested a neuropathological link between low temperature and AD [43]. A recent human study in cognitively normal adults showed low body temperature may be associated with increased tau pathology [44]. Carrettiero et al proposed that temperature abnormalities can affect tau regulation of microtubule function [45]. Low temperature causes destruction of microtubules, loss of synaptic function, and a decrease in neurotransmitter levels [46, 47]. The hippocampus can be affected by these mechanisms, which can lead to problems with memory.

Homeostasis is maintained in large part by the autonomic nervous system, which is intimately linked to temperature control. An inadequate autonomic response to physiological stressors can contribute to lower body temperature and affect cognitive performance. Autonomic dysfunction is common in dementia, which affects core vital functions including temperature control. AD is the most common neurodegenerative dementia with pathology involving tau proteins and microtubules. Tau forms insoluble aggregates and causes neurotoxicity by affecting neuronal microtubule stability. These microtubules play a significant role in neuronal function and may be implicated in the autonomic dysfunction seen in dementia [48, 49]. In fact, autonomic dysfunction can occur with normal aging, and aging itself is a risk factor for dementia [47, 50]. In this way, the novel risk factor of body temperature at or below 36 °C in our study may simply be an indicator of autonomic dysfunction in MCI patients. Thus, these MCI patients would be more likely to progress to dementia. In our study, we used infrared tympanic membrane temperature measurements. Anatomically, the tympanic membrane is close to the hypothalamus, which is the main thermoregulatory center [48].

A few studies, including a recent study in elderly women, have reported that even ambient temperature changes can affect neurocognitive function, including semantic memory and executive function [49, 50]. One study has shown that elevated daytime skin temperature in both AD and elderly controls was associated with more daytime sleepiness in AD subjects [51]. A recent paper by Eggenberger et al measured peak-to-peak body temperature measurements during a 12-h interval, and found that median temperature may be a better predictor of MCI [52]. Even though previous research has shown that low body temperature is associated with both MCI and dementia separately, this study is the first to report an association of low body temperature with conversion to dementia in patients already diagnosed with MCI at baseline. Correcting low body temperature and hypothermia in elderly subjects may prevent or slow down dementia-related cognitive decline [53, 54]. An animal study showed mild hyperthermia with sauna-like treatment in mice reduces tau-phosphorylation [54]. Knekt et al in their study showed frequent sauna bathing in middle-aged men is associated with reduced risk of dementia in later life [54]. Interventions to increase muscle mass, such as regular exercise and reducing sedentary lifestyle can also help to raise body temperature in human subjects [55, 56]. In this sense, low body temperature represents a modifiable risk factor for dementia that can be corrected with appropriate treatment modalities.

In this study, most of the baseline diagnoses were amnestic MCI. Secondly, this study is a retrospective chart review of subjects recruited from a single teaching hospital, which may limit the generalizability of the study results. Furthermore, all the temperatures were tympanic in our study, and rectal temperatures may more closely approximate core body temperature. Additionally, the temperature measurements were taken only once at the point of entry of each patient into the study. In addition, it is possible that diet may induce thermogenesis. Body temperature after meal and physical exercise were not measured in the study which may have an influence on the body temperature. Future studies should consider taking multiple temperature measurements to study how core body temperature changes with progression to dementia. Ambient temperature was not recorded in clinic either, which could have affected the body temperature of participants. As previously noted, lower education is a risk factor for dementia. Information on education level was inconsistent during the chart review and was excluded from the analyses. MCI subjects carrying the apolipoprotein E (APOE) epsilon4 allele showed cognitive profile similar to early AD patients. APOE epsilon4 allele genotype was associated with increased prevalence and risk of AD and early-onset of AD with ages at onset less than 60 years [57-59]. In our study, we did not have information on genetic risk factors including APOE.

This study identified risk factors that put patients diagnosed with MCI at higher risk for progression to dementia. Many of these risk factors have been previously established, such as a positive family history, low scores on cognitive assessments, and aging. Emerging risk factors identified in this study, such as low body temperature, may also affect pathological processes that worsen cognition in MCI patients. Identifying and correcting established and emerging modifiable risk factors is crucial for patients diagnosed with MCI. For example, correcting low body temperature in the elderly may be possible with warm blankets, adjusting room temperature, warm liquid consumption, avoiding alcohol, regular exercise, and sauna baths. Knowing which patients diagnosed with MCI are at highest risk for conversion to dementia allows practitioners to identify which patients to more closely monitor and initiate management strategies for cognitive decline. Novel risk factors like low body temperature indicate that autonomic dysfunction may be the driving force for conversion of MCI to dementia. These practical clinical indicators can easily be collected during geriatric assessments and may have similar utility to expensive laboratory and imaging techniques. Integrating body temperature measurements as part of cognitive assessments should be examined in future studies.

Acknowledgments

None to declare.

Financial Disclosure

Prabhpaul Dhami was funded by a Summer Studentship Award from the Mach-Gaensslen Foundation of Canada.

Conflict of Interest

The authors report no conflict of interest in this work.

Informed Consent

Not applicable.

Author Contributions

Kannayiram Alagiakrishnan contributed to the study design, planning and implementation of the study and preparation of the manuscript. Prabhpaul Dhami retrieved the data from the electronic database of patient charts and contributed to the preparation of the manuscript. Ambikaipakan Senthilselvan conducted the statistical analysis and contributed to the preparation of manuscript.

Data Availability

Data were obtained from Alberta Health Services under strict guidelines for the use of the data for this study and authors are not permitted to share the data.

1. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56(3):303-308.
   doi pubmed
2. Alzheimer’s Association. Alzheimer’s disease facts and figures. Alzheimers Dement. 2020;16:391-460
3. Kraft E. Cognitive function, physical activity, and aging: possible biological links and implications for multimodal interventions. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2012;19(1-2):248-263.
   doi pubmed
4. Modrego PJ. Predictors of conversion to dementia of probable Alzheimer type in patients with mild cognitive impairment. Curr Alzheimer Res. 2006;3(2):161-170.
   doi pubmed
5. Devanand DP, Pradhaban G, Liu X, Khandji A, De Santi S, Segal S, Rusinek H, et al. Hippocampal and entorhinal atrophy in mild cognitive impairment: prediction of Alzheimer disease. Neurology. 2007;68(11):828-836.
   doi pubmed
6. Prasad K, Wiryasaputra L, Ng A, Kandiah N. White matter disease independently predicts progression from mild cognitive impairment to Alzheimer's disease in a clinic cohort. Dement Geriatr Cogn Disord. 2011;31(6):431-434.
   doi pubmed
7. van Rossum IA, Vos S, Handels R, Visser PJ. Biomarkers as predictors for conversion from mild cognitive impairment to Alzheimer-type dementia: implications for trial design. J Alzheimers Dis. 2010;20(3):881-891.
   doi pubmed
8. Gainotti G, Quaranta D, Vita MG, Marra C. Neuropsychological predictors of conversion from mild cognitive impairment to Alzheimer's disease. J Alzheimers Dis. 2014;38(3):481-495.
   doi pubmed
9. Eckerstrom C, Olsson E, Bjerke M, Malmgren H, Edman A, Wallin A, Nordlund A. A combination of neuropsychological, neuroimaging, and cerebrospinal fluid markers predicts conversion from mild cognitive impairment to dementia. J Alzheimers Dis. 2013;36(3):421-431.
   doi pubmed
10. Waalen J, Buxbaum JN. Is older colder or colder older? The association of age with body temperature in 18,630 individuals. J Gerontol A Biol Sci Med Sci. 2011;66(5):487-492.
    doi pubmed pmc
11. Holtzman A, Simon EW. Body temperature as a risk factor for Alzheimer's disease. Med Hypotheses. 2000;55(5):440-444.
    doi pubmed
12. Chang TY, Kajackaite A. Battle for the thermostat: Gender and the effect of temperature on cognitive performance. PLoS One. 2019;14(5):e0216362.
    doi pubmed pmc
13. Rawlings AM, Juraschek SP, Heiss G, Hughes T, Meyer ML, Selvin E, Sharrett AR, et al. Association of orthostatic hypotension with incident dementia, stroke, and cognitive decline. Neurology. 2018;91(8):e759-e768.
    doi pubmed pmc
14. Michaud TL, Su D, Siahpush M, Murman DL. The risk of incident mild cognitive impairment and progression to dementia considering mild cognitive impairment subtypes. Dement Geriatr Cogn Dis Extra. 2017;7(1):15-29.
    doi pubmed pmc
15. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, Brayne C, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413-446.
    doi pubmed pmc
16. American Medical Association (AMA). Behavioral Health Integration in Physician Practices. American Medical Association. 2021. https://www.ama-assn.org/delivering-care/public-health/behavioral-health-integration-physicianpractices.
17. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):270-279.
    doi pubmed pmc
18. Alagiakrishnan K, Mah D, Dyck JR, Senthilselvan A, Ezekowitz J. Comparison of two commonly used clinical cognitive screening tests to diagnose mild cognitive impairment in heart failure with the golden standard European Consortium Criteria. Int J Cardiol. 2017;228:558-562.
    doi pubmed
19. American Psychiatric Association. Diagnosis and statistical manual of mental disorders. Fourth edition (DSM-IV)). Washington DC. 1994;143-147.
20. Katz S, Downs TD, Cash HR, Grotz RC. Progress in development of the index of ADL. Gerontologist. 1970;10(1):20-30.
    doi pubmed
21. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist. 1969;9(3):179-186.
    pubmed
22. Alagiakrishnan K. Current pharmacological management of hypotensive syndromes in the elderly. Drugs Aging. 2015;32(5):337-348.
    doi pubmed
23. Gasim GI, Musa IR, Abdien MT, Adam I. Accuracy of tympanic temperature measurement using an infrared tympanic membrane thermometer. BMC Res Notes. 2013;6:194.
    doi pubmed pmc
24. Moran DS, Mendal L. Core temperature measurement: methods and current insights. Sports Med. 2002;32(14):879-885.
    doi pubmed
25. Mackowiak P. Normal ‘body’ temperature. In Fever. Basic Mechanisms and Management. (Mackowiak PA ed.) Philadelphia, NY: Lippincott-Raven. 1997:207-213.
26. Davey RJ, Jamieson S. The validity of using the mini mental state examination in NICE dementia guidelines. J Neurol Neurosurg Psychiatry. 2004;75(2):343-344.
    pubmed pmc
27. Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-699.
    doi pubmed
28. Pinto E, Peters R. Literature review of the Clock Drawing Test as a tool for cognitive screening. Dement Geriatr Cogn Disord. 2009;27(3):201-213.
    doi pubmed
29. Espinosa A, Alegret M, Valero S, Vinyes-Junque G, Hernandez I, Mauleon A, Rosende-Roca M, et al. A longitudinal follow-up of 550 mild cognitive impairment patients: evidence for large conversion to dementia rates and detection of major risk factors involved. J Alzheimers Dis. 2013;34(3):769-780.
    doi pubmed
30. Silverman JM, Smith CJ, Marin DB, Mohs RC, Propper CB. Familial patterns of risk in very late-onset Alzheimer disease. Arch Gen Psychiatry. 2003;60(2):190-197.
    doi pubmed
31. Lautenschlager NT, Cupples LA, Rao VS, Auerbach SA, Becker R, Burke J, Chui H, et al. Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study: What is in store for the oldest old? Neurology. 1996;46(3):641-650.
    doi pubmed
32. Honea RA, Vidoni ED, Swerdlow RH, Burns JM, Alzheimer's Disease Neuroimaging I. Maternal family history is associated with Alzheimer's disease biomarkers. J Alzheimers Dis. 2012;31(3):659-668.
    doi pubmed pmc
33. Lopez M, Sessler DI, Walter K, Emerick T, Ozaki M. Rate and gender dependence of the sweating, vasoconstriction, and shivering thresholds in humans. Anesthesiology. 1994;80(4):780-788.
    doi pubmed
34. Horwitz BA, Gabaldon AM, McDonald RB. Thermoregulation during aging. In: Functional Neurobiology of Aging. Hof PR, Mobbs CV. 2001, Academic Press. p. 839- 854.
35. Collins K. Hypothermia: the elderly person's enemy. Practitioner. 1995;239(1546):22-26.
    pubmed
36. Xu G, Li T, Huang Y. The effects of intraoperative hypothermia on postoperative cognitive function in the rat hippocampus and its possible mechanisms. Brain Sci. 2022;12(1):96.
    doi pubmed pmc
37. Neil HA, Dawson JA, Baker JE. Risk of hypothermia in elderly patients with diabetes. Br Med J (Clin Res Ed). 1986;293(6544):416-418.
    doi pubmed pmc
38. Vandal M, White PJ, Tournissac M, Tremblay C, St-Amour I, Drouin-Ouellet J, Bousquet M, et al. Impaired thermoregulation and beneficial effects of thermoneutrality in the 3xTg-AD model of Alzheimer's disease. Neurobiol Aging. 2016;43:47-57.
    doi pubmed
39. Le Freche H, Brouillette J, Fernandez-Gomez FJ, Patin P, Caillierez R, Zommer N, Sergeant N, et al. Tau phosphorylation and sevoflurane anesthesia: an association to postoperative cognitive impairment. Anesthesiology. 2012;116(4):779-787.
    doi pubmed
40. Planel E, Miyasaka T, Launey T, Chui DH, Tanemura K, Sato S, Murayama O, et al. Alterations in glucose metabolism induce hypothermia leading to tau hyperphosphorylation through differential inhibition of kinase and phosphatase activities: implications for Alzheimer's disease. J Neurosci. 2004;24(10):2401-2411.
    doi pubmed pmc
41. Diamond PT, Diamond MT. Thermoregulatory behavior in Alzheimer’s disease. J Am Ger Soc. 1991;39:552.
42. Raupach AK, Ehgoetz Martens KA, Memarian N, Zhong G, Matar E, Halliday GM, Grunstein R, et al. Assessing the role of nocturnal core body temperature dysregulation as a biomarker of neurodegeneration. J Sleep Res. 2020;29(5):e12939.
    doi pubmed
43. Whittington RA, Papon MA, Chouinard F, Planel E. Hypothermia and Alzheimer's disease neuropathogenic pathways. Curr Alzheimer Res. 2010;7(8):717-725.
    doi pubmed
44. Blessing EM, Parekh A, Betensky RA, Babb J, Saba N, Debure L, Varga AW, et al. Association between lower body temperature and increased tau pathology in cognitively normal older adults. Neurobiol Dis. 2022;171:105748.
    doi pubmed pmc
45. Carrettiero DC, Santiago FE, Motzko-Soares AC, Almeida MC. Temperature and toxic Tau in Alzheimer's disease: new insights. Temperature (Austin). 2015;2(4):491-498.
    doi pubmed pmc
46. Das G, Ghosh S. Why microtubules should be considered as one of the supplementary targets for designing neurotherapeutics. ACS Chem Neurosci. 2019;10(3):1118-1120.
    doi pubmed
47. Parashar R, Amir M, Pakhare A, Rathi P, Chaudhary L. Age related changes in autonomic functions. J Clin Diagn Res. 2016;10(3):CC11-15.
    doi pubmed pmc
48. McCarthy PW, Heusch AI. The vagaries of ear temperature assessment. J Med Eng Technol. 2006;30(4):242-251.
    doi pubmed
49. Zhao Q, Wigmann C, Areal AT, Altug H, Schikowski T. Effect of non-optimum ambient temperature on cognitive function of elderly women in Germany. Environ Pollut. 2021;285:117474.
    doi pubmed
50. Muller MD, Gunstad J, Alosco ML, Miller LA, Updegraff J, Spitznagel MB, Glickman EL. Acute cold exposure and cognitive function: evidence for sustained impairment. Ergonomics. 2012;55(7):792-798.
    doi pubmed pmc
51. Most EI, Scheltens P, Van Someren EJ. Increased skin temperature in Alzheimer's disease is associated with sleepiness. J Neural Transm (Vienna). 2012;119(10):1185-1194.
    doi pubmed
52. Eggenberger P, Burgisser M, Rossi RM, Annaheim S. Body temperature is associated with cognitive performance in older adults with and without mild cognitive impairment: a cross-sectional analysis. Front Aging Neurosci. 2021;13:585904.
    doi pubmed pmc
53. Guisle I, Gratuze M, Petry S, Morin F, Keraudren R, Whittington RA, Hebert SS, et al. Circadian and sleep/wake-dependent variations in tau phosphorylation are driven by temperature. Sleep. 2020;43(4):1-12.
    doi pubmed
54. Knekt P, Jarvinen R, Rissanen H, Heliovaara M, Aromaa A. Does sauna bathing protect against dementia? Prev Med Rep. 2020;20:101221.
    doi pubmed pmc
55. Blatteis CM. Age-dependent changes in temperature regulation - a mini review. Gerontology. 2012;58(4):289-295.
    doi pubmed
56. Van Someren EJ, Raymann RJ, Scherder EJ, Daanen HA, Swaab DF. Circadian and age-related modulation of thermoreception and temperature regulation: mechanisms and functional implications. Ageing Res Rev. 2002;1(4):721-778.
    doi pubmed
57. Farlow MR, He Y, Tekin S, Xu J, Lane R, Charles HC. Impact of APOE in mild cognitive impairment. Neurology. 2004;63(10):1898-1901.
    doi pubmed
58. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997;278(16):1349-1356.
    pubmed
59. Chartier-Harlin MC, Parfitt M, Legrain S, Perez-Tur J, Brousseau T, Evans A, Berr C, et al. Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region. Hum Mol Genet. 1994;3(4):569-574.
    doi pubmed

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Journal of Clinical Medicine Research is published by Elmer Press Inc.