TYPE Review PUBLISHED 01 December 2022 DOI 10.3389/fendo.2022.1024794 New methods for the diagnosis OPEN ACCESS and monitoring of cognitive EDITED BY Victor Alan Gault, Ulster University, United Kingdom function in patients with REVIEWED BY Weigang Gong, type 2 diabetes Qilu Hospital, Shandong University, China Joana Nicolau, Andreea Ciudin 1,2,3* and Rafael Simó 1,3,4* Son Llàtzer Hospital, Spain Luiz Guilherme Kraemer-Aguiar, 1 Endocrinology and Nutrition Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut Rio de Janeiro State University, Brazil de Recerca (VHIR), Barcelona, Spain, 2 Universitat Autónoma de Barcelona, Department of Human Physiology and Inmunology, Barcelona, Spain, 3 CIBER de Diabetes y Enfermedades Metabólicas *CORRESPONDENCE Asociadas (CIBERDem), Instituto de Salud Carlos III, Madrid, Spain, 4 Universitat Autónoma de Andreea Ciudin Barcelona, Department of Medicine, Barcelona, Spain andreea.ciudin@vallhebron.cat Rafael Simó rafael.simo@vhir.org SPECIALTY SECTION The presence of type 2 diabetes acts as an accelerator of cognitive impairment This article was submitted to Neuroendocrine Science, (mild cognitive impairment and later dementia), with a significant impact on the a section of the journal management of the disease and its complications. Therefore, it is Frontiers in Endocrinology recommended to perform an annual evaluation of cognitive function in RECEIVED 22 August 2022 patients with diabetes older than 65 years. Current guidelines still ACCEPTED 04 November 2022 PUBLISHED 01 December 2022 recommend the use of the Minimental State Evaluation Test (MMSE) as screening test, but it has a modest sensitivity and specificity for identifying CITATION Ciudin A and Simó R (2022) New mild cognitive impairment. This represents an important gap because patients methods for the diagnosis and with mild cognitive impairment are at risk of progressing to dementia. The monitoring of cognitive function in patients with type 2 diabetes. neurocognitive diagnosis is based on complex neuropsychological tests, which Front. Endocrinol. 13:1024794. require specifically trained personnel and are time consuming, making its doi: 10.3389/fendo.2022.1024794 routine incorporation into daily clinical practice unfeasible. Therefore, at COPYRIGHT present there are no reliable biomarkers to identify patients with type 2 © 2022 Ciudin and Simó. This is an open-access article distributed under diabetes at increased risk of developing cognitive impairment. Since the brain the terms of the Creative Commons and the retina have a common embryological origin, our Research Group, has Attribution License (CC BY). The use, worked over the last 10 years evaluating the usefulness of the retina as a distribution or reproduction in other forums is permitted, provided the “window” to the brain. We provided evidence that retinal microperimetry is a original author(s) and the copyright simple, feasible and useful tool for screening and monitoring cognitive function owner(s) are credited and that the in patients with type 2 diabetes. We propose a review of actual tests original publication in this journal is cited, in accordance with accepted recommended for screening of cognitive impairment as well as an update of academic practice. No use, new emerging methods, such as retinal microperimetry. distribution or reproduction is permitted which does not comply with these terms. KEYWORDS type 2 diabetes, mild cognitive impairment, dementia, retinal microperimetry, neuropsychological tests Frontiers in Endocrinology 01 frontiersin.org Ciudin and Simó 10.3389/fendo.2022.1024794 1 Introduction. State of the art Data in the literature showed that about 33% of women and 20% of men over 65 years of age with MCI could develop 1.1 Type 2 diabetes as risk factor and dementia throughout during their lifespan (12). Recent data accelerator for cognitive impairment showed that T2D is an independent risk factor, besides the presence of the APOEe4 allele for conversion to dementia in Current epidemiological data show that type 2 diabetes patients with MCI (1). The presence of MCI can lead to (T2D) increases 2-3 times the risk of developing dementia, in mismanagement of the specific treatment for T2D. This can comparison with non-diabetic population matched by age and favor episodes of severe hypoglycemia, thus worsening the other risk factors (1). patients’ cognitive status, all of which translates into an T2D and dementia, in particular Alzheimer´s disease (AD), increase in direct and indirect healthcare costs (13, 14). share several common pathophysiological mechanisms. Both, in Additionally, hypoglycemia can alter the cognitive function T2D and Alzheimer´s disease insulin resistance, low-grade and accelerates the progression to dementia (15–17). For this inflammation, oxidative stress, high levels of angiotensin-II reason, it is important to diagnose cognitive impairment in early and advanced end-glycation products (AGE) are found and stages in patients with T2D. contribute to the progression of the disease. Furthermore, a common genetic background was described- Additionally, patients with T2D have smaller brain volumes and white 1.2 Actual recommendation for matter disruption as a result of this pathophysiological screening for cognitive impairment in mechanisms- as reflected by Figure 1 (2–5). T2D patients On these bases we hypothesized that T2D could act as an accelerator of cognitive decline in two ways: by inducing a slow Since 2018, the ADA clinical guidelines started to cognitive decline, also called “dementia related to Diabetes”, or recommend screening for early detection of cognitive by precipitating a rapid cognitive decline to AD, in the presence impairment for adults≥ 65 years of age with T2D at the initial of predisposing genetic factors, like APOEϵ4 allele (3). visit and annually as appropriate (18, 19). The current guideline Additionally, the presence of complications related to diabetes (19), recommend for this purpose screening tools such as the (micro and macrovascular), as well as metabolic control and the Mini Mental State Examination (MMSE) and the Montreal episodes of hypoglycemia will accelerate the progression of Cognitive Assessment (MoCA), especially in those patients in cognitive impairment (6–10). whom dementia is suspected. Additionally, annual monitoring is There is a gradual progression from the so-called subjective indicated for adults >65years with T2D for early detection of memory complaints (SMC) to mild cognitive impairment mild cognitive impairment or dementia. (MCI), which is the prelude to dementia. MCI represents a deterioration in cognition superior to that observed with normal 1.2.1 The mini mental state examination test cognitive decline associated with age, but not severe enough to The MMSE, 10-15 minutes test (20)is a test largely used to cause significantly impaired daily function (11) screen for cognitive impairment. A standard MMSE cut score of FIGURE 1 Common mechanisms shared by Type 2 diabetes and Cognitive impairment. Frontiers in Endocrinology 02 frontiersin.org Ciudin and Simó 10.3389/fendo.2022.1024794 24 (≤23) yielded a sensitivity of 0.58 and a specificity of 0.98 in On these bases, we should raise serious questions about the detecting probable and possible Alzheimer’s disease. A cut score accuracy and the applicability of these recommended screening of 27 of a maximum 30 (≤26) resulted in an improved balance of tests at large scale in the population with T2D >65 years, sensitivity and specificity (0.79 and 0.90, respectively). In MCI especially if we intent to detect cognitive impairment in group the standard cut-off score of 24 yielded a sensitivity of 0.38 early stages. and a specificity of 1.00 while raising the cut score to 27 resulted in an improved balance of 0.59 and 0.96 of sensitivity and 1.2.3. Limitations of the actual recommended specificity, respectively (20) (21). Nevertheless, it should be tests for screening noted that these data are supported on limited number of patients. A recent meta-analysis (22), evaluated the usefulness • Low sensitivity and specificity for detecting early stages of MMSE for the detection of dementia in people with MCI. The of cognitive impairment conclusion, based on 11 studies that meet the accuracy criteria, • Results based on studies with small sample size, was that there no reliable evidence to support a substantial role heterogeneous cut-offs, patients with depressive of MMSE in identifying those patients with MCI at risk of symptoms were excluded. developing dementia. The data from the clinical studies that • Depend on the educational level and the mood of the were evaluated is heterogeneous regarding the optimal cut-off, patient. the influence of educational background or the effect of literacy in the accuracy of MMSE. The current guidelines recommend screening of cognitive Regarding the annual monitoring, the same meta-analysis impairment especially in those patients in whom dementia is showed a specificity of 88% and sensitivity of 40% in detecting suspected (28). Nonetheless, the early recognition of cognitive progression of MCI (22). impairment is crucial for a personalized medicine and is an essential issue in diabetes care. The early detection of mild 1.2.2. The Montreal cognitive assessment test cognitive impairment or even subjects with SMC at risk of The MoCA test (23), a 10-15 minutes is the other progression is important because T2D patients with cognitive neurocognitive test recommended for screening of cognitive impairment are more prone to present an impaired self- function in patients with T2D>65years. The cut-off of >26 out management of diabetes, poor glycemic control and an of maximum 30 identified patients with MCI with a sensitivity of increased incidence of diabetes-related complications. In this 91% and specificity of 90%. This test needs previous training and regard, the actually recommended tools have serious limitations periodical certification of the personnel. Furthermore, the result and at present there is gap due to the lack of rapid, reliable tools is influenced by the educational level and the mood of the subject. for early detection of cognitive impairment in patients with A recent study (24) showed that MoCA is superior to MMSE T2D >65years, regardless of the mood or educational level. in detecting patients at higher risk of dementia. Nonetheless, it should be noted that this conclusion is based on small sample size (<100 subjects in total) and different cut-offs were used (19- 20 for MoCA and 23-24 for MMSE). 2 New emerging methods for Additionally, studies that evaluated the usefulness of both screening and monitoring of MMSE or MoCA excluded patients with depressive symptoms, cognitive function evaluated by specific questionnaires, such as geriatric depression scale (GDS) or medical history (22, 24). This represents an In recent years new methods have emerged for the screening important limitation because the associated anxiety-depression and monitoring of the congnitive function in patients with and impaired quality or life (QoL) occur in a significant T2D>65years: the Diabetes Specific Dementia Risk Score proportion of ageing T2D patients. This is important because, (DSDRS) (29) and retinal microperimetry (30). apart from influencing the result of neuropsychological tests, the psychological abnormalities related to a decrease in QoL in T2D patients could play a role in aggravating their cognitive decline. In 2.1 Diabetes specific dementia risk score fact, depression was associated with cognitive decline in the ACCORD-MIND study (25). Additionally, the prevalence of DSRDS was proposed in 2013 by Exalto et al. (29) as a risk depression is two-fold higher in T2D compared with the general score for the prediction of 10-year dementia risk in patients with population worldwide (26) and it has recently been reported of T2D. This score consists of several clinical and demographic 27,5% among T2D patients in the Mediterranean population (27) variables (age, gender, education, history of diabetic foot, acute This prevalence rate could even be higher in the older adults with metabolic events, depression, microvascular disease, cardiovascular diabetes because depressive symptoms may be overlooked (27). disease and cerebrovascular disease) and ranges from a 5% 10-year Frontiers in Endocrinology 03 frontiersin.org Ciudin and Simó 10.3389/fendo.2022.1024794 dementia risk for those with the lowest score up to a 73% risk for invasive way of examining the pathology of the brain: “the eye as the highest score. a window of the brain”. Retinal microperimetry, is a simple, The DSDRS was not initially designed as a screening tool. rapid and non-invasive test that measures retinal sensitivity in Recently, as part of a European project (31),MOPEAD study (32), terms of the minimum light intensity that patients can perceive our research group evaluated the usefulness of the DSDRS as a when spots of light stimulate specific areas of the retina, and also screening tool for MCI, alone or combined with MMSE. The evaluate gaze fixation stability (30, 34). cognitive status of the patients was confirmed by We showed for the first time that the retinal sensitivity neuropsycholgical tests battery performed by trained significantly correlated with brain imaging (MRI and PET) and neuropsychologists at the memory clinic. The results showed that identified patients with MCI and dementia, as confirmed by a cut-off of DSDRS≥7 had a predictive value of AUC 0.739 (CI95%, complete neuropsychological battery- Figure 2. [0.557-0.921]) and of 0.902 (CI 95% [0.840-0.992]) when combined By adding the gaze fixation parameters to the retinal with MMSE (33), suggesting that DSRDS could be a reliable sensitivity the probability to identify cognitive impairment screening tool for cognitive decline in patients with T2D>65 significantly increased in an independent manner, suggesting years with a sensitivity 88.37% CI95% (78.9-97.9) and specificity that retinal sensitivity and gaze fixation explore different 55.26% CI 95% (48.9-60.5). Additionally, a recent study from neuronal circuits and are complementary (35), converting the another group studied the utility of the DSDRS for lower retinal microperimetry into a potential useful tool for the cognitive performance and found similar results, with a sensitivity screening of MCI in patients with T2D >65 years (with a of 83.3% and specificity of 54.3% (31). sensitivity of 72.7% and sensibility of 87.9%). Furthermore, we have recently evaluated the usefulness of retinal microperimetry as a monitoring tool for the cognitive 2.2 Retinal microperimetry function in patients >65 years with T2D (36). We found that the worsening in cognitive function went in parallel with worsening The retina is ontogenically a brain-derived tissue and it has of gaze fixation, suggesting this parameter can be a reliable and been suggested that it may provide an easily accessible and non- more subtle tool for the monitoring of the cognitive function in FIGURE 2 The eye as the window to the brain. Frontiers in Endocrinology 04 frontiersin.org Ciudin and Simó 10.3389/fendo.2022.1024794 patients with type 2 diabetes. These results suggest that since (RECOGNISED study, NCT04281186), aimed at validating the retinal sensitivity is a reliable screening tool for diagnosis, the usefulness of retinal microperimetry and DSRDS as reliable evaluation of gaze fixation could represent a better biomarker for screening and monitoring tools for cognitive impairment in annual follow-up. As previously explained (35), this finding patients with T2D >65 years. These two tests can be easily could be attributed to the fact that the brain areas involved in implemented and applied at large scale in the daily clinic. If our gaze fixation are not the same as in retinal sensitivity. Retinal results are confirmed, the DSDRS could be a screening tool that sensibility relies on the retina and the neural pathway of vision, might easily be implemented and automatically calculated by the which includes the geniculate body and correlated with grey electronic medical records of the patients, as part of the daily matter volumes in brain MRI in T2D patients with MCI and AD clinical practice. Additionally, for the annual microperimetry but not white matter (30), suggesting that could be a marker of performance in the ophthalmology clinic, an automatic software neurodegeneration. On the other hand, gaze fixation depends on could provide reliable data on the patients with T2D>65 years that the complex white matter network (37). present significant changes in gaze fixation and retinal sensitivity It should be noted that fixation eye movements are affected annually, as possible patients at higher risk of progression of their by attention and working memory (38). In this regard, micro- cognitive impairment, on which diabetes care providers should saccade rates transiently decrease during an attentional task focus and make an accurate diagnosis and management. (39).The omnipause neurons (located in the nucleus raphe interpositus of the paramedian pontine reticular formation) or the superior colliculus (SC) are two of the main brain areas 3 Concluding remarks involved in fixation. It is possible that these areas are affected early in the neurodegenerative process (40). While performing Cognitive impairment is an emerging condition in T2D but the retinal microperimetry, the subjects are asked to maintain often remains undiagnosed due to lack of simple tools for their gaze fixated on a central target, while stimuli with different screening at large scale. This is important because T2D patients intensities are presented at 37 points in 3 concentric circles of 2, with cognitive impairment are more prone to present an impaired 6, and 10 degrees of diameter (41). It could be hypothesized that self-management of diabetes, poor glycemic control and an subjects with cognitive impairment are unable to inhibit the increased incidence of diabetes-related complications. saccades triggered by the most eccentric stimuli and maintain Unfortunately, current guidelines still recommend the use of their gaze fixated on a central target. Furthermore, certain areas tests that depend on the mood of the patient and the educational of the cerebral cortex, such as the parietal and frontal cortex level, with modest sensitivity and specificity for identifying mild (frontal eye fields and the dorsomedial prefrontal cortex), show cognitive impairment. This represents an important gap because elevated firing rates during fixation. These areas could contribute patients with mild cognitive impairment are at risk of progressing to the control of fixation through descending projections to the to dementia and the early and reliable identification at large scale SC and the omnipause region (40). will allow the implementation of a patient-centered treatment Retinal microperimetry, used in the daily clinical practice, as based on simplifying the regimes and prioritizing antidiabetic part of the ophthalmological evaluation, is a simple, objective treatments with low capacity to provoke hypoglycemia. Recently, and rapid test that can be largely used for the monitoring of the new methods have emerged as reliable tools for the cognitive cognitive performance, regardless of the educational level. evaluation in patients with T2D>65 years, such as DSRDS and Nevertheless, at present retinal microperimetry as a tool for more importantly, retinal microperimetry, that have the potential the screening and monitoring of cognitive function has some to change the current guidelines if preliminary results are limitations. First, the presence of advanced DR might be a confirmed in a large ongoing European trial (RECOGNISED). limiting factor. However, we propose it as tool for early detection of cognitive impairment and at this stage a large percentage of patients with T2D present only mild or Author contributions moderate DR. Secondly, the device might not be widely available in many primary or even tertiary care settings. Third, AC: Conceptualization, first draft writing, revision. RS: although it seems that the test is not influenced by psychological Supervision, draft revision. All authors contributed to the or mood status, at present there are no studies specifically aimed article and approved the submitted version. at evaluating this issue. For all these reasons we have to still consider retinal microperimetry as an emerging and promising tool that needs further validation and cost-effectiveness analysis. Conflict of interest These preliminary data, both on DSDRS and microperimetry have the potential of changing the current guidelines of clinical The authors declare that the research was conducted in the practice in patients with T2D if the results are confirmed in larger absence of any commercial or financial relationships that could clinical trials. In this regard, a European project is ongoing be construed as a potential conflict of interest. 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