Cognitive dysfunction is increasingly recognized as an important comorbidity of diabetes mellitus. Different stages of diabetes-associated cognitive dysfunction exist, each with different cognitive features, affected age groups and prognoses and probably with different underlying mechanisms. Relatively subtle, slowly progressive cognitive decrements occur in all age groups. More severe stages, particularly mild cognitive impairment and dementia, with progressive deficits, occur primarily in older individuals (>65 years of age). Patients in the latter group are the most relevant for patient management and are the focus of this Review. Here, we review the evolving insights from studies on risk factors, brain imaging and neuropathology, which provide important clues on mechanisms of both the subtle cognitive decrements and the more severe stages of cognitive dysfunction. In the majority of patients, the cognitive phenotype is probably defined by multiple aetiologies. Although both the risk of clinically diagnosed Alzheimer disease and that of vascular dementia is increased in association with diabetes, the cerebral burden of the prototypical pathologies of Alzheimer disease (such as neurofibrillary tangles and neuritic plaques) is not. A major challenge for researchers is to pinpoint from the spectrum of diabetes-related disease processes those that affect the brain and contribute to development of dementia beyond the pathologies of Alzheimer disease. Observations from experimental models can help to meet that challenge, but this requires further improving the synergy between experimental and clinical scientists. The development of targeted treatment and preventive strategies will therefore depend on these translational efforts.
Cognitive dysfunction in diabetes mellitus can manifest itself as diabetes-associated cognitive decrements, mild cognitive impairment (MCI) and dementia.
Owing to the marked differences in affected age groups and trajectories of cognitive decline, diabetes-mellitus-associated cognitive decrements and dementia should be regarded as different entities that probably have different underlying mechanisms.
Mechanisms of MCI and dementia in diabetes have mainly been studied in patients with type 2 diabetes mellitus (T2DM) and involve mixed vascular and neurodegenerative pathologies, often on a background of Alzheimer disease pathology; however, T2DM does not increase the burden of the latter.
Key causative pathways in diabetes-associated cognitive dysfunction need to be identified in order to develop course-modifying therapies.
Experimental models can single out individual causative pathways in ways and at a level of detail that are impossible in humans.
Any potential mechanisms of brain dysfunction that are identified in experimental models of diabetes mellitus must also be evaluated in the complex setting of other morbidities with which they may co-occur in patients.
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The research of G.J.B. is supported by Vici Grant 918.16.616 from the Netherlands Organisation for Scientific Research (NWO). F.D. acknowledges funding from NIH (R01AG053999 and R01AG057290), the Alzheimer’s Association (VMF-15-363458) and the American Stroke Association (16GRNT310200).
Owing to the wide scope of this Review, the references we cite represent a selection of the available literature. Where possible, we refer to published (systematic) reviews that provide a complete overview of available original studies. When we cite original studies on a particular topic and multiple studies were available, we cite the first landmark studies and/or the most recent comprehensive studies that, in our view, represent a major advance to the field. For further background on specific topics, the reader is encouraged to read the cited papers and to explore the additional references provided in those papers.
Nature Reviews Endocrinology thanks J. Morley, H. Umegaki and S. Seshadri for their contribution to the peer review of this work.
Competing interests statement
G.J.B. consults for and receives research support from Boehringer Ingelheim. All financial compensation for these services is transferred to his employer, the University Medical Center Utrecht. F.D. has no potential conflict of interest to disclose.
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- Cognitive dysfunction
Any change from normal cognitive functioning. May range from subtle to severe.
- Cognitive decrements
Subtle cognitive dysfunction not severe enough to meet formal neuropsychological criteria for cognitive impairment.
- Cognitive impairment
Cognitive dysfunction severe enough to be classified as ‘abnormal’ or ‘impaired’ on the basis of neuropsychological test results (mostly 1.5–2 s.d. below normative mean). Entails both mild cognitive impairment and dementia.
- Cognitive domains
Distinct types of cognitive function supporting different aspects of behaviour. Domains include intelligence, attention, language, memory, executive functions (including cognitive flexibility), visual–spatial skills and psychomotor efficiency and may be differentially affected by disease.
- Cohen’s d effect sizes
Cohen’s d is defined as the difference between two group means divided by the pooled standard deviation.
- Amnesic MCI
Mild cognitive impairment (MCI) with the domain memory being affected. Regarded as the prototypical form of MCI preceding Alzheimer dementia.
- Nonamnesic MCI
MCI with the domain memory being intact.
Round or ovoid, subcortical, fluid-filled cavities (signal on MRI similar to cerebrospinal fluid) between 3 mm and ~15 mm in diameter that are consistent with a previous acute small subcortical infarct or haemorrhage in the territory of one perforating arteriole.
- White matter hyperintensities
Signal abnormality of variable size in the white matter that is hyperintense on T2-weighted MRI images such as fluid-attenuated inversion recovery, without cavitation (signal different from cerebrospinal fluid), often due to vascular injury but may have other causes.
- Perivascular spaces
Fluid-filled spaces that follow the typical course of a vessel as it goes through grey or white matter. The spaces have a signal intensity similar to that of cerebrospinal fluid on all MRI sequences49.
- Cerebral microbleeds
Small (generally 2–5 mm in diameter, but sometimes up to 10 mm) areas of signal void with associated blooming seen on T2*-weighted MRI or other sequences that are sensitive to susceptibility effects, mostly representing a haemosiderin remnant after a small previous haemorrhage.
Small lesions of presumed ischaemic origin, detectable with microscopic examination of brain autopsy material but also detectable in vivo with dedicated MRI protocols.
- Neurovascular uncoupling
Neurovascular coupling is the mechanism that links local changes in neural activity and cerebral blood flow involving the so-called neurovascular unit. Neurovascular uncoupling is a disturbance of this mechanism.
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Biessels, G.J., Despa, F. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol 14, 591–604 (2018). https://doi.org/10.1038/s41574-018-0048-7
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