Normal cognitive function depends on a continuous and optimally regulated blood supply, and any pathology that further reduces cerebral blood perfusion in addition to that caused by aging could damage or destroy vulnerable neurons of the brain. Furthermore, glucose serves a crucial role as the primary fuel source for the mammalian brain and any disturbance in its circulating concentrations could directly affect brain function. The term cognitive dysfunction (CD), known also as ‘brain fog’, refers to deficits in attention, verbal and non-verbal learning, short-term and working memory, visual and auditory processing, mathematic problem solving, processing speed, focusing on a specific topic, and motor functioning. CD is the end-point of various cardiovascular, neural, metabolic and immune function impairments. Although CD has a serious impact on patient survival and quality of life, usually it is clinically underestimated. CD is currently assessed using cognitive tests (questionnaires), which have important limitations in their diagnostic capacity, specifically in the preclinical forms of CD. Cognitive tests may not identify subclinical cases of CD but diagnose CD only when symptoms are clinically overt. Furthermore, these tests do not provide information regarding the underlying pathophysiologic background of CD. The aim of the present review is to summarize the existing literature on CD and emphasize the role of combined brain-heart magnetic resonance imaging (MRI) in its early diagnosis, before CD questionnaires are abnormal. Combined brain/heart MRI has the potential to identify patients with CD at an early stage, facilitating risk stratification and early intervention. Furthermore, in parallel with brain assessment, it provides valuable information regarding the effect of the underlying disease on the myocardium. Equipment availability, physician familiarity and cost/effectiveness should be considered before wide clinical application of combined brain/heart MRI is recommended.
Cognition includes intellectual abilities used for perceiving, acquiring, understanding and responding to information presented to a person. The term cognitive dysfunction (CD), known also as ‘brain fog’, refers to deficits in attention, verbal and non-verbal learning, short-term and working memory, visual and auditory processing, mathematic problem solving, processing speed, focusing on a specific topic, and motor functioning (
It has been documented that normal aging is associated with reduction of cerebral blood flow by approximately 20% at age 60, compared to the age of 20 years (
Our aim is to review the existing literature about the assessment of CD and the role(s) of various diseases in the development of this disorder. We will emphasize the added value of a combined brain-heart magnetic resonance imaging (MRI) evaluation in the early diagnosis of CD.
People should be screened for CD in the following cases: i) if the person himself or herself, family members, or others express concerns about changes in his/her memory or thinking, ii) if problems/changes in the patient's memory or thinking are observed by the physician, iii) if the patient is age 80 or older, because the risk of dementia increases rapidly after this age (
Several standardized measures of CF have been used and include the Montreal Cognitive Assessment (MoCA) (
Various diseases have been implicated in the development of CD. The main groups responsible for CD development encompass the following entities:
Cardiovascular diseases (CVD) are classified as cardiomyopathies, coronary artery, valvular, and congenital heart diseases. All these entities may finally lead to rhythm disturbances and heart failure (HF) (
Brain hypoperfusion, as a result of low cardiac output or hypotension may lead to CD (
CD is a common expression of various neural disorders including:
Several types of dementia have been described: AD, vascular dementia (VaD), dementia with Lewy bodies, frontotemporal dementia and dementia associated with Parkinson´s disease. Dementia may also be secondary to the human immuno-deficiency virus (HIV-associated dementia) or other infectious agents and this may be of particular importance in younger adults in specific areas. Other rarer causes of dementia include Huntington's disease, prion disease and head trauma (
AD is the most frequent subtype, corresponding to about 55% of all diagnoses in humans aged >65 years (
CD occurs in 40-65% of multiple sclerosis (MS) patients. It involves complex attention, information processing speed, episodic memory and executive functions. It can be found in both subclinical and clinically overt MS. In pediatric-onset MS, cognition worsens relatively rapidly. CD usually affects personal life and vocational status. In relapsing-remitting MS timely and adequate disease-modifying treatment may stabilize or improve CD. Cognitive behavioral therapy, including exercise and education programs, is a promising intervention to improve CD (
Neuromuscular disorders mainly affect the motor functioning of the patient. However, the cognitive effects of these diseases are also important. This is due to molecular defects that significantly affect neuromotor functioning, but also participate in the functioning of neural networks involved in cognitive processes, leading to impairment of executive, behavioral and psychosocial functions (
Although most Duchenne muscular dystrophy (DMD) patients are not intellectually disabled, the risk for CD is increased, with up to 30% of DMD patients presenting intellectual disability. Apart from intellectual abilities, neurocognitive dysfunction has been frequently reported. Deficits in short-term memory, executive functions, visuospatial ability, as well as deficits in attention, problems with narrative, linguistic and reading skills have been described, irrespective of general intelligence. Moreover, a higher incidence of neuro-psychiatric disorders, such as autism, attention deficit, hyperactivity, obsessive-compulsive disorders and social behavior problems, has also been reported (
There is a broad range of CD in schizophrenia and includes problems in perception, attention, memory and problem-solving (
Neurocognitive deficits are common in mood disorders. In major depression, they can mimic severe dementia (
Patients with obsessive-compulsive disorder (OCD) may show impairment on numerous tests of non-verbal memory including visual reproduction and delayed recognition of figures, maze learning and intermediate/delayed figure copying. Most studies suggest that encoding and retrieval are impaired in OCD, while storage of information remains intact. Patients with OCD often function remarkably well in their daily lives, despite severe symptomatology and cognitive difficulties, which are apparent only on specific testing. In contrast to non-verbal memory deficits, verbal memory is generally preserved in OCD (
Somatic symptoms disorders include somatic, psychopathological and neuropsychological symptoms. Cognitive complaints include poor concentration, decreased memory of recent events and poor word-finding abilities (
Poor performance on tests of executive function, sustained attention and memory, are the most common neuropsychological deficits reported in children and adults with attention deficit/hyperactivity disorder (ADHD). There is little evidence for deficits in basic motor, visual, spatial or sensory functioning in ADHD, with the possible exception of olfactory function (
CD has been identified following substance abuse and affects mental activities that involve acquiring, storing, retrieving, and using information. This dysfunction plays an important role in the development of the addictive process and rehabilitation of substance abusers (
The mechanism of CD in diabetes mellitus (DM) is complex and includes a) factors related to DM per se (direct effect of altered glucose metabolism on the brain) and b) DM-related CVD and microvascular dysfunction. Chronic hyperglycemia triggers neuronal damage and endothelial dysfunction, leading to CD over time (
DM is also a major risk factor for stroke, particularly ischemic stroke, with type 2 DM alone known to increase stroke risk 1.5 to 4-fold (
The effect of DM on cerebrovascular impairment can be explained by the increased burden of inflammatory cytokines e.g., interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), and subsequent chronic inflammation, which contributes to CD (
In contrast to hyperglycemia, the role of hypoglycemia is controversial but the relationship between hypoglycemia and CD may become clear in elderly patients. Although severe hypoglycemia has not been associated with long-term CD in young patients with type 1 DM (DCCT follow-up study) (
For people with autoimmune rheumatic diseases (ARDs) including sarcoidosis, avoiding CD is crucial to successfully perform everyday tasks, including medical treatment adherence or planning activities. Most ARDs have been associated with various degrees of CD, which has been mainly documented in rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and sarcoidosis.
Combined brain/heart MRI images of a case patient with sarcoidosis and doubtful CD tests, are shown in
Patients with rheumatoid arthritis (RA) present an increased risk of stroke, as a consequence of accelerated atherosclerosis (
Inflammation affecting the brain (
A wide range of syndromes in systemic lupus erythematosus (SLE) including stroke, acute confusional state, headaches and mood disorders may lead to CD (
The treatment with neurotoxic/psychoactive medications such as corticosteroids and cyclophosphamide, and the neuropsychiatric manifestations of SLE (NPSLE) such as strokes, seizures, depression or anxiety, can all independently contribute to CD. However, there is an early presentation of NPSLE, with 40% of SLE patients diagnosed with neuropsychiatric symptoms at the time of diagnosis or within the first 3 years post diagnosis (
Antiphospholipid (aPL) antibodies, often coexisting with SLE, are a strong risk factor for NPSLE, due to a stroke, structural damage and associated CD, as a consequence of hypercoagulation (
Although anxiety, depression and mood changes are common, in contrast to other ARDs, CD is rare in systemic sclerosis (SSc) (
According to a recent study, the prevalence of CD in patients with ANCA-associated vasculitis (AAV) was similar to RA and those with CD had high disease activity. Abnormal performance was more frequent in the executive functions, followed by language. Furthermore, psychomotor functions were more frequently affected in AAV patients (
The currently used diagnostic approach for CD diagnosis includes a) assessment of problems with memory or another mental function; b) mental decline over time; c) if overall mental function and daily activities are affected; and d) mental status testing. A neural clinical and laboratory examination is necessary. Finally, cognitive testing and brain CT/MRI provide an integrated image of mental status.
The great diversity of causes and outcomes of CD has motivated a wide search for effective therapies. These include specific neurological medications, interventions to achieve better brain perfusion, occupational therapy and environmental approaches.
Future research includes the development of neuroimaging and genetic testing that help the identification of individuals at increased risk for CD.
MoCA is a quick test, taking only 10 to 15 min to be completed. Various studies have shown that MoCA correctly identifies dementia in approximately 94% of cases. Furthermore, while people in the early or mild stages of dementia might score high enough on other tests (including the MMSE), and the score would indicate that no dementia is present, MoCA has been proven effective for showing early-stage dementia, or mild cognitive impairment. Additionally, MoCA is better than the MMSE at indicating if people with Parkinson's disease present signs of Parkinson's disease dementia. However, between the disadvantages of MoCA is the fact that it must be administered and graded by a healthcare professional and therefore an appointment with a nurse, doctor, or therapist is required, in opposition to other tests that can be taken at home. Furthermore, it does not provide a diagnosis, so it must be evaluated together with other tests including brain scans and a neurological testing, before the final diagnosis will be made (
According to published data, cognitive tests are the more clinically useful screening tools for use in community mental health centers. However, because of their poor sensitivity for detecting CD in this patient population, alternative screening methods should be explored. Therefore, there is great clinical need for an objective tool that can assess early the lesion pathophysiology and can predict the future evolution of the patient's CD.
Currently, the role of brain magnetic resonance (BMR) in patients with CD is primarily supportive than diagnostic. American and European guidelines recommend brain imaging to exclude treatable causes, such as tumor, hydrocephalus or intracranial hemorrhage, but also to distinguish between different dementia subtypes. However, this approach depends not only on guidelines, but also on the availability of imaging techniques at individual centers. Advanced MRI techniques, such as functional connectivity MRI, diffusion tensor imaging and magnetic resonance spectroscopy are now becoming available for clinical use in many specialized centers. The increasing research on CD identification at early stages will definitely increase the use of more objective approaches, such as BMR.
BMR is a robust, versatile modality capable to detect early brain alterations without radiation. In patients with long-standing, uncontrolled type 2 DM, white matter hyperintensity (WMH) in BMR has been associated with decreased processing speed (
Multiple vascular risk factors, including smoking, hypertension, DM and dyslipidemia are associated with CD. Among them, hypertension is more strongly associated with WMH, possibly due to cerebral microcirculation damage. There is currently evidence that intensive treatment of patients with cardiovascular risk factors, including hypertension and dyslipidemia, can slow down the progression of WMH, compared to untreated controls (
In Neurology, volumetric MRI is becoming an increasingly important tool in the early detection and monitoring of people suspected to have mild CD and/or AD (
In Rheumatology, significant negative correlations between cognitive test scores on verbal memory and number/volume of WMH has been found in SLE, while no significant differences in the number or volume of WMH have been identified between subgroups of SLE patients (
Although there is an increasing interest about incorporating BMR in the diagnostic algorithm of CD, there is no published evidence about the role of cardiovascular magnetic resonance (CMR) in the evaluation of CD. However, CMR can reveal silent cardiac lesions in both ischemic and nonischemic diseases that may lead to brain hypoperfusion with consequent CD. In this context, CMR was found to detect various phenotypes in diabetic CVD including myocardial scar, ischemia and non-ischemic cardiomyopathy (
In the Cardiology literature, CMR is represented in the majority of the ESC guidelines (
In the Neurology literature, CMR with late gadolinium enhancement (LGE) is the modality of choice for the detection of early cardiac involvement in patients with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) (
CMR has been also successfully used to identify vulnerable plaques in the thoracic aorta using 3D multi-contrast CMR and estimate the risk of cerebral embolization using 4D flow CMR in cryptogenic stroke patients (
In the domain of Rheumatology, there is recently a considerable increase in literature regarding the use of CMR for early detection/quantification and disease acuity assessment (oedema/fibrosis imaging) of cardiac involvement in various ARDs. In this context, proposals about the use of CMR in Rheumatology have been already published by a panel of specialists in both Cardiology and Rheumatology (
In contrast to CF testing, a combined MRI of brain/heart can reveal early pathophysiological changes that are potentially clinically silent but may seriously affect CF. Using this approach, subclinical brain involvement was found to be highly prevalent in ARD patients with cardiac symptoms and was mostly independent of the severity of cardiac involvement (
CD is the end-point of cardiovascular, neural, metabolic, and immune system impairment. CD testing, which is the most commonly used diagnostic approach, cannot always identify subclinical cases and the underlying pathophysiologic background of CD. A combined brain/heart MRI has the ability to diagnose these patients at an early stage and facilitate the individualization of risk stratification and early intervention. Furthermore, a combined brain-heart MRI is an objective approach that has no limitations of currently used CD tests. However, equipment availability, doctors' familiarity with this approach, and cost effectiveness are at the moment serious obstacles and should be taken into consideration, before brain/heart MRI in the diagnosis of CD is recommended in every day clinical practice.
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GMM, FB and SIM recognized the scientific need for a review article on this topic and conceived the study. GMM, FB, GK, MRP, AG, AP, GDK, GPC and SIM designed the study structure, performed the literature search, screened and interpreted the findings. GMM wrote the initial draft. FB and SIM revised the original draft. GK, MRP, AG, AP, GDK and GPC enriched the manuscript and substantially revised the final draft. All authors read and approved the final manuscript. Data authentication is not applicable.
Not applicable.
Written consent was obtained from the patient for publication of the brain/heart MRI images.
The authors declare that they have no competing interests.
Fluid-attenuated inversion recovery images showing white matter hyperintensity brain lesions (indicated with arrows) in an asymptomatic patient with sarcoidosis and doubtful cognitive dysfunction tests.
Inversion recovery post contrast images showing evidence of pericarditis and subepicardial late gadolinium enhancement (indicated with arrows) indicative of myocarditis in the same patient.
Comparison between testing and combined brain-heart MRI in the detection of CD.
CD evaluation method | Sensitivity | Specificity | Location of lesion | Availability | Cost |
---|---|---|---|---|---|
CD testing | +++ | + | - | ++++ | Low |
Combined brain and heart MRI | ++++ | ++++ | ++++ | ++ | Very high |
CD, cognitive dysfunction; MRI, magnetic resonance imaging. Increasing + symbols indicate increased diagnostic capability of the method.