Clinical practice guidelines on addressing cognitive impairment in vascular dementias

INTRODUCTION Vascular dementia (VD) has been recognized for many centuries and was later meaningfully distinguished from dementias due to other etiologies.[1] VD is recognized as one of the most common types of dementia in the community across the world, second only to dementia due to Alzheimer’s disease (DAT), and the prevalence may be even higher in developing countries such as India.[2] Thus, VD is an important public health challenge and a major contributor to morbidity and mortality worldwide. However, there are issues in the exact classification of the disease and diagnostic criteria. Also, there are no licensed treatments specifically for VD.[3] What sets VD apart from other dementias are the following factors: The etiology of VD is clearly associated with brain tissue loss and dysfunction secondary to vascular pathophysiology in which hypertension seems to be the main reason.[4] While the exact cellular mechanisms are still not clear, it does imply that VD may potentially be largely preventable through better cardiovascular-metabolic risk modification. VD may also arise from other more gross brain insults such as strokes and infarcts that can lead to a sudden and catastrophic loss of cognitive function unlike the usual stepladder pattern or gradual decline that is classically described in VD or observed in other dementias. This is reflected in the various cerebrovascular disorders that have been described and also different terminologies that have been used by different authors to describe cognitive decline due to brain tissue loss and dysfunction due to vascular reasons.[5,6] Thus, cognitive decline due to cerebrovascular pathophysiology can exist on a spectrum from mild to severe and be correlated with a variety of brain lesions of vascular origins. Much of the deficit seen in VD may be attributed to the particular brain area that is involved in the insult. Thus, symptoms may vary from patient to patient. It can present itself as problems with memory and attention, confusion, impaired planning and judgment, uncontrolled laughing and crying, declining ability to pay attention, impaired function in social situations, difficulty finding the right words, changes in personality and behavior, loss of speech and language skills, and sometimes weakness or tremors. Cortical lesions may result in aphasia, apraxia, and seizures, while subcortical lesions may present as executive dysfunction, parkinsonism, abnormal gait, or urinary incontinence. Among the various mechanisms contributing to vascular cognitive impairment (VCI), cerebral small vessel disease (SVD) is likely the most common, playing a significant role in cognitive impairment even in the absence of stroke. SVD involves structural and functional abnormalities in the brain’s small blood vessels, leading to diverse neuroimaging and neurological outcomes, including cognitive decline. CNS small vessel disease has been reported to contribute to nearly 45% of cases of dementia. The small vessels implicated in small vessel disease include penetrating arterioles, capillaries, and venules which are less than 1 mm in diameter. Instead of being a single disorder, SVD comprises a range of sporadic and inherited conditions, influenced by a complex interplay of genetic and vascular risk factors. Subcortical ischemic vascular dementia (SIVaD) describes cases where SVD is the main factor for cognitive decline, with white matter hyperintensities (WMHs) and lacunar infarcts being the most common brain lesions. However, individuals showing neuroimaging evidence of SVD may be diagnosed with SIVaD, post-stroke dementia, or mixed dementia, depending on the timing and presence of other conditions. Vascular cognitive impairment may be divided into mild and major VD. VD can be caused by post-stroke dementia, subcortical ischemic VD, multi-infarct cortical dementia, and mixed dementia (when comorbid with dementias due to other etiologies).[7] Dementia of Alzheimer’s type (DAT) is the most common type of dementia across the world, followed by VD. However, often due to overlap of symptoms, it becomes difficult to distinguish both the dementias clinically in the later stages of dementia. Mixed dementia (which is the co-occurrence of DAT and VD) is estimated to be the third most common type of dementia globally and in India. Even though mixed dementia is common, there are no universally accepted diagnostic criteria for diagnosis of mixed dementia.[8,9] VD can usually be meaningfully clinically distinguished from DAT and other dementias, especially in the early stages, which opens up possibilities for early interventions.[10] This is especially so because most VD seems to have a long incubation period of decades and midlife hypertension seems to be contributory to the development of the same in later life. Unlike DAT, where drugs have been designed for modification of disease process, management of VD has largely focused on prevention through the modification of risk factors and prevention of further deterioration in established VD. In keeping with the mandate provided to the authors, this paper will deal with guidelines that may help clinicians in the prevention and management of VD. The authors have reviewed existing clinical guidelines for VD and vascular cognitive impairment.[11–21] Other existing relevant data have also been reviewed for this purpose. PROCESS OF DEVELOPMENT OF THE GUIDELINE The guideline was developed after extensive review of the scientific literature and based on the clinical experience. The authors searched for relevant peer-reviewed articles published in both international and national medical journals in English with focus on VD or vascular cognitive impairment as well as guidelines from WHO and various international societies that have focused on VD or vascular cognitive impairment. Among the journal articles, meta-analyses were preferred whenever available, followed by systematic reviews and randomized controlled trials. The current guideline, thus developed, was then presented at a workshop to eminent psychiatrists of the Indian Psychiatric Society on August 10, 2024. The comments thus received were incorporated and presented again on August 11, 2024 as well as uploaded on the website of the Indian Journal of Psychiatry for comments and suggestions from all mental health professionals. Following that, the final draft of the guidelines was published. GUIDELINES The guidelines are arranged as follows: First, guidelines that deal with diagnosis of VD will be discussed. This will be followed by guidelines for prevention.[22] Finally, management strategies will be considered. Diagnosis and assessment The complexity of VD often requires a coordinated approach involving multiple specialists – neurologists, endocrinologists, cardiologists, psychiatrists, and psychologists to comprehensively assess and to manage and address the various contributing factors effectively. Regular interdisciplinary consultations and collaborative joint care planning are vital to address the multifactorial nature of VD and for tailoring interventions that target both cognitive symptoms and underlying vascular risk factors. As mentioned above, VD is meaningfully different from other dementias with regard to phenomenology and pathophysiology. This provides clinicians and researchers opportunities for interventions. Therefore, it is imperative that sensitive and specific diagnostic schedules be available. Diagnosis is available in the following modalities in addition to routine clinical and lab investigations. Standardized diagnostic criteria Recommended standardized diagnostic criteria for diagnosis of VD and vascular cognitive impairment are presented in Table 1. Most schedules emphasize on a temporal correlation of the cognitive deficit with a cerebrovascular insult, neuroimaging support for the diagnosis of the insult, characteristic clinical pictures, manifestations of stroke residua, risk factors of stroke, supportive natural history, and familial factors.[23] Some of these diagnostic criteria have shown to have high inter-rater agreement with items in other schedules and have adequate predictive power with regard to conversion to dementia and mortality.[24] These diagnostic schedules may be recommended as aids to clinical diagnoses of VD and cognitive impairment.Table 1: Recommended standardized diagnostic criteria for VD and cognitive impairmentRadiological diagnosis Radiological diagnosis of VD is done preferably via the use of magnetic resonance imaging (MRI) and if not available or contraindicated by the use of computerized tomography (CT) scanning.[16] This is true for clinical and research settings. This is because MRI has a greater sensitivity and specificity for smaller lesions and microbleeds, as well as cortical atrophy that may reflect concomitant disease processes.[27] Recommendations have been made for standardization of imaging protocols for small vessel cerebral disease.[28] It is recommended that MRI should be mandatorily carried out as a part of the diagnostic workup and assessment of any patient with suspected or confirmed VD. In the absence of MRI or if it is contraindicated, CT may be a reasonable alternative. Hachinski ischemic score or hachinski index[29] The Hachinski Ischemic Score (HIS), also known as the Hachinski Index, is a clinical tool, often used to differentiate between VD and Alzheimer’s disease. It was developed by Dr Vladimir Hachinski and colleagues in 1975. The index assesses various clinical features associated with dementia to determine the likelihood that the dementia has a vascular component (abrupt onset, stepwise deterioration, fluctuating course, nocturnal confusion, relative preservation of personality, presence of depressive symptoms, somatic symptoms, emotional incontinence, history of stroke, presence of focal neurological signs, and presence of focal neurological symptoms). A score of 7 or more indicates VD. This is not a diagnostic tool. The index is most effective when combined with other diagnostic tools and tests, including neuroimaging and cognitive assessments. Prevention As mentioned above, VD represents a condition which may be uniquely preventable by modification of noncommunicable disease risk factors. Various risk factors have been described, of which some are modifiable.[30] Modification of many of these risk factors can presumably reduce the risk of developing VD.[31] The various risk factors of VD are enlisted in Table 2.Table 2: Commonly described risk factors for VDUniversal prevention Universal prevention of VD in adults can include strategies for prevention and evidence for prevention of VD in particular. The World Health Organization (WHO) strategies for prevention of dementia may be recommended as a universal population strategy and may be useful in selective and indicated patients as well.[32] These include promotion of age-appropriate physical activity, tobacco cessation interventions, nutritional interventions, alcohol use interventions, cognitive interventions, management of weight, hypertension, diabetes mellitus, and dyslipidemia [Flow Chart 1].Flow Chart 1: Universal preventive strategies for VDSelective and indicated preventive strategies specific to VD While a host of modifiable risk factors have been proposed for the development of VD, research has been focused mainly on prevention and management of hypertension, prevention of stroke and recurrent stroke, and the use of acetylsalicylic acid (ASA) in patients with white matter lesions and in patients with brain infarcts without stroke [Flow Charts 2 and 3].Flow Chart 2: Selective and Indicated preventive strategies specific to VDFlow Chart 3: Treatment guidelines for VDHypertension is an easily identifiable and modifiable risk factor for development of dementia and VD.[33] While the association is well described, the pathophysiology is not so clear. It seems that midlife hypertension may be more contributory to the development of VD than late-life hypertension.[34] Thus, midlife control of hypertension may be a better preventive strategy. There is modest evidence to suggest that blood pressure interventions across modalities may reduce incidence of dementia later.[35] A similar finding exists for lowering of blood pressure in the elderly with a greater cardiovascular risk profile. A modest advantage was reported for intensive blood pressure lowering versus standard lowering interventions on development of eventual cognitive impairment or dementia.[36] However, these studies are not generalizable to patients with pre-existing stroke, dementia, or diabetes. Also, intensive blood pressure lowering is associated with the risk of cerebral hypoperfusion and concomitant falls and syncope. However, it is reasonable to recommend measures to prevent hypertension as a means to prevent VD and vascular cognitive impairment. In middle-aged or elderly patients with hypertension and associated risk factors, a target blood pressure of <120 mm of Hg systolic should be aimed for. In patients with pre-existing cognitive impairment, blood pressure readings of ≥90 mm of Hg or systolic readings ≥140 mm of HG should indicate the need for hypertension therapy.[16] Indian guidelines for hypertension may be useful in this regard.[37] The calcium channel blocker drugs and angiotensin converting enzyme inhibitor classes of antihypertensive drugs may be useful in this regard.[38,39] Stroke prevention is another important aspect of prevention of VD. This includes prevention of first-ever and recurrent stroke. There are various guidelines for stroke prevention, and these guidelines from India may also be useful.[40] Other guidelines include the Berlin manifesto and the Canadian and American guidelines.[18,41,42] Another aspect of prevention of VD is the use of ASA in patients with white matter lesions and brain infarcts without stroke. Both these conditions may be considered to be proximal to the eventual development of VD. While it is reasonable to expect that such patients would benefit from the use of an antiplatelet and anti-inflammatory agent such as ASA, the evidence base suggests that ASA may not have a role in prevention of VD or cognitive decline in either of these populations or in the prevention of dementia.[43–45] Use of ASA must be tempered by the possibility that it may lead to a predisposition to bleeding.[46] Thus, the use of ASA must be tempered by an analysis of the risk–reward ratio. It is worthwhile to suggest that much of what has been discussed above may require a liaison with other specialities such as endocrinology and cardiology; thus, a psychiatrist may be encouraged to seek guidance from other specialists. Treatment options Treatment options Most of the guidelines and literature have focused on prevention of further impairment in VD by reduction of risk factors that can lead to further vascular events. These include management of diabetes, hypertension, and other vascular risk factors using medications, and lifestyle interventions, namely, diet, physical activity, and avoidance of tobacco and alcohol. The WHO guidelines recommend these interventions to reduce the risk of cognitive decline in patients with normal cognition and those with mild cognitive impairment to reduce further cognitive decline. However, its effect in improving the cognition among patients with VD is not known. Due to the multifactorial nature of VD as well as due to the frequent presence of mixed dementia, management should involve active collaboration and liaison among the various specialists, especially cardiologists, endocrinologists, neurologists, psychiatrists, and psychologists By addressing the underlying vascular and metabolic conditions that contribute to cognitive decline through the collaborative approach, along with interventions for improvement of cognitive functions, one can provide effective and targeted treatment, ultimately improving the quality of life for patients with VD. Treatment modalities used are presented in Table 3.Table 3: Evidence base on management of cognitive impairment in vascular dementiaPharmacological interventions No pharmacological treatment modality has been found to consistently lead to clinically significant improvement in treating patients with VD. Some of the pharmacological agents that have been tried in patients with VD have been discussed below: Anticholinesterase agents: Cholinesterase inhibitors that have been tried for cognitive impairment in patients with VD include donepezil, galantamine, and rivastigmine. Multiple Cochrane reviews and multiple meta-analyses have found modest cognitive benefits with cholinesterase inhibitors in patients with mild to moderate dementia.[3,59–62] The latest Cochrane network-meta-analysis has found donepezil and galantamine to have slight but clinically insignificant impairment, while rivastigmine has little to no effect on cognition.[47] However, the use of these medications is also associated with higher risk of adverse effects. The most common adverse events include nausea, vomiting, and diarrhea. Serious adverse events that have been reported include stroke, pneumonia, and myocardial infarction. Most international guidelines support the use of these medications when vascular cognitive impairment has comorbid DAT. However, when there is no comorbid DAT, these medications may be considered for VD if there is no contraindication and after fully informing the patient about the potential benefits and risks of these medications. NMDA antagonist: Memantine is another agent which has been tried for patients with VD and has shown modest benefits in cognition, similar to AChE inhibitors. However, since the effects are modest, their clinical significance is again a matter of debate. While most available international guidelines recommend use of memantine in VD in patients with comorbid DAT, they are divided with respect to recommendations for pure vascular dementia, with some guidelines not recommending its use and some guidelines recommending consideration for use in selected patients. Hence, NMDA antagonist may be tried and may be useful for selected patients, especially when there is comorbid DAT (mixed dementia). Citicoline: Citicoline is an endogenous intermediate in the formation of phosphatidylcholine, the primary neuronal phospholipid. A few studies have tried to assess the efficacy of citicoline mainly in prevention of cognitive impairment after stroke or other cerebrovascular events. 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