Vascular Dementia and Alzheimer's Disease: Diagnosis and Risk Factors

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Dementia is a neurological disease that is associated with aging. The incidence and prevalence of dementia is increasing as the population continues to age. The two most common forms of dementia are Alzheimer's disease (AD) and vascular dementia (VaD). Although these two forms of dementia represent different pathologies and different clinical presentations, they share similar risk factors. It is important to distinguish between the two forms of dementia because of the differing treatments, and because the risk factors for each are often preventable. This article will discuss the classification, risk factors, and diagnosis of AD and VaD, and present distinguishing characteristics between them.

Elise J. Levinoff. Vascular Dementia and Alzheimer's Disease: Diagnosis and Risk Factors. Geriatrics & Aging. 2007;10(1):36-41.

INTRODUCTION

Dementia is defined as a neurological syndrome consisting of impaired cognition that is severe enough to interfere with social or occupational functioning.[1] In 2001 an estimated 364,000 older Canadians lived with dementia;[2] by 2021, that number is projected to total 592,000.[2] Some of the risk factors for dementia are advanced age, family history, educational level, and presence of vascular risk factors.

The two most common forms of dementia are Alzheimer's disease (AD) and vascular dementia (VaD).[3] The prevalence of Alzheimer's disease is 4.4% whereas that of VaD is 1.4%.[2] A clinician should consider a diagnosis of AD for an individual who presents with dementia that is characterized by a gradual and progressive course of short-term memory impairment without lateralizing signs, symptoms, or lateralized cognitive deficits.[4] Alternately, a diagnosis of VaD would be appropriate for an individual who presents with an acute onset and stepwise progression of cognitive impairment.[5]

While the foregoing distinction is useful, it should be noted that the differences between AD and VaD are not always obvious. A myriad of overlapping characteristics exist between them, including the cognitive decline often associated with aging. Impairments associated with normal aging are limited to rote memory and delayed recall. In contrast, patients with AD often manifest impaired abilities to form new memories whereas patients with VaD are cognitively impaired in executive functioning activities such as organizing, planning, and initiating sequential events. The pathological hallmarks of both dementias frequently coexist, as seen in postmortem analyses of older adults with dementia.[6] Furthermore, there is considerable overlap between risk factors associated with AD and VaD. As with all dementias, organic reversible causes such as Vitamin B12 and folate deficiencies as well as thyroid abnormalities must be ruled out in order to make a definitive diagnosis.

Despite these difficulties it is important for clinicians to differentiate between patients with AD and VaD for several reasons. First, differentiating between these two types of dementia will enable researchers to accurately study their prevention, risk factors, and pathophysiology. Second, accurate diagnosing of AD and VaD is required to determine which form of treatment will most benefit the patient. This article will focus on the clinical diagnosis and risk factors associated with AD and VaD, and will examine the overlap between the two.


What Is Vascular Dementia?

It has been argued that the criteria for VaD as outlined by the National Institute of Neurological Disorder and Stroke - Association Internationale pour Recherche et l'Enseignment en Neuroscience (NINDS-AIREN), as well as the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for diagnosing VaD, are too confining and have excluded individuals now recognized as having cognitive decline related to vascular injury.[3,7-9] The term vascular cognitive impairment (VCI) has been used to refer to all forms of mild to severe cognitive impairment that are associated with a vascular insult, whether they meet criteria for vascular dementia or not.[3,7,8,10-12] This form of impairment includes those who have cognitive dysfunction associated with stroke, multiple cortical infarcts, multiple subcortical infarcts, silent infarcts, strategic infarcts, multiple small vessel disease with white matter lesions, and lacunar infarcts.

The term VCI recognizes that the criteria for dementia are very much weighted towards AD and need to be broadened to include individuals with vascular injuries of different etiologies. In an attempt to approach the heterogeneity of the pathophysiology associated with VaD, a number of researchers have subclassified vascular dementia according to the pathophysiology of the lesion that causes the cognitive deficit. For example, one simplified subclassification includes post-stroke dementia, subcortical VaD, and AD and VaD (or AD and cerebrovascular disease).[11] Post-stroke dementia is defined as a cognitive impairment resulting from a thromboembolic or hemorrhagic event causing cognitive symptoms severe enough to impair social and occupational functioning. Subcortical VaD is caused by lacunar infarcts and white matter lesions.


Diagnosis of Vascular Dementia

Three specific elements are required for a clinician to diagnose an individual with VaD (see Table 1 ).[5,13,14] First, as with all dementias, is demonstration of cognitive impairment. There have been attempts to contrast the pattern of cognitive impairment in VaD cases with the predominant memory impairment seen in AD. Many individuals with VaD have a generalized cognitive deficit with less striking memory loss than is found among individuals with AD.[3,10]In fact, a more common form of cognitive impairment associated with VaD is compromised executive functioning, which involves goal-directed behaviour, initiation of sequences, and problem-solving abilities.[3,15] Cerebrovascular subcortical lesions in the prefrontal cortex resulting in subcortical VaD can often cause cognitive impairments associated with executive functioning. To determine if executive impairments exist in individuals with vascular dementia, specific neuropsychological tests of executive functioning such as the Trail-Making Test, the Executive Interview, and the Clock Drawing Test may be used.[3]


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Table 1. Diagnosis of Vascular Dementia (NINDS-AIREN)

I. Criiteria or diagnosis of probable vascular dementia
A. Dementia
B. Cerebrovascular disease
C. A relationship between the above two disorders
i. Onset of dementia within three months of a recognized stroke
ii. Abrupt deterioration in cognitive functions or fluctuating, stepwise progression of cognitive deficits

II. Clinical features consistent with the diagnosis of probable vascular dementia
A. Early presence of gait disturbances
B. History of unsteadiness and provoked falls
C. Early urinary frequency, urgency, and other urinary symptoms not explained by urologic disease
D. Pseudobulbar palsy
E. Persoality and mood changes

III. Features that make the diagnosis of vascular dementia uncertain or unlikely
A. Early onset of memory deficit and progressive worsening of memory and other cognitive funcitons in the absence of corresponding focal brain lesions on imaging
B. Absence of focal neurological consequences other than cognitive disturbances
C. Absence of cerebrovascular damage on brain imaging
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Source: Roman G et al, 1993 (5)
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Second, there are several nonspecific clinical symptoms associated with vascular dementia. Individuals with typical subcortical lesions may display extrapyramidal symptoms and instability leading to falls. Urinary frequency and incontinence, as well as dysarthria and dysphagia, are common symptoms.[11]Clinical paper and pencil tests, such as the Hachinski Ischemic Scale, may be used to aid in the diagnosis of VaD. The Hachinski Ischemic Scale accounts for factors associated with vascular development of dementia such as the onset of the cognitive impairment, the risk factors related to stroke, behavioural abnormalities such as depression and emotional incontinence, and focal neurological symptoms.[16] A score lower than 4 renders a diagnosis of AD, whereas a score of greater than 7 is classified as multi-infarct dementia.[10,17]A final factor required for the diagnosis of VaD is for the cognitive impairment to have occurred within three months of the cerebrovascular event (i.e., a symptomatic stroke). This temporal criterion is being disputed in some recent discussions of taxonomy.[3,8]

Third, the individual must demonstrate some form of cerebrovascular pathology as displayed by brain imaging studies (i.e., computed tomography [CT] or magnetic resonance imaging [MRI]). Brain imaging studies demonstrate vascular lesions that may differ in size depending on the degree of vascular insult. These lesions range from a single lacunar stroke to multiple cortico-subcortical strokes and periventricular white matter ischemia.[3,10]


Risk Factors for Vascular Dementia

Age is the most significant risk factor for any dementia; however, other factors associated with health status earlier in life may predispose older adults to developing VaD. For example, there is little dispute that atherosclerotic risk factors such as smoking, hypertension, myocardial infarctions, hyperlipidemia, and diabetes mellitus predispose older adults to cerebrovascular disease (CVD), causing VaD.[18] Additionally, the presence of stroke-related factors as a consequence of hemorrhagic, ischemic, or embolic events in the brain may also cause VaD.[16] The location (i.e., thalamic or angular gyrus) and size of the stroke (i.e., multiple clinically silent cerebral infarcts, or bilateral cerebral infarction) can also cause significant cerebral tissue loss and white matter disease, leading to VaD.[18]

Two large randomized controlled trials demonstrated that the use of antihypertensive medications reduces the risk of dementia in individuals with cerebrovascular disease.[19,20] The Syst-Eur trial, which involved 3,000 participants, showed a significant reduction in the incidence of dementia in individuals using calcium channel blockers for a period of two years.[19]Similarly, the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial revealed that when blood pressure control was achieved with angiotensin-converting enzyme (ACE) inhibitors, there was a reduction in the likelihood of cognitive decline, but no overall reduction in the incidence of dementia. Further, a recent meta-analysis that examined whether antihypertensive agents reduced the risk of developing dementia in individuals with existing cerebrovascular disease demonstrated no significant effect of preventing dementia.[21]


Definition and Diagnosis of Alzheimer's Disease

The National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) guidelines describe AD as a progressive neurological disease characterized by memory loss, behavioural changes, and global functional impairment in activities of daily living ( Table 2 ).[4] Individuals with AD display an inability to learn or retain new information and may also be limited in their abilities to express or comprehend verbal information.


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Table 2. NINCDS-ADRDA Criteria for the Clinical Diagnosis of Probable Alzheimer's Disease

1. Dementia established by clinical examination and metnal status testing and confirmed by neuropsychological testing

2. Progressive deficits in t least two cognitive domains such as aphasia, apraxia, and agnosia

3. Impaired activities of daily living

4. Progressive cognitive decline, including memory

5. No other possible medical or neurological explanation
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Source: McKhann G et al, 1984
________


Cognitive impairment without impaired activities of daily living is defined as mild cognitive impairment (MCI).[22] Individuals with MCI have defined subjective and objective memory impairment, but intact daily activities of living. It is important to note that not all individuals who are classified as having MCI will progress to develop dementia. The likelihood that an individual with MCI will develop dementia is approximately 5-10 times that of cognitively healthy individuals.[22]

Individuals may present with symptoms of depression that mask the dementia. Tests such as the Hamilton Depression Scale and Yesavage's Geriatric Depression Scale may quantify the degree of depression. Additionally, in the late stages of the disease, individuals may have behavioural changes such as delusions, sleep disturbance, agitation, and hallucinations.[23]

Cognitive tests such as the Mini Mental Status Examination have been helpful in screening for memory deficits associated with AD. This quick, standardized bedside examination with detection sensitivity and specificity of 82% and 83%, respectively, encompasses cognitive domains such as episodic memory, language, orientation, and constructional ability. Usually, a score of less than 24 on a scale of 30 indicates that a patient has some form of cognitive impairment.[1]The Montreal Cognitive Assessment (MoCA) is a 10-minute neuropsychological test that incorporates short-term memory recall, visuospatial abilities, delayed recall, language, orientation, and executive functioning. The preliminary results from its use indicate that the sensitivity is close to 100% for screening for cognitive impairments in individuals with MCI.[24]

These tests are useful aids to help the clinician decide whether to pursue ancillary neuropsychological testing to aid in the diagnosis of AD. Neuropsychological testing often becomes useful when the diagnosis of AD is suspected, but there are other factors that might be associated with the cognitive impairment and lead to a diagnosis of a different dementia (i.e., vascular risk factors as discussed below, depression, strong family history of dementia or other behavioural abnormalities). More importantly, ancillary neuropsychological testing may be helpful for the clinician who suspects that an individual may have MCI with an unclear clinical picture of dementia.

To date, there is no good evidence to suggest that neuroimaging studies are routinely useful for diagnosing AD.[1] From a theoretical perspective, the brains of AD patients show significant atrophy in regions such as the medial temporal lobes, and subcortical regions such as the hippocampus are also markedly atrophic in these patients when compared to age-matched older individuals. The sensitivity of detecting hippocampal atrophy is around 85%, but the specificity is markedly lower.[22] As a result, imaging studies alone are not conclusive diagnostic aids. Furthermore, the pathological hallmarks of AD develop for years before they are detectable by MRI.

The pathological features of AD include amyloid beta deposition in the form of senile plaques, neurofibrillary tangles, phorphorylated tau deposition as well as neuron degeneration, and synaptic loss.[22] As well, biomarkers such as apolipoprotein E (APOE) have added diagnostic value in determining whether an individual has AD, but are not sensitive or specific enough to make a definitive diagnosis of AD.

In summary, there is fair clinical evidence to support that psychometric paper and pencil tests such as the MMSE and the MoCA are strong screening tests for clinicians to detect AD.[1] Ancillary tests such as MRI, PET, and hippocampal volume measurements as well as neurophysiological tests such as EEG are not routinely used by physicians to diagnose dementia as there is insufficient evidence to suggest that these tests will confer a definitive diagnosis.[1] Most often, the diagnosis is made by the physician who takes a detailed history and performs a physical exam to rule out other causes. As well, physicians should serially follow their patients to monitor their course if the diagnosis is unclear at the time of presentation.


Risk Factors for Alzheimer's Disease

As hypertension is a risk factor for stroke and VaD, clinical trials have recently demonstrated that there is a convincing link between hypertension in middle age and development of AD in later life.[25,26] The Honolulu Asia Aging Study identified a relationship between high blood pressure in mid-life and low brain weight and increased neurofibrillary tangles in the hippocampus at postmortem autopsy. An inverse correlation was demonstrated between cognitive functioning in later life and elevated systolic blood pressure.[25] The Rotterdam study, which followed over 7,000 community-dwelling adults 55 years of age and older, investigated the epidemiological risk factors for AD. Within the group of participants with dementia, there was a further subclassification between VaD and AD. The collective data from the Rotterdam Study demonstrated that atherosclerotic risk factors such as smoking, atrial fibrillation, hyperlipidemia and non-insulin-dependent diabetes mellitus were all significant risk factors for development of AD in later life.[26] Similarly, the Framingham Study showed an inverse correlation between systolic blood pressure and cognitive performance in aging individuals with untreated high blood pressure.[27]In summary, there is some evidence to suggest that treating hypertension will reduce the risk of cognitive decline. Whether one form of treatment is better than another (i.e., ACE inhibitors vs. beta-blockers vs. calcium-channel blockers) remains to be determined by future clinical studies. Furthermore, treatment of hypertension is necessary in order to prevent cerebrovascular disease in later life.


Mixed Dementia

Mixed dementia, or mixed AD and cerebrovascular disease, is an overlap between AD and VaD. There are currently no specific established criteria to make a proper diagnosis. As mentioned, the risk factors for AD and VaD are similar. Furthermore, there is a strong association between the pathologies of AD and VaD, both of which have been shown to synergistically affect cognitive functioning.[6] However, scarce epidemiological evidence exists to support the diagnosis of mixed dementia, which has an incidence of 20-40%.[27]This wide variation in incidence is likely due to the difference in recruitment biases among the different studies, the different age populations that were set within each study, and the lack of specific diagnostic criteria for determining mixed dementia.[27] Despite these overlapping factors, it is obvious that clinical heterogeneity exists within one prevalent form of dementia, which makes it difficult for clinicians to diagnose a patient as having purely AD or purely VaD.


Conclusion

Why is it so important to classify patients who have dementia into specific subtypes? With the rising number of older adults in the population, the need to recognize and prevent the symptoms of dementia from developing as early as possible is increasingly important. The challenges of classifying VaD and differentiating between individuals who have AD versus VaD versus a mixed dementia will persist because older adults are susceptible to developing cerebrovascular disease in addition to developing AD. However, more precise classification is required in order to study the risk factors, clinical symptoms, and treatment options of older adults who have dementia that is consistent with AD or VaD. If individuals are misclassified or misdiagnosed then research studies may well report inconsistent results. Finally, the importance of recognizing and distinguishing the two will further help researchers and clinicians in their ability to diagnose, manage, and treat older adults with the best possible guidance.



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Authors and Disclosures

Elise J. Levinoff, MSc, BSc, University of Ottawa, Faculty of Medicine, Ottawa, ON.

Disclosure: No competing interests declared.

Geriatrics and Aging. 2007;10(1):36-41. © 2007 1453987 Ontario, Ltd.
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