Predictors of progression of cognitive decline in Alzheimer’s disease: the role of vascular and sociodemographic factors

Rates of disease progression differ among patients with Alzheimer’s disease, but little is known about prognostic predictors. The aim of the study was to assess whether sociodemographic factors, disease severity and duration, and vascular factors are prognostic predictors of cognitive decline in Alzheimer’s disease progression. We conducted a longitudinal clinical study in a specialized clinical unit for the diagnosis and treatment of dementia in Rome, Italy. A total of 154 persons with mild to moderate Alzheimer’s disease consecutively admitted to the dementia unit were included. All patients underwent extensive clinical examination by a physician at admittance and all follow-ups. We evaluated the time-dependent probability of a worsening in cognitive performance corresponding to a 5-point decrease in Mini-Mental State Examination (MMSE) score. Survival analysis was used to analyze risk of faster disease progression in relation to age, education, severity and duration of the disease, family history of dementia, hypertension, hypercholesterolemia, and type 2 diabetes. Younger and more educated persons were more likely to have faster Alzheimer’s disease progression. Vascular factors such as hypertension and hypercholesterolemia were not found to be significantly associated with disease progression. However, patients with diabetes had a 65% reduced risk of fast cognitive decline compared to Alzheimer patients without diabetes. Sociodemographic factors and diabetes predict disease progression in Alzheimer’s disease. Our findings suggest a slower disease progression in Alzheimer’s patients with diabetes. If confirmed, this result will contribute new insights into Alzheimer’s disease pathogenesis and lead to relevant suggestions for disease treatment.     

Risk factors and mechanisms of post-stroke dementia]

Stroke significantly increases the risk of dementia in subjects aged 55 years or more. Twenty to 25 p. 100 of patients are demented 5 years after a stroke. Age and supratentorial location of the vascular lesion are risk factors for post-stroke dementia. Volume, left side of the lesion, large middle cerebral artery infarction, lesions of the frontal lobe, second stroke, diabetes, aphasia, clinical features expressing the severity of the stroke event in the acute phase, mitral valve prolapse, atrial fibrillation, depression, concomitant hypoxic/ischemic disorders, and white matter changes have also been found as predictors of dementia. There are many different mechanisms of vascular pathology that may lead to dementia: ischemic or hemorrhagic lesions, large vessel disease including multi-infarct and strategic single infarct, small-vessel disease including lacunes and white matter changes, hypoperfusion.... Post-stroke dementia may not be due only to vascular lesion. Some post-stroke dementias have a progressive onset and course. The cognitive decline may pre-exist to the stroke, even when a dementia is not diagnosed. This suggests a degenerative process. Alzheimer's disease is frequent in ages when the majority of strokes occur. Alzheimer's and vascular diseases share common risk factors such as age, APOE4, hypertension, and smoking. Patients with low MMS scores and AD patients are at risk for stroke. Moreover, white matter changes are associated with stroke and Alzheimer's disease and may contribute to the cognitive decline. Many post-stroke dementias could be multifactorial. Even when vascular lesions and degenerative changes (mainly Alzheimer changes) are not severe enough, no their own, to be the cause of dementia, their summation may reduce the preclinical stage of the degenerative process.     

Diagnosis,risk factors,and treatment of vascular dementia

Although the introduction of modern neuroimaging techniques and standardized clinical evaluations has improved the identification of cerebrovascular disease, the clinical diagnosis of vascular dementia (VaD) is still problematic. Neuropathologic studies have found the current clinical criteria for VaD had low sensitivity with high specificity, suggesting that cerebrovascular disease of sufficient severity to cause cognitive deficits is frequently associated with other disease processes (eg, Alzheimer’s disease). The critical factors about the diagnosis of VaD are centered on two issues: definition of dementia and determination of vascular disease. The current clinical criteria for VaD have different definitions of dementia, which are mainly based on an Alzheimer’s disease-like presentation, and severe vascular disease can present with or without history of clinical strokes. Therefore, there is a need for a better definition of VaD. This is extremely important to better understand its risk factors, as well as to create homogenous cohorts suitable for drug trials.     

Why are stroke patients prone to develop dementia?

Stroke patients are more likely to develop dementia than age- and sex-matched controls but the pathogenesis of dementia remains unresolved in most of them. The aim of this review is to determine, from the available literature, the theoretical reasons for a stroke patient to become demented. We found three distinct factors that may explain the occurrence of dementia after a stroke. Firstly, post-stroke dementia may be the direct consequence of the vascular lesions of the brain: this is the most likely cause in patients with normal cognitive functions before a strategic infarct, especially in young patients, in Icelandic-type hereditary amyloid angiopathy and in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. Secondly, post-stroke dementia may be due to an associated asymptomatic Alzheimer pathology; the reasons for such an association are that (1) some cases of dementia occurring after a stroke are progressive and Alzheimer’s disease (AD) is the most frequent cause of progressive dementia; (2) age and APOE ɛ 4 genotype are risk factors for both AD and ischaemic stroke; (3) a vasculopathy is often associated with AD. Lastly, white matter changes may also contribute to dementia because they often indicate small-vessel disease and a higher risk of stroke recurrence, and may lead to slight cognitive impairment. Finally, the summation of vascular lesions of the brain, white matter changes, and Alzheimer pathology might lead to dementia, even when each type of lesion, on its own, is not severe enough to induce dementia. Therefore, in patients followed up after a stroke, the term “post-stroke dementia” is probably more appropriate than that of vascular dementia because it includes all possible causal factors. Received: 15 July 1996 Accepted: 19 October 1996     

Vascular dementia today

This decade witnessed a resurgence of interest in vascular dementia (VaD) as an increasingly important cause of senile dementia. Although definitions of dementia in general, and of VaD in particular, are still controversial recent diagnostic criteria for VaD acknowledge that pathogenetic mechanisms different from multi-infarct dementia are important in dementia causation. These include subcortical strokes, mainly lacunes, global hypoxic-ischemic events during acute stroke, and ischemic periventricular white matter lesions of the Binswanger type. These lesions tend to be manifested primarily by alterations of frontal executive function control. The importance of these ischemic vascular lesions in the clinical expression of Alzheimer's disease (AD) in very old subjects has also been recognized. Clinically, VaD may present in two forms: Acute VaD includes large-vessel infarction, and lacunar dementia due to small-vessel disease, including thalamic and caudate strokes. Subacute VaD includes Binswanger's disease (BD), cerebral angiopathy with leukoencephalopathy and CADASIL. The discovery of CADASIL, a genetic form of VaD mapped to chromosome 19 as a mutation of the Notch 3 gene, opened research avenues into the pathogenesis of BD. Finally, epidemiological evidence suggests that it may be possible to prevent VaD--and perhaps degenerative senile dementia--by controlling hypertension and other vascular risk factors. These findings offer hope for prevention of this growing public health problem.     

Changing concepts of cerebrospinal fluid hydrodynamics: Role of phase-contrast magnetic resonance imaging and implications for cerebral microvascular disease

Phase-contrast magnetic resonance imaging (PC-MRI) or flow-sensitive MRI can be used to noninvasively measure intracranial vascular and CSF flow. Monro-Kellie homeostasis is the complex compensatory mechanism for the increase in intracranial blood volume during systole. Through PC-MRI techniques, our understanding of Monro-Kellie homeostasis and the associated intracranial hydrodynamics has greatly improved. Failure of this homeostatic mechanism has been implicated in a wide range of cerebral disorders, including vascular and Alzheimer’s dementia, late-onset depression, benign and secondary intracranial hypertension, communicating and normal pressure hydrocephalus, and age-related white matter changes. The most common mode of homeostatic failure is due to vascular disease with decreased cerebral arterial compliance. This has wide-reaching implications in the investigation of patients with cerebral vascular disease. Here we discuss the role of PC-MRI in the study of cerebral hydrodynamics and the our understanding of Monro-Kellie homeostasis in both healthy and disease states. Quantitative assessment of the changes in this homeostatic mechanism using PC-MRI has important implications in the development of biomarkers of vascular involvement in disease with application in diagnosis, treatment planning, phenotype identification, and outcome assessment in clinical trials.     

Cholinergic dysfunction in vascular dementia

Vascular dementia (VaD) is the second most common type of dementia in the elderly after Alzheimer’s disease (AD). Evidence is presented indicating the occurrence of cholinergic dysfunction in VaD, independent from AD. Controlled clinical trials of cholinesterase inhibitors (ChEIs) in VaD and in patients with AD plus cerebrovascular disease are reviewed. Compared with placebo, ChEI treatment improves cognition, behavior, and activities of daily living. Cholinergic deficits in patients with VaD may result from ischemia of basal forebrain cholinergic nuclei that are irrigated by penetrating arteries that are highly susceptible to arterial hypertension, or from ischemic lesions in basal ganglia or white matter that sever the extensive cholinergic cortical projections. Cholinergic stimulation produces increases in cortical cerebral blood flow that may be relevant to the therapeutic effect of ChEIs.     

Cerebrovascular disease and dementia

Cerebrovascular disease (CVD) is an important cause of psychiatric disability in the elderly. Much of this disability can be attributed to dementia and lesser degrees of cognitive impairment, which result from strokes and other forms of cerebrovascular pathology. While vascular dementia is common, estimates of its frequency vary due to its clinical and pathologic heterogeneity, the challenges involved in its measurement and its frequent co-occurrence with Alzheimer's disease. Nevertheless the clinical features and natural histories of vascular dementia can be described, and risk factors have been identified and include hypertension, diabetes mellitus, hyperlipidaemia, other conditions that promote atherosclerosis, and rare genetic mutations. While vascular dementia is not curable, treatments are available. For example, a few recent clinical trials suggest that cholinesterase inhibitors have some efficacy. Our knowledge of the risk factors has also provided opportunities for the primary and secondary prevention of vascular dementia, and indicates promising avenues for research.     

Apoptosis in the aged dog brain

Apoptosis similar to that seen in Alzheimer’s disease patients was found in the brain of aged dogs by the TUNEL method of detecting in situ DNA fragmentation. Apoptosis was observed in both neurons and glial cells, and was morphologically characterized by round and swollen cytoplasm and aggregated nuclear chromatin, although these changes were slight. Neurons and astrocytes in the gray matter and oligodendrocytes in the white matter were affected. The number of ApopTag-positive brain cells increased slightly with age, but was not correlated to the number of senile plaques. A good correlation between the number of ApopTag-positive cells and the dementia index was clearly found. The present study indicates that brain cell apoptosis could account for dementia in aged dogs and suggested that aged dogs may be useful as a simplified animal model for Alzheimer’s disease in man. Received: 25 January 1996 / Revised, accepted: 15 March 1996     

Cerebrovascular disease and dementia

Cerebrovascular disease (CVD) is an important cause of psychiatric disability in the elderly. Much of this disability can be attributed to dementia and lesser degrees of cognitive impairment, which result from strokes and other forms of cerebrovascular pathology. While vascular dementia is common, estimates of its frequency vary due to its clinical and pathologic heterogeneity, the challenges involved in its measurement and its frequent co-occurrence with Alzheimer's disease. Nevertheless the clinical features and natural histories of vascular dementia can be described, and risk factors have been identified and include hypertension, diabetes mellitus, hyperlipidaemia, other conditions that promote atherosclerosis, and rare genetic mutations. While vascular dementia is not curable, treatments are available. For example, a few recent clinical trials suggest that cholinesterase inhibitors have some efficacy. Our knowledge of the risk factors has also provided opportunities for the primary and secondary prevention of vascular dementia, and indicates promising avenues for research.     

Vascular factors and Alzheimer disease

Vascular risk factors are normally associated with cerebrovascular disease, which may lead to vascular dementia (VaD). Several recent studies suggest that there is increased risk of developing Alzheimer disease when exposed to these same vascular risk factors. In addition to old age, hypertension, peripheral arterial disease, certain types of cardiovascular disorders, diabetes mellitus, and smoking are now considered risk factors for late-onset Alzheimer disease. In this review, we examine several vascular factors and peripheral vascular pathophysiology implicated in Alzheimer disease and suggest certain mechanisms that might promote the association of vascular factors and late-onset Alzheimer disease. We support the implication that prevention or management of peripheral vascular disease may prevent or delay the onset of Alzheimer disease or mixed dementia.     

Vascular cognitive deterioration and stroke

Vascular cognitive impairment, the recent modification of the terminology related to vascular burden of the brain, reflects the all-encompassing effects of vascular disease or lesions on cognition. It incorporates the complex interactions between vascular aetiologies, risk factors and cellular changes within the brain and cognition. The concept covers the frequent poststroke cognitive impairment and dementia, as well as cerebrovascular disease (CVD) as the second most common factor related to dementia. CVD as well as vascular risk factors including arterial hypertension, history of high cholesterol, diabetes or forms of heart disease are independently associated with an increased risk of cognitive impairment and dementia. Traditional vascular risk factors and stroke are also independent factors for the clinical presentation of Alzheimer's disease (AD). In addition to these vascular factors, CVD/strokes, infarcts and white-matter lesions may trigger and modify the progression of AD as the most common cause of neurodegenerative dementia. The main subtypes of previously defined vascular dementia (VaD) include the cortical VaD or multi-infarct dementia also referred as poststroke VaD, subcortical ischaemic vascular disease and dementia or small-vessel dementia and strategic-infarct dementia. Whilst CVD is preventable and treatable, it is clearly a major factor in the prevalence of cognitive impairment in the elderly worldwide.     

Nuclear magnetic resonance image white matter lesions and risk factors for stroke in normal individuals

The incidence, average number, and localization of lesions of the white matter detected by the T2-weighted nuclear magnetic resonance images among volunteers without cerebrovascular symptoms have been correlated with the number of risk factors for stroke. Accepted risk factors were arterial hypertension, diabetes mellitus, smoking, hypercholesterolemia, and cardiac disease. The 42 subjects examined were divided into Group A (0-1 risk factor, mean age 59.36 +/- 5.73 years), Group B (2 risk factors, mean age 61.54 +/- 8.33 years), and Group C (greater than or equal to 3 risk factors, mean age 62.57 +/- 9.83 years). Multiple risk factors among the age-matched groups was accompanied by a highly significant increase (p less than 0.001, Group A versus Group B; p less than 0.01, Group A versus Group C) of the incidence of white matter lesions. The average number of white matter lesions was increased (p less than 0.001) when Group A was compared with Groups B and C. Ninety-two percent of the white matter lesions were localized in watershed zones. Only 11 of the 155 abnormalities of the white matter detected by nuclear magnetic resonance imaging could be detected by computed tomography. White matter lesions in T2-weighted images appear to be an early stage of cerebrovascular disease.     

Familial frontotemporal dementia with ubiquitin inclusion bodies and without motor neuron disease

Frontotemporal dementia (FTD) is the second most common degenerative dementia after Alzheimer’s disease and its Lewy body variant. Clinical pathology can be subdivided in three main neuropathological subtypes: frontal lobe dementia, Pick’s disease and FTD with motor neuron disease (MND), all characterised by distinct histological features. Until recently the presence of ubiquitin-positive intraneuronal inclusions in the dentate gyrus, and the temporal and frontal cortex was usually associated with the MND type. Such inclusions were also observed in a few sporadic cases of FTD without or with parkinsonism (FTDP) in the absence of MND. We present here clinical, neuropathological and immunohistochemical data about a Swiss FTD family with FTDP-like features but without MND. Spongiosis and mild gliosis were observed in the grey matter. No neurofibrillary tangles, Pick bodies, Lewy bodies, senile plaques or prion-positive signals were present. However, ubiquitin-positive intracytoplasmic inclusions were detected in various structures but predominantly in the dentate gyrus. These observations support the existence of a familial form of FTDP with ubiquitin-positive intracytoplasmic inclusions (Swiss FTDP family). Received: 8 November 1999 / Revised, accepted: 17 January 2000     

Dementia, stroke, and vascular risk factors; a review

Interest in dementia has increased over the past few decades. Stroke is an important cause of cognitive problems. The term vascular cognitive impairment is now used to describe dementia attributed to stroke or deep white matter lesions detected on imaging. Although vascular cognitive impairment is increasingly diagnosed, Alzheimer's disease remains the most common dementia worldwide. The relationship between Alzheimer's disease and vascular cognitive impairment is unclear, although there exists significant overlap, which prompts physicians to consider them opposite ends of a disease spectrum, rather than separate entities. There is also substantial evidence that stroke risk factors such as hypertension, diabetes; lipid disorders, etc. are independently associated with an increased risk of Alzheimer's disease and vascular cognitive impairment. Evidence suggests that these risk factors have a cumulative effect on Alzheimer's disease development but not on vascular cognitive impairment. This is more marked in Alzheimer's disease patients in the presence of the ε4 allelic variant of apolipoprotein E. How these risk factors increase the risk of dementia is largely unknown. Physicians must be aware that stroke causes dementia; that vascular risk factors appear to be independent risk factors in developing dementia, and that poststroke care must include cognitive assessment.     

Pathogenesis of migraine: from neurotransmitters to neuromodulators and beyond

Recent studies suggest strong interactions between cerebrovascular and Alzheimer’s disease (AD) pathology. These conditions share common risk factors and individuals having both frequently show greater cognitive impairment than those affected by only one disease. Many studies point to early vascular dysregulations in AD. The exchange between vascular and neural cells occurs through mechanisms not completely understood, involving interactions among endothelial, glial, neuronal and smooth muscle cells within the neurovascular unit. Studies suggest that the dysregulation of the unit is likely associated with hypertension and other systemic diseases. Associations between hypertension and cognitive decline are not established, but other variables associated with hypertension could create a causal link. Many studies have lacked a consistent, quantitative neuropsychological approach for assessing cognitive functions. This approach is reductive, as the need for a formal neuropsychological assessment has gained broad recognition, and the definition of dementia has gone through revision processes, which are in progress.     

White matter lesion in the elderly

The advent of neuroimaging has brought medical attention to the frequency of unsuspected white matter lesions in the brains of elderly people. In 1987 Hackinski suggested the term “leuko-araiosis” to identify such white matter abnormalities detected by computed tomography and magnetic resonance imaging to emphasize that their etiology and clinical relevance require clarification. Since then, leuko-araiosis has been recognized among approximately ten percent of apparently normal, elderly people over age sixtyfive. The severity and frequency of leuko-araiosis increases with advancing age, risk factors for stroke, history of strokes particularly of the lacunar type and dementia of both the vascular and Alzheimer type. Current concepts concerning the pathogenesis and neurological concomitants of leuko-araiosis are reviewed. The etiology of leuko-araiosis may be heterogeneous but is most likely ischemic in nature. However, as white matter lesions progress among the elderly they are likely to become associated with cognitive impairments and motor dyspraxias presumably resulting from cortico-subcortical disconnections, particularly involving the frontal cortex and basal ganglia and may themselves be considered a radiological “risk factor” or precursor for dementia.     

Cerebral blood flow and oxygen metabolism in patients with vascular dementia of the Binswanger type

We performed clinical and neuroradiologic studies, including positron emission tomography, in five patients with vascular dementia of the Binswanger type. The clinical features of these cases consisted of slowly progressive dementia, together with vascular risk factors such as hypertension and often a history of minor stroke, and characteristic white matter lesions on brain computed tomograms or magnetic resonance images. Digital subtraction angiography of the cervical and intracranial arteries demonstrated no occlusive lesion in any patient. Both cerebral blood flow and the cerebral metabolic rate for oxygen were markedly reduced in the white matter (54-77% of control values), and both were decreased in the parietal (73% of control), frontal (74-80%), and temporal (74-83%) cortices, where no abnormalities were detected by brain computed tomography or magnetic resonance imaging. We conclude that vascular dementia of the Binswanger type may be caused by disconnection between the cerebral cortex and subcortical structures due to ischemic damage in the white matter.     

Effect of the apolipoprotein E epsilon4 allele on white matter hyperintensities in dementia

BACKGROUND AND PURPOSE: The clinical significance of the apoE epsilon4 allele in white matter changes in patients with dementia has been a subject of debate. We studied the association between the apoE epsilon4 allele and white matter hyperintensities (WMHs) before and after control for (1) potential vascular risk factors and (2) the presence of lacunar infarcts in patients with dementia. METHODS: The subjects were 131 patients with dementia who had either Alzheimer's disease or vascular dementia, or a combination of these 2 types of dementia, with or without WMHs, lacunar infarcts, or both. The association of the epsilon4 allele with WMHs was examined before and after control for age, sex, duration of symptoms, education level, severity of dementia, presence of lacunar infarcts, and potential vascular risk factors, including hypertension, diabetes mellitus, lipid disorders, smoking habit, drinking habit, and cardiac diseases. RESULTS: WMHs were observed in 73 (55.7%) of the patients. Neither the number of apoE epsilon4 alleles nor their presence was significantly associated with WMHs before or after control for the potential confounding factors. Multiple logistic regression analyses revealed that age, the presence of hypertension, and the presence of lacunar infarcts were independently associated with WMHs. CONCLUSIONS: The apoE epsilon4 allele was not associated with WMHs in patients with dementia. The fact that WMHs were significantly associated with hypertension and lacunar infarcts may indicate an ischemic origin of WMHs.     

The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia

There is increasing evidence that cerebrovascular dysfunction plays a role not only in vascular causes of cognitive impairment but also in Alzheimer’s disease (AD). Vascular risk factors and AD impair the structure and function of cerebral blood vessels and associated cells (neurovascular unit), effects mediated by vascular oxidative stress and inflammation. Injury to the neurovascular unit alters cerebral blood flow regulation, depletes vascular reserves, disrupts the blood–brain barrier, and reduces the brain’s repair potential, effects that amplify the brain dysfunction and damage exerted by incident ischemia and coexisting neurodegeneration. Clinical-pathological studies support the notion that vascular lesions aggravate the deleterious effects of AD pathology by reducing the threshold for cognitive impairment and accelerating the pace of the dementia. In the absence of mechanism-based approaches to counteract cognitive dysfunction, targeting vascular risk factors and improving cerebrovascular health offers the opportunity to mitigate the impact of one of the most disabling human afflictions.