Survival in Alzheimer's disease and vascular dementias

Over 5 years, we followed 199 patients with dementia of the Alzheimer type (DAT), 69 with multi-infarct dementia (MID), and 43 with mixed dementia (MIX). All three diagnostic categories had comparable progression of behavioral and cognitive impairment and need for home care or institutionalization at follow-up. However, 50% survival from diagnosis was 2.6 years for MID and 2.5 years for MIX, compared with 3.4 years for DAT. The 50% survivals from onset were longer than previous reports would suggest (8.1 years for DAT, 6.7 for MID, and 6.2 for MIX). Vascular dementias have higher mortality than DAT, even when associated with comparable cognitive and behavioral impairment.     

Cross-national comparisons of the occurrence of Alzheimer's and vascular dementias

Summary The relative occurrence of Alzheimer's and vascular dementias is examined in various countries using data of four types: incidence, prevalence, clinic and neuropathological studies. There is clear evidence that Alzheimer's demintia is more common than vascular dementia in Great Britain and North America and, to a lesser extent, in Scandinavia. The evidence from other countries with predominantly Caucasian populations is more limited, but also supports a predominance of Alzheimer's dementia. By contrast, the evidence from Japan generally shows that vascular dementia is more common. The more limited evidence available from China also supports a preponderance of vascular dementia. There is a need for studies directly comparing the occurrence of Alzheimer's dementia in Caucasian and Oriental populations.     

MRI confirms mild cognitive impairments prodromal for Alzheimer's, vascular and Parkinson-Lewy body dementias

OBJECTIVES: MRI assessments were correlated with serial Combined Mini-Mental Cognitive Capacity Screening Examinations (CMC). Vascular-MCI (VMCI), Neurodegenerative MCI (NMCI) and Parkinson-Lewy body MCI (PLB-MCI) were compared during conversions to dementia. Mild cognitive impairments (MCI) are identifiable prodromes for all dementia subtypes. MRI abnormalities are characterized among MCI subjects prodromal for dementia of Alzheimer's disease (DAT), vascular dementia (VaD) and Parkinson-Lewy body dementia (PLBD). METHODS: Aging volunteers (n=166) were recruited from ongoing longitudinal studies of aging, stroke, cerebrovascular disease and dementia. Cognitively normal (CN, n=52), MCIs of neurodegenerative (N-MCI, n=30), vascular (V-MCI, n=35) and Parkinson-Lewy Body (PLB-MCI, n=8) subtypes, plus converted DAT (n=19), VaD (n=17) and PLBD (n=5) were all diagnosed according to established protocol recommendations. Cerebral MRI abnormalities were likewise intercorrelated utilizing quantitative volumetric measurements. RESULTS: V-MCI and converted VaD showed extensive leukoaraiosis with more lacunar infarcts than subjects with N-MCI or PLB-MCI. N-MCI, prodromal for DAT, showed medial temporal atrophy, greater enlargement of temporal horns, and fewer vascular lesions. PLB-MCI, prodromal for PLBD, displayed third ventricular enlargement greater than N-MCI and V-MCI, with similar but less severe atrophy of medial temporal lobe than N-MCI and fewer vascular lesions than V-MCI. Cognitive Impairments due to PLB with vascular features (V-PLB-CI) showed more lacunar and microvascular lesions involving both white matter and basal ganglia with greater frontal horn enlargement. CONCLUSIONS: This study confirms different MCI subtypes prior to conversion to different dementias listed, recognizable by specific MRI abnormalities.     

Differential episodic and semantic memory performance in Alzheimer's disease and vascular dementias.

Differential performance on measures of episodic and semantic memory were examined in AD, cortical vascular dementia (CVaD), subcortica] vascular dementia (SVaD), and controls. Groups were matched on age, education, and gender; dementia groups also were matched on severity. Recognition/retrieval differences were found only between SVaD and AD groups, not between CVaD and AD. Thus, recognition/retrieval differences are likely secondary to subcortical pathology rather than to vascular etiology per se. Similarly, significant numbers of memory errors were associated with cortical pathology, regardless of etiology. Error rate differences were found only between SVaD and AD groups, not between CVaD and AD. Finally, rapid forgetting was unique to AD; however, since no difference was found between SVaD and AD, rapid forgetting may occur only as AD progresses. No semantic memory measure differentiated AD from either CVaD or SVaD subjects. Results suggest that some previously reported episodic differences may be due to cortical versus white matter subcortical pathology, rather than to AD versus vascular etiology.     

Oxidative stress in Alzheimer's and vascular dementias: masking of the antioxidant profiles by a concomitant Type II diabetes mellitus condition

Oxidative stress is associated with Alzheimer's (DAT) and vascular (VD) dementias, as well as Type II diabetes mellitus (DIAB) and affected by hypoglycemic therapy. The population (n = 122; males = 60; mean age = 72.57 +/- 7.06) consisted of controls (CTR), DAT and VD patients, with (DAT + DIAB, VD + DIAB) and without concomitant DIAB, resulting in six groups where the antioxidant profile was determined: copper-zinc superoxide dismutase (SOD), thiobarbituric acid reactive substances (TBARS), and total antioxidant capacity (TRAP). The results were analyzed using a two-way ANOVA design and Bonferroni statistic. The ANOVAs yielded significant differences between groups for all components of the profile: SOD, p = 0.00000006; TBARS, p = 0.0000012; TRAP, p = 0.0000003. The significance level for comparisons between groups was set at alpha = 0.05. The comparisons DIAB vs. CTR, DAT+DIAB vs. DAT, and DIAB demented vs. DIAB non-demented resulted significant for all variables. VD + DIAB vs. VD resulted significant for all variables except TRAP. The antioxidant profiles of DIAB and CTR are different. The differences cannot be directly related with what is observed in dementias. The differences in profiles of demented and non-demented are somewhat hidden when demented patients are affected by a concomitant DIAB condition and/or hypoglycemic treatment, thus conditioning the diagnostic value for dementias of the profiles.     

Immunotherapy for Alzheimer's disease and other dementias

PURPOSE OF REVIEW: The aim of this article is to review the role of immunotherapy in the removal of proteins which accumulate abnormally in neurodegenerative disorders associated with dementia, in particular amyloid-beta accumulation in Alzheimer's disease. RECENT FINDINGS: In both transgenic mouse models and in two trials of amyloid-beta immunotherapy for human Alzheimer's disease, active immunization with amyloid-beta 1-42 results in the removal of amyloid-beta plaques from the cerebral cortex associated with, in the mouse models, improvement in cognitive function. Cerebral amyloid angiopathy and neurofibrillary tangles persist, however, and there is also concern about T lymphocyte immune reactions in the meninges in the human cases. Active immunization schedules are being developed to minimize T lymphocyte reactions and to maximize antibody production and passive immunization protocols are being devised. Immunotherapy for removal of the proteins which accumulate in other neurodegenerative disorders associated with dementia such as prion proteins and alpha-synuclein are in the early stages of development. SUMMARY: Dementias in the elderly are an increasing medical, social and economic problem and current treatments are only effective. In the majority of dementias, proteins accumulate within cells and in the extracellular compartments of the brain. In the most common dementia, Alzheimer's disease, amyloid-beta accumulates as plaques in the extracellular space of the grey matter and in artery walls as cerebral amyloid angiopathy and tau protein accumulates as neurofibrillary tangles within neurons.     

Genetic aspects of Alzheimer's disease, Pick's disease, and other dementias

Although genetic testing is available for some degenerative diseases, in most types of dementia, both genetic and environmental factors are involved. Overall, dementing diseases can be either sporadic or inherited, and in general, the earlier the onset, the more likely a disease is to be inherited. Before genetic testing is performed, the ethical issues, such as the effect the tests might have on asymptomatic children, should be considered. The ethical use of DNA samples in research is another genetic testing issue to be considered.     

Immunotherapy for Alzheimer's disease and other dementias

OBJECTIVE: The aim of this article is to review the role of immunotherapy in the removal of proteins which accumulate abnormally in neurodegenerative disorders associated with dementia, in particular amyloid-beta accumulation in Alzheimer's disease. RESULTS: In both transgenic mouse models and in two trials of amyloid-beta immunotherapy for human Alzheimer's disease, active immunization with amyloid-beta 1-42 results in the removal of amyloid-beta plaques from the cerebral cortex associated with, in the mouse models, improvement in cognitive function. Cerebral amyloid angiopathy and neurofibrillary tangles persist, however, and there is also concern about T lymphocyte immune reactions in the meninges in the human cases. Active immunization schedules are being developed to minimize T lymphocyte reactions and to maximize antibody production and passive immunization protocols are being devised. Immunotherapy for removal of the proteins which accumulate in other neurodegenerative disorders associated with dementia such as prion proteins and alpha-synuclein are in the early stages of development. CONCLUSION: Dementias in the elderly are an increasing medical, social and economic problem and current treatments are only effective. In the majority of dementias, proteins accumulate within cells and in the extracellular compartments of the brain. In the most common dementia, Alzheimer's disease, amyloid-beta accumulates as plaques in the extracellular space of the grey matter and in artery walls as cerebral amyloid angiopathy and tau protein accumulates as neurofibrillary tangles within neurons.     

Differential perceptual-spatial impairment in Huntington's and Alzheimer's dementias

Because the severity of memory disorders exhibited by neuropsychiatric patients overshadows other cognitive deficiencies, we explored the visuoperceptual and constructive abilities of patients with Alzheimer's (AD) or Huntington's (HD) disease. The tasks assessed directional sense with reference to egocentric space, as well as visuodiscriminative and constructive skills of patients and matched controls. A double dissociation was found: the performance of patients with AD was found to be significantly impaired on tasks involving extrapersonal perception and construction but not on the test of egocentric space. In contrast, visuoconstructive performance by patients with HD was not significantly impaired, while salient deficits were apparent when manipulation of personal space was required. These differential patterns of defects may have been aligned with neuropathologic changes in different cortical and subcortical structures, respectively, in patients with AD and HD.     

Synaptic loss in Alzheimer's disease and other dementias

The extent and location of neuronal losses necessary or sufficient to produce dementia in patients with Alzheimer's Disease (AD) is unknown. To approach this question, we studied synaptic terminals in postmortem brain tissue utilizing immunohistochemical techniques. We used antibodies against two proteins found in synaptic terminals--synapsin I and synaptophysin--as synaptic markers in the hippocampal complexes of eight patients with autopsy-proven AD and eight nondemented control subjects. Quantitative microscopy measured the regional density of synaptic staining. All AD patients showed a striking decrease in synaptic staining in the outer half of the molecular layer of the dentate gyrus compared with control brains, where the density of synaptic terminals was uniform throughout. In an additional patient with progressive degenerative dementia but without plaques or tangles on neuropathologic examination, similar depletion of synaptic staining was seen in the dentate gyrus. Quantitative densitometric analyses confirmed the focal decrease in synaptic staining in the outer half of the molecular layer in demented patients. We also found a slight increase in synaptic staining in the inner half of this layer.     

Survival in presenile Alzheimer's and multi-infarct dementias.

Duration of survival in patients who had died of presenile Alzheimer's disease (AD) or presenile multi-infarct dementia (MID) in 13 mental hospitals in Scotland are described and contrasted. The duration of survival was significantly longer from symptom onset to death in AD (mean 7.4 years) than in MID (mean 5.8 years). Most of this difference was accounted for by a longer duration between symptom onset and presentation to hospital care in AD (mean 3.2 years) than in MID (mean 2.4 years). Age at onset and gender did not influence survival duration in AD or MID.     

Alzheimer's disease and other dementias: a review

Dementia and its associated diseases are important causes of disability and morbidity in developed countries, especially in the aged population. As the babyboomers arrive at retirement and individuals over 100 are one of the fastest growing segments of our nation's population, we may realize the substantial cost these diseases bring to society. Dementia is characterized by a significant loss of cognitive function and should be clinically distinguished from an acute delirium or decreased arousal. Its manifestations cause anguish to millions of caregivers and family members, who are pressed to cope with their loved one's unfortunate decline in multiple cognitive domains, functioning, and behavior. Early detection and management may prevent overuse of costly medical resources and allow patients and family members time to prepare for future medical, financial, and emotional challenges. Diagnostic clues to the etiology of the patient's dementia can be found in a medical workup in which the neurologic history and examination (including mental status examination) are essential and neuroimaging is indicated. Herein, the concept of central nervous system (CNS) degenerative diseases as disorders of specific proteins is introduced. This review is intended to summarize clinical, biological, and genetic features of the common subtypes of dementia, and bring light to potential benefits of early and accurate diagnoses to optimize treatment. Details of the various diseases remain only partially uncovered, raising extensive prospects for future research and therapy for patients with dementia.     

Diagnostic value of high signal abnormalities on T2 weighted MRI in the differentiation of Alzheimer's, frontotemporal and vascular dementias

OBJECTIVE: The occurrence of high signal abnormalities on T2 weighted images is strongly age related. The diagnostic value of these changes in a younger population with dementia is not currently known. We studied the potential of high signal changes on magnetic resonance imaging (MRI) in differentiating Alzheimer's disease (AD), frontotemporal dementia (FTD) and vascular dementia (VaD) in younger patients. METHODS: High signal abnormalities were rated, using a previously validated scale, from hard copies of T2 weighted axial images of 102 patients with AD (n=49), VaD (n=31), FTD (n=22) (mean ages 63-65 years). RESULTS: High signal abnormalities were widespread across AD, VaD and FTD. Although they were most frequent and most severe in the VaD group only lacunes and grade III deep white matter hyperintensities (DWMH) were specific for these patients. CONCLUSIONS: High signal changes on T2 weighted images on MRI are common across degenerative (AD and FTD) and vascular dementias. Although lacunes and grade III DWMH are specific for VaD, the low sensitivities (sensitivities: for lacunes, 0.32; for grade III DWMH, 0.16) limit their use as diagnostic markers for VaD. High signal changes on MRI should be interpreted with caution in dementias. Their presence, even in younger patients, should not deter one from diagnosing AD or FTD.     

Cognitive pharmacotherapy of Alzheimer's disease and other dementias.

OBJECTIVE: The objective of this paper is to review the randomized controlled trials (RCTs) on the pharmacotherapy of Alzheimer's disease and other dementias and to provide evidence-based recommendations for treatment of the cognitive impairment associated with these disorders. METHOD: A Medline search was conducted for RCTs, using the following key words: Alzheimer's disease, dementia, therapy, cholinesterase inhibitor, donepezil, rivastigmine, and galantamine. Studies were critically appraised, followed by a review of published major clinical practice guidelines. Recommendations for treatment were made based on best available evidence. RESULTS: The pharmacotherapy of Alzheimer's disease should include the meticulous management of vascular risk factors (for example, hypertension, diabetes, cholesterol, and stroke prophylaxis) and consideration for supplementation with folate, vitamin B complex, and vitamin E. Patients should be offered at least 1 trial of a cholinesterase inhibitor, with the possibility of another trial if the first is poorly tolerated or ineffective. Patients with vascular dementia and dementia with Lewy bodies should also be offered treatment with cholinesterase inhibitors. At this time, we lack sufficient data to recommend the use of hormone replacement or antiinflammatory therapy for treatment of dementia as the primary indication. CONCLUSION: Reasonable evidence exists to provide recommendations for the pharmacotherapy of dementia. Treatment will likely result in modest but important benefits to patients, caregivers, and society.     

The relationship between impaired glucose tolerance, type 2 diabetes, and cognitive function

The present review integrates findings of published studies that have evaluated the cognitive function of treated and untreated type 2 diabetic patients and provides a detailed overview of the neuropsychological assessments conducted. Cognitive deficits are observed in older people with glucose intolerance or untreated diabetes but these deficits appear to be attenuated by treatments that improve glycemic control. Cognitive decrements in treated type 2 diabetic patients are most consistently observed on measures of verbal memory (35% of the measures) and processing speed (45% of the measures) while preserved function is observed on measures of visuospatial, attention, semantic and language function. Some studies suggest that deficits in cognitive functions are associated with poorer glycemic control. A number of other factors, such as depression, cardiovascular and cerebrovascular disease, increase these deficits. We conclude that, in diabetic patients who achieve and maintain good glycemic control, type 2 diabetes only has a small impact on cognitive functions before the age of 70 years. However, early onset of type 2 diabetes, poor glycemic control and the presence of micro- and macrovascular disease may interact to produce early cognitive deficits. In older adults (70 years and over), diabetes likely interacts with other dementing processes such as vascular disease and Alzheimer's disease to hasten cognitive decline.     

Oxidative injury and neuropathy in diabetes and impaired glucose tolerance

Clinical studies suggest that impaired glucose tolerance (IGT) is associated with the development of neuropathy. The aim of the current study was to determine if neuropathy developed in the female Zucker Diabetic Fatty (ZDF) rat, an animal model of IGT and type 2 diabetes. The ZDF rat develops impaired glucose tolerance (IGT) when fed a control diet, and frank diabetes when fed a high fat diet. Following 10 weeks of hyperglycemia, sensory nerve action potentials (SNAP) and compound motor action potentials (CMAP) were reduced and sensory conduction velocities were slowed (distal > proximal) in the tail and hind limb in ZDF animals with IGT and frank diabetes (p < 0.01). Neuropathy was coupled with evidence of increased reactive oxygen species (ROS) and cellular injury in dorsal root ganglion (DRG) neurons from IGT animals. Our study supports the hypothesis that neuropathy develops in an animal model of IGT and is associated with evidence of oxidative injury in DRG and peripheral nerves.