APOE ε4 and risk for Alzheimer's disease: Do regionally distributed white matter hyperintensities play a role?

BackgroundWe previously demonstrated that parietal lobe white matter hyperintensities (WMH) increase the risk for Alzheimer's disease (AD). Here, we examined whether individuals with apolipoprotein E gene (APOE ε4) have increased parietal WMH volume.MethodsParticipants were from the Washington Heights-Inwood Columbia Aging Project (WHICAP; n = 694, 47 with dementia) in northern Manhattan and the Etude Santé Psychologique Prévalence Risques et Traitement study (ESPRIT; n = 539, 8 with dementia) in Montpellier. The association between regional WMH and APOE ε4 was examined separately in each group and then in a combined analysis.ResultsIn WHICAP, ε4 carriers had higher WMH volume particularly in parietal and occipital lobes. In ESPRIT, ε4 carriers had elevated WMH particularly in parietal and temporal lobes. In the combined analysis, ε4 carriers had higher WMH in parietal and occipital lobes. Increased WMH volume was associated with increased frequency of dementia irrespective of APOE ε4 status; those with the ε4 were more likely to have dementia if they also had increased parietal WMH.ConclusionsAPOE ε4 is associated with increased parietal lobe WMH.     

Progression of cerebral white matter lesions in Alzheimer's disease: a new window for therapy?

BACKGROUND: White matter lesions (WML) are a risk factor for Alzheimer's disease. Progression of WML is associated with vascular factors and cognitive decline in population based studies but the course of WML is unknown in Alzheimer's disease. OBJECTIVE: To investigate the prevalence and risk factors for progression of WML in Alzheimer's disease. SUBJECTS: 38 patients with Alzheimer's disease for whom blood pressure measurements and sequential brain MRIs were available. METHODS: The proportion of patients with progression of WML was calculated, stratified on baseline absence or presence of WML by analysis of variance. Odds ratios (OR) were calculated by age and sex adjusted logistic regression to quantify the relation between blood pressure and progression of WML. RESULTS: About 25% of the patients showed progression of WML. Patients with WML at baseline had significantly more progression than those without WML at baseline (adjusted mean difference = 1.2; 95% confidence interval (CI), 0.6 to 1.8). Diastolic blood pressure (DBP) was particularly related to progression of WML (OR = 5.9 (95% CI, 1.0 to 37.6) per 10 mm Hg DBP, p = 0.05). CONCLUSIONS: Alzheimer's disease patients with WML at baseline are at risk for rapid progression of WML. WML may offer a potential treatment target in this disease to ameliorate the rate of cognitive decline.     

MRI-detected white matter lesions: do they really matter?

Despite extensive research over the last decades the clinical significance of white matter lesions (WMLs) is still a matter of debate. Here, we review current knowledge of the correlation between WMLs and cognitive functioning as well as their predictive value for future stroke, dementia, and functional decline in activities of daily living. There is clear evidence that age-related WMLs relate to all of these outcomes on a group level, but the inter-individual variability is high. The association between WMLs and clinical phenotypes exists particularly for early confluent to confluent changes, which are ischaemic in aetiology and progress quickly over time. One reason for the variability of the relationship between WMLs and clinic on an individual level is probably the complexity of the association. Numerous factors such as cognitive reserve, concomitant loss of brain volume, and ultrastructural changes have been identified as mediators between white matter damage and clinical findings, and need to be incorporated in the consideration of WMLs as visible markers of these detrimental processes.     

Do white cells matter in white matter damage?

Support is provided for the hypothesis that activated leukocytes, especially monocytes/macrophages, contribute to cerebral white matter damage in extremely low gestational age newborns. Much of the evidence is indirect and comes from analogies to brain diseases in adults, and from models of brain damage in adult and newborn animals. If the recruitment of circulating cells to the brain contributes to white matter damage in extremely low gestational age newborns, then minimizing the transendothelial migration of circulating cells by pharmacological manipulation might prevent or reduce the occurrence of neonatal white matter damage and the disabilities that follow.     

A voxel-based morphometric study of cortical gray matter volume changes in Alzheimer’s disease with white matter hyperintensities

White matter hyperintensity (WMH) is commonly detected in patients with Alzheimer’s disease (AD), but its role in cortical impairment is unclear. This study investigated the effects of WMH on gray matter (GM) volume in patients with AD. We consecutively enrolled 84 patients with AD and 35 normal controls, who underwent brain MRI and were then classified according to WMH grade, based on a combination of deep white matter hyperintensity (DWMH) and periventricular white matter hyperintensity (PVWMH). The volume changes in GM were observed using voxel-based morphometry. It was found that global GM volume decreased with increasing WMH. Regional atrophies were in the dorsolateral frontal lobes, orbitofrontal gyri and insula (false discovery rate [FDR], p < 0.01). After controlling for PVWMH, DWMH affected cortical atrophy in the frontal lobe, insula and precuneus (FDR, p < 0.05), but PVWMH did not. Thus, WMH in AD is associated with GM volume reduction, especially in the frontal lobe, and DWMH is independently related to cortical atrophy.     

The ε4 genotype of apolipoprotein E and white matter integrity in Alzheimer's disease

BackgroundIn this multicenter study, we investigated a possible association between the APOE ε4 allele and white matter (WM) integrity in Alzheimer's disease (AD) using diffusion tensor imaging (DTI).MethodsWe analyzed fractional anisotropy (FA) and mean diffusivity (MD) as indices of WM integrity in 70 AD patients (35 APOE ε4 carriers, 35 noncarriers) and 56 healthy control (HC) subjects (28 APOE ε4 carriers, 28 noncarriers). APOE ε4 carriers and noncarriers were matched for age and gender within each diagnostic group.ResultsWe found significant effects of diagnosis (P_corrected < .05 [FWE]; i.e., smaller FA values and larger MD values in AD patients compared with HCs) and significant effects (P < .001) of APOE ε4 carrier status on MD in HCs but not in AD subjects.ConclusionsThe results indicate that APOE ε4 has a moderate effect on WM integrity in HCs, but no effect on WM integrity in manifest AD.     

Outcome measures in Alzheimer's disease: do they go far enough?

As the interest in Alzheimer's disease (AD) and its treatment has grown, so has the sophistication of clinical trials of potential drug therapies. In particular, interest has focused on outcomes used to assess the severity of the illness and the effectiveness of treatment. This paper reviews the assessments that are used frequently in trials of AD therapy and describes further measures that may be of value in determining effective treatments for the disease. The review concludes that it is important that evaluation of drug effects on AD is not confined solely to the assessment of cognitive function. To gain a true overview of the impact of AD on patients, carers and society, areas such as activities of daily living, caregiver burden, quality of life, behavioural symptoms and resource utilization need to be comprehensively determined.     

Associations between amyloid β and white matter hyperintensities: A systematic review

Introduction

This systematic review synthesizes current evidence for associations between cortical amyloid β, visualized on amyloid positron emission tomography imaging, and white matter hyperintensity (WMH) burden on magnetic resonance imaging in healthy elderly adults and individuals with cognitive impairment and dementia.

Perseverations in Alzheimer's disease: Memory slips?

Previous studies of verbal fluency tasks reported higher rates of repeated responses in Alzheimer's disease (AD) compared to elderly controls. The present investigation aimed at determining if perseverations are caused by word retrieval deficits or working memory deficits, both of which are commonly observed in AD. Based on current theories of lexical processing and working memory, we derived specific predictions concerning the lag between the first occurrence of a word and its repetition. With word retrieval deficits, repetitions are expected to be progressively less frequent at greater lags; conversely, with working memory deficits, repetitions should occur especially after long lags. These predictions were tested analyzing the performance of 392 AD individuals in verbal fluency tasks. The finding of lags that were significantly longer than would be expected by chance is consistent with the hypothesis that perseverations are primarily caused by working memory deficits. Specifically, we propose that perseverations stem from an impairment affecting the working memory mechanisms that control response monitoring. We also investigated the relationship between perseverations and other cognitive deficits observed in AD. We discuss the implications of our findings for understanding the nature of perseverations, the effects of working memory deficits in AD, and the neural correlates of working memory components.     

APOE ε4 allele status in korean dementia patients with severe white matter hyperintensities

Few studies have investigated the apolipoprotein E (APOE) ε4 allele status of dementia patients with severe white matter hyperintensities (WMH). In this study, we aimed to characterize the APOE epsivlon genotypes and clinical features of dementia patients with severe WMH. Four hundred and thirty nine patients with dementia and 152 subjects with normal cognition (NC) were recruited from multiple centers in Korea, known as the Clinical Research Center for Dementia of South Korea (CREDOS), since November 2005. The WMH were rated using the scale that had been developed by the CREDOS study. Dementia patients with minimal WMH were considered to have Alzheimer's disease (AD) without WMH (AD-WMH: 325), and those with severe WMH were considered to have Subcortical Ischemic Vascular Dementia (SIVD: 50) or AD with severe WMH (AD+WMH: 64). Comparisons of APOE ε4 allelic prevalence were performed using chi-square analysis. The APOE ε4 allele was more prevalent in those with AD than in those with SIVD and NC (p < 0.001). It was not more prevalent in those with SIVD than in those with NC (p = 0.169). APOE ε4 allele status in AD+WMH did not differ from that in AD-WMH (p = 0.625). The APOE ε4 allele was more prevalent in those with AD than in those with SIVD. APOE ε4 may not be associated with SIVD although it is one of the vascular risk factors.     

The pattern of FP-CIT PET in pure white matter hyperintensities–related vascular parkinsonism

ObjectivesTo determine whether vascular parkinsonism (VaP) patients with visually normal dopamine transporter (DAT) scans have presynaptic dopaminergic depletion.MethodsWe enrolled 23 VaP patients who had parkinsonism, relevant diffuse subcortical white matter hyperintensities (WMH), and visually normal DAT scans, 23 Parkinson's disease (PD) patients, and 31 control subjects. By quantitatively analyzing ¹⁸F–N-(3-fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane (¹⁸F-FP-CIT) positron emission tomography, we compared the pattern of striatal DAT availability among groups. The discriminatory power of striatal DAT availability to differentiate VaP patients from control subjects or PD patients was assessed using receiver operating characteristics (ROC) analyses. Additionally, correlation analysis was performed to determine whether WMH severity or Unified Parkinson Disease Rating Scale Part III (UPDRS-III) score is related to presynaptic dopaminergic depletion in VaP.ResultsVaP patients exhibited decreased DAT availability in all striatal subregions, including posterior putamen, compared to control subjects. VaP patients and control subjects had similar patterns of anteroposterior and ventrodorsal DAT gradients in caudate and putamen level, but VaP patients exhibited significantly different patterns at putamen level, relative to PD patients. The severity of periventricular WMH was significantly correlated with all substriatal DAT availability in VaP, but not with UPDRS-III scores. The ROC analysis showed that DAT availability in caudate and posterior putamen had a fair discriminatory power when differentiating VaP patients from control subjects.ConclusionsThis study demonstrates that VaP patients with WMH exhibited diffusely decreased DAT availability without any specific regional gradients of DAT patterns distinct from either control subjects or PD patients.     

Can we do better in developing new drugs for Alzheimer's disease?

The past 30 years have seen multiple attempts at demonstrating the safety and efficacy of drugs for Alzheimer's disease (AD), predominantly to improve symptoms. Only five drugs (tacrine, donepezil, rivastigmine, galantamine, memantine) have obtained regulatory approval in most countries. Their cost-effectiveness from a societal perspective has not been universally recognized, and anybody who thinks these drugs are useful for individual patients will have to agree that the improvement above the starting point of treatment is moderate. Most of the benefit has been in slowing down progression of symptoms rather than a readily detectable improvement above baseline. There have also been attempts at arresting progression of AD, but all have failed until now. Should we change our approach to developing new drugs for AD so as to move forward? This review will highlight some options to consider in the development of future drugs for AD, with emphasis on strategies to prevent AD or arrest its progression.