The presence of leuko-araiosis in patients with Alzheimer's disease predicts poor tolerance to tacrine, but does not discriminate responders from non-responders

Amar, Khaled; Wilcock, Gordon; Scot, Margaret; Lewis, Tim

doi:10.1093/ageing/26.1.25

Cited by 16 publications

(13 citation statements)

References 19 publications

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“…To our knowledge, only one previous study assessed the impact of white matter disease on treatment response in dementia: a high level of leukoaraiosis on CT scans of subjects with AD was associated with poor tolerance to tacrine, but not with clinical response. 38 This is an area of important clinical interest, and CHIPS provides a tool with which to assess the effect of WMH within cholinergic pathways on treatment response.…”

Section: Discussionmentioning

confidence: 99%

A New Visual Rating Scale to Assess Strategic White Matter Hyperintensities Within Cholinergic Pathways in Dementia

Bocti

Swartz

Gao

et al. 2005

Stroke

122

120

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Background and Purpose-One possible mechanism of cognitive decline in individuals with subcortical vascular disease is disruption of cholinergic fibers by ischemic lesions, such as strategically located white matter hyperintensities (WMH). The authors applied a new MRI visual rating scale to assess WMH within cholinergic pathways in patients with Alzheimer Disease (AD) and subcortical ischemic microvascular disease. Methods-Subjects included 60 AD patients with and without WMH, matched for age, as well as 15 control subjects. A visual rating scale was developed based on published immunohistochemical tracings of the cholinergic pathways in humans. On 4 selected axial images, the severity of WMH in the cholinergic pathways was rated on a 3-point scale for ten regions, identified with major anatomical landmarks. A published, consensus-derived, general WMH scale was also applied. All subjects underwent standardized neuropsychological testing. Results-The Cholinergic Pathways HyperIntensities Scale showed reliability and was validated with volumetry of strategic WMH. After accounting for age and education in a multiple linear regression model, The Cholinergic Pathways HyperIntensities Scale ratings were associated with impaired performance on the Mattis Dementia Rating Scale (rϭ0.40; Pϭ0.02) and accounted for 12% of the variance (corrected r 2 ). A similar model was not significant for general WMH scores. Conclusions-The

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Section: Discussionmentioning

confidence: 99%

A New Visual Rating Scale to Assess Strategic White Matter Hyperintensities Within Cholinergic Pathways in Dementia

Bocti

Swartz

Gao

et al. 2005

Stroke

122

120

View full text Add to dashboard Cite

show abstract

“…Responders to tacrine have been suggested to have a greater degree of postural drop in their blood pressure and to be older compared to nonresponders [24,25], while other researchers have characterized responders to have opposite properties [26]. The presence of leukoaraiosis in patients with AD did not differentiate responders from nonresponders [27]. Interestingly, the presence of leukoaraiosis predicted a poor tolerance to tacrine [27].…”

Section: Introductionmentioning

confidence: 99%

“…The presence of leukoaraiosis in patients with AD did not differentiate responders from nonresponders [27]. Interestingly, the presence of leukoaraiosis predicted a poor tolerance to tacrine [27]. Responders are usually defined according to clinical standards as those individuals who respond favorably to treatment during several months of treatment.…”

Section: Introductionmentioning

confidence: 99%

Responder Characteristics to a Single Oral Dose of Cholinesterase Inhibitor: A Double-Blind Placebo-Controlled Study withTacrine in Alzheimer P atients

Almkvist¹,

Jelić²,

Amberla³

et al. 2000

Dement Geriatr Cogn Disord

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A proportion of Alzheimer’s disease (AD) patients treated for several months with cholinesterase (ChE) inhibitors have shown some favorable response on cognition, but the characteristics of the responders are still unclear. This study attempts to identify the characteristics of individuals with a positive behavioral response after a double-blind randomized administration of a single oral dose of tacrine (40 mg) and placebo to AD patients. Furthermore, the relationship between single-dose and long-term responders are examined. Twenty-four mildly to very mildly demented AD patients participated in the study. They all fulfilled the diagnosis of probable AD according to NINCDS-ADRDA criteria. Active treatment (tacrine 40 mg) and placebo was administered in random order on 2 consecutive days, and the effects were evaluated within 2 h using neuropsychological tests (assessing visuospatial ability, episodic memory and attention), registration of EEG activity and measurement of red blood cells (RBC) acetylcholinesterase (AChE), ChE activity and concentrations of tacrine and its metabolites in plasma. Results demonstrated significant improvement, tacrine compared to placebo, in measures of attention, but not in episodic memory or visuospatial ability. A single-dose response was therefore defined in terms of improvement in attention. The tacrine plasma concentration (pcTHA) showed a positively skewed distribution (mean ± SD: 10.5 ± 11.8, range: 1.0–51.8 ng/ml). There were no significant differences between single-dose responders compared to nonresponders in pcTHA, metabolites of tacrine, inhibition of AChE in RBC, tau levels in CSF, AChE activity in CSF or plasma and demographic variables. However, single-dose responders showed a higher right frontal alpha/theta ratio on EEG and had lower glucose metabolism in the parietal-temporal association cortex at baseline. In addition, the frequency of apolipoprotein E (APOE) Ε4 alleles was higher in responders. Interestingly, the single-dose response was related to the long-term response, although not significantly, which probably was due to lack of power. To conclude, the present study identified single-dose responders in terms of improved attentional performance associated with a relatively higher alpha/theta activity in the right frontal regions of the brain measured on EEG and predominance of APOE Ε4 allele.

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“…In normal elderly persons, WMLs are associated with increased risk of developing dementia and gait disturbances [2,3]. In patients with late onset depression [4][5][6][7][8], neurodegenerative conditions [9][10][11], and gait disorders [12], WMLs predicted poor response to pharmacological and non-pharmacological treatment, and greater disease severity. These observations lead to hypothesize that WMLs might impair brain reserve i.e.…”

Section: Introductionmentioning

confidence: 99%

White matter lesions in the elderly: Pathophysiological hypothesis on the effect on brain plasticity and reserve

Galluzzi

Lanni

Pantoni

et al. 2008

Journal of the Neurological Sciences

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The presence of leuko-araiosis in patients with Alzheimer's disease predicts poor tolerance to tacrine, but does not discriminate responders from non-responders

Abstract: AD patients with WMLA can still respond to tacrine, although the rate of withdrawal from treatment is much higher in such patients.

Cited by 16 publications

References 19 publications

A New Visual Rating Scale to Assess Strategic White Matter Hyperintensities Within Cholinergic Pathways in Dementia

A New Visual Rating Scale to Assess Strategic White Matter Hyperintensities Within Cholinergic Pathways in Dementia

Responder Characteristics to a Single Oral Dose of Cholinesterase Inhibitor: A Double-Blind Placebo-Controlled Study withTacrine in Alzheimer P atients

White matter lesions in the elderly: Pathophysiological hypothesis on the effect on brain plasticity and reserve

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