Cerebral White Matter Changes on Therapeutic Response to Rivastigmine in Alzheimer’s Disease

Abstract

Background: Rivastigmine has been approved in the treatment of Alzheimer’s disease (AD) patients as it can inhibit acetyl- and butyryl-cholinesterase and provide neuroprotective effects involving the synapses. White matter changes (WMCs) are frequently observed in AD, and clinical-pathological correlations imply their possible impacts on cognitive function by interference with cortical and subcortical neuronal pathways.

Objective: To evaluate the therapeutic effects of rivastigmine in AD patients with cerebral WMCs.

Methods: Clinically diagnosed AD patients from Kaohsiung Municipal Ta-Tung hospital were recruited together with their cranial magnetic resonance imaging and a series of annual psychometric tests, including Mini-Mental State Examination (MMSE) and sum of boxes of clinical dementia rating scale (CDR-SB). WMCs were rated through the modified Fazekas scale for the periventricular and deep WMCs.

Results: In total, 87 AD patients treated with rivastigmine were enrolled. Patients at severe stage of WMCs, compared to mild stage ones, had significant improvement evaluated by MMSE (periventricular WMCs, p = 0.025; deep WMCs, p = 0.030), but not CDR-SB. Compared to the worsening group, the clinically improving group had a significant higher ratio of pre-existing hypertension in terms of cognitive performance [p = 0.016, odds ratio (OR) = 3.48, 95% CI = 1.25–10.34], while having younger age (p = 0.043, OR = 0.11, 95% CI = 0.01–1.12) in terms of global status.

Conclusion: Rivastigmine may provide better benefits in cognitive function, but not global status, for AD patients with more advanced WMCs. The detailed mechanisms still have to be determined in future studies.

Keywords

Alzheimer’s disease cholinesterase inhibitors rivastigmine white matter changes

INTRODUCTION

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting cognitive functions, behaviors, and activities of daily living. As the aged population is rapidly increasing, AD has become a major public health issue worldwide. To date, acetylcholinesterase inhibitors (AChEIs) are the most common medications for the symptomatic treatment of AD. Rivastigmine, a brain-region selective AChEI, has been approved in treating patients with mild to moderate stages of AD. Clinical evidence has also suggested its efficacy in dementia with Lewy bodies, Parkinson’s disease dementia, and vascular cognitive impairment [1, 2]. Furthermore, rivastigmine is a reversible inhibitor of both AChE and butyrylcholinesterase (BuChE). Dual inhibition of AChE and BuChE may confer additional neuroprotective benefits in AD patients by diminishing amyloid plaque neurotoxicity [3]. However, not all patients are tolerable and responsive to AChEIs and it is important for clinicians to select good candidates before commencing treatment.

Clinical-radiological correlates have shown that white matter changes (WMCs), representing cerebral vascular burden, were frequently observed in both aging and dementia. Diffuse ischemic WMCs may impair information processing and executive functioning, and thus contribute to cognitive decline [4]. Pathological manifestations of WMCs have enrolled ranging from loss of myelin and axons, ischemic change, reactive astrocytosis, and impaired synapses [5]. A recent study disclosed that in the context of significant amyloid-β deposition, WMCs may also contribute to the presentation of AD, reflecting that pathological changes of WMCs were not restricted to small-vessel cerebrovascular disease [6]. With disease progression, the burden of WMCs was found to increase significantly across the continuum of mild cognitive impairment to AD [7].

Frontal-subcortical neuronal circuits are vulnerable to WMCs, cerebral atrophy, and certain forms of neurotransmitter depletion, such as cholinergic deficits [8, 9]. In addition to AChE, BuChE activity is rich in the glia of subcortical and deeper cortical structures. By interfering with projection tracts of cholinergic pathway, WMCs may impact cognitive function. These findings imply that BuChE may also be an important therapeutic target, and several types of dementia involving subcortical pathology could derive particular benefits from cholinesterase inhibitors such as rivastigmine that has dual inhibition for both AChE and BuChE [9].

The effect of WMCs to the therapeutic outcomes of AD patients treating with AChEIs remains controversial. Our study aimed to evaluate the extent and severity of cerebral WMCs, ApoE genotype and common vascular risk factors in AD patients in relation to their therapeutic responses to rivastigmine.

MATERIALS AND METHODS

Study population

Clinically diagnosed AD patients treating with rivastigmine were recruited and examined from the neurological department of Kaohsiung Municipal Ta-Tung hospital, a community hospital in southern Taiwan from October 2010 to April 2014. All of the patients received a comprehensive medical evaluation, including demographic data, past medical history review, physical and neurological examinations, laboratory survey, and neuroimaging study. The diagnosis of AD was made according to the criteria proposed by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) work group [10]. Patients with other medical conditions possibly contributing to the diagnosis of probable AD, or who were lost to follow-up within the study period of rivastigmine therapy were excluded.

To evaluate the impact of cerebral WMCs on therapeutic responses to rivastigmine, we compared the mean change from baseline of cognitive performance and global status of AD patients with different stage of severity of WMCs over a period of one year. Furthermore, we aimed to evaluate clinical indicators including demographic characteristics, common vascular risk factors, ApoE ɛ4 genotype and baseline cognitive status, as well as the extent and severity of cerebral WMCs that influence the treatment outcome to rivastigmine in AD patients.

Diagnosis and grading of white matter changes

In initial evaluation, cranial magnetic resonance imaging (MRI) scans were performed on every patient. The extent and degree of WMCs on brain MRI were separately examined as periventricular and deep WMCs using the modified version of visual scoring system proposed by Fazekas et al. [11, 12]. Periventricular WMCs (PVWMCs) were graded as grade 0 (absent), grade 1 (caps), grade 2 (smooth halo), or grade 3 (irregular and extending into the subcortical white matter) [11]. Deep WMCs (DWMCs) were graded as grade 0 (no lesions, including symmetrical, well-defined caps or bands), grade 1 (focal lesions), grade 2 (beginning confluence of lesions), or grade 3 (diffuse involvement of the entire regions) [12]. Two independent raters (BLH and YHK), who were blinded to the clinical data, rated WMCs severity for all participants. For further analyses to therapeutic response, grades 0 and 1 were considered at mild stage while grades 2 and 3 were classified at severe stage of WMCs severity.

Therapeutic outcomes evaluation

For each recruited participant, the baseline neuropsychological assessments, including the Mini-Mental Status Examination (MMSE) [13], Cognitive Assessment Screening Instrument [14], Neuropsychiatric Inventory [15], and Clinical Dementia Rating (CDR) scale [16] were conducted before starting the rivastigmine treatment. A standard regular follow-up of MMSE and CDR was performed annually to evaluate the therapeutic responses to rivastigmine.

The intra-individual comparison of treatment outcomes was examined mainly by two indicators: cognitive performance by MMSE scores, and global status by the sum of boxes of CDR scale (CDR-SB) [17]. We defined the therapeutic responses as improving if second MMSE score was equal to or greater than the first MMSE score (ΔMMSE≥0), or second CDR-SB was less than or equal to the first CDR-SB (ΔCDR-SB≤0), and otherwise, as worsening response.

Statistical analysis

Demographic comparisons were made using Pearson’s chi-square test for categorical variables, and by independent t-test for continuous variables between the two stages of severity of WMC groups. To estimate the impact of clinical indicators as well as the extent and severity of WMCs on therapeutic outcomes, which were represented by improving or worsening in terms of MMSE and CDR-SB, we conducted multivariate logistic regression to calculate odds ratios, adjusting for age, gender, education level, ApoE ɛ4 status, vascular risk factors, and the severity of PVWMCs and DWMCs. Statistical analyses were performed using SAS 9.3 software (SAS Institute, Inc., Cary, NC, USA). Statistical significance was set at p < 0.05.

RESULTS

A total of 87 AD patients, including twenty-nine with global CDR 0.5, 48 with CDR 1.0, and ten with CDR 2.0, were recruited into our statistical analyses. The mean age of all AD patients was 77.2±7.9 years (range: 59–95), and 60.9% of them were women. Among all patients, 21 individuals (24.1%) were ApoE ɛ4 carriers. Forty-five patients (51.7%) had hypertension and 24 patients (27.6%) had diabetes mellitus. The clinical and demographic characteristics are shown in Table 1.

For PVWMCs, 36 patients (41.4%) were regarded as severe stage (modified Fazekas scale 2 and 3) as well as 20 patients (23%) in terms of DWMCs. There were no significant differences in the age,gender, education level and ApoE ɛ4 status among the two stages of severity in both the PVWMCs and DWMCs groups. In the annual follow-up of therapeutic evaluations, the patients at severe stage of PVWMCs had significant improvement evaluated by MMSE (p = 0.025), but not CDR-SB, compared to mild stage patients (p = 0.473) (Table 2). For DWMCs, the patients at severe stage had significant improvement by MMSE score (p = 0.030), but not CDR-SB (p = 0.337) as did the mild stage patients (Table 2).

In the logistic regression analyses, we tested the effects of clinical indicators including demographic characteristics, common vascular risk factors, ApoE ɛ4 genotype, baseline cognitive status, and the extent and severity of cerebral WMCs on therapeutic responses after one-year treatment with rivastigmine. Hypertension (OR = 3.48, 95% CI = 1.25–10.34, p = 0.016) was significantly associated with better therapeutic response of cognitive function measured by MMSE, but not the extent and severity of cerebral WMCs, age, gender, education level, diabetes, baseline MMSE/CDR-SB or ApoE ɛ4 status (Table 3). Furthermore, age (OR = 0.11, 95% CI = 0.01–1.12, p = 0.043) was a significantly independent indicator of therapeutic outcomes in terms of global status by CDR-SB, but not gender, education level, hypertension, diabetes, ApoE ɛ4 status, baseline MMSE/CDR-SB, or the severity of WMCs (Table 4).

DISCUSSION

Our main finding in the present study is that AD patients with more severe WMCs could exhibit more improvements in cognitive function from rivastigmine therapy. In addition, pre-existing hypertension was linked to significantly better improvement in cognitive performance, and older age was significantly associated with a poor therapeutic response in global status after rivastigmine therapy. ApoE ɛ4 status, gender, baseline cognitive function, and history of diabetes were not significantly related to the therapeutic outcome in cognition and functional status.

The therapeutic outcomes to rivastigmine varied with the evaluating indicators in our study. The severity of WMCs was significantly related to cognitive changes measured by MMSE, but not significantly associated with the therapeutic outcome measured by CDR-SB. The differences may result from MMSE being more sensitive to demonstrate the therapeutic effect of rivastigmine on cognition than was CDR-SB during the initial treatment period. The higher sensitivity of MMSE to reflect the therapeutic responses than that of CDR-SB has also been observed in several other studies [18].

Previous studies have tried to recognize the clinical or neuroradiological characteristics of AD patients in predicting the treatment outcomes to AChEI therapy, including age, baseline cognitive status [19], medial temporal atrophy [20], and rate of disease progression [21]. Male gender, older age, and absence of ApoE ɛ4 allele as well as a higher mean dose of AChEI seem to be related to a more positive longitudinal outcome [22]; however, there are still inconsistencies with respect to their prognostic significance. The diversity of these results implied that these predictors may have complex effects on clinical responses to AChEI treatment.

In general, various degrees of WMC are commonly seen both in the elderly population and in AD patients. In previous community-based epidemiological studies, volumetric assessment of WMCs has been practically used to predict worse executive performance and incident dementia [23, 24]. Both extent and spatial distribution of WMCs were found to be related to increasing cognitive impairment among normal aging and AD, and regional analyses revealed significant spatial differences in the splenium of corpus callosum and posterior periventricular regions [25]. Along with the increasing disease severity, the burden of regional or total WHCs increased significantly as well from the stages of MCI to AD [7, 26]. While physiological and pathological correlates of WMCs in AD remain a matter of debate, this accumulating evidence suggests that WMCs have an essential impact on cognitive function and AD progression.

We found no significant differences concerning the severity and extent of WMCs between groups of responders and non-responders to rivastigmine therapy over the study period. Consistent with previous findings in a cohort of dementia patients, increased WMC severity had no obvious impact on clinical response to AChEI treatment in patients with AD, although it may hasten deterioration in those with dementia with Lewy bodies [27]. On the contrary, other studies have disclosed that the presence of WMCs was associated with increased cognitive response in AD patients after 6–12 months of AChEI therapy [28, 29]. Furthermore, when focusing on the extent of subcortical hyperintensities in the cholinergic pathways, significant improvements in executive function and working memory tasks were noted in patients with higher Cholinergic Pathways Hyperintensities Scale [8]. We speculated that these divergent results may be partly owing to different grading of WMCs in the different studies, and may also reflect that WMCs has been additively influenced by cerebrovascular injury as well as neurodegenerative changes.

From the aspect of cognitive performance, we identified hypertension as a significant factor for predicting the better therapeutic response. Hypertension is highly associated with stroke, silent infarcts, cerebral atherosclerosis, and increased WMCs, but is not essential for their development [30]. In older adults, hypertension was related to increased progression of WMCs as well as whole brain atrophy [31]. The effect of concurrent vascular risk factors on response to AChEI therapy in AD patients is still controversial. Additional symptomatic benefits on disease severity or dementia progression were also observed in patients with AD and concomitant hypertension and other vascular risk factors [32 –34]. The possible mechanisms of the enhancing effect on cognition of rivastigmine, especially when treated in AD patients with coexisting vascular risk factors, are potential neuroprotective properties of preserving pre- and postsynaptic cholinergic function and increasing cerebral blood flow [35, 36]. In contrast, Connelly et al. found that patients with bothhypertension and WMCs showed more decline in functional behavior assessments after AChEI therapy than those with only one or neither of these variables [37].

Our results demonstrated that ApoE ɛ4 carrier was not a significant factor regarding the therapeutic response in terms of cognitive performance examined by MMSE and global status assessed by CDR-SB. Although ApoE ɛ4 is considered the dominant risk factor for AD, the ApoE ɛ4 allele frequency isrelatively lower in Taiwanese [38]. However, similar findings have been reported that the presence of at least one ApoE ɛ4 allele does not determine a difference in the treatment responses to rivastigmine in patients with mild to moderate AD [39]. Furthermore, when taking ApoE ɛ4 status together with concurrent vascular risk factors into consideration, a recent study has identified that the detrimental effects of vascular risk factors on white matter microstructure were exacerbated among APOE ɛ4 carriers[40].

There are a few limitations of this study, including relatively small sample size. First, we chose MMSE and CDR-SB as main therapeutic indicators, and these measurements may not be sufficient to reflect the overall therapeutic outcomes in AD patients. Furthermore, we defined the therapeutic responses just as either improving or worsening by interval change from baseline conditions. A one-point difference likely has limited clinical importance. However, it is noted that the change from baseline for MMSE and for CDR-SB has been also used as therapeutic indicators in other studies. Second, we did not clarify the cumulative maintenance dosage of rivastigmine for each participant. Higher dosing may link to a greater proportion of responders, indicating the dose-response relationship of rivastigmine therapy [32]. In our previous study, the plasma concentration of rivastigmine was also found to be related to different responses in different cognitive subdomains [41]. Third, we used visual ratings method rather than measuring volumes of WMCs in our radiological analysis. Although this semiquantitative scoring was possibly less sensitive, visual rating scales have been commonly used in several studies concerning WMCs. The interrater reliability was good for rating both PVWMCs and DWMCs (intraclass correlation coefficient = 0.940 and 0.915, respectively). Besides, we did not examine the BuChE genotype, which may play an important role in the rate of AD progression and in the response to rivastigmine treatment [36]. However, our study still serves to provide preliminary data on the importance of WMCs in determining the therapeutic responses to rivastigmine.

In conclusion, our results showed that rivastigmine may provide better benefits in cognitive function, but not global status, for AD patients with more advanced WMCs. Patients with hypertension showed more cognitive improvement after one year of rivastigmine therapy, no matter the severity of cerebral WMCs. The detailed mechanisms still have to be determined in future studies.

Footnotes

ACKNOWLEDGMENTS

The authors thank the staff of the Statistical Analysis Laboratory, Department of Medical Research, Kaohsiung Municipal Ta-Tung Hospital for their help.

Authors’ disclosures available online ().

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