Changes in Regional Cerebral Perfusion after Nicergoline Treatment in Early Alzheimer's Disease: A Pilot Study.

BACKGROUND AND
PURPOSE: Nicergoline is an ergoline derivative that is used to treat cognitive deficits in cerebrovascular disease and various forms of dementia. Although therapeutic effects of nicergoline have been established, little is known about its effects on cerebral perfusion in Alzheimer's disease (AD). The aim of this study was to examine the role of nicergoline in regional cerebral blood flow (rCBF) of AD patients using technetium-99m hexa-methyl-propylene-amine-oxime single photon emission computed tomography (SPECT).
METHODS: Sixteen patients with early AD underwent a comprehensive clinical assessment including cognitive testing and SPECT scans before and after nicergoline treatment. Nicergoline (30 mg twice daily) was administered for an average duration of 1.5 years. Clinical and cognitive functioning was assessed using the Mini-Mental State Examination, Clinical Dementia Rating (CDR), CDR-Sum of Boxes, Global Deterioration Scale, Barthel Activities of Daily Living Index, Instrumental Activities of Daily Living, and Geriatric Depression Scale.
RESULTS: Nicergoline treatment induced changes in the severity of dementia, cognitive function, activities of daily living, and depressive symptoms, which were not statistically significant. During the follow-up, the patients showed significant increases in their relative rCBF in the superior frontal gyrus, precentral gyrus, and postcentral gyrus.
CONCLUSIONS: Nicergoline treatment improves perfusion of the frontal and parietal regions in early AD patients. It is possible that the increased perfusion in the superior frontal gyrus may be related to the mechanisms that delay or prevent progressive deterioration of cognitive functions in AD.

INTRODUCTION

Alzheimer's disease (AD) is the most common form of dementia and is clinically characterized by global deficits in cognition.1 Despite differences in etiology, AD and vascular dementia often coexist and have overlapping risk factors and pathologies.2 In addition to old age, the risk factors for AD include hypertension, peripheral arterial disease, cardiovascular diseases, diabetes, and smoking, and the mechanisms underlying AD appear to be closely associated with vascular factors.3

Nicergoline is an ergoline derivative that is used for the treatment of dementia and other age-related cognitive deficits.4 While nicergoline was initially developed as a vasodilator and mainly prescribed for cerebrovascular diseases, it has a wider spectrum of pharmacological and clinical properties leading to its use in various forms of dementia including AD. Several randomized controlled trials have investigated the therapeutic efficacy of nicergoline in patients with dementia and demonstrated that nicergoline treatment improved or prevented the deterioration of cognitive symptoms in AD patients,567 as well as in patients with senile dementia, vascular, or mixed type.891011

Nicergoline plays a role in the molecular and cellular pathophysiology of dementia. In in vitro and animal studies, nicergoline has been reported to act as an α1-adrenoceptor antagonist, resulting in vasodilation and blood flow increase,12 cholinergic neurotransmission,131415 enhanced noradrenaline and dopamine turnover,16 cerebral metabolic activity,1718 and neuroprotection.192021 Moreover, nicergoline has been shown to mediate neuronal signal transduction by modulating phosphoinositide pathway, protein kinase C (PKC) translocation, and PKC-mediated α-secretase processing of amyloid precursor protein implicated in the pathophysiology of AD.222324

While the clinical effects and potential mechanisms of nicergoline on AD have been studied, its effects on the brains of AD patients remain unclear. A single study used electroencephalography to measure neural activities correlated with nicergoline treatment in senile dementia of Alzheimer type and multi-infarct dementia.11 The aim of this study was to elucidate the effects of nicergoline on regional cerebral blood flow (rCBF) in early AD patients using single photon emission computed tomography (SPECT).

METHODS

Participants

Sixteen patients with AD were recruited at Incheon St. Mary's Hospital (Incheon, Korea). The diagnosis of AD was made according to the Diagnostic and Statistical Manual of Mental Disorders-IV criteria,25 and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria.26 Patients with a history of head trauma, epilepsy, stroke, mixed or vascular dementia, radiological findings on magnetic resonance imaging (MRI), or other neurological or psychiatric disorders were excluded from the study.

The study was approved by the Institutional Review Board of the Incheon St. Mary's Hospital. Written informed consent was obtained from all participants.

Nicergoline administration

Patients received oral nicergoline at a dose of 30 mg twice daily for 1.5 years on average. All patients were also undergoing treatment with acetylcholinesterase inhibitors (AChEI) for AD at the time of the study. Safety assessments including adverse events, physical examinations, monitoring of vital signs, electrocardiography, and laboratory tests were performed.

Clinical assessment

All patients underwent a comprehensive clinical assessment including a detailed medical history and neurological examination, by board-certified neurologists. Global cognitive functioning was evaluated with the Mini-Mental State Examination (MMSE).27 Assessments for dementia severity included the Clinical Dementia Rating (CDR),28 CDR-Sum of Boxes (CDR-SB), and Global Deterioration Scale (GDS).29 The Barthel Activities of Daily Living Index (Barthel ADL Index)30 and Instrumental Activities of Daily Living (IADL)31 were used to evaluate functional status. The Geriatric Depression Scale (GDS-Depression) was used to assess depressive symptoms.32

Image acquisition and analysis

SPECT images were acquired with a dual-head gamma camera (Discovery NM640, GE Healthcare, Milwaukee, WI, USA) at the baseline and follow-up visits. Participants were scanned approximately 40 min after a bolus intravenous injection of 1110 MBq of technetium-99m hexamethylpropylene amine oxime. All images were corrected for attenuation and reconstructed in a 128×128 matrix with a voxel size of 3.9×3.9×3.9 mm using filtered back projection.

Data were analyzed using Statistical Parametric Mapping (SPM) 12 (Wellcome Department of Cognitive Neurology, Institute of Neurology, London, UK). All SPECT images were registered and spatially normalized to the SPM SPECT template (Montreal Neurological Institute, McGill University, Montreal, Canada) using a 12-parameter affine transformation and nonlinear warping with 25-mm cutoff and 16 iterations. Images were then re-sliced with a voxel size of 2×2×2 mm and smoothed with a 16-mm full-width half-maximum Gaussian kernel. After spatial normalization, a voxel-based intensity of the images was normalized to the mean value of the cerebellum using the Automated Anatomical Labeling atlas.333435

A paired t-test was used to examine changes in regional perfusion in the follow-up scans compared with the baseline on a voxel-by-voxel basis. Regions with the voxel subsets exceeding a threshold of p<0.001 and a cluster size of 100 or more contiguous voxels were reported as significant.

Statistical analysis

The Shapiro-Wilk test was used to determine the normality of distribution for each variable. Changes in continuous variables between the baseline and follow-up visits were performed with a paired t-test or Wilcoxon signed rank sum test. A two-tailed p value of less than 0.05 was regarded as statistically significant. All analyses were conducted with Stata 13 (Stata Corp., College Station, TX, USA).

RESULTS

Demographic and clinical characteristics of the participants are listed in Table 1. Sixteen patients (6 males and 10 females) with early AD were included in the study. The mean age at the baseline was 77.0±6.4 years. The mean duration between baseline and follow-up assessments was 1.5±0.5 years. The CDR scores remained unchanged during the study period. Moreover, changes in MMSE (t=−0.11, p=0.91), CDR-SB (t=−1.84, p=0.09), GDS (z=−1.00, p=0.32), IADL-C (t=−0.26, p=0.80), IADL-P (t=−1.16, p=0.26), Barthel ADL Index (z=1.84, p=0.07), and GDS-Depression (z=−0.57, p=0.57) scores from baseline to follow-up were not significant.

Table 1

Demographic and clinical characteristics of the participants

*Paired t-test or Wilcoxon signed rank sum test.

ADL: Activities of Daily Living, CDR: Clinical Dementia Rating, CDR-SB: Clinical Dementia Rating-Sum of Boxes, GDS: Global Deterioration Scale, GDS-Depression: Geriatric Depression Scale, IADL: Instrumental Activities of Daily Living-Current Performance (C) and Potential Performance (P), MMSE: Mini-Mental State Examination, SD: standard deviation.

The results of image analysis showed significant increases in relative rCBF of the left superior frontal gyrus (t=4.90, p<0.001, cluster size=465 voxels), left postcentral gyrus (t=5.16, p<0.001, cluster size=112 voxels), and the left precentral gyrus (t=4.56, p<0.001, cluster size=105 voxels) at follow-up compared with baseline (Fig. 1 and Table 2). There were no significant decreases in relative rCBF.

Fig. 1

Brain areas showing significantly increased regional cerebral blood flow in nicergoline-treated Alzheimer's disease patients compared with baseline. Images are shown in neurological convention. Color bar represents the voxel-level t-values.

Table 2

Changes in regional cerebral blood flow after nicergoline treatment

*The coordinates refer to the Montreal Neurological Institute coordinate system.

DISCUSSION

In the present study, we investigated the effects of nicergoline on cerebral perfusion in early AD patients. We found that nicergoline treatment increased the relative rCBF in the left superior frontal gyrus, left postcentral gyrus, and left precentral gyrus. No significant differences in clinical measures were found at follow-up compared with baseline. Previous longitudinal studies investigating AD patients demonstrated a global reduction in rCBF36 and in cognitive and neuropsychiatric performance over a one-year period.3738 Deterioration in cerebral perfusion and cognitive performance represent the natural course of the disease. Our results suggest that nicergoline may have beneficial effects on AD by interfering with the degenerative processes.

Apart from the medial temporal lobe, which has been widely implicated in the pathophysiology of early AD,363940 previous neuroimaging studies of normal aging, mild cognitive impairment (MCI), and AD also found structural and functional deficits in the frontal and parietal regions. Using MRI, cross-sectional studies of normal aging have reported a non-linear and regional atrophy within the brain, and the prefrontal cortex declined more rapidly than the other brain regions.414243 A longitudinal study showed that gray matter atrophy was more prominent in the frontal and parietal cortices than temporal and occipital cortices in healthy older adults.44 In functional imaging studies using positron emission tomography and SPECT, studies have demonstrated a reduction in glucose metabolism and blood flow in the frontal and parietal regions in patients who progressed from MCI to AD.4546 Furthermore, regional decreases in cerebral metabolism and perfusion in the frontal and temporo-parietal regions were found in the early stages of AD.47484950

Our findings suggest that nicergoline treatment improved the brain perfusion in the frontal and parietal regions of early AD patients. In particular, the largest cluster was found in the superior frontal gyrus, which is associated with higher cognitive functions such as working memory.51 Moreover, our study found increased cerebral perfusion in the precentral and postcentral gyri, which correspond to the primary motor and sensory cortices. While sensory and motor dysfunctions in AD have received relatively little attention in the field of AD research, recent evidence suggests that sensory and motor changes may precede the cognitive symptoms associated with AD pathogenesis.52 Taken together, it is possible that increased perfusion in the frontal and parietal regions may delay or prevent progressive deterioration of cognitive functions in AD.

Limitations of the study include the relatively small sample size and the lack of a control group. Moreover, cognitive evaluation with a more comprehensive neuropsychological battery may have facilitated the detection of subtle changes in cognitive function during the study period. Finally, it is possible that the rCBF changes observed in our study may have been affected by AChEI. However, previous SPECT studies involving AD patients treated with long-term AChEI therapy showed no increases in rCBF535455 or the effects were mainly localized to the frontal lobe.5657

In conclusion, this was the first SPECT study, to our knowledge, to examine cerebral perfusion changes associated with nicergoline treatment in early AD patients. Nicergoline treatment resulted in a favorable outcome involving cerebral perfusion during early AD. Moreover, the clinical symptoms of AD remained stable without deterioration during the study period. Further studies involving larger sample sizes and placebo-controlled design are required to confirm, and elucidate the treatment effects and the underlying neural mechanisms of nicergoline in AD.