Galantamine Elevates Attention

In Alzheimer’s disease patients with cerebrovascular disease …

How can you expect to keep up with the acceleration in advanced biomedical discoveries in 2017 (and beyond) if you don’t improve your ability to concentrate and enhance your powers of attention?

Without these enhancements, your chances of staying healthy (and perhaps even staying alive) greatly diminish.

We now know that it is possible to increase the effects of an acetylcholinesterase inhibitor(AChEI) such as galantamine with the addition of choline alphoscerate. Other choline donors such as citicoline and choline (as in choline citrate) are also thought to improve the power of galantamine [See sidebar, “Combined Administration of AChEIs and Choline Donors.”] Galantamine and choline are good for concentration and attention, especially when taken together. Thus, disturbances of memory and attention in Alzheimer’s disease (AD) and other memory disorders can be improved (see “Enhancing the Power of Galantamine” in the September 2016 issue).

Investigating Attention Deficits

Impaired attention is one of the cognitive deficits detected in the early stages of AD. Degraded attention diminishes the ability to socially interact with other people1 and severely impairs specific skills, such as driving.2 This deficit can also increase the caregivers’ burden.1

Some of the other attentional impairments seen in AD can be ascribed to an alteration of the basal forebrain cholinergic system, in particular the nucleus basalis of Meynert(see Fig. 1), which undergoes significant neuronal loss in AD.3 The basal forebrain cholinergic system provides the cholinergic innervation to the thalamus, prefrontal cortex and parietal lobes, all structures known to be involved in attentional operations.

 
Figure 1. In the central nervous system, most acetylcholine (ACh) tracts originate in the nucleus basalis of Meynert and adjacent nuclei situated in the basal forebrain [a rostral (taking the shape of a beak) portion of the brainstem]. These nuclei project their cholinergic tracts throughout the cerebral cortex but particularly to the hippocampus, amygdala, and cortical association areas.
The debilitating memory disruptions are even greater when cerebrovascular disease (CVD) is present. CVD is the most common coexistent pathology observed in AD. A cerebrovascular disease is a vascular disease of the cerebral circulation. Arteries supplying oxygen to the brain are affected, resulting in one of a number of cerebrovascular diseases. Most commonly, this is a stroke or mini-stroke, and sometimes can be a hemorrhagic stroke. Any of these can result in vascular dementia. Hypertension (high blood pressure) is the most important contributing cause because it damages the blood vessel lining, exposing collagen where platelets aggregate to initiate a repair. [For more on how to reduce hypertension, see “Potassium Bicarbonate Supplementation—A Low Cost Way to Improve Health,” in the April 2009 issue.] If maintained, hypertension can change the structure of blood vessels (narrowing and deforming them).

AD Patients with CVD Study

The aim of a new study was to investigate the effect of galantamine on attention in Korean AD patients with CVD.4 In this open trial, 1512 patients with AD and CVD were recruited from 71 nationwide hospitals between July 2008 and May 2009. The patients were given galantamine for 16 weeks. The primary outcome result was the score on the Attention Questionnaire Scale (AQS), which measures the patients’ attention in their daily lives. In this result, scores can range from 0 (severe attention deficit) to 30 (no attention deficit). The secondary outcome measures were the scores on the Korean Mini-Mental State Examination, the Clinical Dementia Rating (CDR) scale and the Global Deterioration Scale (GDS). Efficacy measures were calculated both at the beginning (baseline) and at the end of the treatment, which lasted 16 weeks.

The debilitating memory disruptions 
are even greater when 
cerebrovascular disease (CVD) is 
present. CVD is the most common 
coexistent pathology observed in AD.

Significant Improvements

The responders’ rate on the AQS (change of the AQS from baseline >0) was 60.6% in AD patients with CVD. At the end of the treatment, both the AQS (15.0 ± 5.7 vs 16.3 ± 5.8) and the Korean Mini-Mental State Examination scores (17.8 ± 4.8 vs 18.1 ± 5.1) showed a significant improvement relative to the baseline performance.

The Clinical Dementia Rating (1.25 ± 0.59 vs 1.22 ± 0.63) and Global Deterioration Scale (3.82 ± 0.94 vs 3.76 ± 0.96) scores also showed a significant decrease at the end of the treatment.

According to the researchers’ best knowledge, no study to date has examined the effect of a AChEI (such as galantamine) on attention in AD patients with CVD. Recently, a brief informant-based Attention Questionnaire Scale (AQS) was developed, under the premise that a patient’s attention in everyday life might reflect real-life situations much better than the artificial laboratory attention tasks. The AQS significantly correlated with attention tasks. The AQS might also be useful in a “real-world” clinical setting without a neuropsychometrician or in a brief evaluation of attention in a study carried out in several clinics.

Combined Administration of AChEIs and Choline Donors

Citicoline (aka CDP-Choline) can have beneficial effects both in degenerative and in vascular cognitive decline in a variety of ways. These include apoptosis inhibition, neuroplasticity potentiation, and phospholipid and acetylcholine (ACh) synthesis. Acetylcholinesterase inhibitors (AChEIs) such as galantamine have been used for treatment of Alzheimer's disease (AD).

When co-administered with cholinergic precursors, the two nutrients are able to increase the intrasynaptic levels of ACh more than when the single nutrients are given alone. In a very recent study, researchers set out to show the effectiveness of oral citicoline plus AChEIs in patients affected with AD.1 As a retrospective case-control study, the research was conducted at seven Centers for Cognitive Impairment and Dementia in Italy. The subjects were aged 65 years old or older affected by AD. Of these, 197 patients were treated with an AChEI including rivastigmine, donepezil, and galantamine, while 251 were treated with an AChEI + citicoline at 1000 mg/day given orally.

Cognitive functions were assessed by the Mini–Mental State Examination (MMSE), along with daily life functions, behavioral, comorbidities, and mood tests. These were administered at baseline, and after 3 and 9 months.

When co-administered with cholinergic 
precursors, the two nutrients are able to 
increase the intrasynaptic levels of ACh 
more than when the single nutrients 
are given alone.

The primary outcomes were effects of combined administration versus AChEIs given alone on cognitive functions assessed by MMSE. The secondary outcomes were side effects or adverse events of combination therapy versus AChEIs alone.

Patients treated with citicoline plus an AChEI showed a statistically significant increase in MMSE during the first three months (16.88±3.38 versus 17.62±3.64) and during the next six months (17.62±3.64 versus 17.89±3.54).

This study demonstrates the efficacy of combined administration of cholinergic precursors and acetylcholinesterase inhibitors in disease management by slowing disease progression.

Reference

  1. Gareri P, Castagna A, Cotroneo AM, Putignano D, Conforti R, Santamaria F, Marino S, Putignano S. The Citicholinage Study: Citicoline Plus Cholinesterase Inhibitors in Aged Patients Affected with Alzheimer’s Disease Study. J Alzheimers Dis. 2016 Dec 30. doi: 10.3233/JAD-160808. [Epub ahead of print]

The aim of the present study was to investigate the effect of galantamine on attention measured with the AQS in AD patients with CVD. The patients were aged 50–85 years, and had a Korean Mini-Mental State Examination (K-MMSE) score between 10 and 25. They were also in the care of a caregiver who was able to provide the investigator with the information necessary to complete the study. The AQS includes eight negative items (e.g. “Does he/she easily become inattentive?”) and seven positive items (e.g. “Is he/she good at concentrating on one thing?”). Each item was rated on a three-point scale (0 = none or never, 1 = intermediate or sometimes, 2 = many or always). The total score was calculated by tallying up the score of responses that would suggest probable attention deficits (– negative item score + positive item score). Scores can range from 0 (severe attention deficit) to 30 (no attention deficit).

A total of 1512 patients were enrolled and took at least one dose of galantamine. Among these, 365 patients (24.1 %) dropped out. The safety population comprised 1512 patients, and the per-protocol population for efficacy evaluation comprised 1147 patients. There were no significant differences in age, sex and K-MMSE score at baseline between the subjects who discontinued the study and those who completed it. At the end of the treatment, 574 (38.0%), 697 (46.1 %) and 241 (15.9%) patients were receiving 8 mg, 16 mg and 24 mg of galantamine, respectively. The average daily dose of galantamine was 14.2 ± 5.6 mg.

The responder rate of the AQS (change of the AQS from baseline > 0) was 60.6% in AD patients with CVD. The responder rate in AD patients with CVD from the present study was within the 95% CI (54.7–60.7%) of the responder rate of the AQS in 1393 patients having AD without CVD at week 16 after taking galantamine from our previous study (unpubl. data).

The patients showed a significant increment in the AQS at week 16, compared with the baseline score (15.0 ± 5.7 vs 16.3 ± 5.8). In the previous study (unpubl. data), 1393 patients having AD without CVD also showed a significant increment in the AQS at week 16 after taking galantamine, compared with the baseline score (14.9 ± 5.7 vs 16.0 ± 5.8). They also had a significant increment in K-MMSE, and significant decrements in Clinical Dementia Rating and Global Deterioration Scale at week 16 compared with the baseline scores.

Attention Improvement

Overall, the results show that galantamine is associated with improvement of attention on the AQS in AD with CVD. Galantamine is effective in improving attention in the daily lives of AD patients with CVD. Galantamine might be more beneficial in AD patients with CVD, because they have greater attentional deficits compared with AD.

Reference

  1. Vellas B, Cunha L, Gertz HJ et al. Early onset effects of galantamine treatment on attention in patients with Alzheimer’s disease. Curr Med Res Opin. 2005; 21: 1423–9.
  2. Duchek JM, Hunt L, Ball K, Buckles V, Morris JC. The role of selective attention in driving and dementia of the Alzheimer type. Alzheimer Dis Assoc Disord.1997;11:48–56.
  3. Lawrence AD, Sahakian BJ. Alzheimer disease, attention, and the cholinergic system. Alzheimer Dis Assoc Disord 1995;9 (Suppl 2):43–49.
  4. Park JJ, Choi SH, Kim S, Lee AY, Moon SY, Lee JH, Kwon JC, Park KW, Ku BD, Han HJ, Kim EJ, Shim YS. Effect of galantamine on attention in patients with Alzheimer’s disease combined with cerebrovascular disease. Geriatr Gerontol Int. 2016 Dec 9. doi: 10.1111/ggi.12934. [Epub ahead of print] PubMed PMID: 27935239.