Some Ministrokes Increase Risk of Dementia; Statins Leave Amyloid Untouched

Transient episodes of neurological symptoms—muscle weakness, double vision, or other signs that last less than 24 hours—reveal underlying circulatory problems in the brain. When these “ministrokes” show themselves with focal symptoms that affect one part of the body, they are diagnosed as transient ischemic attacks (TIAs) and are associated with an elevated risk of stroke going forward. But attacks that present with more diffuse, non-localized signs like amnesia or acute confusion are harder to diagnose and are often not treated, and have generally been considered less harmful.

That thinking may change with a new report that people who experience nonfocal transient neurological symptoms also have a higher risk for subsequent stroke and dementia as well. The work, from Monique Breteler and colleagues at the Erasmus Medical Center, Rotterdam, the Netherlands, suggests a new classification of transient neurological attack (TNA) that encompasses nonfocal symptoms as potential indicators of serious underlying problems. The study was published in the December 26 issue of JAMA.

In the study, lead author Michiel Bos and coworkers analyzed TNAs among 6,062 residents of Rotterdam aged 55 or older who were followed up for 12-15 years. In 60,535 person-years of follow-up, they found nonfocal TNAs almost as frequently as focal TNAs. The incidence of mixed episodes was much lower. Participants who suffered a focal TNA had about double the risk of stroke, an elevation slightly lower than that seen in previous studies. Those with nonfocal TNA also had a higher risk of stroke, but also dementia, especially vascular dementia. Mixed TNAs carried the worst prognosis, with increased risk of stroke, ischemic heart disease, vascular death, and dementia compared to subjects without TNA.

The study’s strengths come from the large population studied, with nearly complete follow-up in collaboration with primary care doctors. However, diagnoses were made from medical records and patient recall, which may not be entirely reliable. Nonetheless, the authors write, “Our findings challenge the strong but unfounded conviction that nonfocal TNAs are harmless. On the contrary, our findings suggest that nonfocal TNAs are not only a risk factor for stroke, but also for dementia.”

In an accompanying editorial, S. Claiborne Johnston of the University of California, San Francisco, writes, “Most physicians already are appropriately concerned about patients with TIA, but the study by Bos et al. extends that concern to those often diagnosed as possible TIA or left without a diagnosis. Even though TNA is likely to be only of transient utility because clinicians must quickly move to more specific diagnoses to provide appropriate treatment for patients, this entity should be considered a rally cry for more extensive evaluation or consultation in these patients, as well as for further research.”

After a diagnosis of TIA, statins are often prescribed to reduce the risk of subsequent stroke. This action of statins has been cited as one mechanism by which they could slow the development of dementia, but the relationship between statins, cognitive decline, and AD is still unclear. In a study published online January 16 in Neurology, investigators at Rush University Medical Center, Chicago, Illinois, report that statin use is not associated with changes in cognitive function or Alzheimer neuropathology measured at autopsy.

In the study, lead author Zoe Arvanitakis and colleagues assessed changes in cognitive function or Alzheimer neuropathology in 929 participants of the Religious Orders Study of older Catholic clergy, of which 119 were statin users. The participants, free of dementia at baseline, were evaluated for up to 12 years. The group included 262 who were followed through to brain autopsy. The results are nearly all negative, indicating that statin use was not related to incident AD, or to any changes in either global or domain-specific cognition. Statin use had no effect on global AD pathology (extent of plaques and tangles upon autopsy). People taking statins were less likely to have amyloid pathology, but among those users with amyloid, there was no relation between statin use and amyloid load.

Within the limitation of the small study, the authors conclude that “overall, these studies do not support a relation between statins and AD or cognitive decline among older persons.” The results conflict with another study examining statin use and AD pathology, which showed a reduction in neurofibrillary tangle pathology in statin users (Li et al., 2007). It is also at odds with several epidemiological studies, including a large one that indicated simvastatin, at least, protected against AD and Parkinson disease (see ARF related news story and comment).—Pat McCaffrey

Comments

  1. Statins have been shown to be beneficial in preventing many different diseases in addition to cardiovascular disease, from osteoporosis to prostate cancer. Whether statins might be beneficial for those at risk of Alzheimer disease or suffering from the disease remains unclear. The most recent manuscript on this subject is a study by David Bennett’s group, examining cases from the Nun Study. Arvanitakis et al. have examined 929 cases from the Nun Study to investigate whether statins modify the pathology associated with AD. The group finds a striking absence of any effect in every measure examined. The group examined whether statin use was associated with any differences in incident Alzheimer cases but failed to observe any effect. They also examined whether statin use was associated with any change in plaque or tangle production, but also failed to observe any effect. The absence of any effects is an important finding, but is difficult to interpret because it comes on the heels of other studies, some of which are positive, others that are negative.

    One of the key considerations in evaluating a study such as this is numbers. Large numbers of cases are needed to examine the effects of medications on disease parameters because typically only a small fraction of patients are taking any particular medication and only a fraction of those exhibit the specific phenotype of interest. In the current study, the group started with 929 cases, with 119 cases positive for statin use. The use of lipid-lowering medication is presumably by self-report, and there is no description of duration of medication utilization, whether the medication was taken continuously or dosing. The group first used these cases to examine incident AD. Next, the group went on to examine effects on pathology. Only 199 or 231 out of the 989 cases had amyloid or tangle pathology, respectively; 16.6 percent of these cases used statins, which corresponds to 33 or 38 cases for amyloid or tangle pathology. Presumably, only about one-third of these cases, approximately 10-12 cases, used a brain penetrant statin, such as simvastatin. Obtaining statistical significance with such small numbers of cases is difficult.

    Regardless of the considerations of number or power, I am struck by the absence of any effect associated with the statins. There was no overall effect for virtually any measure. The group did stratify the results by type of medication—lipophilic statin, lipophobic statin or non-statin agent—as well as by ApoE genotype. These stratifications could be important because other groups have observed more significant effects in ApoE4 subjects (Kivipelto et al., 2005; Rovio et al., 2005). In addition, our results suggest that the potent brain penetrant statin, simvastatin, is more effective than lovastatin, which is brain penetrant but less potent and also more effective than atorvastatin, which is not brain penetrant (Wolozin et al., 2007). Stratification by lipophilicity did not produce a statistically significant effect in most outcomes, but the data suffer from very large confidence interval, suggesting that statistical power was a significant issue. The problem is that the numbers get very small very quickly, which could easily lead to a false negative result. One measure, amyloid load, did show a weakly significant effect for users of lipophilic statins (simvastatin and lovastatin).

    The lack of any effect is striking and contrasts with a recent study from the Cache County cohort in which Li et al. observed that subjects taking statins showed a significant reduction in neurofibrillary plaque formation, but no change in neuritic plaque formation (Li et al., 2007). In a smaller study published previously, we examined plaque pathology and markers of inflammation. We observed no change in plaque pathology, but a striking decrease in inflammation (Wolozin et al., 2006). Both of these studies parallel observations by Ling Li in the APP transgenic mouse model showing that simvastatin is associated with improved memory function that is not correlated with changes in amyloid load (Li et al., 2006). It is unfortunate that Bennett’s group did not examine inflammatory markers, which are known to decrease in subjects taking statins. Two prospective trials have been done specifically focused on the issue of statins and AD. The trial by Simons used simvastatin (Simons et al., 2002), and a more recent trial by Sparks used atorvastatin (Sparks et al., 2005). Both showed some benefit to patients with AD, but both suffered from low power and benefits were observable mainly after post-hoc analysis of subgroups. Interestingly, both prospective studies suggest that there might be some effect on amyloid levels, which contrasts with the studies of pathology in animals and humans. One other study of relevance is that by Hinerfeld et al., which observed reduced CSF amyloid in subjects with PS1 mutations taking simvastatin, but not in sporadic AD cases and not with other statins (Hinerfeld et al., 2007).

    The discrepancy between the work by Arvanitakis et al. and the previously published manuscripts is difficult to reconcile. It could be that in studies of pharmaco-epidemiology, medication-use history and large numbers are both as important as accurate diagnostic criteria for evaluating data. Without these factors, studies might be prone to discrepant results. As the data accumulate, a meta-analysis might be informative.

    References:

    Hinerfeld DA, Moonis M, Swearer JM, Baker SP, Caselli RJ, Rogaeva E, St George-Hyslop P, Pollen DA. Statins differentially affect amyloid precursor protein metabolism in presymptomatic PS1 and non-PS1 subjects. Arch Neurol. 2007 Nov;64(11):1672-3. PubMed.

    Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kåreholt I, Winblad B, Helkala EL, Tuomilehto J, Soininen H, Nissinen A. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol. 2005 Oct;62(10):1556-60. PubMed.

    Li G, Larson EB, Sonnen JA, Shofer JB, Petrie EC, Schantz A, Peskind ER, Raskind MA, Breitner JC, Montine TJ. Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease. Neurology. 2007 Aug 28;69(9):878-85. PubMed.

    Li L, Cao D, Kim H, Lester R, Fukuchi K. Simvastatin enhances learning and memory independent of amyloid load in mice. Ann Neurol. 2006 Dec;60(6):729-39. PubMed.

    Rovio S, Kåreholt I, Helkala EL, Viitanen M, Winblad B, Tuomilehto J, Soininen H, Nissinen A, Kivipelto M. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease. Lancet Neurol. 2005 Nov;4(11):705-11. PubMed.

    Simons M, Schwärzler F, Lütjohann D, von Bergmann K, Beyreuther K, Dichgans J, Wormstall H, Hartmann T, Schulz JB. Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: A 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol. 2002 Sep;52(3):346-50. PubMed.

    Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Browne P, Wasser D, Johnson-Traver S, Lochhead J, Ziolwolski C. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol. 2005 May;62(5):753-7. PubMed.

    Wolozin B, Wang SW, Li NC, Lee A, Lee TA, Kazis LE. Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease. BMC Med. 2007;5:20. PubMed.

    Wolozin B, Manger J, Bryant R, Cordy J, Green RC, McKee A. Re-assessing the relationship between cholesterol, statins and Alzheimer's disease. Acta Neurol Scand Suppl. 2006;185:63-70. PubMed.

    View all comments by Benjamin Wolozin

  2. In this paper, the Rotterdam group confirmed that persons with focal transient neurologic attacks (TNAs or TIAs) were at higher risk for stroke than people without TNA, although both groups appeared to have the potential for developing ischemic heart disease and dementia. The kicker in this study is that individuals with non-focal (or global) TNA symptoms showed not only a higher risk for stroke when compared to a control group without TNA but also revealed a higher risk for dementia.

    Even worse were patients identified with mixed TNA showing focal and non-focal symptoms who apparently had a higher risk for stroke, ischemic heart disease, dementia, and vascular-related death when compared to control subjects without TNA.

    This study by Breteler and her colleagues points to an important gap in management that physicians need to bridge when evaluating people who present with focal, non-focal, or mixed signs associated with TNA. Because TNAs are almost always accompanied by a brief interruption of local cerebral blood flow in the absence of neurologic injury, conventional neuroimaging in patients experiencing TNAs is advisable. This should be done in a hospital setting where the patient can be monitored and observed. Swift neuroimaging, echocardiography, and risk factor assessment may identify the presence of brain hypoperfusion, a silent stroke, or cardiac pathology that can be managed to prevent escalation to irreversible cognitive dysfunction. Rapid treatment to control the cause or recurrence of focal or non-focal TNAs may provide an excellent opportunity to prevent permanent neuronal damage from continuous brain hypoperfusion or incomplete infarction (1).

    TIAs are similar to angina pectoris, since both are signals of temporary ischemia and both can lead to serious infarcts. Although several studies have reported that cognitive impairment can follow a TNA attack, the report by Breteler and her group indicates that non-focal and mixed TNA can also lead to the development of vascular dementia. We should point out, no conclusive study has yet shown TNAs can lead to an increased risk of Alzheimer disease, though we have predicted (1) this is only a matter of time due to the brain hypoperfusion that accompanies each attack.

    References:

    de la Torre JC. How do heart disease and stroke become risk factors for Alzheimer's disease?. Neurol Res. 2006 Sep;28(6):637-44. PubMed.

    View all comments by Jack de la Torre

  3. The recent study by Arvanitakis et al. shows no effect of statins on incident AD, cognitive decline, and related neuropathology in a group of elderly Catholic clergy. But their data may support a different conclusion. Presumably, participants treated with statins were at elevated cardiovascular risk compared to those not treated. In fact, the authors caution that a weakness of the study is derived from “the likely possibility of indication bias (statin exposure is non-random).” Numerous studies have demonstrated a positive correlation between increased cardiovascular risk and AD. Based on this, one might expect the statin-treated group in the present study to show accelerated cognitive decline and increased AD, but they did not. Does this mean a lack of effect of statins or a positive effect (i.e., normalization of dementia risk in a high cardiovascular risk population)?

    View all comments by William Netzer

  4. This is a very carefully performed prospective study discriminating two types of transient neurological events, either focal attacks or more diffuse disturbance in neurological dysfunction in which loss of consciousness is the most prominent symptom. It is difficult for me as a basic scientist to evaluate how readily classifiable these events are, or how likely it might be for individuals to simply not report such events. Nonetheless, the results imply that focal events (TIAs) are linked to increased risk of stroke, and more diffuse events (TNAs) are more closely associated with risk of dementia, both Alzheimer and vascular variants, and to a lesser extent increased risk of stroke. Perhaps the most surprising outcome was the absence of increased risk for vascular dementia with TIAs, but the small number of incident cases (one for the entire study) probably indicates statistical power was inadequate.

    The primary conclusion of the authors is that transient neurological attacks, those without focal symptoms, are not benign as had been previously argued and led to increased risk for stroke and dementia. The more focal symptoms associated with TIAs, evidently, did not lead to increased risk of dementia, and a slightly greater risk of stroke than patients with TNAs. One potential explanation is that the neurological dysfunctions underlying these two disorders may be different. For TIAs, there appears to be stenosis or occlusion of a specific artery leading to ischemia in a restricted portion of the brain, and this results in focal symptoms. It seems logical to predict these would be harbingers of similar events from which recovery was less than complete, in which case it would be called a stroke. The TNAs, on the other hand, might be associated with more general declines in blood flow, but also may reflect underlying deterioration of neurological functions due to Alzheimer-type pathology. This pathology may be subthreshold for traditional symptoms of dementia, but when combined with loss of blood flow, may predispose towards more diffuse symptoms, such as loss of consciousness, due to the localization of Alzheimer pathology outside the sensorimotor areas most clearly involved in the focal symptoms of stroke. Obviously, further work leading to greater understanding of the triggers for TNAs will be needed to address the specific mechanisms involved in these events.

    View all comments by Dave Morgan

Make a Comment

To make a comment you must login or register.

References

News Citations

  1. Statins—New Data Suggest Benefits for AD/PD

Paper Citations

  1. Li G, Larson EB, Sonnen JA, Shofer JB, Petrie EC, Schantz A, Peskind ER, Raskind MA, Breitner JC, Montine TJ. Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease. Neurology. 2007 Aug 28;69(9):878-85. PubMed.

Further Reading

Primary Papers

  1. Bos MJ, van Rijn MJ, Witteman JC, Hofman A, Koudstaal PJ, Breteler MM. Incidence and prognosis of transient neurological attacks. JAMA. 2007 Dec 26;298(24):2877-85. PubMed.
  2. Johnston SC. Transient neurological attack: a useful concept?. JAMA. 2007 Dec 26;298(24):2912-3. PubMed.
  3. Arvanitakis Z, Schneider JA, Wilson RS, Bienias JL, Kelly JF, Evans DA, Bennett DA. Statins, incident Alzheimer disease, change in cognitive function, and neuropathology. Neurology. 2008 May 6;70(19 Pt 2):1795-802. PubMed.

Annotate

To make an annotation you must Login or Register.