Alzheimer's Research & Therapy - Latest Comments

Affiliation correction

Eloise Kok — 2011-05-13T10:24:28Z

Dr. Teemu Luoto's affiliation should be corrected to Department of Neurosciences and Rehabilitation,
Tampere University Hospital, Biokatu 4, 33521 Tampere, Finland.

Ginkgo biloba has a proven benefit

Siegfried Kasper — 2010-12-07T14:04:27Z

Tian et al. arrive at a negative conclusion with regard to Ginkgo biloba for the treatment of Alzheimer's disease by relying on a Cochrane Review [1] and a study that did not really address the question they were trying to answer [2]. Unfortunately, the cited Cochrane review is flawed in that it lumps together studies using different Ginkgo products that can by no means be considered bioequivalent as well as studies in patients with different diseases or ailments (merely subjective memory complaints, mild cognitive decline, overt dementia). Obviously, it does not make sense to estimate a common effect size for 0.57 mg flavone glycosides and 0.97 mg ginkgolides per day in subjective cognitive complaints [3] and 58.8 mg flavone glycosides and 14.4 mg terpene lactones per day in dementia [4], as done in Birks' analysis no. 1.15. Furthermore, it is not true that three of the four most recent trials showed no difference between Ginkgo and placebo: the trials by Napryeyenko [4] and Mazza [5] showed significant superiority of Ginkgo biloba extract over placebo. The DIGGER trial [6] was an attempt to address two questions at the same time and was seriously underpowered after repeated downward calculation of the sample size due to recruitment problems.
Finally, Snitz et al. [2] reported on a prevention trial in elderly people who were cognitively healthy or had MCI. It is not possible to draw any conclusions with respect to efficacy of Ginkgo biloba extract in the treatment of Alzheimer's disease from a prevention trial. It is also inappropriate to conclude from this trial that Ginkgo extract does not reduce cognitive decline, since there was no cognitive decline to be reduced, neither in the Ginkgo group nor in the control group.
Recent meta-analyses that adequately considered inclusion diagnoses, extract type and dosing confirmed the efficacy of Ginkgo biloba leaf extracts standardized according to the European Pharmacopoeia at a daily dose of 240 mg in dementia and Alzheimer's disease [7,8,9,10].

References
1. Birks J, Grimley Evans J: Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2009, 1:CD003120.
2. Snitz BE, O'Meara ES, Carlson MC, Arnold AM, Ives DG, Rapp SR, Saxton J, Lopez OL, Dunn LO, Sink KM, DeKosky ST; Ginkgo Evaluation of Memory Study: Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial. JAMA 2009, 302:2663-2670.
3. Brautigam MRH, Blommaert FA, Verleye G, Castermans J, Jansen Steur ENH, Kleijnen J: Treatment of age-related memory complaints with Ginkgo biloba extract: a randomized double blind placebo-controlled study. Phytomedicine 1998, 5:425-434.
4. Napryeyenko O, Borzenko I; GINDEM-NP Study Group: Ginkgo biloba special extract in dementia with neuropsychiatric features. A randomized, placebo-controlled, double-blind clinical trial. Arzneimittelforschung 2007, 57:4-11.
5. Mazza M, Capuano A, Bria P, Mazza S: Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer's dementia in a randomized placebo-controlled double-blind study. Eur J Neurol 2006, 13:981-985.
6. McCarney R, Fisher P, Iliffe S, van Haselen R, Griffin M, van der Meulen J, Warner J: Ginkgo biloba for mild to moderate dementia in a community setting: a pragmatic, randomised, parallel-group, double-blind, placebo-controlled trial. Int J Geriatr Psychiatry 2008, 23:1222-1230.
7. IQWiG Institute for Quality and Efficiency in Health Care. IQWiG Reports ¿ Commission No. A05-19B, Ginkgo in Alzheimer's disease. Executive Summary. Köln: IQWiG, 2008: http://www.iqwig.de/download/A05-19B_Executive_Summary_Ginkgo_in_Alzheimers_disease.pdf.
8. Kasper S, Schubert H: Ginkgo biloba extract EGb 761® in the treatment of dementia: Evidence of efficacy and tolerability [Ginkgo-Spezialextrakt EGb 761® in der Behandlung der Demenz: Evidenz für Wirksamkeit und Verträglichkeit]. Fortschr Neurol Psychiat 2009; 77: 494-506.
9. Weinmann S, Roll S, Schwarzbach C, Vauth C, Willich SN: Effects of Ginkgo biloba in dementia: systematic review and meta-analysis. BMC Geriatr 2010, 10:14.
10. Wang BS, Wang H, Song YY, Qi H, Rong ZX, Wang BS, Zhang L, Chen HZ: Effectiveness of Standardized Ginkgo biloba Extract on Cognitive Symptoms of Dementia with a Six-Month Treatment: A Bivariate Random Effect Meta-Analysis. Pharmacopsychiatry 2010, 43:86-91.

Traumatic brain injury and Alzheimer¿s disease

Rovshan Ismailov — 2010-11-24T12:30:07Z

I agree with Dr. Gavett and colleagues that cohort studies with both detailed and accurate neuropathological assesement of patients diagnosed with head injury are needed. However, we also need more studies that would examine the mechanism of the association between traumatic brain injury and Alzheimer¿s disease.

Several population based studies favored an association between traumatic brain injury and subsequent Alzheimer¿s disease[1,2]. For instance, a hazard ratio of 2.32 (confidence interval = 1.04 to 5.17) for moderate traumatic brain injury and a hazard ratio of 4.51 (confidence interval = 1.77 to 11.47) for severe head injury was observed in a historical cohort study of 548 World War II veterans[3]. We have reported that the proportion of patients diagnosed with both traumatic brain injury and Alzheimer¿s disease was nearly twice as high as the proportion of patients diagnosed with Alzheimer¿s disease and any other comorbidities (p less than 0.001). In the adjusted (for age, gender, length of stay and primary source of payment) logistic regression analysis, patients diagnosed for traumatic brain injury were 1.82 times more likely to be diagnosed with Alzheimer¿s disease (95% confidence interval 1.28 ¿ 2.58)[4]. A recent meta-analysis of case-control studies confirmed that men diagnosed with traumatic brain injury are at increased risk of developing Alzheimer¿s disease[5]. However, no serious consideration of the mechanism has been provided.

Obviously, trauma may damage any structure of the brain; however, cerebral vascular wall could be at particular high risk due to the presence of ¿internal¿ forces acting inside the vessel (i.e. shear stress). On the other hand, with the appearance of the ¿hypoperfusion¿ theory as well as findings from numerous population-based studies linking Alzheimer¿s disease to vascular disorders (i.e. hypertension, atherosclerosis etc.), it became evident that the important task for understanding Alzheimer¿s disease is to thoroughly examine hemodynamics and blood rheology. Such approach may also result in finding of successful treatments of Alzheimer¿s disease.

Thus, the mechanism of the association between traumatic brain injury and Alzheimer¿s disease is complex. For instance, genetic influence (i.e. having apolipoprotein E epsilon4) can worsen prognosis of Alzheimer¿s disease after traumatic brain injury[6,7]. Animal-based experiments observed an increase of amyloid ß peptide following traumatic brain injury[8]. The vascular component of the mechanism of traumatic brain injury-related Alzheimer¿s disease should take into account both direct and indirect trauma to brain vessels, and therefore changes to local hemodynamic and rheological factors[4]. Traumatic compression of the vessel can lead to the appearance of zones with high shear stress (as the result of injury to part of the vessel) and low or zero shear stress (within the zone of boundary layer separation)[9]. We have reported that high shear stress (exceeding the physiological value) may potentially damage the endothelium[9] and increase platelet aggregation[10,11], possibly leading to thrombus formation. On the other hand, trauma may lead to boundary layer separation, resulting in the appearance of a zone with zero shear stress and zero yield velocity[9]. According to current research, this may result in an increase of blood viscosity through increased erythrocyte aggregation and rouleaux formation[4]. As noted above, hyperviscosity may worsen the blood circulation and cause ischemia and local necrosis through deterioration in capillary perfusion[12]. Finally, trauma may lead to the appearance of zones of boundary layer separation, which, in turn, may directly influence the velocity of the movement of the regional brain extravascular fluid[4]. The above consideration of regional brain extravascular fluid dynamics is particularly important in light of the fact that certain waste products such as glutamate or calcium can accumulate there causing degradation of certain cellular components thus playing an important role in the pathogenesis of Alzheimer¿s disease[13,14].

Rovshan M Ismailov, M.D., M.P.H., Ph.D.

References

[1] Lye TC, Shores EA. Traumatic brain injury as a risk factor for Alzheimer's disease: a review. Neuropsychol Rev 2000; 10(2):115-29.
[2] Jellinger KA. Head injury and dementia. Curr Opin Neurol 2004; 17(6):719-23.
[3] Plassman BL, Havlik RJ, Steffens DC et al. Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias. Neurology 2000; 55(8):1158-66.
[4] Ismailov RM. New insights into the mechanism of Alzheimer's disease: A multidisciplinary approach . edn. Amazon Kindle, 2010.
[5] Fleminger S, Oliver DL, Lovestone S, Rabe-Hesketh S, Giora A. Head injury as a risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication. J Neurol Neurosurg Psychiatry 2003; 74(7):857-62.
[6] Teasdale GM, Nicoll JA, Murray G, Fiddes M. Association of apolipoprotein E polymorphism with outcome after head injury. Lancet 1997; 350(9084):1069-71.
[7] Chiang MF, Chang JG, Hu CJ. Association between apolipoprotein E genotype and outcome of traumatic brain injury. Acta Neurochir (Wien) 2003; 145(8):649-53; discussion 653-4.
[8] Blasko I, Beer R, Bigl M et al. Experimental traumatic brain injury in rats stimulates the expression, production and activity of Alzheimer's disease beta-secretase (BACE-1). J Neural Transm 2004; 111(4):523-36.
[9] Ismailov RM, Shevchuk NA, Schwerha J, Keller L, Khusanov H. Blunt trauma to large vessels: a mathematical study. Biomed Eng Online 2004; 3(1):14.
[10] Jen CJ, McIntire LV. Characteristics of shear-induced aggregation in whole blood. J Lab Clin Med 1984; 103(1):115-24.
[11] Wagner CT, Kroll MH, Chow TW, Hellums JD, Schafer AI. Epinephrine and shear stress synergistically induce platelet aggregation via a mechanism that partially bypasses VWF-GP IB interactions. Biorheology 1996; 33(3):209-29.
[12] Kwaan HC, Bongu A. The hyperviscosity syndromes. Semin Thromb Hemost 1999; 25(2):199-208.
[13] Mattson MP. Calcium as sculptor and destroyer of neural circuitry. Exp Gerontol 1992; 27(1):29-49.
[14] Khachaturian ZS. The role of calcium regulation in brain aging: reexamination of a hypothesis. Aging (Milano) 1989; 1(1):17-34.

Comment on Viewpoint Article - Con: Can neuropathology really confirm the exact diagnosis of dementia?

Kurt Jellinger — 2010-06-28T10:39:53Z

Analysing 1,677 cases with antemortem diagnosis of dementia from the National Alzheimer's Coordination Registry, Nelson et al [1] recently commented on those cases that fall outside the National Institute on Aging and Reagan Institute (NIA-RI) recommendations. 82.4% fell into diagnostic "boxes" within the rubric of the consensus recommendations. Two specific categories were considered: (1) "tangle-intensive" cases with the highest density of neurofibrillary tangles but only moderate density of neuritic plaques (9.4% of the overall) were considered more likely to be designated as "high likelyhood" that dementia was due to AD, whereas (2) "plaque-intensive" patients with high density of amyloid plaques and intermediary severity tangles (6.0% of total) were typically designated as "intermediate likelyhood". Unfortunately, both these categories appear not to be identical with the "tangle-dominant" type (TDD) (with 3- and 4-repeat tau pathology similar to NFTs in "classical" AD but often restricted to the limbic system, absence of neuritic plaques and no or very little amyloidosis) accouting for 5-7% of oldest-old demented [2-4], and the "plaque-predominant" type with abundant amyloid plaques, no or very little neuritic pathology restricted to the limbic system and lacking overt tangle formation, accounting for 3.5-8% of demented subjects aged 85+ years [5-7]. While Nelson et al's [1] "plaque-intensive" type may be similar to the "hippocampal" type of AD (neuritic Braak stages III/IV) with frequent neuritic plaques [8], the TDD phenotype appears to correspond to a recently described form with medial temporal lobe neurofibrillary tangles but no neuritic plaques accounting for 5.2% of an autopsy cohort of 502 elderly persons suggested to have pathogenetic aspects from AD [9]. Like the TDD patients, this group often lacked profound antemortem cognitive impairment (last MMSE scores 14-30 [9], while TDD patients had only mildly increased final MMSE scores compared to "classical" AD (mean 9.0 vs. 2.0) [2, 3], and "tangle-intensive" cases (Braak stage VI) encompassing 1.3% of Nelson et al's [1] demented cohort approximated those of severe AD. Despite these deviations concerning "atypical" AD cases, together with Nelson et al [1] one can conclude that consideration of the impact of frequent "mixed pathology" in aged persons in the diagnostic challenge [10], more exact categories and a better understanding of the pathology of early phases of the disease may be helpful for guiding neuropathologists in the diagnosis of AD.

References:
1. Nelson PT, Kukull WA, Frosch MP: Thinking outside the box: Alzheimer-type neuropathology that does not map directly onto current consensus recommendations. J Neuropathol Exp Neurol 2010, 69:449-454.
2. Jellinger KA, Attems J: Tangle dominant dementia. In Neuroscience Research Advances. Edited by Figueredo B, Meléndez F. Hauppauge, NY: Nova Science Publishers; 2009: 135-155
3. Jellinger KA, Attems J: Neurofibrillary tangle-predominant dementia: comparison with classical Alzheimer disease. Acta Neuropathol 2007, 113:107-117.
4. Bancher C, Jellinger KA: Neurofibrillary tangle predominant form of senile dementia of Alzheimer type: a rare subtype in very old subjects. Acta Neuropathol 1994, 88:565-570.
5. Terry RD, Hansen LA, DeTeresa R, Davies P, Tobias H, Katzman R: Senile dementia of the Alzheimer type without neocortical neurofibrillary tangles. J Neuropathol Exp Neurol 1987, 46:262-268.
6. Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J: The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology 2004, 62:1984-1989.
7. Jellinger KA: Criteria for the neuropathological diagnosis of dementing disorders: routes out of the swamp? Acta Neuropathol 2009, 117:101-110.
8. Mizutani T, Amano N, Sasaki H, Morimatsu Y, Mori H, Yoshimura M, Yamanouchi H, Hayakawa K, Shimada H: Senile dementia of Alzheimer type characterized by laminar neuronal loss exclusively in the hippocampus, parahippocampus and medial occipitotemporal cortex. Acta Neuropathol 1990, 80:575-580.
9. Nelson PT, Abner EL, Schmitt FA, Kryscio RJ, Jicha GA, Santacruz K, Smith CD, Patel E, Markesbery WR: Brains with medial temporal lobe neurofibrillary tangles but no neuritic amyloid plaques are a diagnostic dilemma but may have pathogenetic aspects distinct from Alzheimer disease. J Neuropathol Exp Neurol 2009, 68:774-784.
10. Jellinger KA, Attems J: Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropathol 2010, 119:421-433.