It is a dream of neurologists to cure degenerative diseases. The big brothers, Alzheimers’ and Parkinsons’ disease have always been a huge burden of the population but are now, in the millennium of increasing population age becoming a scourge of humanity. While everybody is acknowledging this, both PD1 and AD2 communities of clinician researchers and basic researchers are preparing to attack the problem fundamentally frequently unnoticed by the general neurology community.
How difficult it is to slow down the development of these diseases has been shown as many studies aiming at neuroprotection and disease modification have failed PD and AD.2, 3 There are several studies now in AD showing subtle signs for treatment efficacy in very early stages of the condition. Therefore attempts at treatment have to intervene very early – best in the stage before the clinical symptoms are encountered.
But what is needed to treat degenerative diseases at a presymptomatic stage? As these patients do not have symptoms a screening tool is mandatory to enrich the subgroup who can then further be phenotyped as presymptomatic AD or PD. Tests are needed which finally identify candidates carrying a >90% probability to develop PD or AD. This step has been significantly moved forward as epidemiologic data have proven the minimal-cognitive-impairment syndrome carrying a high risk to develop into AD and familial AD does exist. Further laboratory tests can identify the candidates which develop AD with a likelyhood above 90%. For PD the research criteria for prodromal PD have just been published4 and several validation studies are underway. I addition, REM-sleep behavioral disorder is a condition which results in PD at a very high percentage in PD and also genetic variants of PD with a high probability to convert are known. These populations may have the largest potential for therapeutic benefit.
Presymptomatic patients do not necessarily have clinical symptoms which can be followed and, hence, disease markers are needed which allow to monitor the effect of therapy. This is mainly imaging for AD and PD but also biopsies of innervated skin in the intestine or dermis may prove to serve this purpose.5
In terms of symptomatic therapy we have much to offer for patients with PD which can be successfully treated until the late stages of the disease while much less symptomatic improvement with medication is available for AD. But similar hope is for both diseases on drugs which can reduce the burden of pathological changes in the brain might this be β-Amyloid, Tau or α-Synuclein. Experimental drugs degrading these pathologic depositions in the brain and elsewhere or vaccination strategies to destroy these deposits immunologically are currently developed.
The paper selected as the EAN-paper of this month6 has elegantly used many of these new innovations for early AD to study the effects of a new human monoclonal antibody aducanumab in a mouse model mouse of AD and man. This antibody enters the brain and reduces β-amyloid- plaques which are one but not the only pathologic hallmark of AD. This has been shown in the mouse model and more importantly in patients with and without aducanumab using amyloid PET-imaging. The patients with prodromal or very early AD were receiving aducanumab as infusion monthly for a year. The clinical study was only exploratory as not sufficiently powered for efficacy. Surprisingly both clinical outcome measures, the clinical dementia rating-sum of boxes and the mini mental state examination showed a significant dose-dependent slowing of clinical progression while other dementia outcomes were not significant. Many patients developed dose- dependent amyloid-related imaging abnormalities which may indicate drug-related inflammatory response of the brain. Clearly the results of the currently ongoing two phase III studies need to be awaited before making any final conclusions.*
Despite the many limitations this approach, it is representing an excellent example how the interaction of basic and clinical research may use all the newly developed tools to identify and monitor prodromal disease and test the effect of drugs on possibly disease-related pathological markers. It is giving hope that we can finally treat neurodegenerative disease with such approaches.
*The paper is more extensively discussed in the paper of the month section of this edition of EAN-pages.
1. Brundin P, Atkin G, Lamberts JT. Basic science breaks through: New therapeutic advances in Parkinson’s disease. Movement disorders : official journal of the Movement Disorder Society 2015;30(11):1521-1527.
2. Winblad B, Amouyel P, Andrieu S, et al. Defeating Alzheimer’s disease and other dementias: a priority for European science and society. The Lancet Neurology 2016;15(5):455-532.
3. Kalia LV, Kalia SK, Lang AE. Disease-modifying strategies for Parkinson’s disease. Movement disorders : official journal of the Movement Disorder Society 2015;30(11):1442-1450.
4. Berg D, Postuma RB, Adler CH, et al. MDS research criteria for prodromal Parkinson’s disease. Movement disorders : official journal of the Movement Disorder Society 2015;30(12):1600-1611.
5. Doppler K, Volkmann J, Sommer C. Skin biopsies in the differential diagnosis of parkinsonism: are we ready for simplified protocols? Brain : a journal of neurology 2016;139(Pt 1):e5.
6. Sevigny J, Chiao P, Bussiere T, et al. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature 2016;537(7618):50-56.