Why do only some people with Parkinson’s disease decline cognitively? Scientists have proposed various theories, including that coincident Alzheimer’s pathology is to blame. Researchers led by Joseph Winer and William Jagust at the University of California, Berkeley, tested this by measuring amyloid and tau levels in vivo with PET. In the December 11 JAMA Neurology, they reported that PD patients with mild cognitive impairment had no more tau tangles on average than did cognitively normal PD patients or healthy controls. “From this study and others, there is converging evidence that tau pathology does not relate to the cognitive decline in Parkinson’s,” Winer said. The study excluded people with Parkinson’s disease dementia.
- Alzheimer’s pathology does not explain mild cognitive impairment in PD.
- The culprit could be cortical α-synuclein, but testing this will require a PET tracer.
- It remains possible that co-morbid AD pathology causes PD dementia.
Other researchers found the data intriguing. “The current thinking is that Alzheimer’s pathology, i.e. tau and amyloid, is the driving force behind cognitive deficits, even in people without clinical Alzheimer’s disease. This study… shows that the reality is more sophisticated and nuanced,” M. Arfan Ikram at Erasmus Medical Center in Rotterdam, the Netherlands, wrote to Alzforum.
Parkinson’s disease is primarily a movement disorder marked by aggregates of α-synuclein, but over time a majority of patients go on to develop cognitive problems or dementia as well (Aarsland et al., 2003). Because tau tangles correlate with cognitive decline in Alzheimer’s, researchers wonder if the same holds true in Parkinson’s. The evidence has been mixed. Two studies suggested this was the case for people with PD dementia or dementia with Lewy bodies, but another reported little tau pathology in PD patients with mild cognitive impairment, and no relationship between tau PET signal and cognition (Mar 2013 conference news; Sep 2016 news; Hansen et al., 2017). None of these in vivo studies included amyloid imaging, leaving it unclear whether the PD patients also had AD.
Winer and colleagues measured amyloid using PiB and tau with AV-1451, and administered several cognitive and neuropsychological tests. They recruited 29 PD patients who were being treated at the University of California, San Francisco; 15 of them were cognitively healthy and 14 had mild cognitive impairment. The researchers compared them with 49 healthy controls enrolled in the Berkeley Aging Cohort Study.
The scans turned up little evidence of AD pathology in Parkinson’s. Only about 20 percent of PD patients had a positive amyloid scan, as compared to about half of the control group. Age may explain this difference, because amyloid pathology incidence increases with age and the members of the PD cohort were younger than controls, with an average age of 66 versus 74. Among six amyloid-positive PD patients, only one was cognitively impaired. At least for the other 13 PD patients with cognitive problems, something besides AD must be to blame, Winer noted.
In the whole cohort, tau pathology correlated with age and with amyloid status. Thus, among the PD patients, only the six with positive amyloid scans had elevated tau. As a group, PD patients with MCI bound the same average amount of tau tracer as did cognitively normal PD and amyloid-negative controls, while amyloid-positive controls had an overall elevated tau PET signal.
Importantly, tau accumulation followed the Braak pattern of cortical distribution seen in normal aging and AD. This implies it was not a direct consequence of α-synuclein pathology, which occurs predominantly in one location in early PD, the substantia nigra. “In our PD patients, AD pathology develops in the same way as it does in normal aging, and does not explain their cognitive impairment,” Winer concluded.
What does explain it? Possibilities include α-synuclein pathology that spreads into the cortex, cerebrovascular disease, or a loss of dopamine signaling. Lending weight to the first idea, Tiago Outeiro at the University Medical Center, Göttingen, Germany, recently reported that α-synuclein oligomers interact with cellular prion protein to harm synapses in mouse models of synucleinopathy (Ferreira et al., 2017). Other research has found that cognitive decline may even precede motor symptoms in PD, again hinting that cognitive problems could stem from the α-synuclein pathology intrinsic to the disease (Sep 2017 news). Testing this idea will require PET tracers for aggregated α-synuclein, which are under development (May 2017 conference news). “That’s the key missing piece to the puzzle,” Winer said.
At the same time, it remains possible that co-morbid Alzheimer’s pathology leads to dementia in PD, Winer noted. He plans to follow this PD cohort to see if those who accumulate amyloid go on to develop dementia. Kejal Kantarci at the Mayo Clinic in Rochester, Minnesota, suggested that the AD pathology seen in the six PD patients in this study might not yet have reached the threshold required to affect cognition (see comment below).
Others said the jury is still out on the effect of tau pathology. Allan Hansen at Aarhus University, Denmark, noted that PD patients might have a lower tolerance for tau pathology than healthy controls do because they already carry a heavy pathological burden (see comment below). Animal studies have found that some strains of aggregated α-synuclein can seed tau deposits, suggesting there could be an interaction in some people (Jul 2013 news). Notably, the tau tracer used in this study, AV-1451, detects only the paired helical filaments that characterize AD tau tangles, leaving open the possibility that other types of tau pathology might be present in people with PD.—Madolyn Bowman Rogers
- Dementia in Movement Disorders: What Causes It?
- Tau Deepens Cognitive Trouble in Lewy Body Diseases
- Cognitive Decline an Early Warning of Parkinson’s Disease?
- α-Synuclein Antibodies Enter Phase 2, Sans Biomarker
- An Extra Strain on the Brain—α-Synuclein Seeds Tau Aggregation
- Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sørensen P. Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol. 2003 Mar;60(3):387-92. PubMed.
- Hansen AK, Damholdt MF, Fedorova TD, Knudsen K, Parbo P, Ismail R, Østergaard K, Brooks DJ, Borghammer P. In Vivo cortical tau in Parkinson's disease using 18F-AV-1451 positron emission tomography. Mov Disord. 2017 Jun;32(6):922-927. Epub 2017 Mar 3 PubMed.
- Ferreira DG, Temido-Ferreira M, Miranda HV, Batalha VL, Coelho JE, Szegö ÉM, Marques-Morgado I, Vaz SH, Rhee JS, Schmitz M, Zerr I, Lopes LV, Outeiro TF. α-synuclein interacts with PrP(C) to induce cognitive impairment through mGluR5 and NMDAR2B. Nat Neurosci. 2017 Nov;20(11):1569-1579. Epub 2017 Sep 25 PubMed.
- Winer JR, Maass A, Pressman P, Stiver J, Schonhaut DR, Baker SL, Kramer J, Rabinovici GD, Jagust WJ. Associations Between Tau, β-Amyloid, and Cognition in Parkinson Disease. JAMA Neurol. 2018 Feb 1;75(2):227-235. PubMed.