The majority of patients with Parkinson disease eventually develop dementia, but what pathology underlies this decline? In PD, as well as in dementia with Lewy bodies (DLB), intracellular aggregates composed primarily of α-synuclein gum up the specific dopaminergic neurons, but PD patients live with these Lewy bodies for many years before they experience cognitive losses. Intriguingly, scientists have found evidence of amyloid-β (Aβ) pathology in both Parkinson disease dementia (PDD) and DLB, suggesting a role for Aβ in these diseases. Now, two new papers firm up that idea. In the August 18 Neurology online, researchers led by Andrew Siderowf at the University of Pennsylvania, Philadelphia, report on the first longitudinal study to examine changes in the Alzheimer’s marker Aβ42 in the cerebrospinal fluid (CSF) of PD patients. They found that low levels of Aβ42 predicted significant cognitive decline within the next two years, hinting that Aβ pathology is involved in Parkinson’s dementia. Meanwhile, in the August 23 Lancet, scientists led by Murat Emre at Istanbul University, Turkey, describe the largest trial to date studying the efficacy of the N-methyl D-aspartate (NMDA) receptor antagonist memantine, which is approved for treatment of AD, in patients with PDD and DLB. Emre and colleagues found that memantine provides a moderate benefit to DLB patients. Together, these studies raise intriguing questions about the interrelatedness of these disorders, with implications for research, diagnosis, and treatment.

The importance of CSF Aβ as a biomarker has already been demonstrated in AD, with studies showing that in people with mild cognitive impairment, low CSF levels of Aβ and high levels of tau predict cognitive decline and conversion to AD (see, e.g., Hansson et al., 2006 and Shaw et al., 2009). Low CSF Aβ levels are thought to reflect the sequestration of Aβ into amyloid plaques. For PD patients, several cross-sectional studies have shown an association between cognitive impairment and CSF levels of Aβ and tau as well (see Mollenhauer et al., 2005; Bibl et al., 2006; Compta et al., 2009; Alves et al., 2010), but longitudinal data were missing.

To fill this gap, Siderowf and colleagues performed a prospective cohort study. They collected CSF from 45 Parkinson’s patients at baseline and again one year later, and measured levels of Aβ42, total tau, and phosphorylated tau. About half the patients also completed a two-year follow-up. The patients’ cognitive status was assessed at each visit using the Mattis Dementia Rating Scale, version 2 (DRS-2), which measures general cognitive ability. At the beginning of the study, Siderowf and colleagues found no association between the DRS-2 score and the levels of CSF biomarkers. Low CSF Aβ at baseline, however, did strongly correlate with a decline in the DRS-2 score over time, a relationship not seen for total tau or phosphorylated tau. Because other studies have identified a CSF Aβ42 level of 192 pg/mL or lower as a diagnostic cutoff for AD (see ARF related news story), Siderowf and colleagues analyzed their data with respect to this limit. They found that patients with an initial CSF Aβ level of 192 pg/mL or less declined about six points more per year on the DRS-2 scale than those with starting levels above 192 pg/mL. Subjects with CSF Aβ42 below the cutoff dropped into the dementia range within two years, while patients with initial Aβ levels above 192 remained cognitively normal two years later.

“To my knowledge, this is the first time that a biological marker has been able to give important prognostic information for PD patients,” Siderowf said. He added that the result still needs to be replicated in other Parkinson’s populations, which his group is now pursuing. Siderowf said they also plan to follow their patients to autopsy and correlate biomarker data with brain pathology to see if low CSF Aβ levels are indicative of amyloid plaques in PD patients, as might be predicted.

The CSF Aβ finding, Siderowf said, is just the beginning of scientists’ search for PD biomarkers. For example, coauthor Les Shaw at the University of Pennsylvania pointed out, the Michael J. Fox Foundation is sponsoring a large-scale hunt for biomarkers, the Parkinson’s Progression Markers Initiative (PPMI), which is patterned after the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

“We’ve seen an enormous focus in the last few years on AD [biomarkers],” said Douglas Galasko of the University of California San Diego. “This paper provides an added impetus to study biomarkers in Parkinson disease.” Galasko predicted that eventually researchers will use a panel of biomarkers to better understand the pathological events in PD, and he also emphasized the importance of combining biomarker information with imaging data from PD patients.

The correlation between Aβ levels and PD dementia raises the question of how similar the underlying AD and PDD pathologies might be, but the consensus among researchers in the field seems to be that it is too early to draw any conclusions. Siderowf said the data support the idea that there is a role for Alzheimer’s pathology in PD, but since phosphorylated tau did not show up in the CSF of Parkinson’s patients in their study, PD dementia probably has a distinct biochemical signature from AD he suggested. Galasko speculated on one possible mechanism for PD dementia: Aβ might be worsening α-synuclein pathology in PD patient brains, as has been seen to happen in transgenic mouse models (see ARF related news story on Masliah et al., 2001 and ARF related news story on Clinton et al., 2010). Another possibility, Galasko said, is that some patients with PD are independently developing AD. “Without additional characterization of the patients,” Galasko said, “it’s going to be quite hard to tell the difference between those two possibilities.”

Thomas Montine, of the University of Washington in Seattle, who has seen similar correlations with low CSF Aβ and cognitive decline in his PD patients (paper in press), said that it is not yet clear if the falling CSF Aβ levels in PD patients mean that amyloid plaques are forming. Studies using positron emission tomography (PET) have found that amyloid fibrils are common in patients with DLB, but much less prevalent in PDD (see Lippa et al., 2007 and Brooks, 2009). However, if amyloid pathology does turn out to drive PD dementia, Montine said, then “all of the therapeutic interventions that are under development for Aβ in AD may have relevance to patients with PDD.”

The Lancet paper provides an early hint of this possibility, as Emre and colleagues found some benefits for PDD and DLB patients from an approved AD drug. Their study included almost 200 volunteers, about half with PDD and the others with DLB, recruited from 30 centers around Europe. In a randomized, double-blind trial, subjects received either placebo or 20 mg/day memantine for 24 weeks. At the end of the trial, DLB patients who received memantine showed greater improvement than those who received placebo, on both the Alzheimer’s disease Cooperative Study (ADCS)-Clinical Global Impression of Change scores, and on neuropsychiatric-inventory scores that measure behavioral factors such as hallucinations, anxiety, depression, and eating disorders. There were no significant differences in cognitive test scores or ADCS-Activities of Daily Living scores between the treatment groups. Those with PDD did not show statistically significant changes in any tests.

These results stand in contrast to two previous smaller trials of memantine for Lewy body dementias in which the drug did show benefit for PDD. In a 22-week trial of 25 subjects, PDD patients who received memantine deteriorated when it was withdrawn, suggesting that the drug had been ameliorating the disease process (see Leroi et al., 2009), while a 24-week trial of 72 patients with PDD or DLB found that patients with either disorder showed improved Clinical Global Impression of Change scores while on memantine (see Aarsland et al., 2009).

Even 200 patients is a relatively small sample, considering there were two subgroups, Emre said, so it is possible their trial missed a PDD patient benefit. He noted that PDD subjects in their study did show some trends toward improvement, but the data did not reach statistical significance. Emre speculated that memantine might have worked better in the DLB population because these patients have been shown to have a higher amyloid burden than PDD patients, and therefore DLB might have more Alzheimer’s-like pathology than PDD. Despite the promising results of this trial, Emre said he thinks it is unlikely there will be a larger trial with memantine in the Lewy body patient population. Not only are such studies expensive, Emre said, but it will be difficult to find patients. Many people with PDD and DLB take the cholinesterase inhibitor rivastigmine, which is licensed for PDD and has been shown to have benefit for both Lewy body disorders. Rivastigmine would be a confounding factor in memantine trials, but because of the benefits of this medicine, “it will be difficult to suggest to [patients] that they should remain on placebo for six months,” Emre said. Instead of a larger trial, Emre suggested that the next logical move would be a meta-analysis of pooled data from the three memantine studies, to see if the results hold up in a larger group.

Stuart Lipton, University of California in San Diego, who is an author on memantine patents worldwide, said the benefits of the drug for Lewy body disorders appear relatively modest, but even small gains can mean a lot to patients and their families. For example, in Alzheimer’s trials of memantine, he said, some patients who had stopped recognizing family members began to recognize them again. Lipton said he is encouraged that three separate trials of memantine for Lewy body patients showed some benefit, but “what we’d all like to see is two Phase 3 trials that agree, and then we really have very firm evidence that a drug works.” Lipton also suggested that a combination therapy that includes anti-cholinesterase drugs such as rivastigmine or donepezil, and NMDA receptor antagonists such as memantine, might provide greater benefit for DLB and PDD patients than either drug alone, and should be tested.

One of the most important features of memantine, Lipton said, is that it is well tolerated by the brain, with few side effects. In a related paper in the August 18 Journal of Neuroscience, Lipton and colleagues show that memantine acts by blocking extrasynaptic glutamate receptor activity, while sparing normal synaptic activity, an idea that his lab has pursued for some time (see Chen et al., 1992 and ARF related news story on Okamoto et al., 2009). Extrasynaptic glutamate signaling has been shown to be toxic in animal models, and to contribute to protein misfolding, Lipton said, and they believe this aberrant signaling may be a common factor in every major neurodegenerative disease. Synaptic signaling, on the other hand, is crucial for normal brain functioning, and Lipton said the fact that memantine spares this activity may explain its lack of side effects. Lipton said that memantine also has an unusual uncompetitive mode of action, in which the drug works better when more agonist is present, i.e., when the disease is more severe. Because of this, the dosing of memantine is critical and has to be quite different for patients at different stages of the disease, Lipton said. Lipton said his group is working on a class of drugs with similar modes of action to memantine, and they now have a series of memantine derivatives in the pipeline called NitroMemantines that in preliminary results seem to be twice as effective as memantine itself.—Madolyn Bowman Rogers


  1. This interesting study strengthens the general association of β amyloid pathology with cognitive decline. The study is important since it both illustrates the importance of disturbed β amyloid metabolism in conditions other than Alzheimer disease (AD), and gives clues to the roots of cognitive decline in Parkinson disease (PD).

    Cognitive decline in PD was associated with low cerebrospinal fluid (CSF) Aβ1-42 at baseline, but not with total tau or phospho-tau levels. This suggests that brain amyloid pathology contributes to cognitive decline in PD. The findings may be viewed in relation to studies of brain amyloid pathology in normal aging. Brain amyloid accumulation is present in a high proportion of cognitive healthy elderly and in many elderly with stable mild cognitive impairment (1-5). Although this might represent cases of incipient AD, it also suggests individual differences in resistance to amyloid pathology. Concomitant PD pathology might aggravate the toxicity of amyloid, pushing patients over a critical threshold in the amyloid disease cascade. The mechanism behind this could be interactions between α-synuclein and amyloid, since these molecules promote each other’s respective accumulation and aggregation (6). In this regard, PD might be a force that drives age-associated subclinical amyloid pathology into clinical symptoms.

    To further understand these interesting associations, detailed studies are needed on interactions between α-synuclein and amyloid in vivo in humans. Follow-up investigations of the subjects in the current study would be valuable. Specifically, it would be interesting to know if amyloid pathology at baseline predicted biomarker measurements of neuronal degeneration at follow-up, such as CSF total tau or MRI findings of atrophy.


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    View all comments by Niklas Mattsson-Carlgren
  2. Amyloid-β is likely an intermediate in the development of dementia and neuronal cell death in Alzheimer disease and in some cases of Parkinson disease, whereas peroxynitrites may be the principal culprit. Through oxidation and nitration, peroxynitrites disrupt neurotransmissions and lead to a critical shortage of acetylcholine, which is involved in the retrieval of short-term memories. Polyphenols can be used to scavenge peroxynitrites and to partially reverse both peroxynitrite-mediated oxidation and nitration of proteins. The progression of certain types of dementia may thus not only be stopped, but partially reversed.


    . In vitro activity of the essential oil of Cinnamomum zeylanicum and eugenol in peroxynitrite-induced oxidative processes. J Agric Food Chem. 2005 Jun 15;53(12):4762-5. PubMed.

    . Protective capacities of certain spices against peroxynitrite-mediated biomolecular damage. Food Chem Toxicol. 2008 Mar;46(3):920-8. PubMed.

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News Citations

  1. Triple Confirmation: AD Footprint in CSF of Cognitively Normal People
  2. Aβ Abets α-Synuclein
  3. Triple Trouble: AD Mice Decline Faster With Lewy Bodies
  4. NMDA Receptors Play Good Cop, Bad Cop in Huntington’s Model

Paper Citations

  1. . Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 2006 Mar;5(3):228-34. PubMed.
  2. . Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann Neurol. 2009 Apr;65(4):403-13. PubMed.
  3. . Tau protein, Abeta42 and S-100B protein in cerebrospinal fluid of patients with dementia with Lewy bodies. Dement Geriatr Cogn Disord. 2005;19(2-3):164-70. PubMed.
  4. . CSF amyloid-beta-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia. Brain. 2006 May;129(Pt 5):1177-87. PubMed.
  5. . Cerebrospinal tau, phospho-tau, and beta-amyloid and neuropsychological functions in Parkinson's disease. Mov Disord. 2009 Nov 15;24(15):2203-10. PubMed.
  6. . CSF amyloid-beta and tau proteins, and cognitive performance, in early and untreated Parkinson's disease: the Norwegian ParkWest study. J Neurol Neurosurg Psychiatry. 2010 Oct;81(10):1080-6. Epub 2010 Jun 14 PubMed.
  7. . beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12245-50. Epub 2001 Sep 25 PubMed.
  8. . Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci. 2010 May 26;30(21):7281-9. PubMed.
  9. . DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology. 2007 Mar 13;68(11):812-9. PubMed.
  10. . Imaging amyloid in Parkinson's disease dementia and dementia with Lewy bodies with positron emission tomography. Mov Disord. 2009;24 Suppl 2:S742-7. PubMed.
  11. . Randomized controlled trial of memantine in dementia associated with Parkinson's disease. Mov Disord. 2009 Jun 15;24(8):1217-21. PubMed.
  12. . Memantine in patients with Parkinson's disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial. Lancet Neurol. 2009 Jul;8(7):613-8. PubMed.
  13. . Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. J Neurosci. 1992 Nov;12(11):4427-36. PubMed.
  14. . Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med. 2009 Dec;15(12):1407-13. PubMed.

External Citations

  1. Parkinson’s Progression Markers Initiative

Further Reading

Primary Papers

  1. . CSF amyloid {beta} 1-42 predicts cognitive decline in Parkinson disease. Neurology. 2010 Sep 21;75(12):1055-61. PubMed.
  2. . Memantine for patients with Parkinson's disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010 Oct;9(10):969-77. PubMed.
  3. . Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J Neurosci. 2010 Aug 18;30(33):11246-50. PubMed.