Published Ahead of Print on December 9, 2015 as 10.1212/WNL.

0000000000002268

EDITORIAL

Milk consumption and the risk of nigral

degeneration

Honglei Chen, MD, PhD In the era of genetic research for neurodegenerative
Karen Marder, MD,
diseases, less attention has been paid to epidemioloMPH
gists search for potential environmental risk factors
for Parkinson disease (PD). Epidemiologic evidence
suggests that cigarette smoking is associated with
Correspondence to
about 50% lower risk of PD1 and exposure to certain
Dr. Chen:
pesticides such as rotenone and paraquat is associated
chenh2@niehs.nih.gov
with doubled risk.2 Recent studies also suggest that

higher concentration of serum urate, an endogenous

Neurology 2016;86:12
antioxidant, is associated with a lower risk of PD.3
Compared with these observations, another epidemiologic finding has been largely neglected. Several prospective studies,47 including the Honolulu-Asia
Aging Study (HAAS),6 have reported that higher consumption of dairy products, or milk alone, was associated with higher risk for PD.
A new study in the current issue of Neurology8
may offer a potential clue that links these seemingly
unrelated epidemiologic findings. Using data from
the HAAS, Abbott et al.8 report that consumption
of more than 2 cups of milk per day in midlife was
associated with approximately 40% fewer neurons in
the ventrolateral, ventromedial, and dorsolateral
quadrants of the substantia nigra, as measured at
autopsy, among individuals who were followed longitudinally and never developed PD. This association
was observed only among nonsmokers. Higher milk
consumption was also associated with the detection of
heptachlor epoxide in the brains of decedents without
PD, again only in nonsmokers. Heptachlor is an
organochlorine insecticide that had been used in the
Hawaii pineapple industry for decades prior to 1980.
Contamination of milk with heptachlor, probably via
cattle feed, was identified in Hawaii in 19811982 as
part of routine state inspections.9 No one knows for
sure how long or widespread milk contamination was
present before it was detected.
The current study makes heptachlor contamination a plausible culprit for higher PD risk among frequent milk drinkers in HAAS. This study may not
offer a good explanation for the association of milk
or dairy consumption and PD in other cohorts,4,5,7

where evidence of milk contamination is lacking.

Another potential explanation for the milk and PD
relationship may be that milk consumption lowers
plasma urate,10 which in turn leads to a higher risk
for PD over time. However, serum uric acid concentration was not related to substantia nigra neuronal
density in the current study.
The HAAS was launched in 1991 as an extension
of the Honolulu Heart Program (HHP), which
enrolled 8,006 Japanese American men, aged 4568
years, from 1965 to 1968. A dietary assessment was
conducted at HHP enrollment using a 24-hour dietary recall. The mean age of the study population at
the time of the dietary assessment was 51.4 6 4.9
years. Death occurred on average at age 85.7 6 5.2
years, approximately 30 years after the assessment.
Neuropathologic assessment was conducted blinded
to clinical information. The HAAS has an exceedingly
long follow-up that allows examinations of midlife
risk factors for late-life neurodegenerative diseases.
More importantly, the rich data collection over time
on diet, lifestyle, environmental factors, prodromal
symptoms (e.g., sense of smell), and brain pathology
has enabled the HAAS to make a number of important contributions to our understanding of the natural history and etiology of PD.
Although the results are exciting, they should be
interpreted within context. First, the accelerated neuron loss was observed only among nonsmokers who
drank more than 2 cups of milk per day. The sample
size is relatively small (n 5 12 for this category), and
there was minimal or no neuron loss for nonsmokers
who drank less than 2 cups of milk per day. Therefore
the possibility of chance association cannot be
excluded. In addition, milk consumption was assessed
only once at enrollment, and we have to assume that
this measurement represented participants dietary
habits over time. Further, it is unclear whether milk
consumption is related to incidental Lewy bodies or
prodromal symptoms, such as the sense of smell,
among individuals without clinical PD. Affirmative
findings would strengthen the authors claim that

See page XXX

From the Epidemiology Branch (H.C.), National Institute of Environmental Health Sciences, Research Triangle Park, NC; and the Department of
Neurology (K.M.), College of Physicians and Surgeons, Taub Institute for Research on Alzheimers Disease and the Aging Brain, Columbia
University, New York, NY.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial.
2015 American Academy of Neurology

2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

milk consumption is an early to midlife risk factor for

PD. Finally, although contamination of milk with
heptachlor is a reasonable explanation for the findings, the study did not directly show that the brain
heptachlor was from milk rather than from other
sources.
Nevertheless, this study sets an excellent example
of how epidemiologic studies can contribute to the
search for causal mechanisms underlying PD. It
further challenges others to adapt existing cohorts
with extensive nongenetic data for PD research, a
cost-effective approach. It also challenges ongoing
large clinical studies of PD to collect environmental
data so they are better able in the future to address
critical questions such as these. Brain donation should
also be considered in these valuable cohorts. This lifecourse approach to unveiling the complicated process
of neurodegeneration should be encouraged.
ACKNOWLEDGMENT
The authors thank Dr. Freya Kamel for suggestions on the editorial.

STUDY FUNDING
No targeted funding reported.

DISCLOSURE
Dr. Chen is supported by the Intramural Research Program of the NIH,
the National Institute of Environmental Health Sciences. He serves on
the editorial boards of the American Journal of Epidemiology, International
Journal of Molecular Epidemiology and Genetics, and the American Journal
of Neurodegenerative Disease. Dr. Marder receives research support from
the NIH 1UL1 RR024156-01 (Director PCIR), PO412196-G (Co-I),
the Parkinson Disease Foundation, Huntingtons Disease Society of
America, the Parkinson Study Group, CHDI, the Michael J. Fox

Neurology 86

Foundation, and TEVA. She received compensation for participating

on the steering committee for U01NS052592. Go to Neurology.org
for full disclosures.

REFERENCES
1. Chen H, Huang X, Guo X, et al. Smoking duration,
intensity, and risk of Parkinson disease. Neurology 2010;
74:878884.
2. Tanner CM, Kamel F, Ross GW, et al. Rotenone, paraquat, and Parkinsons disease. Environ Health Perspect
2011;119:866872.
3. Weisskopf M, OReilly E, Chen H, Schwarzschild M,
Ascherio A. Plasma urate and risk of Parkinsons disease.
Am J Epidemiol 2007;166:561567.
4. Chen H, OReilly E, McCullough ML, et al. Consumption of dairy products and risk of Parkinsons disease. Am J
Epidemiol 2007;165:9981006.
5. Chen H, Zhang SM, Hernan MA, Willett WC, Ascherio A.
Diet and Parkinsons disease: a potential role of dairy products in men. Ann Neurol 2002;52:793801.
6. Park M, Ross GW, Petrovitch H, et al. Consumption of
milk and calcium in midlife and the future risk of Parkinson disease. Neurology 2005;64:10471051.
7. Kyrozis A, Ghika A, Stathopoulos P, Vassilopoulos D,
Trichopoulos D, Trichopoulou A. Dietary and lifestyle
variables in relation to incidence of Parkinsons disease
in Greece. Eur J Epidemiol 2013;28:6777.
8. Abbott RD, Ross GW, Petrovitch H, et al. Midlife milk
consumption and substantia nigra neuron density at death.
Neurology 2016;86:xxxx.
9. Smith RJ. Hawaiian milk contamination creates alarm: a sour
response by state regulators. Science 1982;217:137140.
10. Choi HK, Liu S, Curhan G. Intake of purine-rich foods,
protein, and dairy products and relationship to serum levels of uric acid: the Third National Health and Nutrition
Examination Survey. Arthritis Rheum 2005;52:283289.

February 9, 2016

2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Milk consumption and the risk of nigral degeneration

Honglei Chen and Karen Marder
Neurology published online December 9, 2015
DOI 10.1212/WNL.0000000000002268
This information is current as of December 9, 2015
Updated Information &
Services

including high resolution figures, can be found at:

http://www.neurology.org/content/early/2015/12/09/WNL.0000000000
002268.full.html

Subspecialty Collections

This article, along with others on similar topics, appears in the

following collection(s):
Cohort studies
http://www.neurology.org//cgi/collection/cohort_studies
Dementia with Lewy bodies
http://www.neurology.org//cgi/collection/dementia_with_lewy_bodies
Parkinson's disease/Parkinsonism
http://www.neurology.org//cgi/collection/parkinsons_disease_parkinso
nism

Permissions & Licensing

Information about reproducing this article in parts (figures,tables) or in

its entirety can be found online at:
http://www.neurology.org/misc/about.xhtml#permissions

Reprints

Information about ordering reprints can be found online:

http://www.neurology.org/misc/addir.xhtml#reprintsus

Neurology is the official journal of the American Academy of Neurology. Published continuously since
1951, it is now a weekly with 48 issues per year. Copyright 2015 American Academy of Neurology. All
rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.