CME

Are Hemoglobin Levels Tied to Long-Term Dementia Risk?

Disusun Oleh :
Inka Putri Kosita G4A019004

Pembimbing:
dr. Wahyu Djatmiko, Sp.PD, KHOM

SMF ILMU PENYAKIT DALAM

RSUD PROF. DR. MARGONO SOEKARJO
PURWOKERTO
2019
 LEMBAR PENGESAHAN

CME
Are Hemoglobin Levels Tied to Long-Term Dementia Risk?

Disusun oleh:
Inka Putri Kosita G4A019004

Diajukan untuk memenuhi syarat mengikuti Kepaniteraan Klinik di Bagian Ilmu

Penyakit Dalam RSUD Prof. Dr. Margono Soekarjo Purwokerto

Telah disetujui dan dipresentasikan

Pada Tanggal : Oktober 2019

Purwokerto, Oktober 2019

Pembimbing,

dr. Wahyu Djatmiko, Sp.PD, KHOM

 CME / ABIM MOC / CE
Are Hemoglobin Levels Tied to Long-Term Dementia Risk?
Authors:News Author: Megan Brooks; CME Author: Laurie Barclay, MDFaculty
and Disclosures
CME / ABIM MOC / CE Released: 9/13/2019

Valid for credit through: 9/13/2020 CM E / ABIM M OC / CE Releas ed: 9/13/201Valid for credi t throu gh: 9/13/2 02

Clinical Context
Low levels of hemoglobin are a major health concern worldwide and have been
associated with adverse outcomes including coronary heart disease, stroke, and
mortality. Dementia prevalence is expected to triple in future decades, particularly
in countries with the highest prevalence of anemia. Little is known about the
association of hemoglobin with risk for AD, but the iron-containing heme site of
hemoglobin binds to β-amyloid, and hemoglobin is often found within the plaques
and vascular amyloid deposits in the brains of patients with AD.

The goals of this analysis from the population-based Rotterdam Study by Wolters
and colleagues were to examine the long-term association of hemoglobin levels
and anemia with risk for dementia and to evaluate associated brain MRI findings.

Study Synopsis and Perspective

Abnormal hemoglobin levels -- both low and high -- are associated with an
increased risk of developing subsequent dementia, new research shows.

The latest results from the Rotterdam Study -- a large, longitudinal population-
based study -- show individuals with anemia were 41% more likely to develop
AD and 34% more likely to develop any dementia type compared with individuals
without anemia. The investigators also found that individuals with high
hemoglobin were also at greater risk of developing dementia.

"Low hemoglobin levels, including anemia, could directly lead to neuronal

damage due to reduced oxygen delivery, or via concomitant vascular or metabolic
changes, for example changes in binding to amyloid-beta-42, which is an
important marker of Alzheimer pathology," study investigator Frank J. Wolters,
PhD, department of epidemiology and neurology, Erasmus Medical Center,
Rotterdam, The Netherlands, told Medscape Medical News.
 "High levels of hemoglobin and hematocrit increase the risk of stroke, and may as
such contribute to the development of dementia. However, various other diseases
can give rise to erythrocytosis and these might contribute to dementia via other
ways, even though our results remained unchanged after excluding individuals
with these other common causes of erythrocytosis," he added.

The study was published online July 31 in Neurology.

 al sample, limiting generalizability.

Implications for Brain Health

 Serum hemoglobin was measured in 12,305 participants (mean age, 64.6±9.5
years; 58% women). A total of 1520 people developed dementia during a mean
follow-up of 12.1 years, 1194 of whom had AD.
 The results showed a U-shaped association between hemoglobin levels and
dementia (P =.005), such that both low and high hemoglobin levels were
associated with increased dementia risk.
 The hazard ratio was 1.29 (95% CI: 1.09, 1.52) for the lowest vs middle quintile
and 1.2 (95% CI: 1, 1.44) for the highest vs middle quintile.
 The overall prevalence of anemia was 6.1%, and anemia was associated with a
34% increased risk for dementia (hazard ratio (HR)=1.34 [95% CI: 1.11, 1.62])
and 41% increased for AD (HR=1.41 [95% CI: 1.15, 1.74]).
 The researchers also studied imaging markers of vascular brain disease, structural
connectivity, and cerebral perfusion in a subset of 5267 participants without
dementia who underwent brain MRI.
 Similar to dementia risk, volume of white matter hyperintensities (P =.03) and
structural connectivity (in particular, for mean diffusivity, P <.0001) were worse
in both the lower and upper ranges of hemoglobin levels. Mean diffusivity was
also higher, indicating worse structural connectivity, in individuals with anemia
than in patients without.
 Cerebral microbleeds were more common in the presence of anemia, and
hemoglobin levels inversely correlated to cerebral perfusion (P <.0001).
 "Given the potential implications for the burden of dementia globally, studies are
needed to identify biological substrates, potentially focusing around disturbances
in structural brain connectivity and cerebral blood flow regulation," wrote Dr
Wolters and colleagues.
 "Anemia is often under diagnosed and under treated, which may have detrimental
implications for brain health," Dr Wolters told Medscape Medical News;
"[h]owever, before we can use these findings to recommend interventions, it is
important that additional studies are done to establish whether hemoglobin is in
fact the culprit, or that, for example, concomitant vascular or metabolic changes
lead to increased dementia risk," he added.
Confirmatory Findings
Commenting on the findings for Medscape Medical News, Steven T. DeKosky,
MD, the Aerts-Cosper Professor of Alzheimer's Research at the University of
Florida College of Medicine and a fellow of the American Academy of
Neurology, said the study is "interesting and a strong confirmation of what we
have known for a while. However, these are much longer-term data and a larger
set of variables that aid in trying to determine possible mechanisms of action and
eliminate others, such as diseases that drive hematocrit up or down."

The study is also "noteworthy," said Dr DeKosky, "because it is a very large

population, followed for a long time, with a lot of careful thought about what
possible confounders or medical factors might cause some of the findings."

Also commenting for Medscape Medical News, Ashley I. Bush, MBBS, PhD,
director of the Melbourne Dementia Research Centre and professor of psychiatry
and neuroscience at University of Melbourne, Melbourne, Australia, said the
study is "very interesting and the results are consistent with findings we published
in a cross-sectional study of the Australia Imaging Biomarker and Lifestyle
(AIBL) study. It is exciting to see the phenomena we picked up a few years ago
being reflected in another important cohort."

Results to date, said Dr Bush, "support the likelihood that Alzheimer's disease
impacts on hemoglobin formation peripherally, and that hematological changes
impact of Alzheimer's disease and the risk of dementia.

"Clinically, the current finding underscore the importance of not using iron
supplements for treating anemia in older patients where there is no clear evidence
of iron deficiency. There is growing concern that higher brain iron levels are
associated with more aggressive disease in both AD and Parkinson's disease," said
Dr Bush.

"We do not know whether nutritional iron levels are associated with either
diseases, but the current paper highlights the need for a better understanding of the
mobilization of nutritional iron and the formation of hemoglobin in the risk for
these diseases," he added.

Members of the healthcare team should assess and monitor hemoglobin levels and
use of iron supplementation. Further research on anemia and the risk for dementia
should be explored by healthcare team members in collaboration to add to this
current body of research.

The study was supported by The Netherlands Cardiovascular Research Initiative;

Erasmus Medical Center; Erasmus University Rotterdam; The Netherlands
Organization for Scientific Research; The Netherlands Organization for Health
Research and Development; Research Institute for Diseases in the Elderly; The
Netherlands Genomic Initiative; Dutch Ministry of Education, Culture and
Science, Dutch Ministry of Health, Welfare and Sport; European Commission;
 Municipality of Rotterdam; The Netherlands Consortium for Healthy Aging; and
the Dutch Heart Foundation. Wolters, DeKosky, and Bush have disclosed no
relevant financial relationships.

Neurology. Published online July 31, 2019.[1]

Study Highlights
 The study sample consisted of 12,305 participants in the population-based
Rotterdam Study who were free of dementia at baseline and who underwent
testing of serum hemoglobin.
 Mean age was 64.6±9.5 years; 57.7% were women.
 Risk for dementia and AD (until 2016) were examined in relation to hemoglobin
and anemia.
 In a subset of 5267 participants without dementia who had brain MRI, the
investigators also studied the association of hemoglobin with vascular brain
disease, structural connectivity, and global cerebral perfusion.
 Dementia developed in 1520 participants (1194 with AD) during follow-up
(mean, 12.1 years).
 Hemoglobin levels showed a U-shaped association with dementia (P =.005), in
that low and high hemoglobin levels were associated with increased dementia risk
(HR for lowest vs middle quintile=1.29 [95% CI: 1.09, 1.52]; highest vs middle
quintile=1.2 [95% CI: 1, 1.44]).
 Anemia had an overall prevalence of 6.1%, which sharply increased with age to
~30% in the very elderly, and it was associated with a 34% increased risk for
dementia (95% CI: 11%, 62%) and for AD (41% [95% CI: 15%, 74%]).
 In the group that underwent brain MRI, there were similar U-shaped associations
of hemoglobin with white matter hyperintensity volume (P =.03) and with
structural connectivity (P <.0001 for mean diffusivity) but not with presence of
cortical and lacunar infarcts.
 Cerebral microbleeds were more common with anemia.
 Hemoglobin levels and cerebral perfusion were inversely correlated (P <.0001).
 The observed associations persisted after controlling for C-reactive protein and
other variables.
 According to their findings, the investigators concluded that low and high levels
of hemoglobin are associated with increased risk for dementia and AD, which
may be explained by differences in white matter structural connectivity, cerebral
perfusion, and potentially microbleeds.
 The findings warrant longitudinal (interventional) imaging studies to examine the
role of these MRI markers as potential mediators underlying dementia risk.
 If the association of hemoglobin with dementia is causal, it may have implications
for dementia burden worldwide, as long-term associations with anemia occurred
even in the low-normal range of hemoglobin.
 It is still unclear whether hemoglobin levels directly explain this increased risk
(eg, by reduced tissue oxygenation) or whether underlying or accompanying
vascular or metabolic changes, such as those involving iron and vitamins
B9 (folate) and B12 may explain the associations.
 Reduced oxygenation can cause hypoxia and subsequent inflammation harmful to
neurons.
 The tight correlation of hemoglobin and cerebral blood flow suggests a
compensatory mechanism to maintain cerebral oxygen delivery, which may be
essential if oxygen extraction is impaired and autoregulatory mechanisms fail
because of cerebral small vessel disease.
 A wide range of chronic conditions may accompany anemia, some of which, such
as iron deficiency and inflammation, are common and could contribute to
cognitive decline via pathways unrelated to hemoglobin.
 Clinical stroke did not explain the observed associations nor was there any
association between low hemoglobin and infarcts on brain MRI, suggesting more
subtle, chronic processes involved in cognitive decline.
 High hemoglobin may be harmful or associated with harmful factors, as lysis of
erythrocytes could elevate hemoglobin measurements in patients with functional
anemia and excess of free iron.
 In addition, erythrocytosis may occur secondary to systemic reductions in blood
oxygenation, often caused by smoking, heart failure, chronic obstructive
pulmonary disease, or chronic renal disease, all of which are risk factors for
dementia.
 Higher blood viscosity may also predispose to ischemia, but this study showed no
association of high hemoglobin with infarcts on MRI.
 Future research should examine whether these findings are attributable to high
viscosity, lower tissue oxygenation with very high levels of hematocrit, or higher
hematocrits in persons with microangiopathy.
 Study limitations include possible residual confounding (eg, by transport of iron
and B vitamins), but this was thought to be minimal; higher educational level and
greater use of lipid-lowering medication in the subset undergoing MRI; and Dutch
population predominantly of European descent, limiting
You are a member of the healthcare team for a 67-year-old woman seeking
lifestyle recommendations to improve health and longevity. On the basis of the
prospective cohort study of WHS participants by Lee and colleagues, which one
of the following statements about associations of number of steps per day and
stepping intensity with all-cause mortality among US women is correct?

Clinical Implications
Both low and high levels of hemoglobin were associated with increased long-term
risks for dementia and AD among the general population, according to an analysis
from the Rotterdam Study by Wolters and colleagues.

Members of the healthcare team should be aware that: If the association of

hemoglobin with dementia is causal, it may have implications for dementia
burden worldwide, as long-term associations with anemia occurred even in the
low-normal range of hemoglobin.

Implications for the Healthcare Team: Longitudinal studies are needed to identify
biological substrates underlying this association, focusing on disturbances in
structural brain connectivity and cerebral blood flow regulation.
Question 1 of 2
1. You are a member of the healthcare team for a 67-year-old man with low
hemoglobin. According to the analysis from the population-based Rotterdam
Study by Wolters and colleagues, which of the following statements about the
long-term association of hemoglobin levels and anemia with risk for dementia and
AD, as well as associated brain MRI findings, is correct?

Low, but not high, hemoglobin levels were associated with increased
dementia risk

Anemia was associated with a 34% increased risk for dementia (95% CI:
11%, 62%) and of AD (41% [95% CI: 15%, 74%])

There were significant U-shaped associations of hemoglobin with presence of

cortical and lacunar infarcts

Hemoglobin levels were directly correlated to cerebral perfusion (P <.0001)

Question 2 of 2
2. According to the analysis from the population-based Rotterdam Study by
Wolters and colleagues, which of the following statements about clinical
implications of the long-term association of hemoglobin levels and anemia with
risk for dementia and AD, as well as associated brain MRI findings, is correct?

The associations may be explained by differences in white matter structural

connectivity, cerebral perfusion, and potentially microbleeds

The study proves that low or high hemoglobin levels cause dementia and AD

Reduced tissue oxygenation with low hemoglobin levels is the only

explanation for increased dementia risk

Chronic conditions that may accompany anemia are unlikely to explain the
association, because their prevalence is too low