This document presents an overview of a presentation on the association between long-term exposure to lithium in drinking water and the incidence of dementia. The presentation includes background on lithium's neuroprotective mechanisms and related studies. It then summarizes a large nationwide nested case-control study from Denmark that found a non-linear association between higher long-term lithium exposure through drinking water and lower incidence of dementia. The study used health registry data and estimated lithium levels in municipal drinking water to assess over 73,000 cases of dementia and 733,000 controls. It controlled for potential confounding factors and found lower median lithium exposure in cases compared to controls.
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JOURNAL CLUB - Association of Lithium in Drinking Water With the Incidence of Dementia
1. Presenter
Dr Rachit Sharma
Junior Resident (Psychiatry)
Armed Forces Medical College,
Pune
Total slides – 58
Moderator
Dr VS Chauhan
Assoc Prof (Psychiatry)
Armed Forces Medical College,
Pune
2. Overview
INTRODUCTION
• Background
• Related studies
ARTICLE
• Aim and Objectives
• Material and Methods
• Statistical Methods
• Results
• Discussion
• Strengths & Limitations
• Critique
2
4. Processing of amyloid precursor
protein
Pan Y, Khalil H, A Nicolazzo J. The Impact of Docosahexaenoic Acid on Alzheimer’s Disease: Is There a Role of
the Blood-Brain Barrier?. Current clinical pharmacology. 2015 Aug 1;10(3):222-41.
Neuronal function and
cerebral development
5. Background: Neuro-protective
effects of Lithium
1. Inhibition of GSK-3β, an enzyme linked to apoptosis
induced by various neural insults
2. Induction of Brain derived neurotrophic factor
(BDNF), which plays a key role in neuronal
development, plasticity, and survival
3. Increased expression of vascular endothelial growth
factor (VEGF), which induces neuronal proliferation
and neurovascular remodeling
5
Sadock BJ, Sadock VA, Pedro Ruiz. Comprehensive Textbook of Psychiatry.LW&W. 10th edi. 2018.
6. Background: Neuro-protective
effects of Lithium
4. Inhibition of NMDA receptor-mediated
calcium influx and downstream apoptotic
pathways, resulting in decreased glutamate
mediated excitotoxicity
5. Inhibition of phosphoinositol phosphatase
and regulation of apoptosis, a critical process
for neuronal survival and functioning
6. Induce autophagy (enhanced clearance of
toxic cellular substrates)
6
Sadock BJ, Sadock VA, Pedro Ruiz. Comprehensive Textbook of Psychiatry.LW&W. 10th edi. 2018.
7. Amyloid cascade hypothesis
Diniz BS, Machado-Vieira R, Forlenza OV. Lithium and neuroprotection: translational evidence and implications for
the treatment of neuropsychiatric disorders. Neuropsychiatric disease and treatment. 2013;9:493.
8. Mechanisms of action of lithium
Diniz BS, Machado-Vieira R, Forlenza OV. Lithium and neuroprotection: translational evidence and implications for
the treatment of neuropsychiatric disorders. Neuropsychiatric disease and treatment. 2013;9:493.
10. Mechanisms of action of lithium
Diniz BS, Machado-Vieira R, Forlenza OV. Lithium and neuroprotection: translational evidence and implications for
the treatment of neuropsychiatric disorders. Neuropsychiatric disease and treatment. 2013;9:493.
12. Related Study 1
Aim: To evaluate the effect of long-term lithium
treatment on cognitive and biological outcomes
in people with amnestic mild cognitive
impairment (aMCI)
12
13. Related Study 1
Method- Forty-five participants with aMCI were
randomised to receive lithium (0.25–0.5 mmol/l)
( n = 24) or placebo ( n = 21) in a 12-month,
double-blind trial
Results –significant decrease in CSF concentrations of
P-tau ( P = 0.03) and better performance on the cognitive
subscale and in attention tasks
Overall tolerability of lithium was good and the
adherence rate was 91%
13
14. Related Study 2
14
Aim: To summarize the current understanding of
lithium benefits in trace or low doses in dementia
prevention and for other behavioral or medical
benefits
16. Related Study 2
Methods –systematic review identified 24 clinical,
epidemiological, and biological reports that met inclusion
criteria of assessing lithium in standard or low doses
Results-Lithium, in both standard and trace doses,
appears to have biological benefits for dementia, suicide,
and other behavioral outcomes
16
17. Related Study 3
Aim: To investigate whether treatment with
lithium in patients with mania or bipolar
disorder is associated with a decreased rate
of subsequent dementia
17
18. Related Study 3
Methods – Retrospective cohort study from 01 Jan
95 to 31 Dec 05
Outcome - Diagnosis of dementia with the number
of prescriptions of lithium, anticonvulsants,
antidepressants, and antipsychotics
Results- Continued use of lithium was associated
with a decreased rate of dementia when
compared to anticonvulsants, antidepressants or
antipsychotics
18
20. JAMA Psychiatry
1. Since 1919
2. Impact Factor 2017 – 16.642
3. SJR 2017 – 8.067
4. Rank - 01/ 525 Psychiatry journals
5. Editor in chief-
• Dr Dost Öngür M.D. Ph.D.
• Professor of Psychiatry and Chief of the Psychotic disorders
wing, McLean Hospital, Harvard University
20
http://www.scimagojr.com/journalrank.php?category=2738&area=2700&year=2017
21. Lead Author
21
Dr. L V Kissing, MD
Professor
Psychiatric centre,
University of Copenhagen
Copenhagen (Denmark)
Publications – 250+
Areas of interest – Bipolar disorder, Psychiatric
epidemiology
22. Research Question
• Is a higher Lithium level in drinking water
associated with a decreased incidence of
Dementia?
22
23. Aim
To explore the association between long term
exposure of lithium in drinking water and the
incidence of dementia
23
24. Objective
To investigate whether the incidence of
dementia in the general population varies with
long-term exposure to microlevels of lithium in
drinking water
24
26. Material and Methods
• Study Population - Danish population
• Nature of Study
– Nationwide, Population based
– Nested Case – Control study
• Period of Study - 01 Jan 1995 – 31 Dec 2013
• Nature of data – Individualized longitudnal
data
26
27. Material and Methods
• Source of Data
1. Unique personal identification number of
residents
2. Statistics Denmark (Data on municipality
of residence for 28 years; 1986 - 2013)
3. Danish national patient register (19 years;
1995 -2013 )- OPD & IPD
4. Danish psychiatric central research register
5. Danish register of cause of death 27
31. Material and Methods
• Data : Selection of cases
–All patients with a hospital contact, with
diagnosis of dementia as an inpatient or
outpatient (ICD-10 codes F 00-09 and G
30.0-30.9)
–From 1 January 1995 to 31 December 2013
–Age 50 - 90 years
–Date of first time diagnosis – Index date
31
32. Material and Methods
• Data : Selection of controls
–Selected from a random sample of
registered persons in the Danish population
as on 01 Jan 1995 (15,00,000)
–For each patient of dementia- 10 randomly
selected controls from age and sex matched
subpopulation
–Not having dementia at the index date of
the patient with dementia
32
33. Exclusion criteria
1. Patients in the registers with a diagnosis of
dementia before entry into the study
2. No information on municipality of residence
between 1986 and the index date
33
34. Lithium exposure assessment
1. Drinking water samples from 151 waterworks
taken from 2009 to 2010 and 2013
2. Kriging interpolation method -
– A time constant mean lithium level was
calculated
– Lithium level in drinking water for the entire
country was estimated (275 municipalities)
3. Alternative interpolation method - Inverse
distance weighing was used for confirmation
34
35. Lithium exposure assessment
4. Municipality to which the home address of a
study participant belonged was obtained for
all years from 1986 to the index date
5. As per addresses, Participant specific mean
level of lithium in drinking water was
computed for all study participants
35
37. Statistical Analysis
1. Distribution of mean lithium exposure in
drinking water (04 groups) was compared
between cases and controls
2. Incidence rate of dementia in both the groups
was estimated by cox proportional hazards
model and IRR was calculated
3. Association between mean exposure to
Lithium in drinking water and IRR of dementia
was analysed by using restricted cubic splines
37
39. Results
• Cases (Diagnosis of Dementia)–
– 74,100 (-0.30 %) 73,731
• Median age – 80.3 yrs ( 74.9 – 84.6 yrs)
• Controls
– 7,40,100 (- 0.49%) 7,33,653
39
Male 28, 971
Female 44, 760
Participants Age group
9038 (12.3%) 50 -70 years
26 420 (35.8%) 70 - 80 years
38 273 (51.9%) 80 to 90 years
40. Results
• Mean (SD) lithium level in drinking water -
11.6 (6.8) μg/L
• Range - 0.6μg/L (western Denmark) to
30.7μg/L (eastern Denmark)
40
41. Results
• The distributions of the mean lithium
exposure were statistically significantly
different among patients with a diagnosis of
dementia and among controls P < .001
41
Patients Median - 11.5 μg/L
IQR - 6.5-14.9 μg/L
Controls Median - 12.2 μg/L
IQR - 7.3-16.0 μg/L
45. Discussion
A non-linear association was found between
higher, long-term lithium exposure from
drinking water and lower incidence of
dementia
45
46. Strengths (as per author)
First nation wide, population based nested
case-control study exploring association
between long term exposure of lithium in
drinking water and the incidence of dementia
46
47. Limitations (as per author)
1. Variability in diagnosing dementia especially
during early stages (due to accessibility to health
care services in different regions)
2. Confounding factors - Unobserved
environmental and social care factors related
3. Chances of long term changes in lithium
levels in drinking water (1986 – 2009)
47
48. My comments (Limitations)
1. Variability in patient’s presentation
2. Confounding factors like education,
socioeconomic, and multiple health factors
and medical comorbidities were not
considered
3. Low levels of lithium exposure Increased
the risk of dementia (Neurodegenerative
disorder) ?
48
49. My comments
4. Latitudnal attriibutes were not considered.
Low latitude, more southern residence
Lower risk of dementia
49
Russ TC, Gatz M, Pedersen NL, Hannah J, Wyper G, Batty GD, Deary IJ, Starr JM. Geographical variation in
dementia: examining the role of environmental factors in Sweden and Scotland. Epidemiology (Cambridge,
Mass.). 2015 Mar;26(2):263.
51. 51
Criteria Yes
(2)
Partial
(1)
No
(0)
NA
5 Results reported in sufficient detail
(Participants/descriptive data/outcome
data/main results) ?
√
6 Statistical method described/justified &
appropriate?
√
7 Conclusions supported by the results
(with limitations/ interpretation/
generalisability)?
√
8 Controlled for confounding? √
9 Outcome measures well-defined and
robust to measure bias?
Means of assessment reported
√
52. Critique
• Clear message: 3/5
• Contribution to literature: 3/5
• Potential to change thinking or practice: 2/5
• Quality of manuscript: 3/5
53. Take home message
1. Available literature – Lithium does help in
improving cognition by various
neuroprotective mechanisms
2. Prospective observational studies and
multicentric experimental studies with a
larger sample are warrant to reach a definite
conclusion
53
Good afternoon everyone. Today I ll be presenting a journal article which was published online in Oct 2018.
the dementia process likely begins biologically at least a decade before the first clinical signs, with the largest biological changes occurring within the fifth decade of life. During this age threshold about 40% of individuals at high risk for AD (e.g. apoE4 carriers) have senile plaques, despite the absence of clinical signs of dementia (Schrauzer and De Vroey, 1994). Thus, true biological prevention may need to begin in individuals before even the earliest clinical phase of dementia In animal studies, when lithium has been compared at lower versus higher concentrations, neuronal viability seems to be enhanced with any concentration of lithium. generally do not measure lithium levels below 0.2. But, in some of the available animal research, even concentrations below 0.2 lead to enhanced neuronal viability (Hashimoto et al., 2002)
Non-amyloidogenic and amyloidogenic processing of amyloid precursor protein (APP). During non-amyloidogenic processing, the
α-secretase cleaves APP releasing sAPPα and an 83-residue carboxy-terminal fragment C83. C83 subsequently undergoes regulated
intramembranous proteolysis by γ -secretase, a protein complex with presenilin 1 at its catalytic core, liberating extracellular p3 and the
amyloid intracellular domain (AICD). Amyloidogenic processing is initiated by a β-secretase, releasing sAPPβ. The retained C99 is digested
by γ-secretase, resulting in Aβ and AICD
6. Induce autophagy - via inositol monophosphatase (IMPase) inhibition, which leads to free inositol depletion and reduced myo-inositol-1,4,5-triphosphate (IP3) levels
The mechanism and targets of lithium against Alzheimer’s disease-related pathology. (A) The main components of the amyloid-β cascade hypothesis of Alzheimer’s disease pathophysiology. (B) The possible targets and effects of lithium in the amyloid-β cascade. Notes: Red arrows: activation of pathways; blue arrows: inhibition of pathways. Abbreviation: GSK-3β, glycogen synthase kinase-3β.
The mechanism and targets of lithium against Alzheimer’s disease-related pathology. (A) The main components of the amyloid-β cascade hypothesis of Alzheimer’s disease pathophysiology. (B) The possible targets and effects of lithium in the amyloid-β cascade. Notes: Red arrows: activation of pathways; blue arrows: inhibition of pathways. Abbreviation: GSK-3β, glycogen synthase kinase-3β.
Putative mechanisms of action of lithium. (A) Lithium inhibits GSK-3β activity by dislocating magnesium ions from the catalytic core (direct pathway). Lithium can also inhibit GSK-3β activity by increasing the phosphorylation of Ser9 residue. This is secondary to the lithium-induced activation of kinases (eg, Akt- SERINE THREONINE KINASE) and/or inhibition of phosphatases (eg, protein phosphatase-2) (indirect pathway). (B) Lithium increases autophagy by inhibiting the activity of IMP and IPP and, consequently, reducing IP3 levels Notes: Red color: active enzyme; blue color: inactive enzyme.
Abbreviations: BDNF, brain-derived neurotrophic factor; GSK-3β, glycogen synthase kinase-3β; IMP, inositol monophosphatase; IP3, inositol triphosphate; IPP, inositol polyphosphate 1-phosphatase; Ser9, serine-9; VEGF, vascular endothelial growth factor.
(C) Lithium can also directly stimulate the production of neurotrophic factors BDNF and VEGF by activation of gene expression in the nucleus.
-- concentration of brain-derived neurotrophic factor (BDNF)is increased after only 10 weeks of lithium treatment inmild AD (Leyhe et al., 2009).
of the Alzheimer’s Disease Assessment Scale
standard doses of lithium may have cognitive benefits for dementia prevention, and, although trace levels have not been studied for that outcome, trace lithium levels may have a range of other medical/behavioral benefits
Monthly, peer-reviewed medical journal published by the American Medical Association.
The Archives of Neurology & Psychiatry began publication in 1919 and, in 1959, became 2 separate journals: Archives of Neurology and Archives of General Psychiatry. In 2013, their names changed to JAMA Neurology and JAMA Psychiatry, respectively.
Impact Factor - The 2013 impact factor of a journal would be calculated as follows:
2013 impact factor = A/B.
where:
A = the number of times that all items published in that journal in 2011 and 2012 were cited by indexed publications during 2013.
B = the total number of "citable items" published by that journal in 2011 and 2012. ("Citable items" for this calculation are usually articles, reviews, proceedings, or notes; not editorials or letters to the editor).
Impact Factor The IF is the frequency with which articles from a journal published in the past two years have been cited in a particular year.
number of current year citations total number of articles published in the two years
Calculated each year by the Institute for Scientific Information (ISI). a measure reflecting the yearly average number of citations to recent articles published in that journal. It is frequently used as a proxy for the relative importance of a journal within its field; journals with higher impact factors are often deemed to be more important than those with lower ones. The impact factor was devised by Eugene Garfield, the founder of the Institute for Scientific Information. Impact factors are calculated yearly starting from 1975
Niall trained in medicine at Oxford University and subsequently on the University College London psychiatry rotation. His interests include suicide research, trauma, old age psychiatry, and social and transcultural aspects of mental health
Impact Factor - The 2013 impact factor of a journal would be calculated as follows:
2013 impact factor = A/B.
where:
A = the number of times that all items published in that journal in 2011 and 2012 were cited by indexed publications during 2013.
B = the total number of "citable items" published by that journal in 2011 and 2012. ("Citable items" for this calculation are usually articles, reviews, proceedings, or notes; not editorials or letters to the editor).
Impact Factor The IF is the frequency with which articles from a journal published in the past two years have been cited in a particular year.
number of current year citations total number of articles published in the two years
Calculated each year by the Institute for Scientific Information (ISI). a measure reflecting the yearly average number of citations to recent articles published in that journal. It is frequently used as a proxy for the relative importance of a journal within its field; journals with higher impact factors are often deemed to be more important than those with lower ones. The impact factor was devised by Eugene Garfield, the founder of the Institute for Scientific Information. Impact factors are calculated yearly starting from 1975
SJR is a measure of scientific influence of journals that accounts for both the number of citations received by a journal and the importance or prestige of the journals where such citations come from. It measures the scientific influence of the average article in a journal, it expresses how central to the global scientific discussion an average article of the journal is.
Psychiatric or non psychiatric hospitals or wards
Sampling a nested case-control study with one control per case, using time since study recruitment as the timescale. The solid lines represent the time period over which individuals are observed. Cases occur over the course of follow-up (•), individuals may leave the population or may survive to the end of the follow-up period or maximum age of observation. The dotted lines pass through members of the risk set at each event time. One control () is selected for each case from its risk set
Sampling a nested case-control study with one control per case, using age as the timescale. The solid lines represent the time period over which individuals are observed. Cases occur over the course of follow-up (•), individuals may leave the population or may survive to the end of the follow-up period or maximum age of observation. The dotted lines pass through members of the risk set at each event time. One control () is selected for each case from its risk set
By sampling controls from the risk set at 1. the dates of dementia diagnosis and 2. by matching for age, we determined that the association between mean lithium exposure and dementia IRR can be interpreted as IRRs between individuals living constantly during the same age interval (since beginning of exposure ascertainment and since birth) in areas with given lithium levels in drinking water
Kriging is based on spatial autocorrelation estimates obtained by fitting a semivariogram. Different semivariograms were used to evaluate the effect of the selected spatial autocorrelation estimates on the estimated kriging map. Spatial autocorrelation quantifies a basic principle of geography: things that are closer are more alike than things farther apart
with 5 knots set at the quantiles of the mean lithium exposure in drinking water.
By sampling controls from the risk set at 1. the dates of dementia diagnosis and 2. by matching for age, we determined that the association between mean lithium exposure and dementia IRR can be interpreted as IRRs between individuals living constantly during the same age interval (since beginning of exposure ascertainment and since birth) in areas with given lithium levels in drinking water
To find the median, we arrange the observations in order from smallest to largest value. If there is an odd number of observations, the median is the middle value
The distributions of the mean lithium exposure were statistically significantly different among patients with a diagnosis of dementia
(median, 11.5 μg/L; IQR, 6.5-14.9 μg/L) and among controls (median, 12.2 μg/L; IQR, 7.3-16.0 μg/L; P < .001).
Association Between Mean Lithium Exposure in Drinking Water on a Continuous Scale and the Overall Dementia Rate Data are the incidence rate ratios (IRRs) in relation to the mean (4 µg/L) of the lowest group on a logarithmic scale. Shaded area indicates 95% CIs.
A non-linear association was found between higher, long-term lithium exposure from drinking water and lower incidence of dementia
Due to health care services.
Dietary, economic, stressors, exposure to chemicals, medications, medical conditions, substance abuse, head injuries
Presumably, maximum benefits from treatment are subject to the early diagnosis of Alzheimer’s disease, preferentially at mild cognitive impairment stages or earlier, when the pathological changes are still incipient and the restoration of normal physiological status is more likely to occur
the dementia process likely begins biologically at least a decade before the first clinical signs, with the largest biological changes occurring within the fifth decade of life. During this age threshold about 40% of individuals at high risk for AD (e.g. apoE4 carriers) have senile plaques, despite the absence of clinical signs of dementia (Schrauzer and De Vroey, 1994). Thus, true biological prevention may need to begin in individuals before even the earliest clinical phase of dementia
