Elevated parathyroid hormone levels and cognitive function: A systematic review

Journal Pre-proof Elevated Parathyroid Hormone Levels and Cognitive Function: A Systematic Review Wen Jiang, Cheng-yang Hu, Feng-li Li, Xiao-guo Hua, Kai Huang, Xiu-jun Zhang

PII:

S0167-4943(19)30228-6

DOI:

https://doi.org/10.1016/j.archger.2019.103985

Reference:

AGG 103985

To appear in:

Archives of Gerontology and Geriatrics

Received Date:

16 March 2019

Revised Date:

30 October 2019

Accepted Date:

14 November 2019

Please cite this article as: Jiang W, Hu C-yang, Li F-li, Hua X-guo, Huang K, Zhang X-jun, Elevated Parathyroid Hormone Levels and Cognitive Function: A Systematic Review, Archives of Gerontology and Geriatrics (2019), doi: https://doi.org/10.1016/j.archger.2019.103985

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Title: Elevated Parathyroid Hormone Levels and Cognitive Function: A Systematic Review Short Title: Parathyroid Hormone Levels and Cognitive Function

Authors: Wen Jiang, MDa, Cheng-yang Hu, MDa, Feng-li Li, MDa, Xiao-guo Hua, MDa, Kai Huang, MDa & Xiu-jun Zhang, PhDa

aDepartment

of Epidemiology and Biostatistics, School of Public Health, Anhui Medical

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University, Hefei 230032, China;

Corresponding Author: Xiu-jun Zhang, PhD, Department of Epidemiology and

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Biostatistics, School of Public Health, Anhui Medical University, Anhui Province Key

Laboratory of Major Autoimmune Diseases, Hefei, Anhui 230032, China; Tel: +86 551

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5167743; Fax: +86 551 5167743; E-mail: [email protected];

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Highlights

Hyperparathyroidism patients reported poorer cognition compared with controls.

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Limited data presented the association between elevated PTH levels and cognition.

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Identified studies show mixed results to support an association between PTH and

High-quality studies are needed to improve the evidence base.

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cognition.

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

Abstract

Objective: To systematically estimate the association between elevated parathyroid hormone (PTH) levels and cognitive function.

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Methods: This review was conducted on ten papers identified through database searches from inception to 31 October 2018. The quality of studies was assessed using the Downs and Black checklist. Results: There is a low volume of data reporting on the impact of elevated PTH levels on cognitive impairment. The quality of the identified studies ranged from poor (37%) to good (76%). Although the results from studies were mixed, one cross-sectional study and one prospective study suggested

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a link between elevated PTH levels and a decrease in the Mini-Mental State Examination (MMSE) score. Three cross-sectional studies that assessed

other cognitive domain in specific domains, such as language, memory and

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executive function provided mixed results for an association between elevated PTH levels and cognitive function. Two studies showed mixed evidence for a

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link between elevated PTH levels and poor executive function. One

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prospective study, one cross-sectional study and three case-control studies provide mixed evidence for an association between higher PTH levels and Alzheimer´s disease (AD). Two studies showed limited evidence for an

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association between elevated PTH levels and vascular dementia. Conclusion: This review presented that the level of evidence available to

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support an association between elevated PTH levels and cognitive function

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was generally weak and inconsistent. Future studies with more better methodological quality are needed.

Keywords: cognitive function; parathyroid hormone; systematic review

1. Introduction

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The prevention of cognitive deterioration is of major importance in older age. Considering the public health impact of cognitive impairment and the absence of disease-modifying or curative treatments, preventing the onset of the disease and slowing cognitive impairment progression is particularly important. Higher PTH levels may play a role in impaired cognition, given that PTH receptors have been identified in the cerebral arteries (Usdin et al., 1995, Macdonald et al., 2002). In vitro, a study demonstrated that PTH increases

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intracellular Ca2+ concentration and might have adverse effects on cell deterioration in rat hippocampal slices (Hirasawa et al., 2010). Prior studies

suggest that PTH may induce subclinical and overt cerebrovascular diseases

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through endothelial dysfunction, vascular stiffness, and inflammation

(Ballegooijen et al., 2014, Bosworth et al., 2013, Hagström et al., 2015,

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Hagström et al., 2009, Hendy and Canaff, 2016). PTH and vitamin D regulate

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circulating calcium levels (Lu'O'Ng and Nguyên, 2011). Calcium influx into cells is an important mediator of cellular metabolism, but unbuffered intracellular calcium could be a risk for neurotoxicity and brain cells death

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(Shetty et al., 2011). Dysregulated hippocampal Ca2+ homeostasis plays an important role in the pathogenesis of cognitive decline (Olivier et al., 2007,

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Navakkode et al., 2018). Primary hyperparathyroidism is diagnosed by

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elevated serum calcium levels, elevated serum intact parathyroid hormone (iPTH) levels (normal = 10-69 pg/mL), and normal serum creatinine levels (Roman et al., 2011). Increased odds of impaired cognitive function have been associated with higher levels of PTH (Vogels et al., 2012, Walker et al., 2009). Primary hyperparathyroidism patients often reported significant deficits in memory when compared with controls (Babinska et al., 2012, Bell et al.,

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2017). Significant improvements in cognitive function following parathyroidectomy for primary hyperparathyroidism were described (Babinska et al., 2012, Shah-Becker et al., 2017). The cognitive function of control subjects was better than that of those with secondary hyperparathyroidism (Rolf et al., 2006). Furthermore, patients with symptomatic secondary hyperparathyroidism can improve cognition after parathyroidectomy (Chou et al., 2008).

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Though several prior systematic reviews have described the relationship between primary hyperparathyroidism or parathyroidectomy and cognition

(Benge et al., 2009, Coker et al., 2005, Lourida et al., 2015, Sanziana and

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Julie Ann, 2007), limited data exist linking elevated PTH levels with cognitive function and the results have been inconsistent. Evidence has never been

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assessed in a systematic manner for all the available research in this area.

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Therefore, the main aim of our systematic review is to summarize and evaluate the current research for the association of elevated PTH levels with

2. Methods

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cognitive function.

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A narrative synthesis was carried out to summarize the findings of the

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included studies, because of the great variability in the study designs, techniques used for cognitive assessments (for example, MMSE, AD or other), statistical analyses and inadequate reporting (Fleiss, 1993).

2.1. Search Strategy

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The search was carried out for all scientific publications by using four online databases (PubMed, Web of Science, EBSCOhost and Cochrane). The search was undertaken from inception to 31 October 2018 by two independent authors (W. Jiang and C.Y. Hu). The search strategies were developed by all authors of this manuscript. The following search terms were used: ‘cognitive’ OR ‘memory’ OR ‘Alzheimer’ OR ‘dementia’ AND ‘parathyroid’ OR ‘parathormone’ OR ‘hyperparathyroidism’. A manual review

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was also carried out within the references lists of studies that have been included in this review to identify potentially eligible articles.

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2.2. Study Selection

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Two independent authors (W. Jiang and C.Y. Hu) reviewed all studies identified and determined whether the articles were eligible for this review. To

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reach consensus, all discrepancies were discussed.

The inclusion criteria for the studies in the present review were: (1) peer-

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reviewed published articles; (2) measured and reported baseline serum PTH as exposure; (3) reported the outcome of interest as cognitive function or

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dementia or AD; and (4) published in English; Studies were excluded if primary hyperparathyroidism, secondary hyperparathyroidism or

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hypoparathyroidism was reported as exposure.

2.3 Data Extraction A self-designed standardized form was used to summarize the pertinent information about each eligible article. Two reviewers (W. Jiang and F.L. Li) independently extracted data relating to study information, study design, 5

sample size, study population age, covariates, the method of cognitive assessment and relevant outcomes. Any discrepancy was resolved through consensus.

2.4 Assessment of Study Quality The quality of the included studies was assessed using the Downs and Black checklist (Downs and Black, 1998) by two independent reviewers (W. Jiang

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and F.L. Li). The Downs and Black checklist is used for evaluating the

methodological quality of both randomized and non-randomized studies. Any disagreement was resolved via discussion and consensus.

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The 27-item standard checklist is comprised of five subscales that measured

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reporting (items 1-10), external validity (items 11-13), internal validity-bias (items 14-20), internal validity-confounding (items 21-26), and power (item 27).

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Three items (8, 13,and 19) were omitted from the checklist in this review, because of the specificity of the included studies. The total maximum score

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for the checklist was 25 with all individual items rated as either yes (= 1) or no/unable to determine (= 0), except for item five, which was allotted values of

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no (= 0), partially (= 1) or yes (= 2). The ranges of scores were grouped into four overall quality indicators: excellent (0.90 to 1), good (0.71 to 0.89), fair

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(0.54 to 0.70), and poor (0.53 and less) (Joplin et al., 2018).

3. Results

The flow diagram of the study selection is shown in Figure 1. The search of all databases identified a total of 1656 articles. No additional relevant articles

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were provided by checking the references lists of studies that have been included in this review. After the screening process, 10 papers were included.

3.1 Study Characteristics Of the included ten studies, one was conducted in Europe, two in Sweden, two in Japan, one in France, one in the US, one in Greece, one in Finland and one in Australia (as shown in Table 1). The majority participants in the

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identified studies were older than 50 years. The investigations differed in their design: three were prospective studies (Björkman et al., 2010, Emil et al.,

2014, Kim et al., 2017), four were cross-sectional studies (Bradburn et al.,

2016, Kalaitzidis et al., 2013, Ogihara T, 1990, Puy et al., 2018) and three

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were case-control studies (Johansson et al., 2013, Kipen et al., 1995, Sato

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and Asoh, 1998). Three prospective studies (Björkman et al., 2010, Emil et al., 2014, Kim et al., 2017) and one cross-sectional study (Bradburn et al., 2016)

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were population-based study. One cross-sectional study (Puy et al., 2018) enrolled a population of patients with chronic kidney disease (CKD). One

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cross-sectional study (Kalaitzidis et al., 2013) enrolled a population of patients with CKD or hypertension. Two case-control studies (Kipen et al., 1995, Sato

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and Asoh, 1998) and one cross-sectional study (Ogihara T, 1990) included only female participants, and one prospective study (Emil et al., 2014)

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included only male participants.

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Table 1. Overview of group studies included in this review Study design; follow-up length

Sample size (n)

Age, mean ± range SD (y)

Sample characteristics

Outcomes and cognitive domains examined

Puy et al. 2018, France24

Cross-sectional

40

62.6 ± 11.0

Single-centre study of a population of patients with CKD

Kim et al. 2017, US20

Prospective; 20 years

12964

57 ± 6

4 US regions

Bradburn et al. 2016, Europe23

Cross-sectional

225

Age range 69–81

Emil et al. 2014, Sweden22

Prospective; 15.8 years

998

71

Johansson et al. 2013, Sweden28

Case-control

69

Kalaitzidis et al. 2013, Greece26

Cross-sectional

190

Björkman et al. 2010, Finland21

Prospective; 1, 5, 10 years

One-year followup: MMSE 433, CDR 457; fiveyear follow-up: CDR 304; ten-

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Study

Covariates adjusted for in analysis

Weight, stroke volume, brain tissue volume, glycaemia, Uric acid

A global Z score: the average of the Z scores from each of the 3 individual cognitive tests (DWR, DSS, and WF)

Age, race/centre, sex, education, smoking status, alcohol, body mass index, physical activity, cardiovascular factors, and 25(OH)D (ng/mL), calcium (mg/dL), and phosphorus (mg/dL)

Collected from centres located in Manchester, UK; Paris, France; Leiden, the Netherlands; Tartu, Estonia and Jyväskylä, Finland

Working memory capacity, episodic memory, executive functioning, global cognition

NR

All 50-year-old men born in 1920–1924 living in Uppsala, Sweden

AD, vascular dementia

Hypertension, diabetes mellitus, smoking, hypercholesterolemia, BMI, educational level, S-calcium, S-phosphate, S-albumin, P-25-OH vitamin D < 37.5 nmol/L, glomerular filtration rate, blood draw season (winter, summer)

Case: primary evaluation of cognitive impairment in a memory clinic Control: spouses of the included patients and by advertisements in local newspapers

AD dementia or mild cognitive impairment

NR

Hypertensions: 53.0 ± 1.5; CKD III: 50.2 ± 11.8; CKD III: 63.1 ± 9.4; CKD IV: 64.1 ± 12.2

Hypertensive subjects or patients in CKD stages I–IV

Global cognitive function, the executive function and dementia

NR

Age range 75–85

General and specialized health care

MMSE and CDR

Age, gender, baseline MMSE or CDR, ionized calcium, creatinine and apolipoprotein E allele 4

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The global cognitive summary score: the average of the scores in the five domains (language, long-term memory, action speed, and executive function)

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Age range 69–78

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year follow-up: MMSE 138, CDR 141 Case-control

186

Controls: 80.0 ± 4.7; Patients: 81.3 ± 5.4

Patients met DSM-III (revised) criteria for dementing disease and the criteria for probable AD admitted to a nursing home

Dementing disease and the criteria for probable AD

NR

Kipen et al. 1995, Australia27

Case-control

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Controls: 72.1 ± 6.7; Patients: 76.4 ± 4.5

Case: women with mild dementia at North West Hospital. Control: from a study of heritability of bone mass in elderly female twins

Mild dementia and probable AD

NR

Ogihara et al. 1990, Japan25

Cross-sectional

60

79 ± 7

Hospitalized female

AD, vascular dementia, cognitive impairment

NR

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Sato and Asoh. 1998, Japan29

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Abbreviations: AD, Alzheimer´s disease; CDR, Clinical Dementia Rating; CKD, chronic kidney disease; DSS, Digit Symbol Substitution; DWR, the Delayed Word Recall; MMSE, Mini-Mental State Examination; NR, not reported; WF, Word Fluency.

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3.2 Methodological Quality The methodological quality ratings of the ten included studies are shown in Table s1. The quality of the included studies ranged from poor (37%, n = 2) to good (76%, n = 3). A further five studies were classified as being of fair quality (56–64%). Some common limitations of the included studies were observed using the checklist. No study received a point on the following items (1) blind study subjects to the intervention (item14), (2) blind those measuring the main

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outcomes of the intervention (item 15), and (3) whether randomized interventions were concealed from both patients and health care staff until

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completion of recruitment (item 24).

10

2

3

4

5

6

7

8

9

10

11

12

13

14

15

Puy et al. 201824

1

1

1

0

2

1

0

NA

0

1

0

0

NA

0

0

Kim et al. 201720

1

1

1

1

2

1

1

NA

0

0

1

0

NA

0

0

Bradburn et al. 201623

0

1

1

0

1

0

0

NA

0

0

0

0

NA

0

0

Emil et al. 201422

1

1

1

1

2

1

1

NA

1

1

1

1

NA

0

0

Johansson et al. 201328

1

1

1

1

2

1

0

NA

1

0

0

Kalaitzidis et al. 201326

0

1

1

1

0

1

1

NA

0

Björkman et al. 201021

1

1

1

1

2

1

1

NA

0

Sato and Asoh. 199829

0

1

1

1

2

1

0

NA

1

1

Kipen et al. 199527

0

1

1

1

1

1

0

NA

1

Ogihara et al. 199025

0

0

1

1

0

NA

17

18

19

20

21

22

23

24

25

26

27

Sum /Max

Overall quality %

1

1

1

NA

1

1

1

0

0

1

0

1

15/25

60 (fair)

1

1

1

NA

1

1

1

0

0

1

1

1

18/25

72 (good)

1

1

1

NA

1

1

1

NA

0

0

0

0

9/24

37 (poor)

1

1

1

NA

0

1

1

0

0

1

0

1

19/25

76 (good)

e-

1

β

1

1

0

0

NA

0

0

1

1

1

NA

1

1

1

NA

0

1

0

1

14/24

58 (fair)

1

1

1

NA

0

0

1

1

1

NA

1

1

1

0

0

1

0

1

19/25

76 (good)

0

0

NA

0

0

1

1

1

NA

1

1

0

0

0

0

1

0

14/25

56 (fair)

0

0

0

NA

0

0

1

1

1

NA

1

1

1

1

0

0

1

0

14/25

56 (fair)

0

0

0

NA

0

0

1

1

1

NA

1

1

1

0

0

0

0

0

11/25

44 (poor)

0

NA

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16

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1

1

Internal validity-confounding

Internal validity-bias

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External validity

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Table s1. Quality assessment: Downs and black checklist Study Reporting

0

0

1

1

NA

1

1

1

0

0

1

0

1

16/25

64 (fair)

Abbreviations: NA, not applicable. β=Power; Item 5 represents values of 0, 1 or 2; All other items represent values of 0 or 1.

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3.3 Parathyroid Hormone An immunoradiometric method was used to determine the serum PTH of all included studies, except for one study (Puy et al., 2018), which broadly described that PTH was measured using laboratory tests. PTH was analysed as a continuous variable in all included studies. Three studies also modelled PTH as a categorical variable in analyses, two by quartiles and another one by tertiles. Although there were some inconsistent definitions of elevated PTH between different studies, we used the PTH categories for elevated PTH level or referent PTH level as defined by

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each study (more detail relevant to PTH can be found in Table 2).

3.4 Cognition

Different cognitive assessment tools were used to test and determine cognitive function across the

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included studies (Table 2).

MMSE was used in two studies. One cross-sectional study (Kalaitzidis et al., 2013) using

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continuous models found that PTH (odds ratio [OR] = 1.01, 95% confidence interval [CI] = 1.00– 1.01, p = 0.010) was independently associated with MMSE score in hypertensive subjects or in

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patients in CKD stages I–IV. Another prospective study (Björkman et al., 2010) reported that elevated PTH concentrations (OR = 2.24, 95% CI = 1.17–4.28) were associated with MMSE score

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within a one-year follow-up, but the association disappeared at ten years. This study also reported a tendency for elevated baseline PTH concentrations in participants who had undergone cognitive

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decline and died before the date of the ten-year follow-up. Taken together, although the results from the studies were mixed, two studies suggest a link between elevated PTH levels and

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decrease in MMSE score.

Three cross-sectional studies that used between three and five tests that assessed cognitive function in specific domains, such as language, memory and executive function provided mixed results. Two studies (Bradburn et al., 2016, Kim et al., 2017) reported no associations were observed between high PTH levels and cognitive impairment in the general population. A significant result (β = -1.655×10-3, standard error [SE] = 5.673×10-4, p = 0.007) was reported in 12

another one study (Puy et al., 2018) in CKD patients whose PHT concentrations were very high (mean = 145.18 pg/mL, standard deviation [SD] = 162.6), and previously diagnosed cognitive impairment or dementia participants were excluded. Only one study (Bradburn et al., 2016) reported on the association between PTH levels and memory. Using Spearman correlation analysis, this cross-sectional study reported that there was no association between higher PTH levels and memory. Executive function was examined in two studies using the One Touch Stockings of Cambridge test or the Instrumental Activity of Daily Living (IADL) test. Using Spearman correlation analysis, a

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cross-sectional study (Kalaitzidis et al., 2013) assessed a significant association between elevated PTH levels and executive function in hypertensive subjects or patients in CKD stages I–IV, and the concentration of PTH was quite high in the CKD stage IV participants (322.9 pg/mL, SD = 171.8).

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One other cross-sectional study (Bradburn et al., 2016) showed no correlation in the general population, and participants who achieved less than 23 points on the MMSE were excluded before

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analyses. In summary, studies showed mixed evidence for a link between elevated PTH levels and poor executive function.

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One prospective study, one cross-sectional study and three case-control studies provide evidence for an association between PTH and AD. AD was diagnosed according to the criteria from the

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DSM in four studies, while the remaining study (Ogihara T, 1990) evaluated AD using the Dementia Screening Scale of Hasegawa and the ischaemic score. Two case-control (Kipen et al.,

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1995, Sato and Asoh, 1998) studies and one cross-sectional study (Ogihara T, 1990) reported significantly higher serum PTH in women with AD compared to controls. Conversely, findings from

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one prospective study (Emil et al., 2014) in men and one case-control study (Johansson et al., 2013) showed no significant association between higher PTH levels and AD. Taken together, these studies showed mixed evidence for an association between elevated PTH levels and AD. Vascular dementia was assessed in two studies. One study diagnosed vascular dementia according to the State of California Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC) core criteria. Another study evaluated vascular dementia using the Dementia Screening 13

Scale of Hasegawa and the ischaemic score. One prospective study (Emil et al., 2014) in men showed that participants in the highest tertile of PTH had a higher risk of developing vascular dementia compared with those in the first tertile (OR = 1.94, 95 % CI = 1.01–3.73) and in tertiles 1–2 (OR = 2.10, 95 %CI = 1.21–3.65). While one cross-sectional study (Ogihara T, 1990) in women showed no association between PTH and vascular dementia, using spearman's rank correlation analysis and without adjusting for potential confounding variables showed no association between PTH and vascular dementia in women. Overall, two studies showed limited

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evidence to support an association between elevated PTH and vascular dementia.

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Table 2. Main findings of studies on the association of PTH levels and cognitive function Study Study design; Serum PTH levels (pg/mL) Elevated PTH levels MMSE Other cognitive Memory Executive Vascular Follow-up domains function dementia length Kim et al. Prospective; 20 42.0±16.4 1st quartile (reference group): 10— 201720 years 31pg/mL; 2nd quartile 31-39pg/mL; 3rd quartile 39-49pg/mL; 4th quartile 49-189pg/mL Emilröm et al. Prospective; 3.99 (3.0, 5.3) pmol/L 1st tertile (reference group): <3.36 ↑ 201422 15.8 years pmol/L; 2nd tertile 3.36-4.7 pmol/L; 3rd tertile >4.7 pmol/L Björkman et Prospective; 1 MMSE score <24 group: ↑ ≥62 ng/L (quartile 4) al. 201021 year 63.5±104.1 MMSE score ≥24 group: 49.3±27.0 NR Björkman et Prospective; 10 MMSE score <24 group: — al. 201021 years 63.5±104.1 MMSE score ≥24 group: 49.3±27.0 Puy et al. Cross-sectional 145.2±162.6 Continuous models ↑ 201824 Kim et al. Cross-sectional 42.0±16.4 Higher PTH levels (quartiles 2–4) — 201720 compared with the reference lowest quartile Bradburn et Cross-sectional NR Continuous models — — — al. 201623 Kalaitzidis et Cross-sectional Hypertensivesion group: Continuous models ↑ ↑ al. 201326 40.2±13.2; CKD I-II group: 49.1±36.2; CKD III group: 82.3±69.2; CKD IV group: 322.9±171.8 Ogihara et al. Cross-sectional NR Continuous models — 199025 Johansson et Case-control AD group: 54.5 (46.5, 71.5); Compared to controls al. 201328 controls: 45.0 (41.5, 58.8) Sato and Case-control Controls: 35.0±11.4; patients: Compared to controls Asoh. 199829 51.8±25.1 Kipen et al. Case-control Controls: 2.9±1.7 pmol/L; Compared to controls 199527 patients: 4.9±2.1 pmol/L Abbreviations: AD, Alzheimer´s disease; CKD, chronic kidney disease; MMSE, the Mini-Mental State Examination; NR, not reported; PTH, parathyroid hormone. Values are mean ± SD for normally distributed continuous variables and median (Q1, Q3) for skewed variables. ↑: Compared to the reference or controls indicating that elevated parathyroid hormone levels were harmful (p <. 05), or that continuous models presenting high PTH levels were harmful. –: No statistically significant association/difference (p <. 05) observed in the tests. 15

↑ — ↑ ↑

4. Discussion The aim of this review was to identify the evidence regarding elevated PTH levels and cognitive function. Included studies employed great variability in cognitive assessment tools. The heterogeneity of study designs, techniques used for cognitive assessments, statistical analyses and inadequate reporting prevented the conduction of a meta-analysis. This review replaces a previous review (Lourida et al., 2015) that included studies published between 1978 and 2013 and suggested potential associations between abnormal PTH levels and cognition.

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Two studies (Kalaitzidis et al., 2013, Puy et al., 2018) in CKD or hypertensive subjects showed that cognitive impairment was associated with large excess PTH levels. Previous studies have presented that CKD was associated with an increased prevalence of cognitive impairment

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(Tamura et al., 2008, Weiner et al., 2017). A review presented that CKD was associated with endothelial dysfunction and vascular calcification, which may have direct neuronal toxicity in CKD

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patients (Chillon et al., 2016). An increase in brain calcium content, leading to cognitive dysfunctions was identified in rats with CKD (Smogorzewski, 2001).

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The parathyroid glands have 1-OHase activity, and the local production of 1,25(OH)2D influences the expression and synthesis of parathyroid hormone (Holick, 2007, Shieh et al, 2018). Vitamin D

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exerted neuroprotective actions by downregulating calcium ion channels (Brewer et al., 2001, Fleet, 2017), and a developmental deficiency in vitamin D could be a risk factor for abnormal brain

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development (Eyles et al., 2013). Milder hypercalcaemia may be related to changes in cerebral metabolism, as both calcium and PTH have been identified to have an effect on vasoconstriction

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(Navakkode et al., 2018, Nilsson et al., 1999). Only two studies (Emil et al., 2014, Kim et al., 2017) adjusted for vitamin D and calcium as potential confounders. One study showed no association between PTH levels and cognitive function in the general population, whose PTH levels were largely in normal ranges (42.0 pg/mL, SD = 16.4 pg/mL). Animal models demonstrated that PTH in large excess may induce cognitive impairment (Khudaverdian and Asratian, 1992). The other study in men presented that elevated 16

PTH levels were associated with vascular dementia but not with other dementia. This study also identified that PTH was associated with chronic cerebral small-vessel disease. Elevated PTH levels contributed to vascular stiffness, endothelial dysfunction, and atherosclerosis (Perkovic et al., 2002, Walker et al., 2009), which may be associated with cerebral small vessel disease and vascular dementia (Sahathevan et al., 2015, Thal et al., 2012). One study (Björkman et al., 2010) adjusted for calcium as a potential confounder, and the results identified that elevated PTH predicted cognitive decline within a five-year follow-up, but the association disappeared at ten years. At the same time, there was a tendency for high PTH

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concentrations in subjects who had died before the date of the follow-up and who had undergone poor cognition. A potential mechanism may be that sustained high levels of PTH due to Ca overloading via the activation of dihydropyridine-sensitive Ca channels (Hirasawa et al., 2000).

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The dysregulation of intracellular Ca homeostasis plays a critical role in the pathogenesis of cognitive function (Lerdkrai et al., 2018, Olivier Thibault, 2007).

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Several potential mechanisms may explain the association between elevated PTH levels and cognitive impairment. First, PTH receptors have been demonstrated in the cerebral arteries in

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animals (Weaver et al., 1995). Second, previous studies suggest that PTH may contribute to cerebrovascular diseases through endothelial dysfunction, vascular stiffness, and inflammation

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(Hendy and Canaff, 2016, Perkovic et al., 2002, Walker et al., 2009). Third, 1,25-dihydroxyvitamin D concentration is tightly regulated by plasma parathyroid hormone and serum calcium levels

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(Holick, 2007, Fleet, 2017), higher S-25OHD concentrations are linked to a reduced risk of AD (Larsson et al., 2018). Last, high levels of PTH regulate circulating calcium levels via the activation

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of dihydropyridine-sensitive Ca channels. (Lu'O'Ng and Nguyên, 2011) Current evidence suggests that it is a possibility that more modest levels of PTH elevation may not independently induce cognitive impairment. A prospective study identified that elevated PTH was not an independent risk marker for incident cardiovascular disease (Folsom et al., 2014), which was linked to cognitive impairment (Attems and Jellinger, 2014, Broce et al., 2018). A recent mendelian randomization study reported that no significant association was found between higher 17

PTH concentrations and AD (Larsson et al., 2018). Reverse causality may explain the observed association in some previous studies. In summary, the identified studies provide mixed evidence to support an association of cognitive function with PTH levels. Some studies were of relatively low quality, were not able to consider potential mediating variables and had small sample sizes; therefore the results may be affected by a function of various sample characteristics. Future studies with better methodological quality are needed. The current review has a number of limitations. First, the identified studies presented high levels of

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cognitive assessment and methodological diversity. Therefore, this review is limited by this diversity. Second, limited studies were included in this manuscript and high-quality data are lacking. Additionally, participants across the identified studies were varied, but we cannot consider

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subgroup analyses due to the limited available studies.

5. Conclusions

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Identified studies provide mixed evidence to support an association with PTH levels and cognitive function. With the consideration of methodological shortcomings and mixed findings, future studies

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with more better methodological quality are needed. Ideally, future studies should obtain large sample sizes, so that more sophisticated statistical analyses can be employed to identify the

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impact of many sample characteristics.

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Declarations of Interest: none.

Conflict of Interest: The authors report no conflicts of interest relevant to this manuscript.

Author Contributions: Study conception and design: W. Jiang, X.J. Zhang, C.Y Hu, F.L Li. Literature search and data extraction: W. Jiang, C.Y Hu, F.L Li. Quality evaluation: W. Jiang, F.L Li. Data synthesis and analysis: W. Jiang, X.J. Zhang, C.Y Hu, K. Huang, X.G. Hua. Manuscript 18

preparation: W. Jiang, X.J. Zhang, K. Huang, X.G. Hua. All authors provided critical revisions of the manuscript, and approved the final version for submission. Sponsor’s Role: The sponsor had no role in any part of this project.

Acknowledgements Financial Disclosure: This study was supported by the Nature Science Foundation of the Anhui Provincial Higher Education Institutions of China [KJ2017A187] and Fund of Excellent Talents in

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Colleges and Universities of Anhui Province, China [gxbjZD07].

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Figure 1

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