A Pilot Study of Cognition Among Hypoparathyroid Adults

Mishaela R. Rubin; Gaia Tabacco; Beatriz Omeragic; Rukshana Majeed; Christiane Hale; Adam M. Brickman

J Endo Soc. 2022;6(3)

Abstract and Introduction

Abstract

Purpose: Hypoparathyroid patients describe cognitive deficits, yet data regarding objective assessment of cognitive function are limited. We assessed cognition in a pilot study of hypoparathyroid patients using the National Institutes of Health Toolbox® Adult Cognitive Battery (NIHTB-CB). We also sought to determine whether cognition relates to emotion, quality of life, and hypoparathyroidism-related biochemistries.

Methods: Nineteen hypoparathyroid patients were studied. Objective cognition was assessed with NIHTB-CB. Impairment was defined as fully demographically adjusted T-score < 1.5 SD in at least 1 cognitive domain or < 1 SD in 2 or more domains.

Results: Of the 19 participants (17 women; median age 49; 18 postsurgical), impaired demographically adjusted NIHTB-CB cognition scores were observed in 13 subjects (68%). Cognition scores correlated with self-reported perception of general health. Processing speed was the most commonly impaired cognitive domain, with T-scores that were ≤2 SD in 6 subjects (32%). Processing speed correlated with serum calcium (r = 0.53, P = 0.023) and inversely with serum phosphate (r = −0.48, P = 0.042) levels.

Conclusions: Impaired cognition using the NIHTB-CB was common in this small pilot cohort of hypoparathyroid patients. Slower processing speed was present and associated with lower serum calcium and higher serum phosphate levels. Larger controlled studies with additional neuropsychological testing are needed to investigate cognitive function in hypoparathyroidism.

Introduction

Hypoparathyroidism is a rare endocrine disorder that leads to hypocalcemia, hypercalciuria, and hyperphosphatemia.^[1] Cognitive deficits are frequently reported by hypoparathyroid patients. A common complaint is "brain fog," with slowed thinking and an inability to perform day-to-day tasks.^[2] Yet data regarding objective assessments of cognitive function in hypoparathyroidism are scarce. Most of the available reports have used the Short Form Health Survey (SF-36) scale,^[3–10] which is a self-report of impaired quality of life (QoL). It is thus unclear to what extent objective, performance-based, and clinically meaningful measures of cognitive function are abnormal in hypoparathyroidism.

The National Institutes of Health (NIH) Toolbox® Cognition Battery (NIHTB-CB) is a validated and reliable method for objective assessment of cognitive function.^[11–14] This instrument assesses the cognitive domains of language, episodic memory, executive function, attention, working memory, and processing speed. It has been validated with the item response theory method and is considered to have comparable precision with traditional neuropsychological measures.^[15,16] It generates cognitive outcomes that are adjusted for age, sex, race, ethnicity, and education based on normative data collected in a large US nationally representative sample. We hypothesized that the NIHTB-CB would provide preliminary data regarding cognition in a pilot cohort of hypoparathyroid individuals.

Given that depression and anxiety are increased in hypoparathyroidism,^[17–19] we also questioned whether cognitive abilities relate to emotional function. The NIH Toolbox® Emotion Battery (NIHTB-EB), also normed on large US nationally representative samples, was created to assess emotional functioning.^[20,21] We anticipated that the NIHTB-EB would reveal psychological symptoms that would relate to cognition and to QoL as measured by the SF-36.

We also considered that serum calcium levels relate to neurological findings in hypoparathyroidism, with hypocalcemia causing neuromuscular irritability.^[1] We therefore further hypothesized that cognition as a continuous construct would be associated with hypoparathyroidism-related biochemical abnormalities.

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Abstract and Introduction
Methods
Results
Discussion
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Table 1. Characteristics of the study cohort (n = 19)
Variable	Results
Age, years^a	49 (30–56) [22–60]
Sex
Male	2 (11)
Female	17 (89)
Premenopausal	9 (47)
Postmenopausal	8 (42)
Race
White	16 (84)
Black	1 (5)
Asian	2 (11)
Ethnicity
Not Hispanic or Latino	16 (84)
Body mass index	26.5 (24.8–28.2) [20.9–40.9]
Education
High school graduate	3 (16)
Some college/associate's degree	6 (31)
Bachelor's degree	7 (37)
Postgraduate	3 (16)
Education, years	20 (18–20) [16–22]
Occupation^b
Partly skilled/unskilled	2 (11)
Skilled occupation-manual and nonmanual	5 (26)
Professional, managerial and technical	12 (63)
Etiology of hypoparathyroidism
Postsurgical	18 (95)
Idiopathic	1 (5)
Duration of hypoparathyroidism, years	5 (2–10) [1–39]
History of kidney stones	0
History of fractures
Yes	1 (5)^c
No	18 (95)
Calcium dose, g/day	2.0 (1.2–3.0) [0–6.3]
Calcitriol dose, μg/day	0.25 (0.25–0.75) [0–5.0]
Vitamin D dose, IU/day	1500 (0–5000) [0–7142]
HCTZ dose, mg/day	0 (0–12.5) [0–25]
Corrected serum calcium, mmol/L	2.10 (1.95–2.27) [1.38–2.42]^d
PTH, ng/L	6.0 (1.0–10.0) [1.0–23.5]^e
Serum phosphate, mmol/L	1.45 (1.26–1.58) [1.10–1.84]^f
24-hour urinary calcium excretion, mmol/24 hours	67.25 (41.75–84) [9.25–144.50]^g
Chronic kidney disease stage by GFR, mL/min/1.73m²
Normal (G1: ≥90)	6 (32)
Mildly decreased (G: 60–89)	7 (37)
Mildly to moderately decreased (G3a: 45–59)	5 (26)
Moderately to severely decreased (G3b: 30–44)	0
Severely decreased (G4: 15–29)	1 (5)
Kidney failure (G5: <15)	0
25-hydroxyvitamin D, nmol/L	114.82 (92.35–129.79) [82.37–254.59]
TSH level, mU/L
Low ( <0.4)	5 (26)
Normal (0.4–4.0)	9 (47)
High ( >4.0)	2 (11)
Not available	3 (16)

Data are given as median (interquartile range) [range] or n (%).
Abbreviations: GFR, glomerular filtration rate; HCTZ, hydrochlorothiazide; PTH, parathyroid hormone; TSH, thyroid-stimulating hormone.
^aMedical history: depression (n = 2), bipolar disorder (n = 1), hypertension (n = 3), acne (n = 1), hyperlipidemia (n = 1), renal transplant (n = 2), gout (n = 1), type 2 diabetes (n = 2). Medications: fluoxetine (n = 1), duloxetine and temazepam (n = 1), lamotrigine and clonazepam (n = 1), metoprolol (n = 1), labetalol (n = 1), losartan (n = 2), spironolactone (n = 1), simvastatin and fenofibrate (n = 1), prednisone (n = 2), allopurinol (n = 1), and metformin (n = 1).
^bCharacterized by National Statistics Socioeconomic Classification [36].
^cMetacarpal.
^dNormal range: 2.15–2.6 mmol/L.
^eNormal range: 10–65 ng/L.
^fNormal range: 0.81–1.45 mmol/L.
^gNormal range: female < 6.3 mmol/d; male < 7.5 mmol/d.

Table 2. Distribution of overall and domain-specific NIHTB-CB (fully adjusted) and NIHTB-EB (age- and sex-adjusted) T-scores
Test	Score, mean (SD) [range]	Patients with T-scores within each interval, n (%)^a
Test	Score, mean (SD) [range]	0.5 to < 1.0 SD	1.0 to < 1.5 SD	1.5 to < 2.0 SD	>2.0 SD
NIHTB-CB
Fluid cognition composite	44.7 (13.1) [15.1–75]	1 (5)	4 (21)	2 (11)	2 (11)
Flanker inhibitory control and attention	49.3 (12.4) [24.6–71.5]	2 (11)	2 (11)	0	2 (11)
Dimensional change card sort (executive function)	55.2 (15.0) [24.3–76.3]	1 (5)	0	3 (16)	1 (5)
List sorting working memory	45.9 (9.9) [28.8–65.9]	2 (11)	3 (16)	2 (11)	1 (5)
Pattern comparison processing speed	40.0 (12.0) [8.0–56.9]	4 (21)	3 (16)	2 (11)	6 (32)
Picture sequence episodic memory	45.9 (12.1) [26.3–67.2]	1 (5)	2 (11)	3 (16)	2 (11)
Crystallized cognition composite	52.7 (9.6) [38.4–69]	2 (11)	2 (11)	0	0
Picture vocabulary	51.8 (11.6) [27.9–70.9]	2 (11)	1 (5)	1 (5)	1 (5)
Oral reading recognition	53.3 (8.1) [39.4–69.4]	1 (5)	1 (5)	0	0
Cognition total composite: composite FCC and CCC	48.2 (11.1) [24.7–75.3]	2 (11)	1 (5)	0	2 (11)
NIHTB-EB
Negative affect (anger-affect, anger-hostility, sadness, fear-affect, perceived stress)	57.2 (10.5) [36.1–83]	6 (32)	3 (16)	1 (5)	2 (11)
Social satisfaction (friendship, loneliness, emotional support, instrumental support, perceived rejection)	43.2 (12.1) [12.6–62.9]	3 (16)	3 (16)	3 (16)	2 (11)
Psychological well-being (positive affect, general life satisfaction, meaning and purpose)	45.6 (9.4) [20.3–59.2]	3 (16)	2 (11)	2 (11)	1 (5)

Abbreviations: NIHTB-CB, NIH Toolbox® Adult Cognitive Battery; NIHTB-EB, NIH Toolbox® Emotion Battery.
^aEach category represents the number of participants within a predefined interval measured by SD units below the mean (NIHTB-CB, NIHTB-EB for social satisfaction score, psychological well-being score) and above the mean (NIHTB-EB for negative affect score). The rates are calculated as the number of participants within each category divided by the total number of study participants (n = 19).

Table 3. Correlations between NIHTB-CB, NIHTB-EB, and SF-36 scores
Fully corrected NIHTB-CB and age- and sex-corrected NIHTB-EB and SF-36 scores
	NIHTB-CB
	Flanker inhibitory control and attention	Dimensional change card sort (executive function)	List sorting working memory	Pattern comparison processing speed	Picture sequence episodic memory	Picture vocabulary	Oral reading recognition
NIHTB-EB
Negative affect	−0.01	0.08	−0.13	−0.03	−0.10	0.23	0.12
Social satisfaction	0.04	0.02	−0.21	0.13	−0.14	−0.21	−0.15
Psychological well-being	0.16	0.12	−0.16	0.28	−0.03	−0.23	−0.03
SF-36
PF	−0.06	−0.03	0.15	−0.14	0.03	−0.23	−0.26
RF	−0.06	0.03	0.21	−0.11	0.18	−0.10	0.05
BP	−0.13	−0.10	0.11	0.24	−0.11	0.01	−0.03
GH	0.53*	0.58*	0.40	0.68**	0.16	−0.02	0.38
VT	0.17	−0.07	0.19	0.07	0.32	−0.01	0.23
SF	0.23	0.14	0.08	0.13	0.24	−0.18	−0.04
RE	0.24	0.26	0.29	0.07	0.20	−0.33	−0.19
MH	0.08	−0.01	0.20	0.10	0.22	−0.29	−0.23
SF-36 and age- and sex-corrected NIHTB-EB scores
	SF-36
	PF	RF	BP	GH	VT	SF	RE	MH
NIHTB-EB
Negative affect	−0.43	−0.48*	−0.47	−0.11	−0.58*	−0.19	−0.71**	−0.80**
Social satisfaction	0.44	0.27	0.62**	0.39	0.44	0.16	0.46	0.41
Psychological well-being	0.20	0.57*	0.62**	0.18	0.31	0.24	0.36	0.66**

*P < 0.05, **P < 0.01. Bolded values indicate statistical significance.
Abbreviations: BP, bodily pain; GH, perception of general health; MH, mental health; NIHTB-CB, NIH Toolbox® Adult Cognitive Battery; NIHTB-EB, NIH Toolbox® Emotion Battery; PF, physical functioning; RE, role limitations caused by emotional health problems; RF, role limitations caused by physical health problems; SF, social functioning; SF-36, Short Form Health Survey; VT, vitality.

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A Pilot Study of Cognition Among Hypoparathyroid Adults

Abstract and Introduction

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