QoL and Cognitive Function in Patients With Hypoparathyroidism
Condition: Hypoparathyroidism; Pseudo Hypoparathyroidism
MeSH terms: Pseudohypoparathyroidism; Pseudopseudohypoparathyroidism; Hypoparathyroidism
Study type: Observational

Summary: 
      Hypoparathyroidism (HypoPT) is a disease with inadequate production of parathyroid hormone
      (PTH) from the parathyroid glands leading to hypocalcemia. The most common form is
      postsurgical HypoPT due to neck surgery resulting in removed or damaged parathyroid glands.

      HypoPT is a complex disease with a reduced Quality of life, mild cognitive impairment and in
      some patients have brain calcifications.

      The aim of the present study is to investigate the cognitive function in patients with
      postsurgical and non-surgical (HypoPT) by neuropsychological assessments and magnetic
      resonance imaging (MRI).

      The investigators will apply a contrast-enhanced MRI based method to HypoPT patients and age-
      and gender matched controls to examine whether capillary dysfunction can be detected, and
      whether symptom severity across patients correlates with the degree of capillary dysfunction
      in certain brain regions. To our knowledge there have been no previous studies on cognitive
      impairment and its origin in patients with HypoPT. The investigators hypothesize that the
      symptoms of HypoPT patients represent various degrees of capillary dysfunction, which
      interfere with their brain function.
    

Detailed description: 
      Hypoparathyroidism (HypoPT) is a disease with inadequate production of parathyroid hormone
      (PTH) from the parathyroid glands leading to hypocalcemia. The most common form is
      postsurgical HypoPT due to neck surgery resulting in removed or damaged parathyroid glands.
      Postsurgical HypoPT has a prevalence of 22/100,000 inhabitants in Denmark. Nonsurgical HypoPT
      is most often caused by mutations in different genes or on an autoimmune basis, the
      prevalence of nonsurgical HypoPT is 2.3/100,000 inhabitants in Denmark. If the gene mutation
      is within the GNAS gene or upstream of the GNAS complex locus it causes PseudoHypoPT (PHP),
      which is characterized by target organ resistance to PTH, also resulting in hypocalcaemia and
      hyperphosphatemia as in post- and nonsurgical HypoPT, but in this case with high or normal
      levels of plasma PTH. PHP is a very rare disease with a prevalence of 1/100,000 inhabitants
      in Denmark.

      Others and the investigators have previously shown that HypoPT and/or hypocalcemia may affect
      quality of life (QoL). In most cases, severe symptoms and findings diminished or disappeared
      when plasma calcium levels are restored to normal, but as some of the above mentioned studies
      have shown, the reduced QoL is still present despite normal calcium levels. Symptoms are
      describes as minor cognitive impairment (MCI), with confusion, forgetfulness, and lack of
      focus and mental clarity. Another important finding in some of the patients with HypoPT is
      calcifications of the basal ganglia as described in several case reports, the knowledge of
      the origin and importance of these is so far limited. Patients with PHP have previously been
      described to have a higher risk of calcifications of the lens and subcutaneous
      calcifications, and therefore might also be at higher risk of calcifications in the brain.

      The oxygen availability in brain tissue is traditionally thought to depend on regional
      cerebral blood flow (CBF). Accordingly, brain oxygenation is only expected to impair brain
      function in cases where CBF is critically reduced, cerebral ischemia. This paradigm was
      recently shown to be in error: While CBF determines the oxygen supply, the microscopic
      distribution of blood flows across the capillary bed determines the extent to which this
      oxygen can be extracted by the tissue. In fact, capillary flow patterns can become so
      disturbed that the metabolic needs of brain function and survival can no longer be met -
      although CBF remains inconspicuous. Capillary dysfunction denotes this overlooked source of
      hypoxia: A state in which capillary flow patterns cannot homogenize, giving rise to tissue
      hypoxia, oxidative stress, local inflammation, and - if severe - long-term neurodegeneration.
      The investigators hypothesize that the symptoms of HypoPT patients represent various degrees
      of capillary dysfunction, which interfere with their brain function.

      The purpose of the study is to investigate whether HypoPT patients are affected by capillary
      dysfunction, a condition in which capillary flow disturbances interfere with brain
      oxygenation.

      The hypothesis derives from findings that cerebral calcifications similar to those found in
      HypoPT are observed in familial idiopathic basal ganglia calcification (IBGC), which is a
      disease of cerebral pericytes. Pericytes are localized in the basement membrane of
      capillaries, where they maintain blood brain barrier (BBB) function and - in close
      interaction with endothelial cells - basement membrane and capillary wall integrity. They are
      contractile and take part in blood flow regulation. They control the trafficking of immune
      cells across the vessel wall and possess stem/progenitor cell functions. As such, they play a
      key role in tissue repair, scarring, and fibrosis, and along with endothelial cells, they
      seemingly have the potential to become bone-forming cells.

      Pericytes (now referred to as 'mural cells') are characterized by several membrane proteins,
      one of which (SLC9A3R1 - solute carrier family 9, isoform A3, regulatory factor 1, also known
      as EBP50, NHERF) binds to parathyroid hormone 1 receptor (PTH1R) on one hand, and to plasma
      derived growth factor (PDGF) receptor β (PDGFβ) on the other, potentiating its activity. The
      physiological role of these receptors is poorly understood. Receptors for PTH and Parathyroid
      hormone-related protein (PTH-rP) have been observed in both pericytes and smooth muscle cells
      of various tissue types, while PTH-rP is expressed in the endothelium, acting as a
      vasodilator. There is hence reason to believe that the function of capillary pericytes - and
      hence capillary flow patterns - could be altered in HypoPT.

      The investigators have developed a contrast-enhanced, magnetic resonance imaging (MRI) based
      method to detect disturbances in microvascular flow patterns in the human brain and
      demonstrated that knowledge of these flow patterns - as indexed by the capillary transit-time
      heterogeneity (CTH) - allow us to better predict oxygen extraction efficacy as determined by
      a gold-standard positron emission tomography (PET). The investigators have now found abnormal
      microvascular flow patterns in patients with Alzheimer's disease (AD) or mild cognitive
      impairment (MCI) compared to healthy, age-matched controls without cardiovascular risk
      factors, and demonstrated that the degree of capillary dysfunction correlated with their
      cognitive impairment. The investigators found a similar correlation in another AD patient
      cohort, and most recently detected capillary dysfunction in patients with late-onset
      depression compared to controls. In view of these findings, and the similarity between the
      symptomatology of HypoPT and depression, the investigators now propose to apply our MRI
      method to HypoPT patients and age- and gender matched controls to examine whether capillary
      dysfunction can be detected, and whether symptom severity across patients correlates with the
      degree of capillary dysfunction in certain brain regions.

      The aim is to investigate the cognitive function in patients with postsurgical, non-surgical
      and pseudoHypoPT by neuropsychological assessments and MRI. The contrast-enhanced MRI based
      method will be applied to HypoPT patients and age- and gender matched controls to examine
      whether capillary dysfunction can be detected, and whether symptom severity across patients
      correlates with the degree of capillary dysfunction in certain brain regions.

      The investigators hypothesize that the symptoms of HypoPT patients represent various degrees
      of capillary dysfunction, which interfere with their brain function.

      Methods:

      MRI scans: The investigators plan to acquire the following MRI sequences:

        1. Dynamic susceptibility contrast perfusion MRI will be applied for measurement of
           capillary function and regional blood flow and volume as estimated by our by parametric
           approach.

        2. For further characterization of the microcirculation, resting state functional MRI will
           be acquired. This sequence can be acquired in combination with the perfusion scan and
           thus requires very little extra scanning time.

        3. Fluid attenuated inversion recovery (FLAIR) images will be acquired for estimation of
           white matter hyperintensities (WMH) and possible subcortical infarcts or lacunas.

        4. A fast diffusion kurtosis imaging (DKI) sequence will be applied for estimation of
           microstructural integrity of gray and white matter (e.g. dendrite density and white
           matter tract integrity).

        5. T1-weighted MRI will be utilized for accurate morphological characterization of cerebral
           structures, such as hippocampus, basal ganglia, cortex and major tracts. In addition,
           the high-resolution images enable accurate mapping of the functional data (perfusion,
           fMRI, DKI).

      Neuropsychological testing (NPT): The standard neuropsychological test battery consists of
      validated tests to assess cognitive domains including verbal and visual memory, attention,
      language, visuospatial and executive functioning.

      Cognitive batteries: Cogstate battery for assessing cognitive function in adults with mild
      cognitive impairment (MCI). The tests used are D-KEFS: TrailMaking A and B, Verbal Fluency
      Test, and Color-Word Interference Test. The WAIS-IV: Coding, Symbol search, Digit span, and
      Arithmetic. The BVMT-R: delayed recall and total learning. Lastly the RAVLT: delayed recall
      and total learning.

      Questionnaires: SF36v2, WHO-5 well-being index, Symptom questionnaire, and a general
      questionnaire on background information, medication and diet, and HPQ28.

      Biochemistry: Ionized calcium, PTH, phosphate, magnesium, eGFR, creatinine, High sensitive
      CRP, 25-hydroxyvitamin D, calcitriol, and white blood cell count. Neuroinflammation and
      systemic inflammatory markers (pro-inflammatory cytokines), and 24-hr urine.

      Statistical Analysis Plan: Group difference will be examined using student T test for
      continuous variables and Pearsons X^2 test for categorical variables. Statistical maps of
      differences in perfusion parameters between patients and controls will be calculated at each
      surface vertex using a vertex specific general linear model with cortical thickness, white
      matter hyperintensity load ((WMHL) given as percentage white matter hyperintensities volume
      of whole brain volume)), age, and gender as covariates. The investigators will add cortical
      thickness as covariate to account for any systematic effects of cortical thickness on the
      perfusion measurements, such as partial volume effects. All statistical maps will be
      thresholded at p=0.05 (uncorrected and corrected). All statistical tests for the MRI scans
      are carried out using R version 3.2.2 (The R Foundation for Statistical Computing) and SPM12
      (Wellcome Trust Centre for Neuroimaging) running on Matlab R2016a (MathWorks Inc). Other
      statistical test will be carried out by SPSS 24 (IBM, USA) Justification for sample size: In
      a previous study by Eskildsen et al. the contrast-enhanced MRI based method has been applied
      to 18 patients with Alzheimer's disease or MCI compared to 19 healthy, age-matched controls
      without cardiovascular risk factors and it demonstrated that the degree of capillary
      dysfunction correlated with their cognitive impairment. The investigators found a similar
      correlation in another patient cohort with Alzheimer's disease, and most recently detected
      capillary dysfunction in patients with late-onset depression compared to controls. Taking the
      above mentioned results and the sizes of the cohorts in consideration, the investigators have
      estimated that our sample size is enough to show if there is a correlation between cognitive
      impairment measured by neuropsychological assessment and capillary transit time
      heterogeneity.

      Safety and ethnical evaluations: The investigators will follow the standard operating
      procedures regarding contrast enhanced MRI scans. Peripheral venous catheter will be used for
      administration of PET tracers and MRI contrast. It can result in mild local pain and a
      hematoma. The risk of infection is negligible. There are no known risks (neither short- nor
      long-term) related to MRI. Gadolinium-chelate (Gd) contrast is used. The standard dose of
      gadolinium (Gd)-containing MRI-contrast is 0.1 mmol/kg, but in this study there will be used
      up to 0.3 mmol/kg.

      Perspectives: If successful and study findings provides a basis for improved understanding of
      cognitive symptoms in HypoPT, further investigations on effects of PTH replacement therapy on
      investigated indices should be considered. A future project could be performing the MRI scan
      before and after injection of PTH to determine whether a change in capillary transit time
      heterogeneity could be detected.
    

Intervention name(s): MRI scans; Neuro cognitive tests; Questionnaires on Quality of Life; Blood samples; 24 hr urine samples
Intervention type(s): Diagnostic Test; Diagnostic Test; Diagnostic Test; Diagnostic Test; Diagnostic Test
Intervention description(s): Contrast-enhanced, magnetic resonance imaging (MRI) based method to detect disturbances in microvascular flow patterns in the human brain; Standard neuropsychological test battery consists of validated tests to assess cognitive domains including verbal and visual memory, attention, language, visuospatial and executive functioning.; SF36v2, WHO-5 well-being index, HPQ28, Symptom questionnaire, and a general questionnaire on background information, medication and diet.; Markers of calcium homeostasis, inflammatory markers and hematology.; 24 hr urine content of calcium, phosphate, magnesium, and creatinine.
Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        The patients with postsurgical, non-surgical and pseudo hypoparathyroidism will be invited
        from our outpatient clinic to participate in the study.

        The healthy controls will be randomly recruited from the background population by an
        extract from the CPR register and an invitation to participate in the study will be send by
        electronic letter.
      
Biospecimen description: 
      Plasma, serum and 24hr urine samples
    
Keywords: Quality of Life; MRI; Cognitive Impairment; Hypoparathyroidism; Pseudohypoparathyroidism