<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04458207</url>
  </required_header>
  <id_info>
    <org_study_id>Tugg&amp;Tänk</org_study_id>
    <nct_id>NCT04458207</nct_id>
  </id_info>
  <brief_title>Cognitive Changes and Neural Correlates After Rehabilitation of Masticatory Function in Elderly -an Intervention Study</brief_title>
  <official_title>Cognitive Changes and Neural Correlates After Rehabilitation of Masticatory Function in Older Adults - an Intervention Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Folktandvården Stockholms län AB</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Karolinska Institutet</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Folktandvården Stockholms län AB</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Today in elderly tooth loss and loss of oral function is widespread, but it is an&#xD;
      underexplored modifiable risk factor potentially contributing to the development of dementia.&#xD;
      In this interventional study a &quot;cause-effect&quot; relationship between mastication and cognition&#xD;
      in humans will be investigated.&#xD;
&#xD;
      A total of eighty (80) participants, 65-80 years of age, indicated for prosthodontic&#xD;
      rehabilitation will be randomly assigned to either the experimental or the control group.&#xD;
      Participants will be randomized into two different groups, measurements are going to be&#xD;
      conducted before and after prosthetic rehabilitation. The difference between the two groups&#xD;
      is that the control group are going to do two measurements before undergoing the&#xD;
      rehabilitation, this to control for the test-re-test effect.&#xD;
&#xD;
      The aim with this study is to determine if the rehabilitation of chewing function will cause&#xD;
      changes in the neurocognitive assessments of episodic memory and learning.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      -  Dementia is a general term of several neurodegenerative diseases that jointly affects&#xD;
           approximately 7% of the general population older than 65 years, and 30% older than 80&#xD;
           years (O'Brien, 2003). Importantly, these statistics are expected to almost double every&#xD;
           20 years (Prince, 2013), making disorders of cognition a priority for healthcare&#xD;
           (O'Brien, 2014).&#xD;
&#xD;
        -  Animal and human studies have shown associations with mastication and cognitive function&#xD;
           through the medial temporal lobe (i.e., hippocampus) and its role in learning and&#xD;
           memory. (Ono, 2010. Weijenberg, 2011. Ohkubo, 2012. Teixeira, 2014. Klineberg, 2014)&#xD;
&#xD;
        -  Although tooth loss and loss of oral function is widespread in older people, it is still&#xD;
           an underexplored modifiable risk factor contributing to the development of dementia.&#xD;
&#xD;
        -  The aim of this study is to conduct an intervention study on elderly people where&#xD;
           rehabilitation of masticatory functions is performed and evaluated, with cognitive&#xD;
           measures and brain imaging, to investigate a &quot;cause-effect&quot; relationship between&#xD;
           mastication and cognition in humans.&#xD;
&#xD;
        -  The hypothesis is that rehabilitation of masticatory function will improve cognition&#xD;
           primarily in the performance of episodic memory and executive function tests along with&#xD;
           the corresponding neural changes mainly in hippocampus and prefrontal cortex.&#xD;
&#xD;
        -  A total of eighty (80) participants, 65-80 years of age, indicated for prosthodontic&#xD;
           rehabilitation at Eastmaninstitutet (Stockholm, Sweden) will be randomly assigned to&#xD;
           either the experimental or the control group. The difference between the groups is that&#xD;
           the participants in the experimental group will begin with the rehabilitation&#xD;
           immediately after the first measurement while the control group will do one more&#xD;
           measurement before the onset of the rehabilitation procedure. The two measurements&#xD;
           conducted before treatment in the control group are to rule out for test-retest effects.&#xD;
           Three months and one year after completed prosthodontic treatment participants will&#xD;
           conduct the last measurements, as a post-test to evaluate potential treatment effect.&#xD;
&#xD;
        -  The neuropsychological assessments will be conducted together with MRI assessments, oral&#xD;
           health-related quality of life instrument, chewing function test (two coloured chewing&#xD;
           gum) and saliva samples recorded at different time points (i.e., pre-test, post-test 1,&#xD;
           post-test 2, post-test 3) in both the groups.&#xD;
&#xD;
        -  The data from the study will be entered in a Microsoft Excel sheet and exported to&#xD;
           Statistics is a software package SPSS Inc, Statistica, StatSoft Inc (or similar advanced&#xD;
           analytics software package for analysis). The result from the cognitive testing will be&#xD;
           analysed as repeated measure Analysis of covariance (ANCOVAs) with groups (experimental&#xD;
           and control) and time (pre- and post-rehabilitation) as factors. Group-by-time&#xD;
           interaction, main effect of group, and main effect of time will be evaluated. To compare&#xD;
           the magnitude of gains, the effect size (partial eta-square) will also be calculated. By&#xD;
           using time-length between pre- and post-tests as a covariate of interest with aiming to&#xD;
           better control group differences. Models that mainly predicts cognitive test measures&#xD;
           (neuropsychological assessments) will by developed to predict the intervention outcomes.&#xD;
           Predictive ability is defined as the amount of variance in the outcome that can be&#xD;
           explained by pre-test cognitive status (slope method). Explained variance in outcome&#xD;
           will be obtained by analysing linear regressions.&#xD;
&#xD;
        -  Preprocessing and statistical analyses of MRI data will be performed with Statistical&#xD;
           Parametric Mapping (SPM) run in Matlab (MathWorks). Movement correction will be&#xD;
           performed by realign and unwarp to the first image in the series. To consider&#xD;
           group-specific anatomical brain differences, all participants will be normalized to&#xD;
           Monteral Neurological Institute (MNI) echoplanar-imaging template. Cortical thickness&#xD;
           measures will not be normalized but rather used in their raw form. For cortical&#xD;
           segmentation, a Freesurfer pipeline will be applied to the MRI images to produce&#xD;
           regional cortical thickness and volumetric measures. To investigate&#xD;
           rehabilitating-related changes repeated measures ANCOVAs will be performed with the&#xD;
           groups (experimental and control) and time (pre- and post-rehabilitation) as factors.&#xD;
           The Bonferroni-Holm method will be used to control for multiple comparisons.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 2, 2018</start_date>
  <completion_date type="Anticipated">December 30, 2025</completion_date>
  <primary_completion_date type="Anticipated">December 30, 2024</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Longitudinal randomized controlled trial. After screening and informed consent the participants are randomly allocated to exeperimental or control group. Both groups undergoing intervention but the participants in the control group undergo one more test before the intervention to rule out the test-retest effect.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>The investigator doing the cognitve assements is not informed about the allocation of the participants.It is not possible to mask the participants during the neuropsycological assessements.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Brief Visuospatial Memory Test Revised (BVMT-R)</measure>
    <time_frame>1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.</time_frame>
    <description>Measuring non-verbal episodic memory. Measured in correct answers. Score: 0-36. A high score indicates a better performance.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Rey Auditory Verbal Learning Test (RAVLT).</measure>
    <time_frame>1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.</time_frame>
    <description>Measuring verbal episodic memory. Measured in correct answers. Scale: 0-90. A high score indicates a better performance.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Trail Making Test from Delis Kaplan Executive Function System (D-KEFS)</measure>
    <time_frame>1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.</time_frame>
    <description>Measuring executive function. Measured in seconds and number of faults (maximum 150 seconds). A low score indicates a better performance.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Digit-Span from Wechsler Adult Intelligence Scale (WAIS):IV</measure>
    <time_frame>1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.</time_frame>
    <description>Measuring working memory. Measured in correct answers. Score: 0-48. A high score indicates better performance.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Digit-symbol from Wechsler Adult Intelligence Scale (WAIS):IV</measure>
    <time_frame>1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.</time_frame>
    <description>Measuring motor and mental speed. Measured in correct answers. Score: 0-135. A high score indicates better performance.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Color-Word Interference Test from Delis Kaplan Executive Function System (D-KEFS word)</measure>
    <time_frame>1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.</time_frame>
    <description>Measuring executive memory. Measured in seconds to complete test (maximum 90 seconds). Higher score indicates a poorer performance.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in verbal fluency from Delis Kaplan Executive Function System (D-KEFS-F)</measure>
    <time_frame>1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.</time_frame>
    <description>Measuring executive memory. Measured in correct answer during a time limit (60 seconds). A high score indicates a better performance.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Title: Changes in blood perfusion in the brain tissue by measuring cerebral blood flow (CBF) in the brain over time with magnetic resonance imaging (MRI).</measure>
    <time_frame>1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.</time_frame>
    <description>Measured with MRI using the Pseudo- Continuous Arterial Spin Labeling (pCASL) technique. The unit of measurement is ml of blood per 100 gram tissue per unit of time (ml/100g/min).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in brain activity (BA) over time measured with magnetic resonance imaging (MRI).</measure>
    <time_frame>1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.</time_frame>
    <description>Measuring changes in functional connectivity over time with MRI using the Blood Oxygen Level Dependent (BOLD) technique under resting state conditions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of the masseter muscle volume (MMV) with magnetic resonance imaging (MRI).</measure>
    <time_frame>1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.</time_frame>
    <description>Measured with MRI using a PD-weighted SPACE sequence to determine the pre- and post-muscle volume. Volume increase indicates volume increase in muscle masseter.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in mixing ability (MA) two-coloured chewing gum (Orophys chewing gum)</measure>
    <time_frame>1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.</time_frame>
    <description>Two-coloured Orophys chewing gum. More mixed colour in the sample indicates better chewing ability.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in measure of cortisol level (CL) in saliva</measure>
    <time_frame>1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.</time_frame>
    <description>Biological measures. Low level of cortisol indicate lower stress hormone levels.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Oral Health Impact Profile, short version (OHIP-14).</measure>
    <time_frame>1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.</time_frame>
    <description>Questionnaire measuring impact on daily life coast by oral problems. Scale: 0-56. Higher score indicates more impact or oral problems.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in psychological wellbeing the day of psychological assessment by using Hospital Anxiety and Depression scale (HAD).</measure>
    <time_frame>1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.</time_frame>
    <description>Questionnaire measuring Depression and Anxiety. Scale: 0-42. A low score indicate a more positive outcome.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">80</enrollment>
  <condition>Chewing Problem</condition>
  <condition>Cognitive Decline</condition>
  <condition>Magnetic Resonance Imaging</condition>
  <condition>Degenerative; Dementia</condition>
  <condition>Mastication Disorder</condition>
  <condition>Neurocognitive Dysfunction</condition>
  <arm_group>
    <arm_group_label>Experimental group (EG), the immediate rehabilitation group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The experimental group will begin with the rehabilitation immediately after the first measurement of cognitive tests (pre-test). Three months after complete rehabilitation the first post-test (post-test 1) will be conducted on all participants. Participants will be recalled after about a year for a long-term follow up (post-test 2). The OHIP-14, chewing function test, saliva samples, neuropsychological assessments together with MRI assessments will also be recorded at different time points (i.e., pre-test, post-test 1 and post-test 2).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group (CG), the test-retest group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The control group will be tested with the cognitive tests two times (pre-test + post-test 1) at an interval of about three months or more inbetween tests and before the onset of the prosthodontic rehabilitation. Three months after complete rehabilitation the post-test (post-test 2) will be conducted on all participants. Further, participants will be recalled after about a year for a long-term follow up (post-test 3). The OHIP-14, chewing function test, saliva samples, neuropsychological assessments together with MRI assessments will also be recorded at these time points (i.e., pre-test, post-test 1, post-test 2 and post-test 3).</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Oral prosthetic rehabilitation</intervention_name>
    <description>Individual treatment options will be discussed with the participants individually and rehabilitation will be provided as agreed by the dentist and the participant. The rehabilitation will include fixed prosthodontics. The procedures will involve a control phase involving scaling, root planing oral hygiene instructions etc., extractions and bone augmentation when needed and temporary removable dentures. Restoration of the lost vertical dimension (if needed) with occlusal splints, tooth preparations, placement of dental implants (if needed) and finally cementation of dental crowns. The rehabilitation phase is estimated to take approximately 3-18 months, or more.</description>
    <arm_group_label>Control group (CG), the test-retest group</arm_group_label>
    <arm_group_label>Experimental group (EG), the immediate rehabilitation group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  65-80 years of age at start&#xD;
&#xD;
          -  Impaired chewing ability (Eichner index B2-B4, C1-C4)&#xD;
&#xD;
          -  Dental rehabilitation with fixed prosthodontics, implant and/or tooth supported&#xD;
             (overdentures included) &gt;10 occluding units&#xD;
&#xD;
          -  Mini Mental State Examination (MMSE) score &gt;25&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Brain trauma or stroke &lt;6 months&#xD;
&#xD;
          -  Neurological disease (stroke, dementia, Alzheimer disease, Parkinson disease).&#xD;
&#xD;
          -  Intellectual disability&#xD;
&#xD;
          -  Psychological disorders&#xD;
&#xD;
          -  Participants with chronic pain, depression or sleeping disorders&#xD;
&#xD;
          -  Daily analgesic medication that may affect cognitive and/or executive performance of&#xD;
             the brain&#xD;
&#xD;
          -  Poor Swedish language skills, reading disabilities&#xD;
&#xD;
          -  Severely reduced hearing or vision&#xD;
&#xD;
          -  Prosthetic treatment with removable dentures (full or partial)&#xD;
&#xD;
        MRI exclusion criteria:&#xD;
&#xD;
          -  Claustrophobia&#xD;
&#xD;
          -  Difficulties in lying down in a supine position for about an hour, or any other&#xD;
             difficulties related to the MRI head coil&#xD;
&#xD;
          -  Participants with metal or medical implants in the body contraindicating MRI scan&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>65 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mats Trulsson, Prof. DDS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Karolinska Institutet, Stockholm, Sweden</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Linn B Hedberg, DDS, PhDs</last_name>
    <phone>08-123 156 00</phone>
    <phone_ext>+46</phone_ext>
    <email>linn.hedberg@sll.se</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Mats Trulsson, Prof. DDS</last_name>
    <phone>08-524 880 36</phone>
    <phone_ext>+46</phone_ext>
    <email>mats.trulsson@ki.se</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Eastmaninstitutet Folktandvården Stockholm AB</name>
      <address>
        <city>Stockholm</city>
        <zip>11324</zip>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Linn Hedberg, PhDs, DDS</last_name>
      <phone>08-12315600</phone>
      <phone_ext>+46</phone_ext>
      <email>linn.hedberg@sll.se</email>
    </contact>
    <contact_backup>
      <last_name>Pia Skott, PhD, DDS</last_name>
      <phone>08-123 166 00</phone>
      <phone_ext>+46</phone_ext>
      <email>pia.skott@sll.se</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <reference>
    <citation>O'Brien JT, Erkinjuntti T, Reisberg B, Roman G, Sawada T, Pantoni L, Bowler JV, Ballard C, DeCarli C, Gorelick PB, Rockwood K, Burns A, Gauthier S, DeKosky ST. Vascular cognitive impairment. Lancet Neurol. 2003 Feb;2(2):89-98. doi: 10.1016/s1474-4422(03)00305-3.</citation>
    <PMID>12849265</PMID>
  </reference>
  <reference>
    <citation>Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013 Jan;9(1):63-75.e2. doi: 10.1016/j.jalz.2012.11.007.</citation>
    <PMID>23305823</PMID>
  </reference>
  <reference>
    <citation>O'Brien JT, Markus HS. Vascular risk factors and Alzheimer's disease. BMC Med. 2014 Nov 11;12:218. doi: 10.1186/s12916-014-0218-y.</citation>
    <PMID>25385509</PMID>
  </reference>
  <reference>
    <citation>Ono Y, Yamamoto T, Kubo KY, Onozuka M. Occlusion and brain function: mastication as a prevention of cognitive dysfunction. J Oral Rehabil. 2010 Aug;37(8):624-40. doi: 10.1111/j.1365-2842.2010.02079.x. Epub 2010 Mar 2.</citation>
    <PMID>20236235</PMID>
  </reference>
  <reference>
    <citation>Weijenberg RA, Scherder EJ, Lobbezoo F. Mastication for the mind--the relationship between mastication and cognition in ageing and dementia. Neurosci Biobehav Rev. 2011 Jan;35(3):483-97. doi: 10.1016/j.neubiorev.2010.06.002. Epub 2010 Jun 12.</citation>
    <PMID>20547177</PMID>
  </reference>
  <reference>
    <citation>Ohkubo C, Morokuma M, Yoneyama Y, Matsuda R, Lee JS. Interactions between occlusion and human brain function activities. J Oral Rehabil. 2013 Feb;40(2):119-29. doi: 10.1111/j.1365-2842.2012.02316.x. Epub 2012 May 25.</citation>
    <PMID>22624951</PMID>
  </reference>
  <reference>
    <citation>Teixeira FB, Pereira Fernandes Lde M, Noronha PA, dos Santos MA, Gomes-Leal W, Ferraz Maia Cdo S, Lima RR. Masticatory deficiency as a risk factor for cognitive dysfunction. Int J Med Sci. 2014 Jan 10;11(2):209-14. doi: 10.7150/ijms.6801. eCollection 2014.</citation>
    <PMID>24465167</PMID>
  </reference>
  <reference>
    <citation>Klineberg I, Palla S, Trulsson M. Contemporary relevance of occlusion and mastication. Int J Prosthodont. 2014 Sep-Oct;27(5):411-2. doi: 10.11607/ijp.2014.5.e. No abstract available.</citation>
    <PMID>25191880</PMID>
  </reference>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>June 26, 2020</study_first_submitted>
  <study_first_submitted_qc>June 30, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 7, 2020</study_first_posted>
  <last_update_submitted>March 17, 2022</last_update_submitted>
  <last_update_submitted_qc>March 17, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 18, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Folktandvården Stockholms län AB</investigator_affiliation>
    <investigator_full_name>Linn Hedberg</investigator_full_name>
    <investigator_title>DDS, Senior Consultat, PhDs</investigator_title>
  </responsible_party>
  <keyword>Magnetic resonance imaging</keyword>
  <keyword>Chewing efficiency</keyword>
  <keyword>Cognitive impairment</keyword>
  <keyword>Masticatory dysfunction</keyword>
  <keyword>Prosthetic rehabilitation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cognitive Dysfunction</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04458207
org study id: Tugg&Tänk
nct id: NCT04458207
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Today in elderly tooth loss and loss of oral function is widespread, but it is an
      underexplored modifiable risk factor potentially contributing to the development of dementia.
      In this interventional study a "cause-effect" relationship between mastication and cognition
      in humans will be investigated.

      A total of eighty (80) participants, 65-80 years of age, indicated for prosthodontic
      rehabilitation will be randomly assigned to either the experimental or the control group.
      Participants will be randomized into two different groups, measurements are going to be
      conducted before and after prosthetic rehabilitation. The difference between the two groups
      is that the control group are going to do two measurements before undergoing the
      rehabilitation, this to control for the test-re-test effect.

      The aim with this study is to determine if the rehabilitation of chewing function will cause
      changes in the neurocognitive assessments of episodic memory and learning.
-  Dementia is a general term of several neurodegenerative diseases that jointly affects
           approximately 7% of the general population older than 65 years, and 30% older than 80
           years (O'Brien, 2003). Importantly, these statistics are expected to almost double every
           20 years (Prince, 2013), making disorders of cognition a priority for healthcare
           (O'Brien, 2014).

        -  Animal and human studies have shown associations with mastication and cognitive function
           through the medial temporal lobe (i.e., hippocampus) and its role in learning and
           memory. (Ono, 2010. Weijenberg, 2011. Ohkubo, 2012. Teixeira, 2014. Klineberg, 2014)

        -  Although tooth loss and loss of oral function is widespread in older people, it is still
           an underexplored modifiable risk factor contributing to the development of dementia.

        -  The aim of this study is to conduct an intervention study on elderly people where
           rehabilitation of masticatory functions is performed and evaluated, with cognitive
           measures and brain imaging, to investigate a "cause-effect" relationship between
           mastication and cognition in humans.

        -  The hypothesis is that rehabilitation of masticatory function will improve cognition
           primarily in the performance of episodic memory and executive function tests along with
           the corresponding neural changes mainly in hippocampus and prefrontal cortex.

        -  A total of eighty (80) participants, 65-80 years of age, indicated for prosthodontic
           rehabilitation at Eastmaninstitutet (Stockholm, Sweden) will be randomly assigned to
           either the experimental or the control group. The difference between the groups is that
           the participants in the experimental group will begin with the rehabilitation
           immediately after the first measurement while the control group will do one more
           measurement before the onset of the rehabilitation procedure. The two measurements
           conducted before treatment in the control group are to rule out for test-retest effects.
           Three months and one year after completed prosthodontic treatment participants will
           conduct the last measurements, as a post-test to evaluate potential treatment effect.

        -  The neuropsychological assessments will be conducted together with MRI assessments, oral
           health-related quality of life instrument, chewing function test (two coloured chewing
           gum) and saliva samples recorded at different time points (i.e., pre-test, post-test 1,
           post-test 2, post-test 3) in both the groups.

        -  The data from the study will be entered in a Microsoft Excel sheet and exported to
           Statistics is a software package SPSS Inc, Statistica, StatSoft Inc (or similar advanced
           analytics software package for analysis). The result from the cognitive testing will be
           analysed as repeated measure Analysis of covariance (ANCOVAs) with groups (experimental
           and control) and time (pre- and post-rehabilitation) as factors. Group-by-time
           interaction, main effect of group, and main effect of time will be evaluated. To compare
           the magnitude of gains, the effect size (partial eta-square) will also be calculated. By
           using time-length between pre- and post-tests as a covariate of interest with aiming to
           better control group differences. Models that mainly predicts cognitive test measures
           (neuropsychological assessments) will by developed to predict the intervention outcomes.
           Predictive ability is defined as the amount of variance in the outcome that can be
           explained by pre-test cognitive status (slope method). Explained variance in outcome
           will be obtained by analysing linear regressions.

        -  Preprocessing and statistical analyses of MRI data will be performed with Statistical
           Parametric Mapping (SPM) run in Matlab (MathWorks). Movement correction will be
           performed by realign and unwarp to the first image in the series. To consider
           group-specific anatomical brain differences, all participants will be normalized to
           Monteral Neurological Institute (MNI) echoplanar-imaging template. Cortical thickness
           measures will not be normalized but rather used in their raw form. For cortical
           segmentation, a Freesurfer pipeline will be applied to the MRI images to produce
           regional cortical thickness and volumetric measures. To investigate
           rehabilitating-related changes repeated measures ANCOVAs will be performed with the
           groups (experimental and control) and time (pre- and post-rehabilitation) as factors.
           The Bonferroni-Holm method will be used to control for multiple comparisons.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Longitudinal randomized controlled trial. After screening and informed consent the participants are randomly allocated to exeperimental or control group. Both groups undergoing intervention but the participants in the control group undergo one more test before the intervention to rule out the test-retest effect.
primary purpose: Treatment
masking: None (Open Label)
masking description: The investigator doing the cognitve assements is not informed about the allocation of the participants.It is not possible to mask the participants during the neuropsycological assessements.
measure: Change in Brief Visuospatial Memory Test Revised (BVMT-R)
time frame: 1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.
description: Measuring non-verbal episodic memory. Measured in correct answers. Score: 0-36. A high score indicates a better performance.
measure: Change in Rey Auditory Verbal Learning Test (RAVLT).
time frame: 1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.
description: Measuring verbal episodic memory. Measured in correct answers. Scale: 0-90. A high score indicates a better performance.
measure: Change in Trail Making Test from Delis Kaplan Executive Function System (D-KEFS)
time frame: 1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.
description: Measuring executive function. Measured in seconds and number of faults (maximum 150 seconds). A low score indicates a better performance.
measure: Change in Digit-Span from Wechsler Adult Intelligence Scale (WAIS):IV
time frame: 1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.
description: Measuring working memory. Measured in correct answers. Score: 0-48. A high score indicates better performance.
measure: Change in Digit-symbol from Wechsler Adult Intelligence Scale (WAIS):IV
time frame: 1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.
description: Measuring motor and mental speed. Measured in correct answers. Score: 0-135. A high score indicates better performance.
measure: Change in Color-Word Interference Test from Delis Kaplan Executive Function System (D-KEFS word)
time frame: 1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.
description: Measuring executive memory. Measured in seconds to complete test (maximum 90 seconds). Higher score indicates a poorer performance.
measure: Change in verbal fluency from Delis Kaplan Executive Function System (D-KEFS-F)
time frame: 1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.
description: Measuring executive memory. Measured in correct answer during a time limit (60 seconds). A high score indicates a better performance.
measure: Title: Changes in blood perfusion in the brain tissue by measuring cerebral blood flow (CBF) in the brain over time with magnetic resonance imaging (MRI).
time frame: 1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.
description: Measured with MRI using the Pseudo- Continuous Arterial Spin Labeling (pCASL) technique. The unit of measurement is ml of blood per 100 gram tissue per unit of time (ml/100g/min).
measure: Changes in brain activity (BA) over time measured with magnetic resonance imaging (MRI).
time frame: 1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.
description: Measuring changes in functional connectivity over time with MRI using the Blood Oxygen Level Dependent (BOLD) technique under resting state conditions.
measure: Change of the masseter muscle volume (MMV) with magnetic resonance imaging (MRI).
time frame: 1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.
description: Measured with MRI using a PD-weighted SPACE sequence to determine the pre- and post-muscle volume. Volume increase indicates volume increase in muscle masseter.
measure: Change in mixing ability (MA) two-coloured chewing gum (Orophys chewing gum)
time frame: 1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.
description: Two-coloured Orophys chewing gum. More mixed colour in the sample indicates better chewing ability.
measure: Change in measure of cortisol level (CL) in saliva
time frame: 1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.
description: Biological measures. Low level of cortisol indicate lower stress hormone levels.
measure: Change in Oral Health Impact Profile, short version (OHIP-14).
time frame: 1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.
description: Questionnaire measuring impact on daily life coast by oral problems. Scale: 0-56. Higher score indicates more impact or oral problems.
measure: Change in psychological wellbeing the day of psychological assessment by using Hospital Anxiety and Depression scale (HAD).
time frame: 1: Baseline pre-test. 2: Change pre-test/post-test1, CG 3months after baseline, EG 3months after intervention (Int). 3: Change post-test1/post-test2, CG 3months after Int, EG 1year after Int. 4: Change post-test1/post-test2, CG 1year after Int.
description: Questionnaire measuring Depression and Anxiety. Scale: 0-42. A low score indicate a more positive outcome.
arm group label: Experimental group (EG), the immediate rehabilitation group
arm group type: Experimental
description: The experimental group will begin with the rehabilitation immediately after the first measurement of cognitive tests (pre-test). Three months after complete rehabilitation the first post-test (post-test 1) will be conducted on all participants. Participants will be recalled after about a year for a long-term follow up (post-test 2). The OHIP-14, chewing function test, saliva samples, neuropsychological assessments together with MRI assessments will also be recorded at different time points (i.e., pre-test, post-test 1 and post-test 2).
arm group label: Control group (CG), the test-retest group
arm group type: Active Comparator
description: The control group will be tested with the cognitive tests two times (pre-test + post-test 1) at an interval of about three months or more inbetween tests and before the onset of the prosthodontic rehabilitation. Three months after complete rehabilitation the post-test (post-test 2) will be conducted on all participants. Further, participants will be recalled after about a year for a long-term follow up (post-test 3). The OHIP-14, chewing function test, saliva samples, neuropsychological assessments together with MRI assessments will also be recorded at these time points (i.e., pre-test, post-test 1, post-test 2 and post-test 3).
intervention type: Procedure
intervention name: Oral prosthetic rehabilitation
description: Individual treatment options will be discussed with the participants individually and rehabilitation will be provided as agreed by the dentist and the participant. The rehabilitation will include fixed prosthodontics. The procedures will involve a control phase involving scaling, root planing oral hygiene instructions etc., extractions and bone augmentation when needed and temporary removable dentures. Restoration of the lost vertical dimension (if needed) with occlusal splints, tooth preparations, placement of dental implants (if needed) and finally cementation of dental crowns. The rehabilitation phase is estimated to take approximately 3-18 months, or more.
arm group label: Control group (CG), the test-retest group
arm group label: Experimental group (EG), the immediate rehabilitation group
criteria: 
gender: All
minimum age: 65 Years
maximum age: 80 Years
healthy volunteers: No
last name: Mats Trulsson, Prof. DDS
role: Principal Investigator
affiliation: Karolinska Institutet, Stockholm, Sweden
last name: Linn B Hedberg, DDS, PhDs
phone: 08-123 156 00
phone ext: +46
email: linn.hedberg@sll.se
last name: Mats Trulsson, Prof. DDS
phone: 08-524 880 36
phone ext: +46
email: mats.trulsson@ki.se
facility: 
status: Recruiting
contact: 
contact backup: 
country: Sweden
citation: O'Brien JT, Erkinjuntti T, Reisberg B, Roman G, Sawada T, Pantoni L, Bowler JV, Ballard C, DeCarli C, Gorelick PB, Rockwood K, Burns A, Gauthier S, DeKosky ST. Vascular cognitive impairment. Lancet Neurol. 2003 Feb;2(2):89-98. doi: 10.1016/s1474-4422(03)00305-3.
PMID: 12849265
citation: Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013 Jan;9(1):63-75.e2. doi: 10.1016/j.jalz.2012.11.007.
PMID: 23305823
citation: O'Brien JT, Markus HS. Vascular risk factors and Alzheimer's disease. BMC Med. 2014 Nov 11;12:218. doi: 10.1186/s12916-014-0218-y.
PMID: 25385509
citation: Ono Y, Yamamoto T, Kubo KY, Onozuka M. Occlusion and brain function: mastication as a prevention of cognitive dysfunction. J Oral Rehabil. 2010 Aug;37(8):624-40. doi: 10.1111/j.1365-2842.2010.02079.x. Epub 2010 Mar 2.
PMID: 20236235
citation: Weijenberg RA, Scherder EJ, Lobbezoo F. Mastication for the mind--the relationship between mastication and cognition in ageing and dementia. Neurosci Biobehav Rev. 2011 Jan;35(3):483-97. doi: 10.1016/j.neubiorev.2010.06.002. Epub 2010 Jun 12.
PMID: 20547177
citation: Ohkubo C, Morokuma M, Yoneyama Y, Matsuda R, Lee JS. Interactions between occlusion and human brain function activities. J Oral Rehabil. 2013 Feb;40(2):119-29. doi: 10.1111/j.1365-2842.2012.02316.x. Epub 2012 May 25.
PMID: 22624951
citation: Teixeira FB, Pereira Fernandes Lde M, Noronha PA, dos Santos MA, Gomes-Leal W, Ferraz Maia Cdo S, Lima RR. Masticatory deficiency as a risk factor for cognitive dysfunction. Int J Med Sci. 2014 Jan 10;11(2):209-14. doi: 10.7150/ijms.6801. eCollection 2014.
PMID: 24465167
citation: Klineberg I, Palla S, Trulsson M. Contemporary relevance of occlusion and mastication. Int J Prosthodont. 2014 Sep-Oct;27(5):411-2. doi: 10.11607/ijp.2014.5.e. No abstract available.
PMID: 25191880
responsible party type: Principal Investigator
investigator affiliation: Folktandvården Stockholms län AB
investigator full name: Linn Hedberg
investigator title: DDS, Senior Consultat, PhDs
mesh term: Cognitive Dysfunction