Hyposmia, Cholinergic Denervation and Incipient Cognitive Decline in PD

Summary

Principal Investigator: NICOLAAS IDA BOHNEN
Affiliation: University of Michigan
Country: USA
Abstract: DESCRIPTION (provided by applicant): Olfactory dysfunction is common in Parkinson disease (PD) and has been attributed to early deposition of a-synuclein pathology in the olfactory bulb. The pathophysiology of hyposmia in PD, however, remains poorly understood. Neurodegeneration within more central or limbic cortical components of the olfactory system may contribute to PD hyposmia. Deficits of olfactory function in PD are described in odor identification, odor discrimination, threshold detection, and odor recognition memory. A preferential decline in odor identification rather than odor detection suggests impairment in odor memory, possibly due to hippocampal dysfunction. We reported previously that impaired odor identification in (very) early PD is more closely correlated with hippocampal than striatal dopaminergic denervation. These findings suggest that hippocampal dopaminergic denervation and/or dysfunction may contribute to PD hyposmia. Olfactory impairments, however, are not affected by dopaminergic medications, and do not correlate with PD disease stage or duration of motor features of PD. This suggests an early "floor" phenomenon in the effect of dopaminergic denervation on hyposmia. Hyposmia occurs also in Alzheimer disease (AD) and increases with severity of dementia. Higher density of entorhinal cortex and hippocampal neurofibrillary tangles correlates with greater odor identification deficits, suggesting a role for hippocampal formation dysfunction in AD hyposmia. Another contributor to AD hippocampal dysfunction is loss of basal forebrain cholinergic innervation, an early phenomenon in AD. Cholinergic system degeneration is an early feature of PD also, at least in a subset of patients, and worsens with the appearance of dementia. Most studies of olfaction and PD are cross-sectional in nature and do not include subjects with cognitive impairment. However, worsening hyposmia in advancing PD may be associated with cholinergic neuron degeneration and associated cognitive dysfunction. Our preliminary data indicates correlation between the severity of PD hyposmia and declining hippocampal cholinergic innervation. PD hyposmia is predicted, then, to be most marked in PD subjects with evidence of early cognitive dysfunction;a prediction borne out by our preliminary data. The goals of this prospective cohort study are to test 2 hypotheses. One, greater severity of hyposmia is associated with increased risk of cognitive decline in subjects with advancing PD. Two, worsening hyposmia parallels progressive cholinergic hippocampal denervation. If these hypotheses are confirmed, olfactory function evaluations may provide a unique biomarker for efficient clinical screening to identify PD subjects with a central cholinergic deficit at high risk for cognitive decline. PUBLIC HEALTH RELEVANCE: Non-motor features such as dementia, are major determinants of disability and reduced health- related quality of life in Parkinson disease. Olfactory testing, perhaps combined with other tests, could be used to identify Parkinson disease subjects at high risk for cognitive decline. Results of this project may provide the foundation for unique biomarker information to guide annual clinical smell test screening in clinical practice - a window to guide targeted intervention in subjects with a central cholinergic deficit at highest risk of dementia.
Funding Period: ----------------2010 - ---------------2015-
more information: NIH RePORT

Top Publications

  1. pmc The cholinergic system and Parkinson disease
    Nicolaas I Bohnen
    Department of Radiology, University of Michigan, Ann Arbor, MI, USA
    Behav Brain Res 221:564-73. 2011
  2. pmc Diabetes is associated with postural instability and gait difficulty in Parkinson disease
    Vikas Kotagal
    Department of Neurology, University of Michigan, Ann Arbor, MI, USA
    Parkinsonism Relat Disord 19:522-6. 2013
  3. pmc Cholinergic dysfunction in Parkinson's disease
    Martijn L T M Muller
    Functional Neuroimaging, Cognitive, and Mobility Laboratory, Department of Radiology, Division of Nuclear Medicine, University of Michigan, 24 Frank Lloyd Wright Dr, Box 362, Ann Arbor, MI 48105, USA
    Curr Neurol Neurosci Rep 13:377. 2013
  4. pmc Thalamic cholinergic innervation and postural sensory integration function in Parkinson's disease
    Martijn L T M Muller
    1 Department of Radiology, University of Michigan, Ann Arbor, MI, USA
    Brain 136:3282-9. 2013
  5. pmc Risky driving and pedunculopontine nucleus-thalamic cholinergic denervation in Parkinson disease
    Shiao Pei S Weathers
    Department of Neurology, University of Michigan, Ann Arbor, MI, USA
    Parkinsonism Relat Disord 20:13-6. 2014
  6. pmc The pattern of striatal dopaminergic denervation explains sensorimotor synchronization accuracy in Parkinson's disease
    Nathaniel S Miller
    Department of Physical Medicine and Rehabilitation, University of Michigan, 325 East Eisenhower Parkway, Ann Arbor, MI 48109 1109, United States School of Kinesiology, University of Michigan, 1402 Washington Heights, Ann Arbor, MI 48109 2013, United States Electronic address
    Behav Brain Res 257:100-10. 2013
  7. pmc Gait speed in Parkinson disease correlates with cholinergic degeneration
    Nicolaas I Bohnen
    From the Department of Radiology, Division of Nuclear Medicine N I B, K A F, R A K, P J H S, M L T M M, and Department of Neurology N I B, K A F, V K, R L A, University of Michigan Neurology Service and GRECC N I B, R L A, VAAAHS, Ann Arbor, MI and Department of Internal Medicine S S, Division of Geriatrics, University of Pittsburgh, PA
    Neurology 81:1611-6. 2013
  8. pmc Dopamine overdose hypothesis: evidence and clinical implications
    David E Vaillancourt
    Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA Department of Neurology, University of Florida, Gainesville, Florida, USA Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
    Mov Disord 28:1920-9. 2013
  9. pmc Imaging: What can it tell us about parkinsonian gait?
    Nicolaas I Bohnen
    Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA Neurology Service and Geriatric Research, Education, and Clinical Center, VA Ann Arbor Healthcare System, Ann Arbor, Michigan, USA
    Mov Disord 28:1492-500. 2013
  10. pmc In vivo neurochemical imaging of olfactory dysfunction in Parkinson's disease
    Nicolaas I Bohnen
    Department of Radiology, University of Michigan, Ann Arbor, MI, USA
    J Neural Transm 120:571-6. 2013

Scientific Experts

  • NICOLAAS IDA BOHNEN
  • Vikas Kotagal
  • Martijn L T M Muller
  • Robert A Koeppe
  • Roger L Albin
  • Kirk A Frey
  • Myria Petrou
  • Kelvin L Chou
  • Shiao Pei S Weathers
  • David E Vaillancourt
  • Nathaniel S Miller
  • Youngbin Kwak
  • Irene M Lelieveld
  • Daniel Schonfeld
  • Peter J H Scott
  • Rachael D Seidler
  • Praveen Dayalu
  • Rachael Seidler
  • Ronald D Chervin

Detail Information

Publications22

  1. pmc The cholinergic system and Parkinson disease
    Nicolaas I Bohnen
    Department of Radiology, University of Michigan, Ann Arbor, MI, USA
    Behav Brain Res 221:564-73. 2011
    ....
  2. pmc Diabetes is associated with postural instability and gait difficulty in Parkinson disease
    Vikas Kotagal
    Department of Neurology, University of Michigan, Ann Arbor, MI, USA
    Parkinsonism Relat Disord 19:522-6. 2013
    ..Whether diabetes contributes to increased motor dysfunction in Parkinson disease by exacerbating nigrostriatal dopaminergic denervation or through intensification of extranigral pathology is unknown...
  3. pmc Cholinergic dysfunction in Parkinson's disease
    Martijn L T M Muller
    Functional Neuroimaging, Cognitive, and Mobility Laboratory, Department of Radiology, Division of Nuclear Medicine, University of Michigan, 24 Frank Lloyd Wright Dr, Box 362, Ann Arbor, MI 48105, USA
    Curr Neurol Neurosci Rep 13:377. 2013
    ..Recognition of the increased clinical role of cholinergic system degeneration may motivate new research to expand indications for cholinergic therapy in PD. ..
  4. pmc Thalamic cholinergic innervation and postural sensory integration function in Parkinson's disease
    Martijn L T M Muller
    1 Department of Radiology, University of Michigan, Ann Arbor, MI, USA
    Brain 136:3282-9. 2013
    ....
  5. pmc Risky driving and pedunculopontine nucleus-thalamic cholinergic denervation in Parkinson disease
    Shiao Pei S Weathers
    Department of Neurology, University of Michigan, Ann Arbor, MI, USA
    Parkinsonism Relat Disord 20:13-6. 2014
    ..It is unknown whether driving difficulty in Parkinson disease (PD) is attributable to nigrostriatal dopaminergic or extranigral non-dopaminergic neurodegeneration...
  6. pmc The pattern of striatal dopaminergic denervation explains sensorimotor synchronization accuracy in Parkinson's disease
    Nathaniel S Miller
    Department of Physical Medicine and Rehabilitation, University of Michigan, 325 East Eisenhower Parkway, Ann Arbor, MI 48109 1109, United States School of Kinesiology, University of Michigan, 1402 Washington Heights, Ann Arbor, MI 48109 2013, United States Electronic address
    Behav Brain Res 257:100-10. 2013
    ....
  7. pmc Gait speed in Parkinson disease correlates with cholinergic degeneration
    Nicolaas I Bohnen
    From the Department of Radiology, Division of Nuclear Medicine N I B, K A F, R A K, P J H S, M L T M M, and Department of Neurology N I B, K A F, V K, R L A, University of Michigan Neurology Service and GRECC N I B, R L A, VAAAHS, Ann Arbor, MI and Department of Internal Medicine S S, Division of Geriatrics, University of Pittsburgh, PA
    Neurology 81:1611-6. 2013
    ..We investigated dopaminergic and cholinergic correlates of gait speed in Parkinson disease (PD) and non-PD control subjects to test the hypothesis that gait dysfunction in PD may result from multisystem degeneration...
  8. pmc Dopamine overdose hypothesis: evidence and clinical implications
    David E Vaillancourt
    Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA Department of Neurology, University of Florida, Gainesville, Florida, USA Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
    Mov Disord 28:1920-9. 2013
    ..These tasks may continue to be relevant as our society moves to increased technological demands of a digital world that requires newly learned motor sequences and adaptive behaviors to manage daily life activities...
  9. pmc Imaging: What can it tell us about parkinsonian gait?
    Nicolaas I Bohnen
    Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA Neurology Service and Geriatric Research, Education, and Clinical Center, VA Ann Arbor Healthcare System, Ann Arbor, Michigan, USA
    Mov Disord 28:1492-500. 2013
    ....
  10. pmc In vivo neurochemical imaging of olfactory dysfunction in Parkinson's disease
    Nicolaas I Bohnen
    Department of Radiology, University of Michigan, Ann Arbor, MI, USA
    J Neural Transm 120:571-6. 2013
    ..We will discuss also the utility of olfactory testing as an early screening test for neurodegeneration...
  11. pmc β-Amyloid and postural instability and gait difficulty in Parkinson's disease at risk for dementia
    Martijn L T M Muller
    Department of Radiology, University of Michigan, Ann Arbor, Michigan 48105, USA
    Mov Disord 28:296-301. 2013
    ..This finding may explain why the PIGD motor phenotype is a risk factor for the development of PDD...
  12. pmc Rhinorrhea: a common nondopaminergic feature of Parkinson's disease
    Kelvin L Chou
    Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
    Mov Disord 26:320-3. 2011
    ..02). Rhinorrhea is a common nondopaminergic feature of PD, unrelated to olfactory or motor deficits. Further investigations are needed to determine if rhinorrhea correlates with sympathetic denervation or other autonomic symptoms in PD...
  13. pmc Heterogeneity of cholinergic denervation in Parkinson's disease without dementia
    Nicolaas I Bohnen
    Department of Radiology, Division of Nuclear Medicine, University of Michigan, Ann Arbor, Michigan 48105 9755, USA
    J Cereb Blood Flow Metab 32:1609-17. 2012
    ..Results also show independent cognitive effects for both cholinergic and dopaminergic system changes in nondemented PD subjects...
  14. pmc The role of serotonin in sleep disordered breathing associated with Parkinson disease: a correlative [11C]DASB PET imaging study
    Irene M Lelieveld
    Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands
    PLoS ONE 7:e40166. 2012
    ..Neither serotoninergic nor dopaminergic neuron degeneration is likely to play a major role in SDB observed in PD patients...
  15. pmc Aβ-amyloid deposition in patients with Parkinson disease at risk for development of dementia
    Myria Petrou
    Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD, USA
    Neurology 79:1161-7. 2012
    ..The aim of our study was to examine the relationship between corticostriatal Aβ-amyloid deposition and cognitive dysfunction in a cohort of patients with Parkinson disease (PD) at risk for dementia...
  16. pmc Modifiable cardiovascular risk factors and axial motor impairments in Parkinson disease
    Vikas Kotagal
    From the Departments of Neurology V K, R L A, K A F, N I B and Radiology M L T M M, R A K, K A F, N I B, University of Michigan and the Neurology Service and GRECC R L A, N I B, VAAAHS, Ann Arbor, MI
    Neurology 82:1514-20. 2014
    ..Cardiovascular comorbidities associate with neurodegeneration in the elderly and may contribute to extranigral pathologies and medically refractory axial motor features in Parkinson disease (PD)...
  17. pmc Symptoms of rapid eye movement sleep behavior disorder are associated with cholinergic denervation in Parkinson disease
    Vikas Kotagal
    Department of Neurology, University of Michigan, Ann Arbor, USA
    Ann Neurol 71:560-8. 2012
    ..RBD and cholinergic system degeneration are identified independently as risk factors for cognitive impairment in PD. We aimed to assess the association between cholinergic denervation and symptoms of RBD in PD patients without dementia...
  18. pmc Thalamic cholinergic innervation is spared in Alzheimer disease compared to parkinsonian disorders
    Vikas Kotagal
    Department of Neurology, University of Michigan, Ann Arbor, MI 48105, USA
    Neurosci Lett 514:169-72. 2012
    ..Thalamic cholinergic denervation is present in PD, PDD, and DLB but not in AD. Neurodegenerative involvement of thalamic cholinergic afferent projections may contribute to disease-specific motor and cognitive abnormalities...
  19. pmc Leucoaraiosis, nigrostriatal denervation and motor symptoms in Parkinson's disease
    Nicolaas I Bohnen
    Department of Radiology and Neurology, University of Michigan, Ann Arbor, MI 48105 9755, USA
    Brain 134:2358-65. 2011
    ..Comorbid white matter disease is a greater determinant of axial motor impairment than nigrostriatal dopaminergic denervation...