Associations of Peripheral Neuropathy Defined by Monofilament Insensitivity with Mild Cognitive Impairment and Dementia in Older Adults

Introduction: The aim of this study was to assess the association of peripheral neuropathy (PN) as defined by monofilament insensitivity with mild cognitive impairment (MCI) and dementia in older adults with and without diabetes. Methods: We conducted a cross-sectional analysis of 3,362 Black and White participants in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) who underwent monofilament testing at visit 6 (2016–2017, age 71–94 years). Participants’ cognitive status was classified by an adjudication committee as cognitively normal, MCI, or dementia after completing a comprehensive battery of neurocognitive assessments. We used logistic regression to evaluate the association of PN with MCI or dementia overall and stratified by diabetes status after adjusting for traditional dementia risk factors. We also compared age-adjusted brain MRI measures among a subset (N = 1,095) of participants with versus without PN. Results: Overall, the prevalence of MCI (21.9% vs. 16.7%) and dementia (7.8% vs. 3.9%) were higher among participants with versus without PN (both p < 0.05). After adjustment, PN was positively associated with MCI or dementia in the overall study population (OR 1.45, 95% CI 1.23, 1.73). Results were similar by diabetes status (diabetes: OR 1.38, 95% CI 1.03–1.87; no diabetes: OR 1.48, 95% CI 1.20–1.83; p-for-interaction = 0.46). Age-adjusted total and lobar brain volumes were significantly lower in participants with versus without PN (both, p < 0.05). Discussion/Conclusions: PN as defined by monofilament insensitivity was associated with cognitive status independent of vascular risk factors and regardless of diabetes status. Our findings support a connection between PN and cognitive impairment, even in the absence of diabetes.

[1]  K. Matsushita,et al.  Prevalence of peripheral neuropathy defined by monofilament insensitivity in middle-aged and older adults in two US cohorts , 2021, Scientific Reports.

[2]  B. Morel,et al.  Pedobarographic Statistical Parametric Mapping may identify specific plantar pressure patterns in patients with diabetes mellitus among different degrees of peripheral neuropathy: A pilot study , 2021, Diabetic medicine : a journal of the British Diabetic Association.

[3]  M. Montero‐Odasso,et al.  Gait variability across neurodegenerative and cognitive disorders: Results from the Canadian Consortium of Neurodegeneration in Aging (CCNA) and the Gait and Brain Study , 2021, Alzheimer's & dementia : the journal of the Alzheimer's Association.

[4]  E. Selvin,et al.  Association of Peripheral Neuropathy with Erectile Dysfunction in US Men. , 2020, The American journal of medicine.

[5]  E. Selvin,et al.  Epidemiology of Peripheral Neuropathy and Lower Extremity Disease in Diabetes , 2019, Current Diabetes Reports.

[6]  M. Albert,et al.  The Association of Late-Life Diabetes Status and Hyperglycemia With Incident Mild Cognitive Impairment and Dementia: The ARIC Study , 2019, Diabetes Care.

[7]  Yun Huang,et al.  Type 1 diabetes-associated cognitive impairment and diabetic peripheral neuropathy in Chinese adults: results from a prospective cross-sectional study , 2019, BMC Endocrine Disorders.

[8]  C. Jack,et al.  Neural correlates of domain-specific cognitive decline , 2019, Neurology.

[9]  Yuguang Huang,et al.  Functional magnetic resonance imaging reveals differences in brain activation in response to thermal stimuli in diabetic patients with and without diabetic peripheral neuropathy , 2018, PloS one.

[10]  C. Jack,et al.  Diabetes, Prediabetes, and Brain Volumes and Subclinical Cerebrovascular Disease on MRI: The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) , 2017, Diabetes Care.

[11]  P. Sandercock,et al.  Cerebral White Matter Hypoperfusion Increases with Small-Vessel Disease Burden. Data From the Third International Stroke Trial. , 2017, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[12]  R. Freeman,et al.  Diabetic Neuropathy: A Position Statement by the American Diabetes Association , 2016, Diabetes Care.

[13]  Colin L. Masters,et al.  A Conceptualization of the Utility of Subjective Cognitive Decline in Clinical Trials of Preclinical Alzheimer’s Disease , 2016, Journal of Molecular Neuroscience.

[14]  I. Wilkinson,et al.  Diabetic peripheral neuropathy may not be as its name suggests: evidence from magnetic resonance imaging , 2016, Pain.

[15]  M. Albert,et al.  Mild cognitive impairment and dementia prevalence: The Atherosclerosis Risk in Communities Neurocognitive Study , 2016, Alzheimer's & dementia.

[16]  L. Wolfson,et al.  Cardiovascular risk factors and small vessel disease of the brain: Blood pressure, white matter lesions, and functional decline in older persons , 2016, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[17]  Clifford R Jack,et al.  Obesity, Insulin Resistance, and Incident Small Vessel Disease on Magnetic Resonance Imaging: Atherosclerosis Risk in Communities Study , 2015, Stroke.

[18]  S. Mangia,et al.  Impact of diabetes on cognitive function and brain structure , 2015, Annals of the New York Academy of Sciences.

[19]  R. Moreira,et al.  Is cognitive impairment associated with the presence and severity of peripheral neuropathy in patients with type 2 diabetes mellitus? , 2015, Diabetology & Metabolic Syndrome.

[20]  Richard Frayne,et al.  Early Cerebral Small Vessel Disease and Brain Volume, Cognition, and Gait , 2015, Annals of neurology.

[21]  M. Albert,et al.  Diabetes in Midlife and Cognitive Change Over 20 Years , 2014, Annals of Internal Medicine.

[22]  Nick C Fox,et al.  Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration , 2013, The Lancet Neurology.

[23]  M. Szklo,et al.  Risk factors for lacune subtypes in the Atherosclerosis Risk in Communities (ARIC) Study , 2012, Neurology.

[24]  R. Sperling,et al.  Specific Subjective Memory Complaints in Older Persons May Indicate Poor Cognitive Function , 2011, Journal of the American Geriatrics Society.

[25]  I. Wilkinson,et al.  Central Nervous System Involvement in Diabetic Neuropathy , 2011, Current diabetes reports.

[26]  Nick C Fox,et al.  The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[27]  J. Morris,et al.  The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[28]  M. Strachan R D Lawrence Lecture 2010 ^ . The brain as a target organ in Type 2 diabetes: exploring the links with cognitive impairment and dementia , 2011, Diabetic medicine : a journal of the British Diabetic Association.

[29]  Hugh S Markus,et al.  Brain Atrophy and Cerebral Small Vessel Disease: A Prospective Follow-Up Study , 2011, Stroke.

[30]  D. Knopman,et al.  Vascular risk factors and longitudinal changes on brain MRI The ARIC study , 2011 .

[31]  L. S. Tan The clinical use of the 10g monofilament and its limitations: a review. , 2010, Diabetes research and clinical practice.

[32]  Richard B. Lipton,et al.  Neurological gait abnormalities and risk of falls in older adults , 2010, Journal of Neurology.

[33]  M. Engelgau,et al.  Prevalence of lower extremity diseases associated with normal glucose levels, impaired fasting glucose, and diabetes among U.S. adults aged 40 or older. , 2007, Diabetes research and clinical practice.

[34]  Gary A. Ford,et al.  Brain atrophy and white matter hyperintensity change in older adults and relationship to blood pressure , 2007, Journal of Neurology.

[35]  A. Folsom,et al.  Cerebral MRI findings and cognitive functioning , 2005, Neurology.

[36]  G. Gronseth,et al.  Distal symmetric polyneuropathy: A definition for clinical research , 2005, Neurology.

[37]  E. Barrett-Connor,et al.  Diabetes, impaired fasting glucose, and development of cognitive impairment in older women , 2004, Neurology.

[38]  G. Mcclearn,et al.  Type 2 diabetes mellitus contributes to cognitive decline in old age: A longitudinal population-based study , 2004, Journal of the International Neuropsychological Society.

[39]  T. Strandberg,et al.  Predictors of cognitive decline and mortality of aged people over a 10-year period. , 2004, The journals of gerontology. Series A, Biological sciences and medical sciences.

[40]  P. Sönksen,et al.  A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population , 1993, Diabetologia.

[41]  B. Liu,et al.  Role of Nitric Oxide in Inflammation‐Mediated Neurodegeneration , 2002, Annals of the New York Academy of Sciences.

[42]  A. Dale,et al.  Whole Brain Segmentation Automated Labeling of Neuroanatomical Structures in the Human Brain , 2002, Neuron.

[43]  A. Hofman,et al.  Prevalence and Risk Factors of Silent Brain Infarcts in the Population-Based Rotterdam Scan Study , 2002, Stroke.

[44]  C. Jack,et al.  FLAIR histogram segmentation for measurement of leukoaraiosis volume , 2001, Journal of magnetic resonance imaging : JMRI.

[45]  W. Schady,et al.  Sural nerve fibre pathology in diabetic patients with mild neuropathy: relationship to pain, quantitative sensory testing and peripheral nerve electrophysiology , 2001, Acta Neuropathologica.

[46]  J. Rabe-Jabłońska,et al.  [Affective disorders in the fourth edition of the classification of mental disorders prepared by the American Psychiatric Association -- diagnostic and statistical manual of mental disorders]. , 1993, Psychiatria polska.

[47]  S. Ropele,et al.  Risk factors for progression of brain atrophy in aging Six-year follow-up of normal subjects , 2022 .