Relationship between Persistent Dizziness and Markers of Alzheimer's disease – Mayo Clinic Study of Aging

Persistent dizziness or lightheadedness ranks among the most frequent complaints in 2 primary care. Persistent dizziness is frequently described as a consequence or side effect of 3 defined entities such as cardiovascular, infectious, neurological, and otological disease. Persistent dizziness is potentially disabling and has a distinct impact on participation, 5 psychosocial interaction, and quality of life. We examined the relationship between persistent 6 dizziness or lightheadedness and Alzheimer's disease (AD) markers among 924 individuals aged ≥50 years (52.3% male, mean age 74 years) selected from 5707 individuals who participated in 8 the population-based Mayo Clinic Study of Aging 9 Neuropsychiatric symptoms (depression and anxiety), cognitive evaluation (overall and across 10 multiple domains), magnetic resonance imaging for AD-signature "regional thickness," and 11 11Carbon-Pittsburgh compound B positron emission tomography ( 11 C-PiB PET) for Amyloid 12 deposition are all investigated. Significant contributing factors to persistent dizziness in older 13 adults were found and include [age, sex (male), lower education, high comorbidity index, high- 14 density lipoprotein, balance problems, neuropsychiatric symptoms, cognitive impairments, and 15 AD-signature ” regional thickness]. After adjusting for age, sex, education, medical 16 comorbidities, and other variables, a statistically significant association between persistent 17 dizziness/lightheadedness and neuropsychiatric symptoms, and Amyloid- β deposition. This 18 finding implies that the underlying AD biology may drive both the neuropsychiatric symptoms 19 and persistent dizziness or lightheadedness, even before the onset of cognitive impairments and 20 dementia. Further studies are needed to support the findings. This study aimed to examine the relationship between persistent dizziness and AD markers. A study highlighted that the elderly men with lower education, high comorbidity index, 6 high-density lipoprotein, balance problems, neuropsychiatric symptoms, cognitive impairments, 7 and AD markers have a higher risk of persistent dizziness or lightheadedness. After adjusting for 8 age, sex, education, and other variables, our study showed that there is a significant albeit weak 9 association between neuropsychiatric symptoms and risk of persistent dizziness/lightheadedness, but the probability of positive association between persistent dizziness/lightheadedness and elevated brain Amyloid- β deposition was 1.8 times. This implies that the underlying AD biology may drive both the neuropsychiatric symptoms (depression and anxiety) and persistent dizziness or lightheadedness, even before the onset of cognitive impairments and dementia.

The author declares that there is no potential conflicts of interest or lack thereof. Dizziness is a subjective perception of disorientation or involuntary motion that occurs 2 during head or body movement or when the head or body. Dizziness can be further characterized 3 as lightheadedness, which is the sensation of impending loss of consciousness associated with 4 transient diffuse cerebral hypoperfusion. Dizziness and/or lightheadedness is frequently described 5 as a consequence or side effect of defined entities such as cardiovascular, neurological, 6 psychiatric, and neuro-otologic disease. Persistent dizziness and/or lightheadedness, which lasts 7 for three months or more, ranks among the most frequent complaints in primary care as it can be 8 easily provoked by physical activities (i.e., postural change and head and neck movement, Active 9 or passive motion of self ) or environmental or social stimuli (i.e., crowds) or behavioral factors 10 (i.e., high level of anxiety, introverted temperaments, or pre-existing anxiety or depressive 11 disorder) (Sloane, Hartman, & Mitchell, 1994;Tinetti, Williams, & Gill, 2000). In clinical 12 practice, persistent dizziness/lightheadedness lacks uniform criteria for its classification and 13 definition, especially when not better accounted for by vestibular diagnosis (Bösner et al., 2018;14 Iwasaki & Yamasoba, 2014). If left ignored or untreated, persistent dizziness/lightheadedness 15 becomes a potentially disabling disorder that has a distinct impact on participation, psychosocial 16 interaction, and quality of life.

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Previous studies have reported that dizziness may be associated with various cognitive 18 functions including, memory impairment using various cognitive tasks and structural and 19 functional neuroimaging. Alzheimer's disease (AD) is a neurodegenerative pathology that leads 20 to behavioral and changes in memory loss and is ultimately fatal (Alzheimer's Association, 2016).

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One hypothesis for the pathogenesis of AD is the excessive extracellular Amyloid-β plaque 22 deposition, which occurs years before the onset of symptoms and is associated with brain cell 23 death (Jack et al., 2018). Amyloid-β accumulation, which can be detected by 11 Carbon-Pittsburgh 24 compound B positron emission tomography ( 11 C-PiB PET) imaging, causes synaptic dysfunction 1 due to either a breakdown of Amyloid-β clearance or Amyloid-β overproduction (Hatsuta et al., 2 2015). The increased use of 11 C-PiB PET imaging has led to the observation that Amyloid-β is 3 also present in approximately one-third of cognitively normal older adults (Mintun et al., 2006;4 Resnick et al., 2010). A high level of Amyloid-β deposition was found to be associated with 5 deficits in spatial cognition, such as spatial memory and navigation, depression and anxiety, and 6 increased risk of progression to AD (Baker et al., 2017;Mintun et al., 2006;Resnick et al., 2010).

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In addition, the application of structural magnetic resonance imaging (MRI) has revealed a 8 specific pattern of cortical thinning among older adults that appears to be associated with AD risk 9 and progression. This pattern, known as the AD cortical signature, has consistently been found in 10 medial and lateral temporoparietal regions (d'Oleire Uquillas et al., 2017;Dickerson et al., 2009;11 Jack et al., 2008;Jack et al., 2009). Noteworthy, a major projection to this brain area emanates 12 from the semicircular canals of the vestibular labyrinth, with vestibular damage leading to severe 13 degeneration of the medial-temporal region.
14 Vestibular loss as a contributor to the burden of the AD process has been reported in the 15 literature (Harun, Oh, Bigelow, Studenski, & Agrawal, 2016;Nakamagoe et al., 2015;Previc, 16 2013;Smith, 2013). Given that patients with or who are at risk of AD may experience increased 17 rates of vestibular dysfunction, the relationship between AD markers and persistent dizziness 18 remains to be investigated. This study aimed to examine the relationship between persistent 19 dizziness and AD markers. Briefly, all participants of MCSA underwent a face-to-face evaluation including a 5 neurological examination performed by a physician, a risk factor ascertainment conducted by a 6 study coordinator, and standardized neuropsychological testing administered by a psychometrist to 7 assess four cognitive domains (i.e., memory, language, visuospatial skills, executive functions). respectively. The severity of each symptom is rated on an ordinal scale ranging from 0 (low) to 3 17 (high). The total score for both BDI-II and BAI ranges from 0 to 63, with a higher score indicating 18 a higher severity of symptoms.

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Imaging 20 Participants completed MRI and PET scans at a single visit. All MRI scans were 21 completed on one of three General Electric 3T scanners using a sagittal 3D magnetization 22 prepared rapid acquisition gradient recalled echo (MP-RAGE) sequence. Repetition time (TR) was 23 ≈2,300 ms, echo time (TE) ≈3 ms, and inversion time (TI) = 900 ms. Voxel dimensions were ≈1.2 24 × 1.015 × 1.015 mm. Gradient distortion in the sagittal plane was performed on-scanner, and a 1 through-plane correction was performed as part of image processing. Intensity inhomogeneity was 2 corrected using first the N3 algorithm, followed by the SPM5-based bias correction. From these 3 preprocessed images, the cortical surface was segmented, and cortical thickness values were 4 estimated using FreeSurfer version 5.3.0. Cortical thickness estimations were then resampled from 5 FreeSurfer outputs to the input images' native space using FreeSurfer tools.  224 NC). For the analytical assessment of neurocognitive testing and 11 C-PiB PET imaging, the 20 raw scores or tests in each cognitive domain were z-scored, averaged, and scaled to create domain-21 specific cognitive z-scores. Besides, a global z-score for overall cognitive performance was also 22 created by averaging and scaling the four-domain z-scores. Hazard ratios (HR) for potential risk 23 factors for each of the follow-up endpoints were obtained using Cox proportional hazards models.

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Univariate as well as multivariate models were assessed. Multivariate relationships were evaluated 1 adjusting for age, sex, years of education, and other comorbidities. All analyses were considered 2 statistically significant at a P-value <0.05 and were performed using the SAS statistical software 3 version 9.4 (SAS Institute, Cary, North Carolina).

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Demographics and presence of persistent dizziness or lightheadedness 6 The MCSA sample consisted of 5707 participants, of whom 924 who aged ≥ 50 years 7 (52.3% male, mean age 74 years) had reported persistent dizziness/lightheadedness during the 8 follow-up time, which was 14.5 years. For simplification, the 14 years were divided into five 9 events (1 year +/-6months; 3 years; 5 years; 7 years; and 10 +/-2 years). The risk of persistent 10 dizziness/lightheadedness during the follow-up period after the initial visit to the study was 11 estimated using the Kaplan-Meier method. The estimated risk of developing symptoms of 12 dizziness/lightheadedness at 10 years was 49%. Figure 1 represents the survival curve. Participants' characteristics by significant dizziness/lightheadedness at baseline using 14 Wilcoxon signed-rank test or χ2 test as appropriate are presented in Table 1. The potential risk 15 factors for persistent dizziness/lightheadedness over time are presented in Table 2. These include  Table 4.

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This study aimed to examine the relationship between persistent dizziness and AD 5 markers. A study highlighted that the elderly men with lower education, high comorbidity index, 6 high-density lipoprotein, balance problems, neuropsychiatric symptoms, cognitive impairments, 7 and AD markers have a higher risk of persistent dizziness or lightheadedness. After adjusting for 8 age, sex, education, and other variables, our study showed that there is a significant albeit weak 9 association between neuropsychiatric symptoms and risk of persistent dizziness/lightheadedness, 10 but the probability of positive association between persistent dizziness/lightheadedness and 11 elevated brain Amyloid-β deposition was 1.8 times. This implies that the underlying AD biology 12 may drive both the neuropsychiatric symptoms (depression and anxiety) and persistent dizziness 13 or lightheadedness, even before the onset of cognitive impairments and dementia. 1.08 for anxiety and (OR = 1.03; 1.00-1.06) for depression] and elevated brain Amyloid 23 deposition in cognitively normal elderly people (Krell-Roesch et al., 2018). However, when 24 compared to mild cognitive impairment without brain Amyloid-deposition, the elderly with mild 1 cognitive impairment and brain Amyloid-deposition were found to have an increased risk of 2 having neuropsychiatric symptoms. This implies that the underlying AD biology (i.e., brain 3 Amyloid-β deposition) may drive both cognitive and psychiatric symptoms 4 2019). Similarly, a study investigated whether current depressive symptoms are related to brain 5 Amyloid-β deposition (Chung et al., 2016). After controlling for potential confounds, including 6 the history of major depression, they found that current depressive symptoms were not related to 7 brain Amyloid-β deposition. Fourth, a previous study using the Baltimore Longitudinal Study of 8 Aging examined a relationship between measures of vestibular function and brain Amyloid-β 9 deposition in cognitively intact older adults who have peripheral dizziness/vertigo (Kamil, Bilgel, 10 Wong, Resnick, & Agrawal, 2018). While that study did not observe a significant relationship 11 between the two, a study found that the proportion of central dizziness/vertigo tends to increase 12 with dementia (Lee, 2020). In our study, the tendency of the peripheral cause of dizziness was not 13 observed in their medical records. Significant contributing factors to persistent dizziness in older adults were found and 3 include [age, sex (male), lower education, high comorbidity index, high-density lipoprotein, 4 balance problems, neuropsychiatric symptoms, cognitive impairments, and AD-signature regional 5 thickness]. After adjusting for age, sex, education, medical comorbidities, and other variables, a 6 statistically significant association between persistent dizziness/lightheadedness and 7 neuropsychiatric symptoms, and Amyloid-β deposition. This finding implies that the underlying 8 AD biology may drive both the neuropsychiatric symptoms and persistent dizziness or 9 lightheadedness, even before the onset of cognitive impairments and dementia. Further studies are 10 needed to support the findings. The cortical signature of Alzheimer's disease: regionally specific cortical thinning relates to 29 symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloid-30 positive individuals. Hatsuta, H., Takao (2000). Dizziness among older adults: a possible geriatric 6 syndrome. Ann Intern Med, 132(5), 337-344. doi:10.7326/0003-4819-132-5-200003070-00002 7 Yasuno, F., Kazui, H., Morita, N., Kajimoto, K., Ihara, M., Taguchi, A., . . . Nagatsuka, K. (2016). High 8 amyloid-β deposition related to depressive symptoms in older individuals with normal cognition: 9 a pilot study. Int J Geriatr Psychiatry, 31 (8)    159 AD-signature thickness, mm 2.7 (0.2); 2.7 2.7 (0.2); 2.7 2.6 (0.1); 2.7 0.077 Note: data presented as N (%) for categorical and mean (SD); median for continuous characteristics. a 25 missing. b 465 missing data. d Global cognitive z-score was computed after scaling raw cognitive test scores (mean 0 ± 1) using data for cognitively unimpaired participants at baseline. Domain-specific z-scores were summed and scaled to obtain global z-scores.  Table 3. Neuropsychiatric symptoms, Cognitive evaluation, and AD-biomarkers by follow-up events as compared to baseline. (N=1152) 2.6 (0.2) ** 2.6 (N=1216) 2.6 (0.2) ** 2.6 (N=511) 2.6 (0.2) ** 2.6 (N=511) 2.6 (0.2) ** 2.6 (N=78) 2.5 (0.2) ** 2.6