Data_Sheet_1_Autonomic function predicts cognitive decline in mild cognitive impairment: Evidence from power spectral analysis of heart rate variability in a longitudinal study.docx

BackgroundDespite the emerging clinical relevance of heart rate variability (HRV) as a potential biomarker of cognitive decline and as a candidate target for intervention, there is a dearth of research on the prospective relationship between HRV and cognitive change. In particular, no study has addressed this issue in subjects with a diagnosis of cognitive status including cognitive impairment.ObjectiveTo investigate HRV as a predictor of cognitive decline in subjects with normal cognition (NC) or Mild Cognitive Impairment (MCI). Specifically, we tested the literature-based hypothesis that the HRV response to different physical challenges would predict decline in different cognitive domains.MethodsThis longitudinal study represents the approximately 3-year follow-up of a previous cross-sectional study enrolling 80 older outpatients (aged ≥ 65). At baseline, power spectral analysis of HRV was performed on five-minute electrocardiographic recordings at rest and during a sympathetic (active standing) and a parasympathetic (paced breathing) challenge. We focused on normalized HRV measures [normalized low frequency power (LFn) and the low frequency to high frequency power ratio (LF/HF)] and on their dynamic response from rest to challenge (Δ HRV). Extensive neuropsychological testing was used to diagnose cognitive status at baseline and to evaluate cognitive change over the follow-up via annualized changes in cognitive Z-scores. The association between Δ HRV and cognitive change was explored by means of linear regression, unadjusted and adjusted for potential confounders.ResultsIn subjects diagnosed with MCI at baseline a greater response to a sympathetic challenge predicted a greater decline in episodic memory [adjusted model: Δ LFn, standardized regression coefficient (β) = −0.528, p = 0.019; Δ LF/HF, β = −0.643, p = 0.001] whereas a greater response to a parasympathetic challenge predicted a lesser decline in executive functioning (adjusted model: Δ LFn, β = −0.716, p ConclusionOur findings provide novel insight into the link between HRV and cognition in MCI. They contribute to a better understanding of the heart-brain connection, but will require replication in larger cohorts.</p

Spontaneous confabulations in amnestic-mild cognitive impairment due to Alzheimer’s disease: a new (yet old) atypical variant?

<p>Confabulation may be present in Alzheimer’s disease (AD), but usually it is not a primary feature of either its typical or atypical variants. In this report, we describe the case of an AD patient who showed an unusual and enduring neuropsychiatric phenotype characterized by early and prominent spontaneous confabulation. Surprisingly, such atypical AD presentation bears a striking resemblance to presbyophrenia, a subtype of dementia which was described at the beginning of the twentieth century and then sank into oblivion. In discussion, we speculate on the “return” of presbyophrenia as an unrecognized neuropsychiatric variant of AD and its possible neuroanatomical substrates.</p

Autonomic Dysfunction in Mild Cognitive Impairment: Evidence from Power Spectral Analysis of Heart Rate Variability in a Cross-Sectional Case-Control Study

<div><p>Background</p><p>Mild cognitive impairment (MCI) is set to become a major health problem with the exponential ageing of the world's population. The association between MCI and autonomic dysfunction, supported by indirect evidence and rich with clinical implications in terms of progression to dementia and increased risk of mortality and falls, has never been specifically demonstrated.</p><p>Aim</p><p>To conduct a comprehensive assessment of autonomic function in subjects with MCI by means of power spectral analysis (PSA) of heart rate variability (HRV) at rest and during provocative manoeuvres.</p><p>Methods</p><p>This cross-sectional study involved 80 older outpatients (aged ≥65) consecutively referred to a geriatric unit and diagnosed with MCI or normal cognition (controls) based on neuropsychological testing. PSA was performed on 5-minute electrocardiographic recordings under three conditions—supine rest with free breathing (baseline), supine rest with paced breathing at 12 breaths/minute (parasympathetic stimulation), and active standing (orthosympathetic stimulation)—with particular focus on the changes from baseline to stimulation of indices of sympathovagal balance: normalized low frequency (LFn) and high frequency (HFn) powers and the LF/HF ratio. Blood pressure (BP) was measured at baseline and during standing. Given its exploratory nature in a clinical population the study included subjects on medications with a potential to affect HRV.</p><p>Results</p><p>There were no significant differences in HRV indices between the two groups at baseline. MCI subjects exhibited smaller physiological changes in all three HRV indices during active standing, consistently with a dysfunction of the orthosympathetic system. Systolic BP after 10 minutes of standing was lower in MCI subjects, suggesting dysautonomia-related orthostatic BP dysregulation.</p><p>Conclusions</p><p>Our study is novel in providing evidence of autonomic dysfunction in MCI. This is associated with orthostatic BP dysregulation and the ongoing follow-up of the study population will determine its prognostic relevance as a predictor of adverse health outcomes.</p></div

Flow diagram of the study population.

<p>NPS: neuropsychological; NC: normal cognition (controls); MCI: mild cognitive impairment; HRV: heart rate variability.</p

Timeline of the three stages of the experimental protocol.

<p>HRV: heart rate variability.</p

Characteristics of the study subjects during the experimental session

<p>Continuous variables are expressed as mean (SD), categorical variables are expressed as n (%). Significant results are shown in bold typeface. ^a Student's t-test; ^b Mann-Whitney's U-test; ^c Chi-squared test; ^d correction for multiple testing by means of the Benjamini-Hochberg procedure with a 5% False Discovery Rate (FDR). NC: normal cognition (controls); MCI: mild cognitive impairment; SBP: systolic blood pressure; DBP: diastolic blood pressure; Δ respiratory rate: respiratory rate standing- respiratory rate baseline; VAS: visual analogue scale (score range 0–100, higher scores indicate greater stress).</p

Power spectral analysis of heart rate variability in the two groups of subjects

<p>HRV indices, expressed as mean (SD), in baseline conditions and during and in response to (Δ) provocative tests (active standing, paced breathing). Significant results are shown in bold typeface.</p>a<p>statistical analyses performed on log ₁₀ - transformed variable;</p>b<p>correction for multiple testing by means of the Benjamini-Hochberg procedure with a 5% False Discovery Rate (FDR);</p>c<p>adjustment for potential confounders by means of multiple linear regression (see text for details). NC: normal cognition (controls); MCI: mild cognitive impairment; n.u.: normalized units; LFn: low frequency power (normalized); HFn: high frequency power (normalized); LF/HF: LF to HF ratio; Δ standing: standing HRV index - baseline HRV index; Δ paced breathing: paced breathing HRV index - baseline HRV index.</p

Systolic blood pressure after 10 minutes of active standing in the two groups of subjects.

<p>Bars represent the mean and error bars represent one standard deviation (SD). ^a adjustment for potential confounders by means of multiple linear regression (see text for details). SBP: systolic blood pressure; NC: normal cognition (controls); MCI: mild cognitive impairment.</p

Baseline characteristics of the study subjects

<p>Continuous variables are expressed as mean (SD), categorical variables are expressed as n (%). Significant results are shown in bold typeface.</p>a<p>Refers to regular use. Intermittent users (n = 2 in each group) were asked to refrain from use in the two days prior to testing;</p>b<p>Student's t-test;</p>c<p>Mann-Whitney's U-test;</p>d<p>Chi-squared test;</p>e<p>Fisher's exact test. NC: normal cognition (controls); MCI: mild cognitive impairment; BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; AU: alcohol units (1 AU = 10 g of alcohol); MET: metabolic equivalent (energy expenditure index, 1 MET =  1 kcal•kg⁻¹•h⁻¹); CAD: coronary artery disease; LDL: low density lipoprotein; HDL: high density lipoprotein; LVH: left ventricular hypertrophy; IMT: intima-media thickness; ACE-Is: angiotensin converting enzyme inhibitors; ARBs: angiotensin II receptor blockers; CCBs: calcium-channel blockers; SSRIs: selective serotonin reuptake inhibitors; BADL: basic activities of daily living (score range 0–6, higher scores indicate greater functional independence); IADL: instrumental activities of daily living (score range 0–8, higher scores indicate greater functional independence); MMSE: mini mental state examination (score range 0–30, higher scores indicate better cognitive function); CIRS-s: cumulative illness rating scale severity (score range 1–5, higher scores indicate greater comorbidity); CIRS-m: cumulative illness rating scale morbidity (score range 0–13, higher scores indicate more severe comorbidity); STPI-T: state trait personality inventory- trait anxiety subscale (score range 10–40, higher scores indicate greater trait anxiety); GDS-s: geriatric depression scale short form (score range 0–15, higher scores indicate greater depressive symptoms).</p