Heart Rate Variability and Cognition: A Narrative Systematic Review of Longitudinal Studies.

BACKGROUND: Heart rate variability (HRV) is a reliable and convenient method to assess autonomic function. Cross-sectional studies have established a link between HRV and cognition. Longitudinal studies are an emerging area of research with important clinical implications in terms of the predictive value of HRV for future cognition and in terms of the potential causal relationship between HRV and cognition. However, they have not yet been the objective of a systematic review. Therefore, the aim of this systematic review was to investigate the association between HRV and cognition in longitudinal studies. METHODS: The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The Embase, PsycINFO and PubMed databases were searched from the earliest available date to 26 June 2023. Studies were included if they involved adult human subjects and evaluated the longitudinal association between HRV and cognition. The risk of bias was assessed with the Newcastle-Ottawa Scale for Cohort Studies. The results were presented narratively. RESULTS: Of 14,359 records screened, 12 studies were included in this systematic review, with a total of 24,390 participants. Two thirds of the studies were published from 2020 onwards. All studies found a longitudinal relationship between HRV and cognition. There was a consistent association between higher parasympathetic nervous system (PNS) activity and better cognition, and some association between higher sympathetic nervous system activity and worse cognition. Also, higher PNS activity persistently predicted better executive functioning, while data on episodic memory and language were more scant and/or controversial. CONCLUSIONS: Our results support the role of HRV as a biomarker of future cognition and, potentially, as a therapeutic target to improve cognition. They will need confirmation by further, more comprehensive studies also including unequivocal non-HRV sympathetic measures and meta-analyses.

Diencephalic versus Hippocampal Amnesia in Alzheimer's Disease: The Possible Confabulation-Misidentification Phenotype.

BACKGROUND: Alzheimer's disease (AD) is clinically heterogeneous, including the classical-amnesic (CA-) phenotype and some variants. OBJECTIVE: We aim to describe a further presentation we (re)named confabulation-misidentification (CM-) phenotype. METHODS: We performed a retrospective longitudinal case-series study of 17 AD outpatients with the possible CM-phenotype (CM-ADs). Then, in a cross-sectional study, we compared the CM-ADs to a sample of 30 AD patients with the CA-phenotype (CA-ADs). The primary outcome was the frequency of cognitive and behavioral features. Data were analyzed as differences in percentage by non-parametric Chi Square and mean differences by parametric T-test. RESULTS: Anterograde amnesia (100%) with early confabulation (88.2%), disorientation (88.2%) and non-infrequently retrograde amnesia (64.7%) associated with reduced insight (88.2%), moderate prefrontal executive impairment (94.1%) and attention deficits (82.3%) dominated the CM-phenotype. Neuropsychiatric features with striking misidentification (52.9%), other less-structured delusions (70.6%), and brief hallucinations (64.7%) were present. Marked behavioral disturbances were present early in some patients and very common at later stages. At the baseline, the CM-ADs showed more confabulation (p < 0.001), temporal disorientation (p < 0.02), misidentification (p = 0.013), other delusions (p = 0.002), and logorrhea (p = 0.004) than the CA-ADs. In addition, more social disinhibition (p = 0.018), reduction of insight (p = 0.029), and hallucination (p = 0.03) persisted at 12 months from baseline. Both the CA- and CM-ADs showed anterior and medial temporal atrophy. Compared to HCs, the CM-ADs showed more right fronto-insular atrophy, while the CA-ADs showed more dorsal parietal, precuneus, and right parietal atrophy. CONCLUSION: We described an AD phenotype resembling diencephalic rather than hippocampal amnesia and overlapping the past-century description of presbyophrenia.

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

Background: Despite 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. Objective: To 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. Methods: This 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. Results: In 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 (ß) = -0.528, p = 0.019; Δ LF/HF, ß = -0.643, p = 0.001] whereas a greater response to a parasympathetic challenge predicted a lesser decline in executive functioning (adjusted model: Δ LFn, ß = -0.716, p < 0.001; Δ LF/HF, ß = -0.935, p < 0.001). Conclusion: Our 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.

Ischaemic Stroke of the "Hand-Knob" Area Due to Paradoxical Cerebral Air Embolism after Central Venous Catheterization-A Doubly Rare Occurrence: A Case Report and an Overview of Pathophysiology, Diagnosis, and Treatment.

Central venous catheters (CVCs) are increasingly used across specialties for invasive haemodynamic monitoring and for the delivery of fluids, medications, and nutritional support. Cerebral air embolism (CAE) is a rare but potentially fatal complication associated with the insertion, maintenance, and removal of CVCs. It can occur through different mechanisms, including the direct retrograde ascension of air into the cerebral veins and paradoxical embolism due to a right-to-left intracardiac or intrapulmonary shunt. The "hand-knob" area is the cortical region within the primary motor cortex that contains the representation of the hand. It is located in the superior precentral gyrus and is the site of less than 1% of all ischaemic strokes. We report here the case of a patient who experienced an ischaemic stroke of the right "hand-knob" area, due to paradoxical CAE through a previously undiagnosed patent foramen ovale (PFO), after the insertion of a catheter in the right internal jugular vein. We also provide an overview of the pathophysiology, diagnosis, and treatment of CAE. Suspecting CAE in the case of an acute neurological event occurring in close temporal relationship with central venous catheterization is paramount to allow the early recognition and treatment of this uncommon form of iatrogenic stroke.

Socially desirable responding in geriatric outpatients with and without mild cognitive impairment and its association with the assessment of self-reported mental health.

BACKGROUND: Socially desirable responding is a potentially relevant issue in older adults and can be evaluated with the Marlowe-Crowne Social Desirability Scale (MCSDS). However, the eight-item MCSDS has never been specifically administered to geriatric subjects, and there is a dearth of literature on the relationship between social desirability and cognitive impairment. Also, the connection between social desirability and subjective measures of psychological well-being is a matter of controversy. This study has three main aims. First, to determine the psychometric properties of the eight-item MCSDS in geriatric outpatients without dementia (i.e. with normal cognition (NC) or mild cognitive impairment (MCI)). Second, to investigate the link between social desirability and cognitive functioning. Third, to determine the association between social desirability and the assessment of self-reported mental health. METHODS: Community-dwelling outpatients (aged ≥ 65) were consecutively recruited and neuropsychologically tested to diagnose NC or MCI (n = 299). Social desirability was assessed with the eight-item MCSDS. Depressive and anxiety symptoms were measured with the short Geriatric Depression (GDS-s) and the State-Trait Personality Inventory Trait Anxiety (STPI-TA) scales. RESULTS: On principal components analysis, the eight-item MCSDS was found to have a multidimensional structure. Of the initial three-component solution, only two subscales had acceptable internal consistency (Cronbach's alpha > 0.6): "Acceptance of responsibility" and "Integrity". The third subscale ("Kindness towards others") appeared to gauge two distinct constructs of formal (i.e. politeness) versus substantive (i.e. forgiveness) compassion. On binary logistic regression, only higher income was a significant predictor of formal compassion. Test-retest reliability was substantial to excellent (Gwet's AC2 ≥ 0.8). There were no meaningful differences in social desirability between the NC and MCI groups. Likewise, negative Spearman's correlations between social desirability and cognitive Z-scores across the whole sample were weak (rs < |0.3|) and confined to one MCSDS item. Although social desirability was an independent predictor of the STPI-TA score in multiple linear regression, it explained only a marginal amount of incremental variance in anxiety symptoms (less than 2%). CONCLUSIONS: Our results suggest that social desirability need not be a major concern when using questionnaires to assess mental health in geriatric outpatients without dementia.

Different dimensions of social support differentially predict psychological well-being in late life: opposite effects of perceived emotional support and marital status on symptoms of anxiety and of depression in older outpatients in Italy.

BACKGROUND: Social support is important to psychological well-being in late life. However, findings in the literature regarding its effects are mixed, less information is available for anxiety than for depressive symptoms, and few studies have been carried out in Italy. Therefore, the aim of this study was to investigate the influence of social support on symptoms of anxiety and of depression in a sample of geriatric outpatients in Italy. METHODS: This cross-sectional study consecutively enrolled 299 outpatients without dementia (age ≥ 65, all neuropsychologically tested). Social support was assessed with the ENRICHD Social Support Instrument and by interview. Symptoms of anxiety and of depression were evaluated with short versions of the State-Trait Personality Inventory Trait Anxiety and Geriatric Depression scales. The relationship between social support and psychological well-being was examined by multiple linear regression models with socio-demographic and clinical variables, including cognitive performance, as potential confounders. RESULTS: Perceived emotional support was a negative predictor of symptoms of anxiety (standardised beta coefficient (ß) -0.288, standard error (SE) 0.074, P < 0.001) and symptoms of depression (ß -0.196, SE 0.040, P < 0.001). On the contrary, marital status (i.e. being married) was a positive predictor of symptoms of anxiety (ß 0.199, SE 0.728, P = 0.003) and symptoms of depression (ß 0.142, SE 0.384, P = 0.035). CONCLUSIONS: Different dimensions of social support differentially affect psychological well-being. The protective effect of perceived emotional support is consistent with social cognitive models of health. The harmful effect of being married may be capturing the distress of the pre-bereavement period. Alternatively, it may reflect oppression by gender roles within marriage in a predominantly female sample in a traditional society. Our findings provide insight into the relationship between social support and psychological well-being, and identify potential targets for psychosocial interventions promoting mental health in late life.

Corrigendum to "Peripheral Blood Mononuclear Cells as a Laboratory to Study Dementia in the Elderly".

[This corrects the article DOI: 10.1155/2014/169203.].

Autonomic function in amnestic and non-amnestic mild cognitive impairment: spectral heart rate variability analysis provides evidence for a brain-heart axis.

Mild cognitive impairment (MCI) is a heterogeneous syndrome with two main clinical subtypes, amnestic (aMCI) and non-amnestic (naMCI). The analysis of heart rate variability (HRV) is a tool to assess autonomic function. Cognitive and autonomic processes are linked via the central autonomic network. Autonomic dysfunction entails several adverse outcomes. However, very few studies have investigated autonomic function in MCI and none have considered MCI subtypes or the relationship of HRV indices with different cognitive domains and structural brain damage. We assessed autonomic function during an active orthostatic challenge in 253 oupatients aged ≥ 65, [n = 82 aMCI, n = 93 naMCI, n = 78 cognitively normal (CN), neuropsychologically tested] with power spectral analysis of HRV. We used visual rating scales to grade cerebrovascular burden and hippocampal/insular atrophy (HA/IA) on neuroimaging. Only aMCI showed a blunted response to orthostasis. Postural changes in normalised low frequency (LF) power and in the LF to high frequency ratio correlated with a memory test (positively) and HA/IA (negatively) in aMCI, and with attention/executive function tests (negatively) and cerebrovascular burden (positively) in naMCI. These results substantiate the view that the ANS is differentially impaired in aMCI and naMCI, consistently with the neuroanatomic substrate of Alzheimer's and small-vessel subcortical ischaemic disease.

Síndrome de Erasmus y Esclerosis Sistémica / Erasmus Syndrome and Systemic Sclerosis

En el artículo publicado en el primer número del año 2018 de la Revista Americana de Medicina Respiratoria sobre: Síndrome de Erasmus; se expone un caso clínico de esclerosis sistémica, donde se establece una relación con la exposición al sílice, el cual concluye: "La exposición aislada al sílice, en ausencia de silicosis, puede asociarse con un incremento del riesgo de desarrollar enfermedades autoinmunes. En este caso hemos descripto un Síndrome de Erasmus definido por la asociación de exposición al sílice y esclerosis sistémica"1. La afirmación es contradictoria, ya que en el relato de la enfermedad, el paciente presentado sí presentaba silicosis junto con esclerosis sistémica, conformando el Síndrome de Erasmus. Por la falta de congruencia de ideas, planteamos una mala interpretación de la información por parte de los autores. Además, sugeriremos la posibilidad establecer una serie de pruebas de tamizaje que permitan el diagnóstico oportuno de los expuestos y las implicancias que esto conllevaría

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

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.

Familial late-onset Alzheimer's disease: description of an Italian family with four affected siblings and one case of early-onset dementia in the preceding generation.

We describe a family composed of six siblings, four of which affected by late-onset Alzheimer's disease (LOAD). We constructed the family pedigree, evaluated mutations usually associated with early-onset Alzheimer's disease (APP, PSEN1, PSEN2), and assessed polymorphisms in the apolipoprotein E (APOE) gene and in cytokine genes that we had previously found to be associated with a higher risk of LOAD (IL-10, IL-6, TNF-α). Results showed that all subjects carried one ε4 allele of the APOE gene and those with the earliest age of onset exhibited the AA (-1082) IL-10 and the CC (-174) IL-6 genotypes. The only male had a genetic profile which also included the A (-308) TNF-α allele. These data confirm the role of the APOE gene as genetic risk factor in LOAD, and suggest that the risk of developing AD may be governed by a "susceptibility profile" involving polymorphisms in inflammatory genes.

Electrocardiographic monitoring for new prescriptions of quetiapine co-prescribed with acetylcholinesterase inhibitors or memantine from 2005 to 2009. A population study on community-dwelling older people in Italy.

PURPOSE: The aims of this study are to analyse, in community-dwelling people aged 65+ living in Italy's Lombardy Region, electrocardiographic (ECG) monitoring for new users of the atypical antipsychotic quetiapine co-prescribed with acetylcholinesterase inhibitors (AChEIs) or memantine and to find independent predictors of ECG monitoring before and after the starting of this prescription. METHODS: The Lombardy Region's administrative health database was used to retrieve prescriptions of ECG exams as well as prevalence rates of subjects aged 65+ who were prescribed such psychotropic drugs from 2005 to 2009. Multivariable analyses were adjusted for age, sex, number of drugs, treatment with beta-blockers, digoxin, verapamil or diltiazem, any antiarrhythmic drug and antidepressants. RESULTS: Overall 2,623 community-dwelling older people started therapy with quetiapine, co-prescribed with AChEIs or memantine, during these 5 years. At least one ECG was performed in 714 cases (27.2 %) in the 6 months before-and in 398 cases (15.2 %) within 3 months after-the starting of this prescription. ECG monitoring was performed both before and after starting quetiapine in only 160 cases (6.1 %). At multivariable analyses, number of drugs taken, beta-blocker and antiarrhythmic drug use were found to be independent correlates of ECG monitoring whereas female sex was associated with a lower probability of receiving an ECG within 3 months after the initiation of quetiapine (odds ratio 0.78, 95 % CI 0.62-0.98). CONCLUSIONS: ECG monitoring for new prescriptions of quetiapine in older people suffering from behavioural and psychological symptoms in dementia was actually performed infrequently, independently of the age of drug users, especially in women. Our results support the need for greater awareness within the medical community of the importance of such ECG monitoring.

Leukocyte telomere length and prevalence of age-related diseases in semisupercentenarians, centenarians and centenarians' offspring.

Centenarians and their offspring are increasingly considered a useful model to study and characterize the mechanisms underlying healthy aging and longevity. The aim of this project is to compare the prevalence of age-related diseases and telomere length (TL), a marker of biological age and mortality, across five groups of subjects: semisupercentenarians (SSCENT) (105-109years old), centenarians (CENT) (100-104years old), centenarians' offspring (CO), age- and gender-matched offspring of parents who both died at an age in line with life expectancy (CT) and age- and gender-matched offspring of both non-long-lived parents (NLO). Information was collected on lifestyle, past and current diseases, medical history and medication use. SSCENT displayed a lower prevalence of acute myocardial infarction (p=0.027), angina (p=0.016) and depression (p=0.021) relative to CENT. CO appeared to be healthier compared to CT who, in turn, displayed a lower prevalence of both arrhythmia (p=0.034) and hypertension (p=0.046) than NLO, characterized by the lowest parental longevity. Interestingly, CO and SSCENT exhibited the longest (p<0.001) and the shortest (p<0.001) telomeres respectively while CENT showed no difference in TL compared to the younger CT and NLO. Our results strengthen the hypothesis that the longevity of parents may influence the health status of their offspring. Moreover, our data also suggest that both CENT and their offspring may be characterized by a better TL maintenance which, in turn, may contribute to their longevity and healthy aging. The observation that SSCENT showed considerable shorter telomeres compared to CENT may suggest a progressive impairment of TL maintenance mechanisms over the transition from centenarian to semisupercentenarian age.

Peripheral blood mononuclear cells as a laboratory to study dementia in the elderly.

The steady and dramatic increase in the incidence of Alzheimer's disease (AD) and the lack of effective treatments have stimulated the search for strategies to prevent or delay its onset and/or progression. Since the diagnosis of dementia requires a number of established features that are present when the disease is fully developed, but not always in the early stages, the need for a biological marker has proven to be urgent, in terms of both diagnosis and monitoring of AD. AD has been shown to affect peripheral blood mononuclear cells (PBMCs) that are a critical component of the immune system which provide defence against infection. Although studies are continuously supplying additional data that emphasize the central role of inflammation in AD, PBMCs have not been sufficiently investigated in this context. Delineating biochemical alterations in AD blood constituents may prove valuable in identifying accessible footprints that reflect degenerative processes within the Central Nervous System (CNS). In this review, we address the role of biomarkers in AD with a focus on the notion that PBMCs may serve as a peripheral laboratory to find molecular signatures that could aid in differential diagnosis with other forms of dementia and in monitoring of disease progression.

Autonomic dysfunction in mild cognitive impairment: evidence from power spectral analysis of heart rate variability in a cross-sectional case-control study.

BACKGROUND: 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. AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Phenotypic variability associated with the C9ORF72 hexanucleotide repeat expansion: a sporadic case of frontotemporal lobar degeneration with prodromal hyposmia and predominant semantic deficits.

We describe a sporadic case of frontotemporal lobar degeneration, associated with the C9ORF72 mutation, with prominent behavioral changes and semantic deficits. Predominant deficits in naming, vocabulary, word comprehension, and face and object recognition emerged on neuropsychological assessment. Amnesia, behavioral changes, and isolated psychotic symptoms were also present. Hyposmia was an unspecific prodromal sign. Brain imaging showed basofrontal and temporopolar hypometabolism bilaterally, and predominantly left-sided atrophy. Levels of cerebrospinal fluid biomarkers (amyloid-ß, tau and p-tau) were normal. This description further confirms the heterogeneous presentation of the C9ORF72 mutation.