Going beyond the mean: Intraindividual variability of cognitive performance in prodromal and early neurodegenerative disorders

Objective: Intraindividual variability (IIV), generally defined as short-term variations in behavior, has been proposed as a sign of subtle early impairment in neurodegenerative disorders, presumably associated with the disintegration of neuronal network connectivity. We aim to provide a review of IIV as a sensitive cognitive marker in prodromal neurodegenerative disorders.Method: A narrative review focusing not only on theoretical and methodological definitions, including an overview on the neural correlates of IIV, but mainly on results from population-based and clinical-based studies on the role of IIV as a reliable predictor of mild cognitive impairment (MCI) and conversion to dementia in neurodegenerative disorders, mostly Alzheimer’s and Parkinson’s disease.Results: Most studies focus on MCI and Alzheimer’s disease and demonstrate that IIV is a reliable cognitive marker. IIV is partly more sensitive than mean performance in the prediction of cognitive impairment or progressive deterioration and is independent of socio-demographic variables and disease mediators (e.g., genetic susceptibility). Neuroimaging data, mostly from healthy subjects, suggest a relationship between IIV and dysfunction of the default mode network, presumably mediated by white matter disintegration in frontal and parietal areas.Conclusions: IIV measures may provide valuable information about diagnosis and progression in prodromal stages of neurodegenerative disorders. Thus, further conceptual and methodological clarifications are needed to justify the inclusion of IIV as a sensible cognitive marker in routine clinical neuropsychological assessment

Functional connectivity modeling of consistent cortico-striatal degeneration in Huntington's disease

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by a complex neuropsychiatric phenotype. In a recent meta-analysis we identified core regions of consistent neurodegeneration in premanifest HD in the striatum and middle occipital gyrus (MOG). For early manifest HD convergent evidence of atrophy was most prominent in the striatum, motor cortex (M1) and inferior frontal junction (IFJ). The aim of the present study was to functionally characterize this topography of brain atrophy and to investigate differential connectivity patterns formed by consistent cortico-striatal atrophy regions in HD. Using areas of striatal and cortical atrophy at different disease stages as seeds, we performed task-free resting-state and task-based meta-analytic connectivity modeling (MACM). MACM utilizes the large data source of the BrainMap database and identifies significant areas of above-chance co-activation with the seed-region via the activation-likelihood-estimation approach. In order to delineate functional networks formed by cortical as well as striatal atrophy regions we computed the conjunction between the co-activation profiles of striatal and cortical seeds in the premanifest and manifest stages of HD, respectively. Functional characterization of the seeds was obtained using the behavioral meta-data of BrainMap. Cortico-striatal atrophy seeds of the premanifest stage of HD showed common co-activation with a rather cognitive network including the striatum, anterior insula, lateral prefrontal, premotor, supplementary motor and parietal regions. A similar but more pronounced co-activation pattern, additionally including the medial prefrontal cortex and thalamic nuclei was found with striatal and IFJ seeds at the manifest HD stage. The striatum and M1 were functionally connected mainly to premotor and sensorimotor areas, posterior insula, putamen and thalamus. Behavioral characterization of the seeds confirmed that experiments activating the MOG or IFJ in conjunction with the striatum were associated with cognitive functions, while the network formed by M1 and the striatum was driven by motor-related tasks. Thus, based on morphological changes in HD, we identified functionally distinct cortico-striatal networks resembling a cognitive and motor loop, which may be prone to early disruptions in different stages of the disease and underlie HD-related cognitive and motor symptom profiles. Our findings provide an important link between morphometrically defined seed-regions and corresponding functional circuits highlighting the functional and ensuing clinical relevance of structural damage in HD

Incident stroke in patients with Alzheimer’s disease: systematic review and meta-analysis

Abstract Vascular mechanisms are increasingly recognized in the pathophysiology of Alzheimer’s disease (AD), but less is known about the occurrence of stroke in AD patients. We aimed to quantify the risk of stroke in patients with AD and compare the incidence rates (IR) of stroke in individuals without AD. Systematic search of Embase and MEDLINE between 1970 and 2020. Inclusion criteria: reports with ≥ 50 patients with non-familial AD, which reported the occurrence of stroke (all types) and/or ischemic stroke and/or intracerebral hemorrhage (ICH) during follow-up. Meta-analyses of pooled data using random-effects model were performed. IR were calculated for each study. Incidence rate ratios (IRR) were calculated for studies presenting a control-group without AD. Among 5109 retrieved studies, 29 (0.6%) fulfilled the inclusion criteria, reporting a total of 61,824 AD patients. In AD patients the IR were 15.4/1000 person-years for stroke (all types), 13.0/1000 person-years for ischemic stroke and 3.4/1000 person-years for ICH. When compared to controls without AD, incidence rate for ICH in AD patients was significantly higher (IRR = 1.67, 95%CI 1.43–1.96), but similar for ischemic stroke. Incident stroke is not a rare event in AD population. AD is associated with an increased risk of intracerebral hemorrhage which warrants further clarification

Neural correlates of impulse control behaviors in Parkinson’s disease: Analysis of multimodal imaging data

Background: Impulse control behaviors (ICB) are frequently observed in patients with Parkinson's disease (PD) and are characterized by compulsive and repetitive behavior resulting from the inability to resist internal drives.Objectives: In this study, we aimed to provide a better understanding of structural and functional brain alterations and clinical parameters related to ICB in PD patients.Methods: We utilized a dataset from the Parkinson's Progression Markers Initiative including 36 patients with ICB (PDICB+) compared to 76 without ICB (PDICB-) and 61 healthy controls (HC). Using multimodal MRI data we assessed gray matter brain volume, white matter integrity, and graph topological properties at rest.Results: Compared with HC, PDICB+ showed reduced gray matter volume in the bilateral superior and middle temporal gyrus and in the right middle occipital gyrus. Compared with PDICB-, PDICB+ showed volume reduction in the left anterior insula. Depression and anxiety were more prevalent in PDICB+ than in PDICB- and HC. In PDICB+, lower gray matter volume in the precentral gyrus and medial frontal cortex, and higher axial diffusivity in the superior corona radiata were related to higher depression score. Both PD groups showed disrupted functional topological network pattern within the cingulate cortex compared with HC. PDICB+ vs PDICB- displayed reduced topological network pattern in the anterior cingulate cortex, insula, and nucleus accumbens.Conclusions: Our results suggest that structural alterations in the insula and abnormal topological connectivity pattern in the salience network and the nucleus accumbens may lead to impaired decision making and hypersensitivity towards reward in PDICB+. Moreover, PDICB+ are more prone to suffer from depression and anxiety.Keywords: Functional MRI; Impulse control behaviors; Parkinson’s disease; Structural magnetic resonance imaging (MRI)

Quantitative sensory testing and norepinephrine levels in REM sleep behaviour disorder – a clue to early peripheral autonomic and sensory dysfunction?

Introduction!#!Studies have reported autonomic impairment in patients with idiopathic REM sleep behaviour disorder (iRBD), which is considered a prodromal stage of alpha-synucleinopathies. It is still debated whether central or peripheral pathologies are first manifestations of alpha-synucleinopathies. This study aimed to characterize autonomic and somatosensory function in iRBD patients.!##!Methods!#!This cross-sectional prospective case-control study included 17 iRBD patients (mean age 66.3 ± 9.2 years) and 16 healthy controls (HCs, 66.6 ± 11.3 years). Quantitative sensory testing, neurological and neuropsychological assessments, norepinephrine blood plasma levels, tilt table examination with orthostatic blood pressure, and heart rate variability were carried out. Longitudinal data of 10 iRBD patients, including neurological, neuropsychological, and tilt table examination, were assessed.!##!Results!#!iRBD patients more frequently presented with orthostatic dysfunction than HCs (70.6% vs. 6.3%, p < 0.0001). Supine norepinephrine plasma levels were normal, but lower in iRBD (249.59 ± 99.78 pg/ml iRBD, 354.13 ± 116.38 pg/ml HCs, p < 0.05). Quantitative sensory testing revealed impaired cold (CDT) and vibration detection thresholds (VDT) on the foot in iRBD (CDT foot iRBD - 1.24 ± 0.31, HCs - 9.89E-17 ± 0.25, VDT iRBD - 1.11 ± 0.47, HCs - 1.46E-16 ± 0.25, p < 0.05). Cold detection thresholds differed between the foot and hand among iRBD patients (foot - 1.24 ± 0.31, hand - 0.56 ± 0.25, p < 0.05). Longitudinal data revealed an increase in maximum systolic and diastolic orthostatic blood pressure changes and a decrease in the Valsalva ratio in the follow-up group (p < 0.05).!##!Conclusion!#!This study revealed autonomic dysfunction with somatosensory impairment, and decreased norepinephrine levels in iRBD, which may serve as a possible prodromal marker for developing alpha-synucleinopathy