External validity of randomized controlled trials on Alzheimer's disease: the biases of frailty and biological aging

To date, the external validity of randomized controlled trials (RCTs) on Alzheimer's disease (AD) has been assessed only considering monodimensional variables. Nevertheless, looking at isolated and single characteristics cannot guarantee a sufficient level of appreciation of the AD patients' complexity. The only way to understand whether the two worlds (i.e., research and clinics) deal with the same type of patients is to adopt multidimensional approaches more holistically reflecting the biological age of the individual. In the present study, we compared measures of frailty/biological aging [assessed by a Frailty Index (FI)] of a sample of patients with AD resulted eligible and subsequently included in phase III RCTs compared to patients referring to the same clinical service, but not considered for inclusion. The "RCT sample" and the "real world sample" were found to be statistically similar for all the considered sociodemographic and clinical variables. Nevertheless, the "real world sample" was found to be significantly frailer compared to the "RCT sample," as indicated by higher FI scores [0.28 (SD 0.1) vs. 0.17 (SD 0.1);p < 0.001, respectively]. Moreover, when assessing the relationship between FI and age, we found that the correlation was almost null in the "RCT sample" (Spearman'sr = 0.01;p = 0.98), while it was statistically significant in the "real world sample" (r = 0.49;p = 0.02). The application of too rigid designs may result in the poor representativeness of RCT samples. It may even imply the study of a condition biologically different from that observed in the "real world." The adoption of multidimensional measures capable to capture the individual's biological age may facilitate evaluating the external validity of clinical studies, implicitly improving the interpretation of the results and their translation in the clinical arena

Cerebellum-Cortical Interaction in Spatial Navigation and Its Alteration in Dementias

The cerebellum has a homogeneous structure and performs different computational functions such as modulation/coordination of the communication between cerebral regions, and regulation/integration of sensory information. Albeit cerebellar activity is generally associated with motor functions, several recent studies link it to various cognitive functions, including spatial navigation. In addition, cerebellar activity plays a modulatory role in different cognitive domains and brain processes. Depending on the network involved, cerebellar damage results in specific functional alterations, even when no function loss might be detected. In the present review, we discuss evidence of brainstem degeneration and of a substantial reduction of neurons in nuclei connected to the inferior olivary nucleus in the early stages of Alzheimer’s disease. Based on the rich patterns of afferences from the inferior olive nucleus to the cerebellum, we argue that the subtle alterations in spatial navigation described in the early stages of dementia stem from alterations of the neuromodulatory functions of the cerebellum

Overcoming navigational challenges: A novel approach to the study and assessment of topographical orientation

Several studies investigating environmental navigation require participants to navigate in virtual environments, in which the proprioceptive and vestibular components present during real environmental navigation are lost. Here, we aimed to provide a novel computerized ecological navigational battery, investigating whether the absence of proprioceptive and vestibular inputs yields a representation of the navigational space comparable to that acquired ecologically. In Study 1, 38 participants underwent two sets of tasks, one performed in a laboratory-based setting (LBS) and the other in an ecological environment (EE), with both including evaluation of route, landmark, and survey knowledge and a landmark ordering task. All tasks, except the route task, significantly correlated between EE and LBS. In LBS, performance in the landmark ordering task was predicted by that in the survey task, but not by those in the route and landmark tasks. Results of Study 1 were replicated in Study 2, in which 44 participants completed a modified and shorter online version of LBS tests. Reliability of the online LBS tests was also tested and showed a moderate-to-high internal consistency. Overall, results show that the conditions in which tasks are performed affect the acquisition of route knowledge, likely due to the lack of proprioceptive and vestibular information in LBS. However, LBS tasks presented here provide a standard battery of tests that can overcome the replicability problems encountered by ecological navigation tests, while taking into consideration all the complexities of navigational processes in terms of the use of landmark, route, and survey strategies

Beta-Amyloid Peptide in Tears: An Early Diagnostic Marker of Alzheimer’s Disease Correlated with Choroidal Thickness

We aimed to evaluate the diagnostic role of Alzheimer’s disease (AD) biomarkers in tears as well as their association with retinal and choroidal microstructures. In a cross-sectional study, 35 subjects (age 71.7 ± 6.9 years) were included: 11 with prodromal AD (MCI), 10 with mild-to-moderate AD, and 14 healthy controls. The diagnosis of AD and MCI was confirmed according to a complete neuropsychological evaluation and PET or MRI imaging. After tear sample collection, β-amyloid peptide Aβ1-42 concentration was analyzed using ELISA, whereas C-terminal fragments of the amyloid precursor protein (APP-CTF) and phosphorylated tau (p-tau) were assessed by Western blot. Retinal layers and choroidal thickness (CT) were acquired by spectral-domain optical coherence tomography (SD-OCT). Aβ1-42 levels in tears were able to detect both MCI and AD patients with a specificity of 93% and a sensitivity of 81% (AUC = 0.91). Tear levels of Aβ1-42 were lower, both in the MCI (p p p p p = 0.035). No differences were observed for APP-CTF and p-tau relative abundance in tears. Testing Aβ1-42 levels in tears seems to be a minimally invasive, cost-saving method for early detection and diagnosis of AD

Multidimensional assessment of time perception along the continuum of Alzheimer’s Disease and evidence of alterations in subjective cognitive decline

Abstract Timing alterations occur in Alzheimer’s disease (AD), even in early stages (mild cognitive impairment, MCI). Moreover, a stage named subjective cognitive decline (SCD), in which individuals perceive a change in cognitive performance not revealed by neuropsychological tests, has been identified as a preclinical phase of AD. However, no study to date has investigated different dimensions of time processing along the continuum from physiological to pathological aging, and whether timing alterations occur in SCD. Here a sample of participants with SCD, MCI, AD and healthy controls (HC) performed tasks assessing prospective duration estimation, production, reproduction, implicit temporal learning in conditions dependent from external cues (externally-cued learning, ECL) or independent from external cues (internally-based learning, IBL), retrospective duration estimation, the subjective experience of time and the temporal collocation of events. AD patients performed worse than HC and SCD in prospective timing, and in collocating events in time. The subjective experience of time did not differ between groups. Concerning temporal learning, AD performed worse in ECL than in IBL, whereas SCD performed worse in IBL than in ECL. SCD, MCI and AD patients all showed errors greater than HC in retrospective duration estimation. Results point to implicit temporal learning in externally-cued conditions and retrospective time estimation as possible early markers of cognitive decline

Visual hallucinations in Lewy body disease:pathophysiological insights from phenomenology

Visual hallucinations (VH) in Lewy body disease (LBD) have a heterogenous phenomenology classified into minor phenomena (MVH) and complex hallucinations (CVH). Mechanisms underpinning VH and their temporal aspects are largely unknown. According to the hodotopic model, we investigated whether changes in distinct cognitive domains and neural networks in the hallucination trait underpin temporal aspects of MVH and CVH in the hallucination state. 35 LBD patients with VH underwent a complete neuropsychological evaluation and resting-state fMRI. North-East-Visual-Hallucinations-Interview was used to assess their typical VH content, duration, and frequency. We found that MVH was not associated with cognitive impairment, while CVH was associated with impairments in visuoperceptual processes, attention and visual abstract reasoning. In seed-to-seed functional connectivity (FC) analysis we identified functional couplings associated with MVH and CVH temporal severity (duration x frequency), duration and frequency. MVH severity was negatively associated with FC between early visual areas (EVA) and ventral-visual-stream regions, and negatively associated with FC between brainstem and EVA, which may be linked to LBD brainstem neuropathology. CVH duration was positively associated with FC between ventral-visual stream and salience network (SN). CVH frequency was negatively associated with FC between DMN and SN. Functional alterations in distinct visual and attentional networks and their dynamic interaction in trait LBD hallucinators are linked to both the phenomenology of state content and its temporal characteristics. Within a network, VH frequency and duration may be linked to different types of functional alterations: increased connectivity leading to sustained activity prolonging VH (duration) and decreased connectivity increasing dysregulated, spontaneous activity (frequency). These findings support the hodotopic hypothesis of VH and may reflect a link between VH phenomenology, LBD neuropathological progression and the involvement of specific neurotransmitter systems. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00415-022-10983-6