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

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.

Sundowning in Patients with Dementia: Identification, Prevalence, and Clinical Correlates.

BACKGROUND: The term sundowning is used to describe the emergence or worsening of neuropsychiatric symptoms in late afternoon or early evening in people with dementia. OBJECTIVE: Our aim was to evaluate sundowning's prevalence and clinical manifestations among patients attending a tertiary memory clinic and to investigate its clinical and neuropsychological correlates. METHODS: Patients with dementia attending our memory clinic were enrolled in the study. Sundowning was identified through a specifically designed questionnaire. Sociodemographic and clinical features of sundowners and non-sundowners were compared, and a logistic regression was performed to identify the variables associated with the phenomenon. A subgroup of patients underwent a complete neuropsychological assessment. RESULTS: Among 184 recruited patients, 39 (21.2%) exhibited sundowning, mostly expressed as agitation (56.4%), irritability (53.8%), and anxiety (46.2%). Sundowners were significantly older, had a later dementia onset, exhibited more severe cognitive and functional impairment, more frequent nocturnal awakenings, and hearing loss relative to non-sundowners. They were also more likely to use anticholinergic medications and antipsychotics, and less likely to use memantine. In a multi-adjusted model, the factors significantly associated with sundowning were the Clinical Dementia Rating score (OR 3.88; 95% CI 1.39-10.90) and the use of memantine (OR 0.20; 95% CI 0.05-0.74). Participants with and without sundowning obtained similar results in single domain neuropsychological tests. CONCLUSION: Sundowning is commonly experienced by patients with dementia and appears as a multiply determined condition. Its presence should always be evaluated in clinical practice and a multidimensional approach should be adopted to identify its predictors.

Memantine for Refractory Obsessive-Compulsive Disorder: Protocol for a Pragmatic, Double-blind, Randomized, Parallel-Group, Placebo-Controlled, Monocenter Trial.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a psychiatric syndrome characterized by unwanted and repetitive thoughts and repeated ritualistic compulsions for decreasing distress. Symptoms can cause severe distress and functional impairment. OCD affects 2% to 3% of the population and is ranked within the 10 leading neuropsychiatric causes of disability. Cortico-striatal-thalamo-cortical circuitry dysfunction has been implicated in OCD, including altered brain activation and connectivity. Complex glutamatergic signaling dysregulation within cortico-striatal circuitry has been proposed in OCD. Data obtained by several studies indicate reduced glutamatergic concentrations in the anterior cingulate cortex, combined with overactive glutamatergic signaling in the striatum and orbitofrontal cortex. A growing number of randomized controlled trials have assessed the utility of different glutamate-modulating drugs as augmentation medications or monotherapies for OCD, including refractory OCD. However, there are relevant variations among studies in terms of patients' treatment resistance, comorbidity, age, and gender. At present, 4 randomized controlled trials are available on the efficacy of memantine as an augmentation medication for refractory OCD. OBJECTIVE: Our study's main purpose is to conduct a double-blind, randomized, parallel-group, placebo-controlled, monocenter trial to assess the efficacy and safety of memantine as an augmentative agent to a selective serotonin reuptake inhibitor in the treatment of moderate to severe OCD. The study's second aim is to evaluate the effect of memantine on cognitive functions in patients with OCD. The third aim is to investigate if responses to memantine are modulated by variables such as gender, symptom subtypes, and the duration of untreated illness. METHODS: Investigators intend to conduct a double-blind, randomized, parallel-group, placebo-controlled, monocenter trial to assess the efficacy and safety of memantine as an augmentative agent to a selective serotonin reuptake inhibitor in the treatment of patients affected by severe refractory OCD. Participants will be rated via the Yale-Brown Obsessive Compulsive Scale at baseline and at 2, 4, 6, 8, 10, and 12 months. During the screening period and T4 and T6 follow-up visits, all participants will undergo an extensive neuropsychological evaluation. The 52-week study duration will consist of 4 distinct periods, including memantine titration and follow-up periods. RESULTS: Recruitment has not yet started. The study will be conducted from June 2023 to December 2024. Results are expected to be available in January 2025. Throughout the slow-titration period, we will observe the minimum effective dose of memantine, and the follow-up procedure will detail its residual efficacy after drug withdrawal. CONCLUSIONS: The innovation of this research proposal is not limited to the evaluation of the efficacy and safety of memantine as an augmentation medication for OCD. We will also test if memantine acts as a pure antiobsessive medication or if memantine's ability to improve concentration and attention mimics an antiobsessive effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT05015595; https://clinicaltrials.gov/ct2/show/NCT05015595. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/39223.

Parkinsonism Is Associated with Altered SMA-Basal Ganglia Structural and Functional Connectivity in Frontotemporal Degeneration.

BACKGROUND: Patients with frontotemporal degeneration (FTD) often manifest parkinsonism, which likely results from cortical and subcortical degeneration of brain structures involved in motor control. We used a multimodal magnetic resonance imaging (MRI) approach to investigate possible structural and/or functional alterations in FTD patients with and without parkinsonism (Park+ and Park-). METHODS: Thirty FTD patients (12 Park+, 18 Park-) and 30 healthy controls were enrolled and underwent 3T MRI scanning. MRI analyses included: (1) surface-based morphometry; (2) basal ganglia and thalamic volumetry; (3) diffusion-based probabilistic tractography of fiber tracts connecting the supplementary motor area (SMA) and primary motor cortex (M1) to the putamen, globus pallidus, and thalamus; and (4) resting-state functional connectivity (RSFC) between the aforementioned regions. RESULTS: Patients in Park+ and Park- groups showed comparable patterns of cortical thinning in frontotemporal regions and reduced thalamic volume with respect to controls. Only Park+ patients showed reduced putaminal volume and reduced fractional anisotropy of the fibers connecting the SMA to the globus pallidus, putamen, and thalamus, with respect to controls. Park+ patients also showed decreased RSFC between the SMA and putamen with respect to both Park- patients and controls. CONCLUSIONS: The present findings support the hypothesis that FTD patients with parkinsonism are characterized by neurodegenerative processes in specific corticobasal ganglia-thalamocortical motor loops.

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, ß-amyloid peptide Aß1-42 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). Aß1-42 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 Aß1-42 were lower, both in the MCI (p < 0.01) and in the AD group (p < 0.001) when compared to healthy controls. Further, Aß1-42 was correlated with psychometric scores (p < 0.001) and CT (p < 0.01). CT was thinner in the affected patients (p = 0.035). No differences were observed for APP-CTF and p-tau relative abundance in tears. Testing Aß1-42 levels in tears seems to be a minimally invasive, cost-saving method for early detection and diagnosis of AD.

Prevalence and Safety of COVID-19 Vaccination in Community-Dwelling People with Dementia: Findings from a Tertiary Memory Clinic in Italy.

This study aimed to explore the prevalence and safety of SARS-CoV-2 vaccination in individuals with dementia. Patients with mild cognitive impairment or dementia were recruited at a tertiary memory clinic, from March 15 to September 15, 2021. Information on COVID-19 vaccination and adverse events experienced after vaccine administration were collected from caregivers. Two-hundred-seventy subjects were finally recruited. Among them, 253 (93.7%) had received the vaccine and only 69 (27.3%) experienced adverse events. Cognitive and behavioral changes following immunization were only rarely reported. COVID-19 vaccination is safe and well-tolerated in patients with cognitive impairment who should be prioritized in the vaccination campaign.

Cortical complexity alterations in the medial temporal lobe are associated with Alzheimer's disease psychosis.

Psychosis is frequent in Alzheimer's disease (AD) and it is associated with a worse disease course. AD psychosis may represent a distinct AD phenotype, though its specific neurobiological underpinnings have yet to be identified. This study investigated neural underpinnings of AD psychosis using surface-based-morphometry.Data from 32 AD patients, 17 with psychosis (AD-P) and 15 without were analyzed. Average cortical complexity (fractal dimension, FD) was estimated for each theoretically motivated ROI and patient. First, we compared regional FD in AD-P and AD patients. Then we calculated the correlation coefficients between FD and the severity of misidentification and paranoid psychotic symptoms. AD-P showed decreased FD in ventral-visual-stream compared to AD, suggesting that perceptual processes might be pivotal in psychosis. A negative correlation was found between misidentification severity and FD in the entorhinal cortex suggesting that misidentification may be specifically associated with alterations in regions involved in high-level perceptual and contextualization processes.

Blink Rate Study in Patients with Alzheimer's Disease, Mild Cognitive Impairment and Subjective Cognitive Decline.

BACKGROUND: Blink rate (BR) is considered a marker of dopaminergic activity in humans. BR is increased in patients with Mild Cognitive Impairment (MCI), but no study has yet investigated whether BR changes with the progression of cognitive decline from MCI to Alzheimer's disease (AD) and whether BR abnormalities are present in subjects with Subjective Cognitive Decline (SCD). OBJECTIVE: The aim of our study was to assess BR in patients with AD, MCI, and SCD and to correlate BR with demographic and clinical features of cognitive decline. METHODS: We enrolled 22 subjects with SCD, 23 with MCI, and 18 with AD and a group of 20 age-matched healthy controls (HCs). Cognitive function was assessed by testing global cognitive status and frontal, attentional, memory, verbal, and visuospatial functions. BR was measured by counting the number of blinks per minute. RESULTS: MCI subjects had an increased BR (p <0.001), whereas AD subjects had a lower BR than HCs (p <0.05). Conversely, SCD subjects had a BR similar to HCs. No significant correlations emerged between neuropsychological scores and BR in SCD, MCI, and AD subjects. CONCLUSION: Increased BR in MCI likely reflects early compensatory mechanisms occurring before AD, whereas decreased BR in AD suggests dopaminergic system involvement in this condition.

Motor dysfunction in mild cognitive impairment as tested by kinematic analysis and transcranial magnetic stimulation.

OBJECTIVE: Previous studies have demonstrated voluntary movement alterations as well as motor cortex excitability and plasticity changes in patients with mild cognitive impairment (MCI). To investigate the pathophysiology of movement abnormalities in MCI, we tested possible relationships between movement abnormalities and primary motor cortex alterations in patients. METHODS: Fourteen amnestic MCI (aMCI) patients and 16 healthy controls were studied. Cognitive assessment was performed using clinical scales. Finger tapping was recorded by a motion analysis system. Transcranial magnetic stimulation was used to test the input/output curve of motor evoked potentials, intracortical inhibition, and short-latency afferent inhibition. Primary motor cortex plasticity was probed by theta burst stimulation. We investigated correlations between movement abnormalities, clinical scores, and cortical neurophysiological parameters. RESULTS: MCI patients showed less rhythmic movement but no other movement abnormalities. Cortical excitability measures were normal in patients, whereas plasticity was reduced. Movement rhythm abnormalities correlated with frontal dysfunction scores. CONCLUSION: Our study in MCI patients demonstrated abnormal voluntary movement and plasticity changes, with no correlation between the two. Altered rhythm correlated with frontal dysfunction. SIGNIFICANCE: Our results contribute to the understanding of pathophysiological mechanisms of motor impairment in MCI.

Altered speech-related cortical network in frontotemporal dementia.

BACKGROUND: In healthy subjects (HS), transcranial magnetic stimulation (TMS) demonstrated an increase in motor-evoked potential (MEP) amplitudes during specific linguistic tasks. This finding indicates functional connections between speech-related cortical areas and the dominant primary motor cortex (M1). OBJECTIVE: To investigate M1 function with TMS and the speech-related cortical network with neuroimaging measures in frontotemporal dementia (FTD), including the non-fluent variant of primary progressive aphasia (nfv-PPA) and the behavioral variant of FTD (bv-FTD). METHODS: M1 excitability changes during specific linguistc tasks were examined using TMS in 24 patients (15 with nfv-PPA and 9 with bv-FTD) and in 18 age-matched HS. In the same patients neuroimaging was used to assess changes in specific white matter (WM) bundles and grey matter (GM) regions involved in language processing, with diffusion tensor imaging (DTI) and voxel-based morphometry (VBM). RESULTS: During the linguistic task, M1 excitability increased in HS, whereas in FTD patients it did not. M1 excitability changes were comparable in nfv-PPA and bv-FTD. DTI revealed decreased fractional anisotropy in the superior and inferior longitudinal and uncinate fasciculi. Moreover, VBM disclosed GM volume loss in the left frontal operculum though not in the parietal operculum or precentral gyrus. Furthermore, WM and GM changes were comparable in nfv-PPA and bv-FTD. There was no correlation between neurophysiological and neuroimaging changes in FTD. Atrophy in the left frontal operculum correlated with linguistic dysfunction, assessed by semantic and phonemic fluency tests. CONCLUSION: We provide converging neurophysiological and neuroimaging evidence of abnormal speech-related cortical network activation in FTD.

Bradykinesia in Alzheimer's disease and its neurophysiological substrates.

OBJECTIVE: Alzheimer's disease is primarily characterized by cognitive decline; recent studies, however, emphasize the occurrence of motor impairment in this condition. Here, we investigate whether motor impairment, objectively evaluated with kinematic techniques, correlates with neurophysiological measures of the primary motor cortex in Alzheimer's disease. METHODS: Twenty patients and 20 healthy subjects were enrolled. Repetitive finger tapping was assessed by means of a motion analysis system. Primary motor cortex excitability was assessed by recording the input/output curve of the motor-evoked potentials and using a conditioning-test paradigm for the assessment of short-interval intracortical inhibition and short-latency afferent inhibition. Plasticity-like mechanisms were indexed according to changes in motor-evoked potential amplitude induced by the intermittent theta-burst stimulation. RESULTS: Patients displayed slowness and altered rhythm during finger tapping. Movement slowness correlated with reduced short-latency afferent inhibition in patients, thus suggesting that degeneration of the cholinergic system may also be involved in motor impairment in Alzheimer's disease. Moreover, altered movement rhythm in patients correlated with worse scores in the Frontal Assessment Battery. CONCLUSION: This study provides new information on the pathophysiology of altered voluntary movements in Alzheimer's disease. SIGNIFICANCE: The study results suggest that a cortical cholinergic deficit may underlie movement slowness in Alzheimer's disease.

Psychosis of Alzheimer's disease: Neuropsychological and neuroimaging longitudinal study.

OBJECTIVES: Psychosis of Alzheimer's disease (AD) may represent a distinct disease phenotype; however, neuropsychological profile and neural basis linked to this phenotype have not yet been clarified. In this study, we aimed at detecting whether impairment in specific cognitive domains predicts the onset of psychosis in AD patients and what grey matter alterations, their location, and the rate of atrophy are associated with psychosis of AD. METHODS: Longitudinal neuropsychological data from AD patients with and without psychosis were analysed to determine whether the neuropsychological profile can predict the onset of psychosis. A voxel-based morphometry (VBM) on longitudinal T1-weighted images was used to explore differences in grey matter volume and in the rate of atrophy between groups. RESULTS: Noncognitive domain predicted the psychosis onset. However, AD patients with psychosis exhibited greater atrophy in the right anterior-inferior temporal lobe, including the fusiform gyrus (cluster-p-family-wise error [pfwe] < 0.05; peak-p uncorrected [pUNC] < 0.001) as well as greater rate of atrophy in the right insula than nonpsychotic patients (cluster-pFWE = 0.075; peak-pUNC < 0.001). The anterior-inferior temporal lobe is part of the ventral visual stream, and the insula plays a key role in the salience network. CONCLUSIONS: This finding suggests that damage in these areas underpins an impairment in the visual processing of the objects and an impairment in the attribution of salience to the misperceived stimuli, which in turn leads to the onset of psychosis. These findings tie in well with the neuropsychological model of psychosis, according to which the simultaneous presence of two factors, namely misperception and misattribution, underlies psychosis in dementia.

Somatosensory Temporal Discrimination Threshold in Patients with Cognitive Disorders.

BACKGROUND: The temporal processing of sensory information can be evaluated by testing the somatosensory temporal discrimination threshold (STDT), which is defined as the shortest interstimulus interval needed to recognize two sequential sensory stimuli as separate in time. The STDT requires the functional integrity of the basal ganglia and of the somatosensory cortex (S1). Although there is evidence that time processing is impaired in patients with Alzheimer's disease (AD), no study has yet investigated STDT in patients with various degree of cognitive impairment. OBJECTIVE: The aim of our study was to understand how cognition and attention deficits affect STDT values in patients with cognitive abnormalities. METHODS: We enrolled 63 patients: 28 had mild-moderate AD, 16 had mild cognitive impairment (MCI), and the remaining 19 had subjective cognitive deficit (SCD). A group of 45 age-matched healthy subjects acted as controls. Paired tactile stimuli for STDT testing consisted of square-wave electrical pulses delivered with a constant current stimulator through surface electrodes over the distal phalanx of the index finger. RESULTS: STDT values were higher in AD and MCI patients than in SCD subjects or healthy controls. Changes in the STDT in AD and MCI were similar in both conditions and did not correlate with disease severity. CONCLUSIONS: STDT alterations in AD and MCI may reflect a dysfunction of the dopaminergic system, which signals salient events and includes the striatum and the mesocortical and mesolimbic circuits.

Is Losing One's Way a Sign of Cognitive Decay? Topographical Memory Deficit as an Early Marker of Pathological Aging.

Spatial navigation tasks reveal small differences between normal and pathological aging and may thus disclose potential neuropsychological predictors of neurodegenerative diseases. The aim of our study was to investigate which navigational skills are compromised in the early phase of pathological aging as well as the extent to which they are compromised. We performed an extensive neuropsychological evaluation based on working memory and learning tasks (i.e., Corsi Block-Tapping Test and Walking Corsi Test) involving both reaching and navigational vista spaces. We also assessed spatial navigation skills in the real world by asking participants to perform route-learning and landmark-recognition tasks. We conducted a cross-sectional study on nineteen patients with a diagnosis of mild cognitive impairment (MCI) who displayed either an isolated memory deficit (single-domain amnestic MCI, MCIsd; N = 3) or a memory deficit associated with deficits in other cognitive functions (multi-domain MCI, MCImd; N = 16) as well as on nineteen healthy control participants. The groups' performances were compared by means of mixed factorial ANOVA and two-sample t-tests. We found that patients with MCI performed worse than controls, especially when they were required to learn spatial positions within the navigational vista space. Route-learning within the real environment was also impaired whereas landmark-recognition was spared. The same pattern of results emerged in the MCImd subgroup. Moreover, single case analyses on MCIsd patients revealed a dissociation between learning of spatial positions within navigational vista space and within reaching space. These results suggest that topographical learning is compromised in the early phase of MCIsd and MCImd and that spatial navigation tasks may be used to better characterize topographical disorientation in MCI patients as well as for the early diagnosis of pathological aging.

Modulation of the Cannabinoid System: A New Perspective for the Treatment of the Alzheimer's Disease.

The pathogenesis of Alzheimer's disease (AD) is somewhat complex and has yet to be fully understood. As the effectiveness of the therapy currently available for AD has proved to be limited, the need for new drugs has become increasingly urgent. The modulation of the endogenous cannabinoid system (ECBS) is one of the potential therapeutic approaches that is attracting a growing amount of interest. The ECBS consists of endogenous compounds and receptors. The receptors CB1 and CB2 have already been well characterized: CB1 receptors, which are abundant in the brain, particularly in the hippocampus, basal ganglia and cerebellum, regulate memory function and cognition. It has been suggested that the activation of CB1 receptors reduces intracellular Ca concentrations, inhibits glutamate release and enhances neurotrophin expression and neurogenesis. CB2 receptors are expressed, though to a lesser extent, in the central nervous system, particularly in the microglia and immune system cells involved in the release of cytokines. CB2 receptors have been shown to be upregulated in neuritic plaque-associated microglia in the hippocampus and entorhinal cortex of patients, which suggests that these receptors play a role in the inflammatory pathology of AD. The role of the ECBS in AD is supported by cellular and animal models. By contrast, few clinical studies designed to investigate therapies aimed at reducing behaviour disturbances, especially night-time agitation, eating behaviour and aggressiveness, have yielded positive results. In this review, we will describe how the manipulation of the ECBS offers a potential approach to the treatment of AD.

Parkinsonism is associated with altered primary motor cortex plasticity in frontotemporal dementia-primary progressive aphasia variant.

In frontotemporal dementia (FTD), the behavioral variant (bv-FTD) and nonfluent variant of primary progressive aphasia (nfv-PPA) reflect a prominent neurodegenerative involvement of the frontal lobe networks, which may include the premotor and motor areas and thus cause heterogeneous clinical symptoms including parkinsonism. With the technique of transcranial magnetic stimulation, we investigated long-term potentiation- and long-term depression-like plasticity in the primary motor cortex of bv-FTD and nfv-PPA patients, with and without parkinsonism, by using the theta-burst stimulation (TBS) protocol. We applied the intermittent TBS and continuous TBS in 20 FTD patients and 18 age-matched healthy subjects. Results were also compared with those achieved in a cohort of age-matched patients with Parkinson's disease. The responses to TBS were abnormal in FTD patients with parkinsonism. By contrast, the TBS induced normal responses in patients with both nfv-PPA and bv-FTD without parkinsonism. Finally, responses to TBS were comparable in patients with FTD with parkinsonism and patients with Parkinson's disease. We provide evidence of abnormal primary motor cortex long-term potentiation-/long-term depression-like plasticity in patients with FTD and parkinsonism suggesting neurodegenerative processes in the corticobasal ganglia-thalamo-cortical motor networks in these patients.

Cognitive Training in Patients with Alzheimer's Disease: Findings of a 12-month Randomized Controlled Trial.

BACKGROUND: Cognitive training (CT) is a non-pharmacological intervention based on a set of tasks that reflect specific cognitive functions. CT is aimed at improving cognition in patients with cognitive impairment, though no definitive conclusions have yet been drawn on its efficacy in Alzheimer's disease (AD). OBJECTIVE: To assess the effectiveness of a CT program designed to improve cognition in AD patients. METHOD: This is a randomized, controlled, single-blind, longitudinal trial with a no-treatment control condition in mild-to-moderate AD. Treated patients received in-group CT twice a week for six months, whereas controls did not. CT consisted of tasks ranging from paper-and-pencil to verbal-learning exercises. Participants' cognitive levels were assessed at baseline, post-intervention and 6 months later by means of a complete neuropsychological test battery. Repeated measures ANOVA was used to analyze the effect of time on the outcome measures, as well as to compare treated and untreated patients over time, with demographic data considered as covariates. RESULTS: Of the 140 patients enrolled, 45 in the treated group and 85 controls concluded the study. The CT significantly improved treated subjects' cognitive functions immediately after the CT. Six months later, some test scores remained stable when compared with those obtained at baseline. The control group performed significantly worse than the treated group at each time-point, displaying a progressive cognitive decline over time. CONCLUSION: Our results suggest that CT may improve cognitive functions in patients with AD and may help to temporarily slow their cognitive decline.

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's r = 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.

The Impact of Frailty on the Risk of Conversion from Mild Cognitive Impairment to Alzheimer's Disease: Evidences from a 5-Year Observational Study.

The frailty construct has increasingly been adopted in the field of cognitive disorders. The aim of the present study was to measure frailty in a cohort of individuals with mild cognitive impairment (MCI) and to explore whether frailty measures may consent to predict the risk of conversion to dementia. We retrospectively reviewed the clinical charts of outpatients with amnesic MCI (aMCI) consecutively recruited at our Department, and followed-up for 5 years. Individual frailty status was measured by means of a frailty index (FI) consisting of 39 deficits (including signs, symptoms, diagnoses, and disabilities). Univariate analyses were used to compare the socio-demographic and clinical characteristics between subjects converting or not converting to probable Alzheimer's disease (AD) dementia over the follow-up. Risk for conversion to AD dementia was assessed using Cox regression models. Ninety-one subjects with aMCI (mean age 72.7, SD 7.1 years; women 49.5%) were consecutively recruited over a period of 12 months. Low levels of frailty were documented in the sample (mean FI score 10.0, SD 5.3). A statistically significant correlation between age and FI was observed. Overall, 58 participants converted to AD dementia over time. The Cox regression analysis showed that age (HR: 1.04, 95% CI: 1.00-1.08), male sex (HR: 0.52, 95% CI: 0.30-0.91), Mini-Mental State Examination score (HR: 0.85, 95% CI: 0.77-0.94), and FI (HR: 1.11, 95% CI: 1.05-1.18) were all significantly associated with the probability of MCI conversion. Individual's frailty status may increase the risk of conversion from a condition of MCI to overt AD dementia. The adoption of constructs comprehensively reflecting the biological decline of the aging subject may add useful estimates and information in the clinical approach to cognitive disorders.