Cognitive impairment is common among older adults hospitalized for non-neurological conditions but often goes unrecognized, particularly in rehabilitation settings where clinical attention is mainly focused on physical recovery. The COGinREHAB study is a multicenter, prospective, longitudinal interventional study conducted at three rehabilitation centers of the Fondazione Don Carlo Gnocchi in Italy (Florence and Milan). The study will enroll 384 patients aged 45 years or older who are hospitalized for at least 7-10 days in cardiac, pulmonary, or orthopedic intensive rehabilitation units, or in intermediate care units, for conditions unrelated to the nervous system. At admission, all participants undergo a clinical and cognitive screening visit. Patients whose screening results suggest possible cognitive impairment then undergo a more extensive neuropsychological evaluation. In those with confirmed cognitive impairment, additional blood tests are performed to measure biomarkers of neurodegeneration (GFAP, neurofilament light chain, and phosphorylated tau-217), together with APOE genotyping and a non-contrast brain CT scan. In a subset of these patients, resting-state EEG, auditory event-related potentials, actigraphy, and overnight polysomnography are also performed. Patients with confirmed cognitive impairment are invited to a follow-up visit 12 months later to assess whether their cognitive profiles and biological markers have changed. The main purpose of the study is to estimate how frequently cognitive impairment occurs among patients admitted to non-neurological rehabilitation units, including how often it was previously undiagnosed. The study will also describe the clinical, biological, and neurophysiological profile of these patients and examine how cognitive impairment evolves over one year.
Rationale. Cognitive impairment is highly prevalent among hospitalized older adults, with reported rates ranging from approximately 20% to 40% depending on setting and assessment method, yet it remains substantially underdiagnosed in general medical and rehabilitation settings, where clinical priorities are directed toward physical recovery. Undetected cognitive dysfunction has been associated with longer hospital stays, higher rates of medical complications, reduced functional recovery, and increased likelihood of institutionalization. Several conditions commonly managed in non-neurological rehabilitation units - cardiovascular disease, chronic respiratory disease, and depression - are independently associated with an increased risk of cognitive decline, further supporting the need for systematic cognitive screening in these populations. Objectives. The primary objective is to determine the prevalence of cognitive impairment among patients aged ≥45 years admitted for non-neurological conditions to cardiac, pulmonary, or orthopedic intensive rehabilitation units, or to intermediate care units, of the Fondazione Don Carlo Gnocchi. Secondary objectives: 1) to determine the rate of cognitive impairment not previously documented in the clinical history of patients admitted to the rehabilitation wards of the Don Carlo Gnocchi Foundation for non-neurological conditions; 2) to characterize the clinical and demographic profile of patients in whom MCI or cognitive dysfunction is identified during hospitalization; 3) to evaluate modifications of the clinical profile and the progression of cognitive dysfunction at the 12-month follow-up in patients with confirmed cognitive impairment at baseline; 4) to investigate the correlation between plasma biomarkers of neurodegeneration, APOE ε4 allele dose, and cognitive profile at baseline (T0) in patients with confirmed cognitive impairment; 5) to assess longitudinal changes in plasma biomarkers of neurodegeneration and their correlation with the progression of cognitive impairment in patients presenting cognitive dysfunction at baseline (T0); 6) to evaluate longitudinal changes in resting-state EEG indices, and their correlation with the progression of cognitive impairment, in patients with cognitive dysfunction at baseline (T0); 7) to examine the correlation between baseline neurophysiological measures, including auditory P300 parameters and sleep-wake measures derived from actigraphy and polysomnography, cognitive profile at T0 and cognitive impairment progression at follow-up (T1). Design and setting. COGinREHAB is a multicenter, prospective, longitudinal interventional study (single-group, diagnostic purpose) conducted over 36 months (January 2026-December 2028) across three sites of the Fondazione Don Carlo Gnocchi in Italy: IRCCS Fondazione Don Gnocchi (Florence); Fondazione Don Gnocchi, Istituto Palazzolo (Milan); IRCCS Fondazione Don Carlo Gnocchi ONLUS, Santa Maria Nascente (Milan). Procedures. The study protocol comprises two assessment time points (T0 baseline and T1 12-month follow-up), structured as sequential, contingent visits. T0 - Screening Visit (within 10 days of admission, approximately 60 minutes): review of medical records for prior documentation on cognitive status; collection of sociodemographic and clinical data (age, sex, education, diabetes, current pharmacological treatment, Cumulative Illness Rating Scale \[CIRS\], Halm's Clinical Instability Scale \[SIC\]); administration of the Montreal Cognitive Assessment (MoCA), Hospital Anxiety and Depression Scale (HADS), Lifestyle for Brain Health index (LIBRA), Cognitive Reserve Index Questionnaire-Short Version (S-CRIq), Motor Reserve Index Questionnaire (MRIq), and Current Physical Activity Questionnaire (cPAq). Patients with a MoCA Equivalent Score of 0 or 1 (overall or in at least one cognitive domain, including the Memory Index Score) proceed to the Baseline Neuropsychological Assessment. Patients scoring more than 2 standard deviations below normative values (corrected MoCA total score \<15.485) are excluded from further baseline assessment, as this is considered indicative of severe cognitive impairment. T0 - Baseline Neuropsychological Assessment Visit: forward/backward Digit Span and Corsi Span; Rey Auditory Verbal Learning Test (immediate recall, delayed recall, intrusions, recognition, Memory Efficiency Index); Rey-Osterrieth Complex Figure (copy, immediate and delayed recall); Naming subtest of the Screening for Aphasia in NeuroDegeneration (SAND); Trail Making Test A and B; Stroop Colour-Word Test; phonemic, semantic, and alternate verbal fluency. Cognitive impairment is confirmed using neuropsychological criteria adapted from the approach of Jak and Bondi (Jak et al., 2009; Bondi et al., 2014), which require objective evidence of low performance on formal testing rather than reliance on a single test score. Consistent with this approach, impairment on an individual test is defined as an Equivalent Score (ES) ≤1 (Capitani \& Laiacona, 1997), corresponding to performance below the 20th percentile of the demographically adjusted normative distribution and considered comparable to the original Jak/Bondi threshold of \>1 SD below normative means. Cognitive impairment is confirmed when a participant obtains an ES ≤1 on at least two tests within a single cognitive domain, or on at least one test in each of three cognitive domains: (i) memory (Digit Span, Corsi Span, RAVLT, and Rey-Osterrieth Complex Figure recall); (ii) language (SAND naming subtest and semantic verbal fluency); and (iii) attention/executive functioning (Trail Making Test A and B, Stroop Colour-Word Test, and phonemic and alternate verbal fluency). T0 - Baseline laboratory, neurophysiological, and imaging assessments performed only in patients with confirmed cognitive impairment, as defined above: venous blood sampling for APOE genotyping, including determination of APOE ε4 allele dose (0, 1, or 2 copies) and allelic frequency distribution (ε2, ε3, ε4), and quantification of plasma biomarkers of neurodegeneration (GFAP, NfL, and pTau-217, all expressed in pg/mL); non-contrast brain CT scan; multimodal neurophysiological assessment, including resting-state EEG (quantified as relative spectral power in the delta, theta, alpha, and beta bands), auditory oddball P300 event-related potentials (quantified as latency and amplitude), actigraphy-based sleep-wake monitoring (quantified as Sleep Efficiency), and overnight polysomnography (quantified as percentage of total sleep time in each sleep stage: N1, N2, N3, and REM), in a subset of patients. T1 - 12-month Follow-up Visit (patients with confirmed cognitive impairment at T0 only): update of pharmacological treatment and CIRS; re-administration of the MoCA and the same neuropsychological battery used at T0 (alternative forms where available); repeat blood sampling for GFAP, NfL, and pTau-217; repeat resting-state EEG. Statistical analysis. Analyses will be performed using Jamovi software. Data distribution will be assessed with the Kolmogorov-Smirnov test; continuous variables will be summarized as mean ± SD or median (IQR) and categorical variables as frequencies/percentages. The prevalence of cognitive impairment (primary outcome) and the prevalence of previously undiagnosed cognitive impairment will be estimated with 95% confidence intervals using the binomial distribution with normal approximation. Group comparisons across MoCA-defined subgroups will use the Kruskal-Wallis test or chi-square test as appropriate. Longitudinal (T0 vs T1) comparisons will use the Wilcoxon signed-rank test for continuous variables and the McNemar test for dichotomous variables. Correlations between cognitive profile, plasma biomarkers, APOE ε4 allele dose, and neurophysiological indices will be assessed using linear regression models adjusted for sociodemographic and clinical confounders, including length of hospital stay. Ethics. The study is conducted in accordance with the Declaration of Helsinki and was approved by the Comitato Etico Regione Toscana - Area Vasta Centro (protocol no. 28251\_spe, approved 23 September 2025). Written informed consent is obtained from all participants.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
DIAGNOSTIC
Masking
NONE
Enrollment
384
Structured collection of clinical/sociodemographic variables (Cumulative Illness Rating Scale -CIRS-, Halm's Clinical Instability Scale -SIC-) and administration of the Montreal Cognitive Assessment (MoCA), Hospital Anxiety and Depression Scale (HADS), Lifestyle for Brain Health index (LIBRA), Cognitive Reserve Index Questionnaire-Short Version (S-CRIq), Motor Reserve Index Questionnaire (MRIq), and Current Physical Activity Questionnaire (cPAq), performed at baseline (T0) in all participants.
Digit Span/Corsi Span (forward/backward), Rey Auditory Verbal Learning Test, Rey-Osterrieth Complex Figure, SAND naming subtest, Trail Making Test A/B, Stroop Colour-Word Test, and phonemic/semantic/alternate verbal fluency, administered at T0 in participants with screening results suggestive of cognitive impairment, and repeated at the 12-month follow-up (T1) in those with confirmed impairment.
Venous blood draw for APOE genotyping, including APOE ε4 allele dose (0, 1, or 2 copies) and allelic frequency distribution (ε2, ε3, ε4) (T0 only), and quantification of plasma GFAP, NfL, and pTau-217 (all expressed in pg/mL; T0 and T1), performed in participants with cognitive impairment confirmed by the extended neuropsychological assessment.
Single non-contrast brain CT scan performed at T0 in participants with confirmed cognitive impairment.
Resting-state EEG, quantified as relative spectral power in the delta, theta, alpha, and beta bands (T0 and, in participants with confirmed cognitive impairment, repeated at T1); auditory oddball P300 event-related potentials, quantified as latency and amplitude; actigraphy-based sleep-wake monitoring, quantified as Sleep Efficiency; and overnight polysomnography, quantified as percentage of total sleep time in each sleep stage (N1, N2, N3, and REM); performed at T0 in a subset of participants with confirmed cognitive impairment.
IRCCS Fondazione Don Gnocchi ETS
Florence, FI, Italy
RECRUITINGIRCCS Fondazione Don Carlo Gnocchi ETS, Santa Maria Nascente
Milan, Michigan, Italy
RECRUITINGFondazione Don Carlo Gnocchi ETS, Istituto Palazzolo
Milan, Michigan, Italy
RECRUITINGPrevalence of cognitive impairment among patients admitted for non-neurological causes to the rehabilitation wards
Proportion of enrolled patients with cognitive impairment (Unit of Measure: % of patients). Confirmed via a two-stage process: (1) MoCA screening (corrected score range 0-30, higher = better), where an Equivalent Score (ES) of 0-1 in ≥1 domain triggers referral to (2) an extended battery, applying criteria adapted from Jak and Bondi (Jak et al., 2009; Bondi et al., 2014): ES ≤1 (Capitani \& Laiacona, 1997; below the 20th percentile, \~equivalent to \>1 SD below norms) on ≥2 tests within one domain, or ≥1 test in each of 3 domains (memory, language, attention/executive functioning). ES ranges 0-4 (0=worse, 4=better). Calculated as (patients with confirmed impairment / total enrolled) × 100, with 95% CI.
Time frame: Baseline (T0), within approximately 10 days of hospital admission
Rate of previously undiagnosed cognitive impairment
Proportion of patients with confirmed cognitive impairment (Unit of Measure: % of patients with confirmed cognitive impairment; per the neuropsychological criteria defined in the Primary Outcome Measure) who had no prior documented diagnosis of cognitive impairment in their clinical history, calculated as (number of patients with previously undiagnosed cognitive impairment / number of patients with confirmed cognitive impairment) × 100, with 95% CI.
Time frame: Baseline (T0), within approximately 10 days of hospital admission
Clinical and demographic characteristics associated with cognitive status at baseline
Comparison of sociodemographic and clinical variables (Unit of Measure: N/A - descriptive comparison across subgroups) among subgroups defined by Montreal Cognitive Assessment (MoCA) Equivalent Score (ES; derived from the 0-30 corrected MoCA total score, higher scores indicating better performance): ES ≥2 (within normative range), ES=1 (borderline), ES=0 (below normative reference limit, worse performance).
Time frame: Baseline (T0), within approximately 10 days of hospital admission
Change in Montreal Cognitive Assessment (MoCA) Total and Domain Scores
Change between T0 and T1 in MoCA total score (corrected score, range 0-30, higher = better) and MoCA cognitive domain scores, including the Memory Index Score (MIS) and other domain-level indices derived from the Italian MoCA normative reference (Dapor et al., 2025), in patients with confirmed cognitive impairment at baseline: Visuo-spatial (MoCA-V corrected score, range 0-4, higher = better); Attention (MoCA-A corrected score, range 0-6, higher = better); Language (MoCA-L corrected score, range 0-5, higher = better); Executive Functions (MoCA-E corrected score, range 0-4, higher = better); Memory (MoCA-DR corrected score, range 0-5, higher = better); Orientation (MoCA-O corrected score, range 0-6, higher = better); and MIS corrected score, range 0-15, higher = better.
Time frame: Baseline (T0) to 12-month follow-up (T1)
Change in Digit Span Performance
Change in forward and backward Digit Span performance (Unit of Measure: number of digits correctly recalled, range 0-9 forward and 0-8 backward; higher = better) between T0 and T1.
Time frame: Baseline (T0) to 12-month follow-up (T1)
Change in Corsi Block-Tapping Span Performance
Change in forward and backward Corsi Span performance (Unit of Measure: number of blocks correctly reproduced; range 0-9 forward and 0-8 backward; higher = better) between T0 and T1.
Time frame: Baseline (T0) to 12-month follow-up (T1)
Change in Rey Auditory Verbal Learning Test (RAVLT) Recall Performance and Memory Efficiency Index
Change in RAVLT immediate recall (Unit of Measure: number of words recalled, range 0-75; higher = better), delayed recall (number of words recalled, range 0-15; higher = better), recognition (number of words correctly recognized, range 0-15; higher = better) and Memory Efficiency Index (calculated as \[(Delayed Recall/15) / (Total Recall/75)\] + \[(Recognition Hits/15) - (False Positives/Distractors)\]; higher = better) between T0 and T1.
Time frame: Baseline (T0) to 12-month follow-up (T1)
Change in Rey-Osterrieth Complex Figure (ROCF) Performance
Change in ROCF copy, immediate and delayed recall accuracy scores (Unit of Measure: accuracy score, range 0-36; higher = better) between T0 and T1.
Time frame: Baseline (T0) to 12-month follow-up (T1)
Change in Screening for Aphasia in NeuroDegeneration (SAND) Naming Subtest Score
Change in SAND naming subtest score (Unit of Measure: number of items correctly named, range 0-14; higher = better) between T0 and T1.
Time frame: Baseline (T0) to 12-month follow-up (T1)
Change in Trail Making Test (TMT) A and B Completion Time
Change in TMT A and B completion time (Unit of Measure: time to completion in seconds; lower = better; continuous measure, not a bounded scale) between T0 and T1.
Time frame: Baseline (T0) to 12-month follow-up (T1)
Change in Stroop Colour-Word Test Time and Error Interference Score
Change in Stroop Colour-Word Test Time and Error Interference scores (Unit of Measure: Time Interference = T3 - \[(T1+T2)/2\], in seconds; Error Interference = E3 - \[(E1+E2)/2\], in number of errors; where T1/E1 and T2/E2 are word-reading and colour-naming performance and T3/E3 is interference-condition performance; lower = better) between T0 and T1.
Time frame: Baseline (T0) to 12-month follow-up (T1)
Change in Verbal Fluency Performance
Change in phonemic, semantic, and alternate verbal fluency performance (Unit of Measure: number of correct words generated per condition; higher = better; continuous measure, not a bounded scale) between T0 and T1.
Time frame: Baseline (T0) to 12-month follow-up (T1)
Change in Cumulative Illness Rating Scale (CIRS) Scores
Change in CIRS Severity Index (Unit of Measure: mean severity score across organ system categories, range 0-4; higher = worse comorbidity burden) and CIRS Comorbidity Index (Unit of Measure: number of categories with severity score ≥3, i.e., decompensated conditions, range 0-13; higher = worse) between T0 and T1.
Time frame: Baseline (T0) to 12-month follow-up (T1)
Correlation Between Baseline Cognitive Profile and Plasma GFAP Concentration
Correlation between baseline cognitive performance, assessed using the Montreal Cognitive Assessment (MoCA) and a comprehensive neuropsychological battery, and plasma Glial Fibrillary Acidic Protein concentration (Unit of Measure: pg/mL) in patients with confirmed cognitive impairment.
Time frame: Baseline (T0)
Correlation Between Baseline Cognitive Profile and Plasma NfL Concentration
Correlation between baseline cognitive performance, assessed using the Montreal Cognitive Assessment (MoCA) and a comprehensive neuropsychological battery, and plasma neurofilament light chain (NfL) concentration (pg/mL) in patients with confirmed cognitive impairment.
Time frame: Baseline (T0)
Correlation Between Baseline Cognitive Profile and Plasma pTau-217 Concentration
Correlation between baseline cognitive performance, assessed using the Montreal Cognitive Assessment (MoCA) and a comprehensive neuropsychological battery, and plasma phosphorylated Tau-217 concentration (Unit of Measure: pg/mL) in patients with confirmed cognitive impairment.
Time frame: Baseline (T0)
Correlation Between Baseline Cognitive Profile and APOE ε4 Allele Dose
Correlation between baseline cognitive performance, assessed using the Montreal Cognitive Assessment (MoCA) and a comprehensive neuropsychological battery, and APOE ε4 allele dose (Unit of Measure: number of ε4 alleles per patient: 0, 1, or 2), determined by genotyping, in patients with confirmed cognitive impairment.
Time frame: Baseline (T0)
APOE Allelic Frequency Distribution
Distribution of APOE allele frequencies (Unit of Measure: % allelic frequency of ε2, ε3, and ε4, calculated as the proportion of each allele among the total alleles observed) in patients with confirmed cognitive impairment, determined by genotyping.
Time frame: Baseline (T0)
Correlation Between Baseline Cognitive Profile and Resting-State EEG Relative Spectral Power
Correlation between baseline cognitive performance, assessed using the Montreal Cognitive Assessment (MoCA) and a comprehensive neuropsychological battery, and resting-state EEG relative spectral power in the delta, theta, alpha, and beta bands (Unit of Measure: % relative spectral power per band) in patients with confirmed cognitive impairment.
Time frame: Baseline (T0)
Correlation Between Baseline Cognitive Profile and Auditory P300 Latency
Correlation between baseline cognitive performance, assessed using the Montreal Cognitive Assessment (MoCA) and a comprehensive neuropsychological battery, and P300 latency (Unit of Measure: milliseconds; lower latency = faster processing), elicited via an auditory oddball paradigm, in patients with confirmed cognitive impairment.
Time frame: Baseline (T0)
Correlation Between Baseline Cognitive Profile and Auditory P300 Amplitude
Correlation between baseline cognitive performance, assessed using the Montreal Cognitive Assessment (MoCA) and a comprehensive neuropsychological battery, and P300 amplitude (Unit of Measure: microvolts, μV), elicited via an auditory oddball paradigm, in patients with confirmed cognitive impairment.
Time frame: Baseline (T0)
Correlation Between Baseline Cognitive Profile and Actigraphy-Derived Sleep Efficiency
Correlation between baseline cognitive performance, assessed using the Montreal Cognitive Assessment (MoCA) and a comprehensive neuropsychological battery, and actigraphy-derived Sleep Efficiency (Unit of Measure: % Sleep Efficiency; percentage of time in bed spent asleep) in patients with confirmed cognitive impairment.
Time frame: Baseline (T0)
Correlation Between Baseline Cognitive Profile and Polysomnography-Derived NREM Sleep Stage Percentages (N1, N2, N3)
Correlation between baseline cognitive performance, assessed using the Montreal Cognitive Assessment (MoCA) and a comprehensive neuropsychological battery, and the percentage of total sleep time spent in NREM sleep stages N1, N2, and N3 (slow-wave sleep) (Unit of Measure: % of total sleep time per stage), as measured by overnight polysomnography, in patients with confirmed cognitive impairment.
Time frame: Baseline (T0)
Correlation Between Baseline Cognitive Profile and Polysomnography-Derived REM Sleep Percentage
Correlation between baseline cognitive performance, assessed using the Montreal Cognitive Assessment (MoCA) and a comprehensive neuropsychological battery, and the percentage of total sleep time spent in REM sleep (Unit of Measure: % of total sleep time in REM sleep), as measured by overnight polysomnography, in patients with confirmed cognitive impairment.
Time frame: Baseline (T0)
Change in Plasma GFAP Concentration and Correlation With Cognitive Performance Over 12 Months
Change in plasma glial fibrillary acidic protein (GFAP) concentration (Unit of Measure: pg/mL) between baseline (T0) and 12-month follow-up (T1), and its correlation with cognitive performance, assessed using the Montreal Cognitive Assessment (MoCA) and a comprehensive neuropsychological battery, in patients with confirmed cognitive impairment at baseline.
Time frame: Baseline (T0) to 12-month follow-up (T1)
Change in Plasma NfL Concentration and Correlation With Cognitive Performance Over 12 Months
Change in plasma neurofilament light chain (NfL) concentration (Unit of Measure: pg/mL) between baseline (T0) and 12-month follow-up (T1), and its correlation with cognitive performance, assessed using the Montreal Cognitive Assessment (MoCA) and a comprehensive neuropsychological battery, in patients with confirmed cognitive impairment at baseline.
Time frame: Baseline (T0) to 12-month follow-up (T1)
Change in Plasma pTau217 Concentration and Correlation With Cognitive Performance Over 12 Months
Change in plasma phosphorylated tau-217 (pTau217) concentration (Unit of Measure: pg/mL) between baseline (T0) and 12-month follow-up (T1), and its correlation with cognitive performance, assessed using the Montreal Cognitive Assessment (MoCA) and a comprehensive neuropsychological battery, in patients with confirmed cognitive impairment at baseline.
Time frame: Baseline (T0) to 12-month follow-up (T1)
Change in Resting-State EEG Relative Spectral Power and Correlation With Cognitive Performance Over 12 Months
Change in resting-state EEG relative spectral power in the delta, theta, alpha, and beta frequency bands (Unit of Measure: % relative spectral power per band) between baseline (T0) and 12-month follow-up (T1), and its correlation with cognitive performance, assessed using the Montreal Cognitive Assessment (MoCA) and a comprehensive neuropsychological battery, in patients with confirmed cognitive impairment at baseline.
Time frame: Baseline (T0) to 12-month follow-up (T1)
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