Italian Validation of the Dynamic Neurocognitive Adaptation (dNA) Scale and Its Correlation With Neurocognitive Variables
Conditions: Active Aging Individuals Aged 65 and Over, Aging, Mild Cognitive Impairment (MCI), Dementia, Dementia Alzheimer Type, Subjective Memory Complaints, Probable Alzheimer's Disease
Sponsor: Neuromed IRCCS

SAN CAMILLO IRCCS S.R.L. SOCIETÀ UNIPERSONALE 
OSPEDALE NEURORIABILITATIVO | ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO 
SEDE LEGALE 30126 | VENEZIA LIDO | VIA ALBERONI, 70 | TEL. 041 22 07 111 | FAX 041 73 13 30 
P.IVA – Cod.Fis. – N. Reg.Imp. 04554270274 | REA VE 426965 | COD.SDI T04ZHR3 
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Official Study Title: “Italian Validation of the Dynamic Neurocognitive Adaptation (dNA) Scale and its 
Correlation with Neurocognitive Variables” 
Study Acronym: “dNA”  
Study Code: 2024.13  
Document Type: Study Protocol and Statistical Analysis Plan 
Document Version: Version 1.0 
Document Date: 11/27/2024 
Institution: San Camillo S.R.L. 
Principal Investigator 
The study will be conducted by Dr. Giorgio Arcara 
Study sites and principal investigators 
The coordinating institution for the study will be San Camillo IRCCS s.r.l., under the supervision of Dr. 
Giorgio Arcara. 
The affiliated institutions participating in data collection and their respective principal investigators are: 
1. Institution: San Camillo IRCCS s.r.l. Via Alberoni, 70, Lido, VE 
Principal investigators: Giorgio Arcara; Rachele Pezzetta; Cristina Scarpazza 
2. Institution: Università Campus Bio−Medico di Roma, Via Álvaro del Portillo, 21 − 00128 
Roma  
Principal investigators: Francesco Motolese, Vincenzo di Lazzaro 
3. Institution: IRCCS Centro San Giovanni di Dio Fatebenefratelli Via Pilastroni, 4, 25125 
Brescia BS, Italy  
Principal investigators: Cristina Festari, Michela Pievani 
4. Institution: Fondazione IRCCS Istituto Neurologico Naz.le Mondino. Via Mondino, 2, 
27100 Pavia PV, Italy  
Principal investigators: Valentino De Franco, Alfredo Costa 
 
 

SAN CAMILLO IRCCS S.R.L. SOCIETÀ UNIPERSONALE 
OSPEDALE NEURORIABILITATIVO | ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO 
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5. Institution: Istituto Neurologico "Carlo Besta" | Fondazione IRCCS. Via Giovanni 
Celoria, 11, 20133 Milano MI, Italy 
Principal investigators: Monica Consonni; Giuseppe Lauria−Pinter 
6. Institution: Ospedale IRCCS Neuromed. Via Atinense, 18, 86077 Pozzilli (IS) 
Principal investigators: Luana Gilio, Mario Stamponi Bassi, Diego Centonze, Lorena 
Belli 
7. Institution: IRCCS Ospedale San Raffaele (MI). Via Olgettina, 60, 20132 Milano MI, Italy  
Principal investigators: Massimo Filippi, Federica Agosta, Elisa Canu 
8. Institution: IRCCS Ospedale Policlinico San Martino (GE). Largo Rosanna Benzi 10 – 
16132 Genova.  
Principal investigators: Matteo Pardini, Antonio Uccelli 
9. Institution: Università degli Studi G. d’Annunzio di Chieti − CH  
Principal investigators: Michela Balsamo 
10. Institution: Università degli Studi di Foggia – FG 
Ricercatori responsabili: Leonardo Carlucci 
11. Institution: Università degli Studi di Padova – PD 
Ricercatori responsabili: Marco Marino, Cristina Scarpazza 
 
 
 
 
 
 
 

SAN CAMILLO IRCCS S.R.L. SOCIETÀ UNIPERSONALE 
OSPEDALE NEURORIABILITATIVO | ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO 
SEDE LEGALE 30126 | VENEZIA LIDO | VIA ALBERONI, 70 | TEL. 041 22 07 111 | FAX 041 73 13 30 
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Study Design 
A multicenter experimental study involving cognitively healthy older adults, older adults with subjective 
memory complaints, older adults with mild cognitive impairment, and older adults with dementia. 
 
Study Description 
This study aims to validate the instrument known as the dynamic Neurocognitive Adaptation Scale (dNA), 
derived from the identical scale (dynamic Neurocognitive Adaptation – dNA) previously validated in English 
on a sample of 815 subjects residing in the United States. All the clinical centers involved will recruit 
approximately 265 subjects, administer the aforementioned scale, and collect demographic and medical 
history information. This information will be necessary and sufficient for the first part (Stage #1) of the 
instrument’s validation. This phase will be followed by a second part (Stage #2) focused on exploring the 
correlation between the dNA score and neuropsychological variables (particularly those related to memory 
and executive functions), with the aim of investigating a measure of adaptation that is primarily cognitive in 
nature. This adaptation will provide a measure of cognitive efficiency, commonly referred to in the literature 
as cognitive reserve or resilience. In this phase, adherence to a Mediterranean-style diet (i.e., the 
Mediterranean diet, assessed via a specific questionnaire) will also be explored as a protective factor against 
general inflammatory processes and cognitive decline associated with Alzheimer’s disease (AD). During the 
third phase (Stage #3), we will explore a measure of neural adaptation, collecting data on neural efficiency. 
In the literature, this is a form of resilience or adaptation often described as neural reserve. This component 
will be explored using structural magnetic resonance imaging (MRI) and functional magnetic resonance 
imaging (fMRI).  
Demographic information, medical history, dietary habits, and neuropsychological data collected by the 
participating centers will be compiled and managed at the Universities of Chieti and Foggia, under the 
coordination and responsibility of Professor Michela Balsamo (CH) and Professor Leonardo Carlucci (FG), 
respectively, both of whom have established expertise in statistics and psychometrics, particularly in the 
validation of instruments within the field of psychology. The two universities will carry out the data analysis 
phase aimed at validating the scale (Stage #1), also accounting for key demographic variables (age, sex, 
education level). Subsequently, the second phase (Stage #2) will be conducted, in which scale scores will be 
examined in relation to the aforementioned dietary habits and neuropsychological variables, particularly  
 

SAN CAMILLO IRCCS S.R.L. SOCIETÀ UNIPERSONALE 
OSPEDALE NEURORIABILITATIVO | ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO 
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memory and executive functions. All participating clinical centers will collect demographic, medical history, 
dietary habit, neuropsychological, and, where available, imaging data (MRI, fMRI). These data will be used in 
the third phase (Stage #3), which will focus on identifying the neural correlates of adaptation (i.e., neural 
efficiency) during aging. Imaging data collected by the participating clinical centers will be transferred to the 
University of Padua, which will oversee data receipt and analysis under the coordination and responsibility 
of Dr. Marco Marino, whose research focuses on the neural substrates underlying neurocognitive adaptation 
during aging. In this phase, both structural (e.g., volumetric and cortical thickness) and functional (e.g., 
resting-state fMRI) analyses will be performed. This phase will receive scientific support from the University 
of Leuven (Dr. Dante Mantini) and the Cleveland Clinic (Dr. Filippo Cieri); however, these institutions and 
their respective researchers will not have access to the data. 
 
Hypotheses 
Hypothesis #1: We hypothesize that the validation results will be similar to those obtained in the U.S. 
validation study, with similar factor structure/dimensionality, and reliability coefficients and indices 
consistent with the English version. 
Hypothesis #2: We hypothesize a correlation between dNA and cognitive efficiency, specifically a positive 
correlation between scores on the dNA scale and results on neuropsychological tests of memory and 
executive functions. 
Hypothesis #3: Finally, we hypothesize a correlation between dNA and improved functional connectivity (FC) 
at the level of so-called task-negative neural networks, such as the Default Mode Network (DMN). We expect 
this increased FC within the DMN to be associated with a concurrent deactivation of networks FC) at the level 
of so-called task-negative neural networks, such as the Default Network (DN). We expect this increased FC 
within the DN (within networks) to be associated with a concomitant deactivation of task-positive neural 
networks (between networks), such as the Dorsal Attention Network (DAN) and the Frontoparietal Control 
Network (FPCN). 
 
Expected Duration 
The expected duration of this study is 36 months. 
 
 

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Rationale 
According to the recent report by the Lancet Standing Commission 2024: Dementia Prevention, Intervention, 
and Care, 45% of cases of Alzheimer’s disease (AD) dementia could be prevented through the adoption of 
behaviors that protect against neurodegenerative mechanisms (Livingston et al., 2024). Among these 
behaviors, physical, cognitive, and social activity play a key role. Concepts of neurocognitive reserve, 
resilience, resistance, plasticity, and adaptation have led to important advances in the prevention of these 
diseases. Engagement in physical, cognitive, creative, and social activities acts as a protective factor against 
neuropathological mechanisms typical of AD. A scale called Dynamic Neurocognitive Adaptation (dNA) was 
recently validated in English on a sample of 815 individuals residing in the United States (Cieri et al., 
accepted). This tool explores individual engagement in physical, cognitive, social, and creative activities in a 
dynamic manner over time, across the entire lifespan, capable of promoting specific mechanisms of 
neurocognitive efficiency and plasticity. The present study proposes the validation of the American scale in 
Italian, exploring the possibility of greater resistance to age-related pathological aging in those individuals 
who maintain ongoing engagement in physical, cognitive, social, and creative activities. Engagement in such 
activities across the lifespan may enhance neurocognitive efficiency, thereby acting as a protective factor 
against the most prevalent form of dementia, for which no effective pharmacological cure currently exists. 
Understanding the mechanisms underlying these adaptive and efficiency processes is essential for 
developing specific behaviors and targeted interventions for at-risk populations. A second objective is to 
identify crucial periods during which this type of preventive and protective intervention of a non-
pharmacological nature may be most effective. Recent literature underscores the importance of a 
transitional phase between middle age and older age (Dohm-Hansen et al., 2024; Shen et al., 2024), 
highlighting the nonlinear and dynamic temporal nature of age-related changes (Ahadi et al., 2020; Dec et 
al., 2023; Holzscheck et al., 2020; Li et al., 2020; Timmons et al., 2019). These changes in cognitive, physical, 
and physiological domains deserve particular attention (Cieri et al., accepted; Nie, C. et al., 2022; Schaum et 
al., 2020; Wagner et al., 2023).  
Imaging studies have identified a specific pattern of functional connectivity (FC) within the medial temporal 
regions, which make up the DN (Raichle et al., 2001), also referred to as the task-negative network. This 
network comprises brain regions that are active during the resting state condition, when the subject is at rest 
inside the scanner and not engaged in performing any cognitive or motor task. The regions within the DN are 
associated with episodic and autobiographical memory, which are linked to the individual’s sense of self 
(Cieri, 2022; Cieri and Esposito, 2018; 2019; Qin and Northoff, 2011; Yeshurun et al., 2021). Importantly, 
posterior components of the DN (such as the posterior cingulate cortex and the precuneus) are among the  

SAN CAMILLO IRCCS S.R.L. SOCIETÀ UNIPERSONALE 
OSPEDALE NEURORIABILITATIVO | ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO 
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earliest sites of amyloid plaques, a hallmark of this form of dementia (Sperling et al., 2009), and are thought 
to be responsible for the characteristic cognitive decline, especially in mnemonic functions. In cognitively 
healthy individuals, spontaneous brain activity should exhibit a spatiotemporal activation pattern consistent 
with the DN organization. This activation pattern should also show a negative correlation (anti-correlation) 
with the activation of the so-called task-positive networks such as the DAN and the FPCN, which are typically 
active during attention-demanding cognitive tasks (Esposito et al., 2019). With advancing age, this 
coordinated pattern of activation and deactivation – and the balance between correlation and anticorrelation 
– tends to deteriorate (Spreng et al., 2016). Such disruptions are especially pronounced in individuals with 
mild cognitive impairment (MCI) (Esposito et al., 2019), and have been identified as a prodromal sign of 
Alzheimer’s disease (AD). 
 
Objectives 
The project has the following objectives: 
Objective #1: The primary objective of the study is the Italian validation of the scale known as dNA on an 
elderly population (+65 years); the dNA Scale as already been validated in English on an elderly population 
(+65 years) residing in the United States. 
Objective #2: The second objective is to examine the association between the results derived from the scale 
and cognitive measures; specifically, episodic memory and executive functions which are commonly impaired 
in neurodegenerative conditions such as AD will be further explored in order to investigate the relationship 
between the dNa score and cognitive efficiency. 
Objective #3: The third objective is to examine the association between the results derived from the scale 
and neurocognitive measures with neural network activations in the resting state condition (resting-state 
fMRI, rs-fMRI). Specifically, the state of FC of the DN network associated with the deactivation of the so-
called task-positive networks such as the DAN and the FPCN will be explored in order to measure a form of 
neural efficiency. 
The study—both the original American study and its Italian validation and extension, which is the subject of 
this application—focuses on exploring so-called protective factors in cognitive aging, especially pathological 
aging, particularly as it pertains to AD. The scale in question examines participants’ engagement in activities  

SAN CAMILLO IRCCS S.R.L. SOCIETÀ UNIPERSONALE 
OSPEDALE NEURORIABILITATIVO | ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO 
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known to act as protective factors against the pathological mechanisms typical of AD. Although the 
investigation of dietary habits —specifically those typical of a Mediterranean diet—is of a more exploratory 
nature, the study also aims to investigate the role of adherence to a Mediterranean-style diet (typically 
Italian), which has demonstrated a protective role against inflammatory mechanisms also typical of AD.  
The present study explores neurocognitive adaptation mechanisms commonly conceptualized in the 
literature as resilience and reserve. We will explore this form of neurocognitive adaptation into an initial form 
of cognitive efficiency, which will be assessed through the use of neuropsychological testing focused on 
memory and executive functions. In this context, we hypothesize a correlation between dNA scores and 
greater cognitive efficiency. The second form of efficiency, of a neural nature, will be explored through the 
use of functional magnetic resonance imaging (fMRI). Specifically, we expect improved neurophysiological 
efficiency in terms of spontaneous activity in the DN, which is negatively correlated with activation of the 
DAN and FPCN, in association with dNA scores. 
Participants recruited at the participating clinical centers will undergo a clinical interview, during which 
demographic and medical history information will be collected, and the dNA will be administered, along with 
the questionnaire regarding adherence to dietary habits typical of a Mediterranean diet (14-Item 
Mediterranean Diet Adherence Screener; MEDAS). Subsequently, a neuropsychological assessment will be 
conducted, in which the subjects’ general cognitive function will be evaluated, with particular focus on 
episodic memory and executive functions. The subjects will complete the following tests: MMSE (or 
alternatively MoCA), Rey Auditory Verbal Learning Test (RAVLT), Trial Making Test (TMT) Form B, Digits 
Forward and Backward subtest (WAIS or WAIS-III), and Stroop Test. These measures will provide a global 
cognitive assessment (MMSE, MoCA) and more specific measures of memory and executive functions. 
Participants will also complete a survey designed to assess depressive symptoms using the Geriatric 
Depression Scale (GDS) and anxiety symptoms using the Geriatric Anxiety Scale (GAS) (or STAI, State and Trait 
Anxiety Index). Finally, the Cognitive Reserve Index Questionnaire will be administered to estimate Cognitive 
Reserve (CRIq). 
Generalizability 
The association of this scale with demographic and neurocognitive variables, on the one hand, and neural 
variables (neural structures and functions) on the other, provides crucial insights into the study of the 
pathophysiological mechanisms typical of AD. Lifetime engagement in the activities investigated by the scale 
under study will be useful for exploring concepts of neurocognitive adaptation, known in the literature as  

SAN CAMILLO IRCCS S.R.L. SOCIETÀ UNIPERSONALE 
OSPEDALE NEURORIABILITATIVO | ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO 
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cognitive reserve and resilience during aging. The association of this scale with cognitive variables (memory 
and executive functions) and subsequently neural variables (e.g., activation of neural networks via rs-fMRI) 
could reveal protective mechanisms of neurocognitive plasticity and efficiency which are vital to research in 
this field, identifying not only specific behaviors and targeted interventions but also crucial periods for 
preventive and protective, non-pharmacological interventions. 
 
Methodology 
Sample Description 
The study plans to recruit 265 participants, divided into cognitively healthy individuals, those with subjective 
memory complaints, patients with MCI, and patients with AD, probable AD, and possible AD. Each center will 
recruit approximately 30 subjects. The total number of centers is twelve (12), of which three (3) do not 
conduct clinical activities, namely the universities of Chieti, Foggia, and Padua, which will handle data analysis 
(Universities of Chieti and Foggia will handle behavioral data, while University of Padua imaging data), 
without participating in the recruitment phase. Eight (8) centers will actively participate in recruitment, 
enrolling approximately 30 subjects per center (total of approximately 265 subjects). The homogeneity of the 
sample (in diagnostic terms) is not relevant for validation purposes, provided that participants do not have 
established forms of dementia. Greater homogeneity among diagnostic groups is more desirable for the 
subsequent phases of the project, but even in this case, it is not decisive because the study’s objective is the 
association of the scale with the mentioned variables, not the comparison between diagnostic groups, 
provided that the diagnostic categories are clear. 
According to the literature, the number of participants required to validate a 20-item scale, which has already 
been validated in another language (specifically in English on a sample of 815 subjects residing in the United 
States), is approximately 250 subjects (Comrey and Lee, 1992). Approximately 265 participants will be 
recruited, and this number will be experimentally verified during the validation phase using a specific index 
(Kaiser-Meyer-Olkin; KMO) to confirm the appropriateness of the sample (Kaiser, 1974). As mentioned, the 
subjects used for the validation phase will be healthy individuals, people with subjective memory complaints, 
subjects with mild cognitive impairment (MCI), or patients with AD, probable AD, or possible AD. The 
participating clinical centers may also recruit subjects with different diagnoses or suffering from other forms  
 

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of dementia, but these patients will not be used for the first phase (Stage #1) of validation. However, these 
patients may be used for subsequent phases.  
The subjects recruited for the validation phase (Stage #1) will be cognitively healthy individuals (cognitively 
normal; CN), individuals with subjective memory complaints (SMC), individuals with mild cognitive 
impairment (MCI), individuals with AD (Alzheimer’s disease), with possible AD, or probable AD (even without 
confirmation by cerebrospinal fluid (CSF) assays, imaging, or plasma assays; McKhann et al., 1984; 
https://www.centroalzheimer.org/area-familiari/la-malattia-di-alzheimer/malattia-di-
alzheimer/criteridiagnostici/). For the next two phases (Stage #2 & Stage #3), patients with other forms of 
dementia may be recruited. In all three phases (Stage #1, Stage #2, and Stage #3), subjects with depressive 
or anxiety disorders, as assessed by the Geriatric Depression Scale (GDS) and the State-Trait Anxiety Inventory 
(STAI), will be eligible for recruitment, provided that the diagnosis is clearly specified during the clinical 
assessment, including the onset of symptoms. 
Inclusion Criteria (Stage #1) 
Cognitively healthy individuals: 
- age ≥ 65 years, residing in Italy; 
- MMSE score between 24 and 30 inclusive (alternatively, MoCA: score between 26 and 30 inclusive); 
- not depressed, not with MCI, and not affected by any form of dementia; 
- episodic memory score adjusted for years of schooling (Wechsler Memory Scale Logical Memory II 
≥9 for 16 years of schooling or more; ≥5 for 8–15 years of schooling, ≥3 for 0–7 years of schooling; or 
alternatively for Prose Memory Test with scores ≥9 for ≥16 years of schooling → ≥5 items in 
immediate or delayed recall; ≥5 for 8–15 years of schooling → ≥3–4 items in immediate or delayed 
recall; ≥3 for 0–7 years of schooling → ≥2 items in immediate or delayed recall). 
Individuals with Subjective Memory Complaints (SMC): 
- age ≥ 65 years, residing in Italy; 
- MMSE score between 24 and 30 inclusive (alternatively MoCA: score 26–30 inclusive); 
- a significant memory impairment, reported by the subject, a family member, or the clinician; 
- not depressed, not with MCI, and not affected by any form of dementia; 
- episodic memory with a score on the Wechsler Memory Scale Logical Memory II adjusted for years 
of schooling (≥9 for 16+ years of schooling, ≥5 for 8–15 years of schooling, ≥3 for 0–7 years of 
schooling or, alternatively, on the Prose Memory Test with scores ≥9 for ≥16 years of schooling → ≥5  

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items in immediate or delayed recall; ≥5 for 8–15 years of schooling → ≥3–4 items in immediate or 
delayed recall; ≥3 for 0–7 years of schooling → ≥2 items in immediate or delayed recall). 
Individuals with MCI: 
- age ≥ 65 years, residing in Italy; 
- MMSE score between 19 and 23 inclusive (alternatively MoCA); 
- a decline in memory reported by the subject, a family member, or the clinician; 
- not depressed, and not affected by any form of dementia, with preserved ability in activities of daily 
living; 
- objective episodic memory loss on the Wechsler Memory Scale Logical Memory II adjusted for years 
of schooling (≥9 with 16 or more years of schooling, ≥5 for 8–15 years of schooling, ≥3 for 0–7 years 
of schooling). 
Individuals with probable Alzheimer’s disease: 
- Insidious onset: symptoms developed gradually over the course of months 
- A decline in performance compared to the previous level of functioning is evident, as also described 
by a caregiver (often a family member) 
- Onset with memory disturbances, defined as difficulty learning new information or recalling it. 
or 
- Onset with non-mnemonic symptoms 
> Onset with language symptoms, particularly difficulty finding the correct words 
> Onset with visuospatial symptoms: perceptual deficits characterized by failure to recognize 
objects, people, or written words 
> Onset with executive symptoms: difficulties with reasoning and critical thinking 
Criteria for possible Alzheimer’s disease: 
• Atypical course 
Some criteria for probable AD are met, but the onset of symptoms may have been sudden, 
or there is a lack of objective evidence of progressive cognitive decline 
• Mixed etiology presentation 
> All criteria for probable AD are met 
> Concomitant cerebrovascular disorders, or 

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> Features typical of another dementia (e.g., Lewy body dementia), or 
> Evidence of other neurological disorders or non-neurological comorbidities, or possible use 
of medications with effects on cognition. 
Tests: MMSE < 23; MoCA < 25; objective episodic memory loss on the Wechsler Memory Scale Logical 
Memory II adjusted for years of schooling (≥9 with 16 or more years of schooling, ≥5 for 8–15 years of 
schooling, ≥3 for 0–7 years of schooling); 
Exclusion criteria 
Stage #1: 
- subjects under 65 years of age, not residing in Italy, suffering from other forms of dementia. 
Inclusion criteria (Stage #2 & Stage #3) 
- age ≥ 65 years, residing in Italy, residing in Italy; 
- cognitively healthy, or affected by MCI/AD, other forms of dementia, or mental disorders, provided 
that these are described in detail by the clinician, including scores on scales such as anxiety and 
depression, and not included in the validation (i.e., in Stage #1). 
If a subject is already enrolled at a recruitment center and has already undergone a demographic, medical 
history, neuropsychological, or MRI assessment for another research study, and their cognitive status has not 
changed over the past six months, the clinician may administer the dNA (and the Mediterranean diet 
adherence scale) and access the previously collected data, provided that the participant is informed of the 
study’s objectives and gives informed consent. 
Procedures 
This study involves administering the dNA scale, along with a demographic and medical history assessment, 
a questionnaire investigating adherence to a typically Mediterranean diet, and a cognitive assessment using 
neuropsychological testing and neuroimaging via functional magnetic resonance imaging (fMRI). Among the 
demographic variables, particular importance will be given to years of schooling—a proxy typically used in 
the literature to define cognitive reserve—and diet, a protective factor against the inflammatory mechanisms 
present in AD-type dementia. This information will be collected during interviews and through the 
completion of demographic and medical history forms. Following the collection of this information, together 
with the dNA scale, each center will share these data with the Universities of Chieti and Foggia, which will  

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analyze the data with the aim of validating the scale in Italian and associating the aforementioned variables, 
with the exception of MRI images, which will be analyzed by the University of Padua. 
 
Figure 1. The image shows the introductory and explanatory section of the dNA scale (Dynamic Neurocognitive 
Adaptation Scale), which takes approximately 15 minutes to complete. For the complete PDF of the dNA scale, please 
refer to the attachments included in the submitted documentation. 
Neuropsychological variables 
The neuropsychological assessment involves the administration of the following instruments: MMSE (or 
MoCA), Rey Auditory Verbal Learning Test (RAVLT), Trial Making Test (TMT) Form B, Digits Forward and 
Backward subtests (WAIS or WAIS-III), Wechsler Memory Scale Logical Memory II (or Prose Memory), and 
Stroop Test. These measures will provide an overall cognitive assessment (MMSE or MoCA) and more specific 
measures of memory and executive functions. 
Neural variables 
If the volunteer subject has not already undergone an MRI as part of another study conducted at IRCCS San 
Camillo, the neuroimaging assessment will involve the use of magnetic resonance imaging, through which  

SAN CAMILLO IRCCS S.R.L. SOCIETÀ UNIPERSONALE 
OSPEDALE NEURORIABILITATIVO | ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO 
SEDE LEGALE 30126 | VENEZIA LIDO | VIA ALBERONI, 70 | TEL. 041 22 07 111 | FAX 041 73 13 30 
P.IVA – Cod.Fis. – N. Reg.Imp. 04554270274 | REA VE 426965 | COD.SDI T04ZHR3 
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Rev 03 del 2024/05/27 
Pag. 13 di 20 
 
 
 
structural (MRI) and functional (fMRI) data will be collected, specifically during the resting state (resting-state 
fMRI) without the use of any specific cognitive or motor task. 
Participating centers that have the capability may also retrieve information from the patient’s medical record 
regarding biomarkers of pathological aging (e.g., APoE). Similarly, if the behavioral, clinical, or instrumental 
examination has already been performed at the same center, it will be possible to retrieve the data without 
repeating the examination, provided that the participant has given informed consent. 
 
Statistics 
Statistical Analyses 
Analyses Required for Validation 
For the primary objective analyses, a principal component analysis (PCA) and an exploratory factor analysis 
(EFA) will be conducted in parallel, serving as the basis for the subsequent confirmatory factor analysis (CFA) 
in the validation sample. Factors will be extracted without specifying the number and patterns of loadings 
between the observed variables and the latent factors. In CFA, on the other hand, we specify the number, 
meaning, associations, and patterns of free parameters in the factor weight matrices before analyzing the 
data (Morris et al., 1996). While in EFA, factors are extracted without specifying the factor loadings between 
the observed variables and the latent factor variables, in CFA we will specify the number, meaning, 
associations, and model of free parameters in the factor loading matrix before analyzing the data. EFA will 
be useful for determining the underlying factor structure and for identifying latent domains capable of 
explaining the common variance among activity items rather than simply summarizing the maximum amount 
of observed variance, as is done in PCA analysis (Negash et al., 2013). EFA will be used to identify and 
distinguish the key constructs of the dNA instrument. Descriptive statistics (means and standard deviations) 
will be used for continuous variables and percentages for categorical variables to characterize the study 
sample. 
A PCA will be performed with permutation of the raw data to determine the number of components among 
the items. PCA factor loadings will be examined, retaining all factors with eigenvalues >1. Before performing 
EFA, we will assess the adequacy of the sample size using the Kaiser-Meyer-Olkin (KMO) statistic. We will use 
Bartlett’s sphericity test, separately for all seven time windows, to test for homogeneity of variances. 
Cronbach’s alpha (α) will be calculated to assess the internal consistency of the scale, using a threshold of > 
0.8. We will also use direct oblique rotation with Kaiser normalization and examine the consistency of the  

SAN CAMILLO IRCCS S.R.L. SOCIETÀ UNIPERSONALE 
OSPEDALE NEURORIABILITATIVO | ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO 
SEDE LEGALE 30126 | VENEZIA LIDO | VIA ALBERONI, 70 | TEL. 041 22 07 111 | FAX 041 73 13 30 
P.IVA – Cod.Fis. – N. Reg.Imp. 04554270274 | REA VE 426965 | COD.SDI T04ZHR3 
IRCCS 
Rev 03 del 2024/05/27 
Pag. 14 di 20 
 
 
 
 
 
 
items to identify excessively high correlations (r ≥ .80) suggesting multicollinearity or low correlations (r < 
.30) indicating insufficient common variance. 
During the CFA phase, a structural equation modeling (SEM) approach will be used with a maximum likelihood 
estimation method to assess the fit of the factor structure hypothesized based on the EFA results. CFA allows 
for the direct comparison of alternative models of relationships between constructs, which is fundamental 
for establishing construct validity. Model fit indices will be calculated, including chi-square (p-value > 0.05), 
root mean square error of approximation (RMSEA; cutoff ≤ 0.06), normed fit index (NFI), comparative fit 
index (CFI; cutoff ≥ 0.90), Tucker-Lewis index (TLI; cut-off ≥ 0.95), and standardized root mean square residual 
(SRMR; cut-off ≤ 0.08).  
Finally, the coefficient of determination (R²) will be evaluated, which explains how much of a factor’s 
variability is caused by its relationship with another factor. 
Behavioral Correlation Analysis 
Correlation analyses will also be conducted among the various domains within the scale: cognitive, physical, 
creative, and social, using distance correlations, a set of measures that examines potential relationships 
between vectors without the assumptions required for classical product-moment correlations, remaining 
valid under multiple conditions, including when the variables have an implicit assumption of temporality that 
may violate the assumptions of traditional coefficients (Szekely, Rizzo, and Baklrov 2007; Szekely and Rizzo, 
2009). The domains will also be examined across the seven time periods using RM-ANOVA with Greenhouse-
Geisser sphericity corrections. Within-subject comparisons by time and all interactions between time, 
gender, and education level will be calculated. We will examine the role of gender, education, and their 
interaction. We will calculate planned contrasts within domains for paired time comparisons and interactions 
if significant, and examine Bonferroni-Holm corrected paired comparisons between educational levels (as a 
measure of cognitive reserve). Finally, we will calculate the correlations between the scale and adherence to 
a Mediterranean diet, as well as the correlation between the scale and scores on cognitive tests of memory 
and executive functions. Moderation analyses will also be conducted to test the hypothesis that higher dNA 
scores may moderate negative effects on neuropsychological measures (lower scores in memory and 
executive functions) and neurophysiological measures (poor anticorrelation between DN and DAN/FPCN). 
 
 

SAN CAMILLO IRCCS S.R.L. SOCIETÀ UNIPERSONALE 
OSPEDALE NEURORIABILITATIVO | ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO 
SEDE LEGALE 30126 | VENEZIA LIDO | VIA ALBERONI, 70 | TEL. 041 22 07 111 | FAX 041 73 13 30 
P.IVA – Cod.Fis. – N. Reg.Imp. 04554270274 | REA VE 426965 | COD.SDI T04ZHR3 
IRCCS 
Rev 03 del 2024/05/27 
Pag. 15 di 20 
 
 
 
 
fMRI Analysis 
Structural MRI scans will be acquired with a 24 cm field of view, resolution 256×256×170, for voxel 
dimensions of 1×1×1, 2 mm³. A standard echo-planar imaging sequence will be used to acquire rs-fMRI data 
with 140 time points, TR/TE=3000/30 ms, flip angle=80 degrees, 48 slices, spatial resolution=3.3×3.3×3.3 
mm³, and imaging matrix=64×64. The first five volumes will be discarded. Preprocessing steps will include 
slice-timing correction, realignment, co-registration to T1-weighted images with skull stripping, and spatial 
normalization to the 2-mm MNI 152 reference space. 
Seed-based analysis 
The fMRI data will be preprocessed using standard procedures for functional connectivity analysis, including 
correction for head motion, co-registration of functional images to brain anatomy, bandpass filtering (0.01–
0.1 Hz), regression of white matter, cerebrospinal fluid, and, and spatial smoothing with a 6 mm full width 
half maximum kernel (Gavrilescu et al., 2008). Regions of interest (ROIs) will be defined based on the relevant 
literature on cognitive decline. By inverting the spatial transformation required to co-register the MRI image 
in MNI space, the coordinates of the ROIs will be located in individual space. The ROIs will be spherical, 
centered at the coordinates in individual space, and with a radius of 6 mm. We will apply principal component 
analysis to the time series of all voxels included in the spherical ROI. The first principal component will be 
considered representative of the activity of the entire ROI. The fMRI connectivity maps will be calculated by 
correlating the time series of each ROI with the time series of all brain voxels. The maps generated in 
individual space will then be non-linearly co-registered into MNI space to facilitate comparisons between 
different subjects. The group-level connectivity maps will be obtained by calculating the one-sample t-test 
between maps obtained at the individual level. The significance level will be corrected for multiple 
comparisons using the false discovery rate (FDR) approach (Benjamini and Hochberg, 1995). 
Graph theory analysis 
With the functional network generated using the AAL atlas (Tzourio-Mazoyer et al., 2002), graph theory 
analysis will be performed using the GRETNA software (Wang et al., 2015). Five global indices derived from 
the graph analysis will be analyzed and correlated with the results of the dNA scale. In this study, we will 
account for the different diagnostic groups during the analysis phase. We will use an ANCOVA to assess the 
interactive effect of diagnosis and FC indices on memory scores and other neuropsychological tests. A post 
hoc generalized linear regression model will then be applied to test the significance of the association within  

SAN CAMILLO IRCCS S.R.L. SOCIETÀ UNIPERSONALE 
OSPEDALE NEURORIABILITATIVO | ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO 
SEDE LEGALE 30126 | VENEZIA LIDO | VIA ALBERONI, 70 | TEL. 041 22 07 111 | FAX 041 73 13 30 
P.IVA – Cod.Fis. – N. Reg.Imp. 04554270274 | REA VE 426965 | COD.SDI T04ZHR3 
IRCCS 
Rev 03 del 2024/05/27 
Pag. 16 di 20 
 
 
 
 
each diagnostic group. An additional regression analysis will be conducted to compare differences in slopes 
between cognitive scores (such as memory) and indices of FC and graph theory. Age, handedness, and 
education will be included as covariates in the ANCOVA and regression analyses. 
Sample Size Calculation: 
Primary objective: According to the literature, the number of participants required to validate a scale with 
20 items—which has already been validated in another language (specifically in English on a sample of 815 
individuals residing in the United States, Cieri et al., accepted)—is approximately 250 participants (Comrey 
and Lee, 1992). Other studies suggest a minimum of 200 subjects to test cross-cultural consistency and 
reliability (White, 2022). The dNA scale, already validated in English (Cieri et al., accepted), reports a KM O 
index greater than .80 (i.e., good), a specific index (Kaiser-Meyer-Olkin) for confirming the appropriateness 
of the sample (Kaiser, 1974). Specifically, for the CFA, this sample size calculation accounts for the need to 
detect a medium effect size, expressed in terms of Root Mean Square Error of Approximation (RMSEA), with 
an expected value of 0.05, a statistical power (1-β) of 0.80, and a significance level α of 0.05. Taking potential 
dropouts into account, approximately 265 subjects will be recruited to ensure the minimum sample size 
required for statistical power, and this number will be verified experimentally during the validation phase 
using the KMO index. 
Each of the 8 participating centers, depending on their recruitment capacity, will enroll approximately at least 
30 participants. The majority of the final sample (i.e., 265 participants) will consist of healthy older adults 
(HC), while a smaller percentage will include subjects with subjective memory complaints (SCD), mild 
cognitive impairment (MCI), or Alzheimer’s disease (AD). 
Among the centers responsible for recruitment for the primary objective (validation of the dNA scale in 
Italian), an indicative estimate of the types of participants each center will recruit is provided below. 
Specifically: 
- 
IRCCS Campus Biomedico (Rome): HC, AD, MCI, SCD (approximately 5 healthy individuals, 15 
patients) 
- 
IRCCS Centro San Giovanni di Dio Fatebenefratelli (BS): HC, SCD (approximately 20 healthy 
controls, 10 patients) 
- 
IRCCS Fondazione Mondino (PV): HC, AD, MCI, SCD (approximately 10 healthy controls, 40 
patients) 

SAN CAMILLO IRCCS S.R.L. SOCIETÀ UNIPERSONALE 
OSPEDALE NEURORIABILITATIVO | ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO 
SEDE LEGALE 30126 | VENEZIA LIDO | VIA ALBERONI, 70 | TEL. 041 22 07 111 | FAX 041 73 13 30 
P.IVA – Cod.Fis. – N. Reg.Imp. 04554270274 | REA VE 426965 | COD.SDI T04ZHR3 
IRCCS 
Rev 03 del 2024/05/27 
Pag. 17 di 20 
 
 
- 
IRCCS “Carlo Besta” Neurological Institute (Milan): HC, MCI (approximately 15 healthy subjects, 
15 patients) 
- 
IRCCS Neuromed (Isola Sempione): HC, AD, MCI, SCD (approximately 10 healthy subjects, 20 
patients) 
- 
IRCCS San Camillo Hospital (Venice): HC (approximately 30 healthy subjects) 
- 
IRCCS San Raffaele Hospital (MI): HC, AD, MCI, SCD (approximately 10 healthy subjects, 20 
patients) 
- 
IRCCS San Martino (GE): HC, AD, MCI, SCD (approximately 10 healthy subjects, 25 patients) 
 
Expected Results: 
- In terms of validation and factor analysis, we expect results similar to those obtained from the English-
language validation (Cieri et al., accepted), with a four-factor structure and no issues of multicollinearity (r < 
0.95) or non-collinearity (r < 0.3). We expect satisfactory results for the KMO indices (>0.70), Bartlett’s 
sphericity test (<0.01), and Cronbach’s alpha (>0.80). 
- We expect a correlation between greater engagement in the activities under investigation, their dynamic 
maintenance over time, and higher educational attainment. 
- In the association of the scale with neuropsychological measures, holding diagnosis and educational 
attainment constant, we expect better results in terms of episodic memory and executive functions among 
subjects with higher scores on the dNA scale. 
- When associating these data with fMRI measures, we expect, within diagnostic groups, greater activation 
(and segregation) in the so-called task-negative network (DN) associated with greater deactivation of so-
called task-positive networks (DAN and FPCN) in subjects with higher scores on the dNA scale. Measures of 
segregation (within neural networks) and integration (between neural networks) will be explored, associating 
these measures with dNA scale scores. 
 
Data collection and processing: 
All personal and clinical information concerning the patient and/or their family unit collected during this 
study will be kept confidential and handled in compliance with current regulations (Good Clinical Practice 
standards: Ministerial Decree 15.7.1997, Legislative Decree 211/2003, Legislative Decree 200/2007) and data 
protection laws (Legislative Decree 196/2003 and subsequent amendments and updates). It is specified that 
the identity of the data collected will be known exclusively to research team members, healthcare 
professionals involved in the care of the participants, and physicians. The data, processed using electronic  

SAN CAMILLO IRCCS S.R.L. SOCIETÀ UNIPERSONALE 
OSPEDALE NEURORIABILITATIVO | ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO 
SEDE LEGALE 30126 | VENEZIA LIDO | VIA ALBERONI, 70 | TEL. 041 22 07 111 | FAX 041 73 13 30 
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IRCCS 
Rev 03 del 2024/05/27 
Pag. 18 di 20 
 
 
 
 
and other means, may be disseminated in a strictly anonymous form through meetings, conferences, and 
scientific publications; in any case, the name or any other detail capable of identifying the participant and/or 
their family members will not be disclosed, as the data may be presented exclusively in aggregate form or in 
a manner that does not make the study participants identifiable. 
 
Financial Aspects 
There is no specific funding for this project. The costs will be covered by the Institute’s Current Research 
resources. 
 
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SAN CAMILLO IRCCS S.R.L. SOCIETÀ UNIPERSONALE 
OSPEDALE NEURORIABILITATIVO | ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO 
SEDE LEGALE 30126 | VENEZIA LIDO | VIA ALBERONI, 70 | TEL. 041 22 07 111 | FAX 041 73 13 30 
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OSPEDALE NEURORIABILITATIVO | ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO 
SEDE LEGALE 30126 | VENEZIA LIDO | VIA ALBERONI, 70 | TEL. 041 22 07 111 | FAX 041 73 13 30 
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