The aim of this longitudinal observational study is to evaluate the impact of sensory deficits (smell, hearing and balance on cognitive decline and quality of life in the medium term (5 years)) on a population of patients over 55.

Patients will be evaluated by a neurologist, a neuropsychologist and an otolaryngologist who will perform olfactory, auditory and vestibular tests.

The acquired data will then be analyzed with multivariate analysis to understand the effect of multisensory deficit on both cognition and quality of life with a particular focus on depression.

The primary objective will be the evaluation of multiple deficits on cognition, the secondary will be aimed at understanding whether one sensory deficit more than another, e.g. smell versus hearing, will have a greater impact on the patient's conditions.

Evaluation protocol

Enrollment phase: the subjects will be recruited through recruitment at the Department of Neurology of the Fano hospital and the various associations supporting patients with cognitive impairment in the area. The subjects who meet the inclusion and exclusion criteria for the cohort will be contacted and invited for the ENT evaluations that will be carried out in the Department of Otolaryngology of the FANO hospital.

Inclusion criteria: patients between 60 and 85 years of age, in general good health, in the absence of known severe psychiatric disorders, available to be included in the study and to follow the 5-year follow-up.

Exclusion criteria: Obstructive nasal problems, Previous endoscopic nose + paranasal sinus surgery, Chronic use of cortisone spray and/or systemic, Subjects with previous stroke and outcomes, Subjects with history of stroke in the last 3 years without outcomes, Head trauma in the last 24 months, Previous ear surgery, Patients who have been exposed to chemical agents without protection for work, e.g. carpenters and previous Covid with outcomes (olfactory, vestibular, auditory and cognitive "brain fog")

Neurology

Total evaluation time 20-30 minutes

All patients will be clinically evaluated in neurology; specifically, vertical gaze and archaic reflexes (muzzle and palm-chin) will be evaluated. From a laboratory point of view, blood count with formula, AST, ALT, Sodium and Potassium, creatinine, TSH, dosage of Vitamin B12 and folates will be performed.

NeuroPsychology

Total evaluation time 35-65 minutes

Patients will be subjected to the standard battery of neuropsychological tests which includes the MMSE, MoCA, working and short memory tests.

The duration of the psychological tests may vary based on the patient's conditions.

NEUROPSYCHOLOGICAL BATTERY The subjects of the study were administered a neuropsychological battery consisting of the following tests

Mini Mental State Examination (MMSE) (Folstein et al., 1975; Magni et al., 1996): is an 11-item screening test that assesses the level of basic cognitive functioning. This test consists of 11 domains that assess:

• Temporal Orientation;
• Spatial Orientation;
• Mnemonic Recall of 3 items;
• Attention and Calculation;
• Recall of the 3 items mentioned in the previous exercise;
• Language and Practice. The test score ranges from 0 to 30 and the points obtained in each item are added together. The raw score obtained is corrected for the participant's level of education and age.

Montreal Cognitive Assessment (MoCA) (Nasreddine et al., 2005; Conti et al., 2015): This is a test consisting of several trials with a total of 30 items. The short-term memory task (5 items) consists of two learning trials with five names and a delayed recall after about 5 minutes. Visual-spatial ability is assessed with a clock drawing task (3 points) and a copy of a three-dimensional cube (1 point). Several aspects of executive function are assessed with a Trail Making B task (1 point), a phonemic fluency task (1 point) and a two-item verbal abstraction task (2 points). Attention, concentration and working memory are assessed with a sustained attention task (target identification by typing; 1 point), a serial subtraction task (3 points) and a forward and backward digit task (1 point each). Language is assessed using a three-item naming task with unfamiliar animals (lion, camel, rhinoceros; 3 points), the repetition of two words (2 points), the repetition of two syntactically complex sentences (2 points) and the above-mentioned fluency task. Finally, time and place orientation is assessed (6 points). The test score ranges from 0 to 30 and the points obtained in each item are added together. The raw score obtained is corrected for the participant's level of education and age.

Frontal Assessment Battery (FAB) (Dubois et al., 2000; Apollonio et al., 2005): is a screening battery designed to assess global executive functioning. It consists of 6 cognitive and behavioural tests, each of which has a score ranging from 0 to 3 (range 0-18):

• Conceptualisation of similarity: the subject is asked to identify the relationship between three stimuli (e.g. "How are a rose, a daisy and a tulip similar?");
• Phonemic fluency;
• Motor programming (Luria series): the subject has to reproduce the motor series (punching, cutting, flattening) performed by the examiner;
• Response to conflicting instructions: the subject has to carry out a series of exercises several times, together with the examiner, according to the instructions given by the examiner ("Knock twice if I knock once"; "Knock once if I knock twice"). This is a very good test for assessing attention and interference sensitivity;
• Go-no-go task: same principle as the previous test, but in this case the instructions given are more useful for assessing inhibitory control capacity ("Knock once if I knock once"; "Don't knock if I knock twice");
• Prehension behaviour: the subject is asked to place their hands in a "clamshell" position (resting on a surface, palms up). Then, without saying anything, the examiner brings his hands close to those of the respondent and touches their palms. The aim of the exercise is to assess environmental autonomy by inhibiting grasping behaviour.

The raw score is corrected for age and education according to normative reference values.

Digit Span (forward and backward) (Monaco et al., 2013): this test measures verbal short-term memory, in particular the ability to retain and repeat sequences of digits. The examiner reads a sequence of numbers of increasing length and the patient has to repeat the sequence immediately after the presentation. If the patient repeats a sequence correctly, the examiner proceeds with a subsequent longer sequence until the patient makes two consecutive mistakes or fails to repeat a nine-digit sequence correctly. The final score is given by the number of digits of the longest sequence repeated correctly, which varies in length from 3 to 9 digits. The raw score is corrected for age and education according to normative reference values.

Corsi Block Task (forward) (Spinnler and Tognoni, 1987): This is a test that measures the 'span' capacity of visuospatial memory, i.e. the amount of visuospatial information that can be held in short-term memory (STM). The stimulus consists of a 32 cm x 25 cm wooden board on which 9 asymmetrically arranged cubes are glued. The cubes are numbered from the side facing the examiner, not the side facing the patient. The examiner stands in front of the subject and touches the cubes with his index finger in a standard sequence of increasing length (from two to ten cubes). At the end of the demonstration, the examiner asks the subject to reproduce the sequence by touching the cubes in the exact order. If the subject reproduces at least two out of three sequences correctly, the next series is tested. The score is the number of cubes in the longest series for which at least two sequences have been correctly reproduced. The raw score is corrected for age and education according to normative reference values.

Clock Drawing Test (CDT) (Cafarra et al., 2011): is a test that assesses visuoconstructive functions, mental representation, visuospatial orientation, but also planning and symbolic association. The patient is asked to draw the face of a clock, place the numbers correctly and draw the hands to indicate the time '11:10'. The scoring procedure provides for a maximum total score of 15 points, divided into four main categories:

• Contour of the dial (maximum 2 points): evaluation of the shape, closure and proportions of the circle;
• Numbering (maximum 4 points): correctness of the number sequence, positioning, orientation and spacing of the numbers from 1 to 12;
• Hands (maximum 8 points): distinction between the hour and minute hands, correct orientation and congruence with the required time;
• Centre of the watch (maximum 1 point): presence and correct positioning of the centre from which the hands start.

The raw score is corrected for age and education according to the normative reference values.

Symbol Digit Modalities Test (Smith et al., 1968; Amodio et al., 2002): is a test designed to assess cognitive processing speed and working memory. The test consists of a grid containing symbols associated with the numbers 1 to 9. The patient is asked to write down the number corresponding to each symbol and to complete the task as quickly as possible, typically within 90 seconds. During administration, the patient is given the sheet of symbols and must quickly match the number with each symbol. The test can be administered in written form or, if the patient has motor or other difficulties, it can be adapted for oral administration in which the patient verbally states the number corresponding to the symbol. The score is determined by the number of correct answers given by the patient within the time limit, with a score ranging from 0 to 90. The results are compared and corrected with normative values according to age and level of education.

Attention Matrices (Spinnler and Tognoni, 1987): This is a test of selective attention. The test consists of 3 grids, each containing numbers, and the patient has to cross out with a pencil as quickly as possible all the numbers corresponding to those indicated at the top of the matrix. Row A serves as an example. If the subject shows that he/she has understood the task, he/she moves on without further correction to row B, which serves as a warm-up. The subject's performance is counted from line I (line A-B is not counted). The maximum time for each matrix is 45 seconds and is counted from the moment the subject finishes the run-in. The respondent may finish the run-in after the time limit, but only the items correctly crossed out within the time limit will be counted. One point is awarded for each correct item for each of the three matrices presented. The raw score ranges from 0 to 60 and is equal to the sum of the points obtained for the three matrices. The results are compared and corrected with normative values according to age and level of education.

Activities of Daily Living (ADL) (Katz et al., 1963): is a test to assess functional independence in basic activities of daily living. This test is used to measure a person's level of independence in performing essential tasks of daily living. It assesses 6 basic activities:

1. Bathing (washing independently or with partial/full assistance);
2. Dressing (choosing and putting on clothes, fastening buttons, zips);
3. Toileting (getting in and out, using the toilet, toileting);
4. Mobility (getting up and sitting down from bed or chair without assistance);
5. Continence (urinary sphincter and bowel control);
6. Eating (eating alone or with assistance). The total score ranges from 0 to 6 and for each activity the patient receives a binary score: 1 point if the activity is performed independently; 0 points if partial or total assistance is required.

Instrumental Activities of Daily Living (IADL) (Lawton & Brody, 1969): This test assesses a person's ability to perform more complex activities of daily living than ADLs. This test is used to determine whether a patient can perform 8 activities that require planning and the use of cognitive skills:

1. Household and household chores;
2. Taking medication;
3. Getting out of the house;
4. Managing money and household accounts;
5. Preparing meals;
6. Using the telephone or other technology;
7. Using the washing machine;
8. Shopping. The total score ranges from 0 to 8 and for each activity the patient receives a binary score: 1 point if the activity is performed independently; 0 points if partial or total assistance is required.

Neuropsychiatric Inventory (NPI) (Cumming et al., 1994; Binetti et al., 1998): is a questionnaire administered by an expert examiner to the carer. It is a very useful tool for assessing the presence and severity of psychiatric and behavioural disorders in patients with dementia of different aetiologies and their impact on the caregiver's well-being. The questions asked relate to events and changes following cognitive changes. The areas investigated are:

• Delusions;
• Hallucinations;
• Agitation;
• Depression/dysphoria;
• Anxiety;
• Euphoria/exaltation;
• Apathy/indifference;
• Disinhibition;
• Irritability/aggressiveness;
• Motor activity;
• Sleep;
• Appetite and eating disorders. Each behavioural or psychological symptom is rated according to its frequency and severity, and the total score is calculated by combining the two factors for each symptom (frequency × severity), ranging from 0 to 12.

World Health Organisation Quality Of Life Questionnaire-Bref (WHOQOL Group, 1998; De Girolamo et al., 2000): is an abbreviated version of the World Health Organisation Quality Of Live-100 (WHOQOL), a questionnaire developed by the World Health Organisation (WHO) to assess quality of life and subjective well-being in various domains of life. It consists of 26 items, the first two of which measure general quality of life and satisfaction with health. The other 24 items are divided into 4 domains:

1. Physical (pain, energy, sleep, activities of daily living, mobility, medication);
2. Psychological (body image, positive/negative emotions, self-esteem, spirituality);
3. Social (social support, personal relationships, sex life);
4. Environmental (safety, economic resources, leisure, housing, transport, health, information).

Each item is rated on a 5-point Likert scale, with 1 indicating a low quality of life and 5 indicating a high quality of life. To calculate a domain, the average of the scores of the items composing it is calculated. The average scores thus obtained are multiplied by 4 to make them comparable to those of the WHOQOL-100 and then converted to a scale from 0 to 100. Some items are subtracted from 6 because in the WHOQOL-Bref some questions are worded in the opposite way to the meaning of the scale.

Otorhinolaryngology Total time for all tests including complete smell test 40- 60 minutes

1. Sniffin' sticks smell test for threshold (T), detection (D) and identification (I) assessment. Patients will be assessed first by nasal endoscopy and Sniff Test. To ensure objectivity in the analysis, the physician who will perform the Sniffin' checks at the various follow-ups will be blinded to the group to which the patient belongs at the time of the test. Olfactory function will be assessed using the Sniffin' Sticks battery following the standardized TDI (threshold, discrimination, identification) procedure. The Sniffin' Sticks battery consists of pen-like devices filled with odors. Three subtests will be performed to assess orthonasal olfactory function: detection threshold (the lowest concentration at which an odor can be perceived), odor discrimination (the ability to distinguish between odors), and odor identification (the ability to name odors). The odor detection threshold will be identified for each participant using a three-alternative, single-ladder forced-choice procedure with the odor n-butanol. Therefore, participants will be presented with triplets of odorant pens and asked to identify the pen containing n-butanol between two empty distractor pens. In the second test, odor discrimination ability will be assessed using 16 triplets of odorants: within each triplet, two pens will contain the same odorant, while the third pen will contain a different odorant. In a forced-choice procedure, participants will be asked to detect the odd-numbered pen for each triplet. During the odor identification task, participants will be presented with 16 common odorants. Using a multiple-choice format, they will be asked to select which of four odor labels corresponds to each odor presented. Possible scores range from 1 to 16 for the subtest of detection threshold and from 0 to 16 for the other two subtests. The total TDI score is obtained by adding the scores from all three subtests. Normosmia is defined by a TDI score ≥31, hyposmia by a TDI score of 17 to 30.75, and anosmia by a TDI score <17.
2. Tonal and vocal audiometric test
3. Vestibular tests: - nose indices, - Romberg, spontaneous and gaze-evoked NY, Dix-Halpike, Head Shaking Ny,

Radiological investigations

3T brain magnetic resonance with and without contrast, with evaluation of the cortical thickness of the entire brain and of the temporal lobe and evaluation of micro-angiopathy using Fazekas score.

Doppler of the epiaortic vessels of the neck

In case of diagnostic doubt: PET with FdG and Scintifigraphy with dat Scan

Inclusion Criteria:

• Patients between 60 and 85 years of age
• in general good health
• the absence of known severe psychiatric disorders
• available to be included in the study and
• to follow the 5-year follow-up.

Exclusion Criteria:

• Obstructive nasal problems
• Previous endoscopic nose + paranasal sinus surgery
• Chronic use of cortisone spray and/or systemic
• Subjects with previous stroke and outcomes
• Subjects with history of stroke in the last 3 years without outcomes
• Head trauma in the last 24 months
• Previous ear surgery
• Patients who have been exposed to chemical agents without protection for work, e.g. carpenters
• previous Covid with outcomes (olfactory, vestibular, auditory and cognitive "brain fog")

Patients affected by mild cognitive impairment (MCI), Alzheimer Disease in Early stage, Parkison Disease in early stage