Major Neurocognitive Disorder: The Role of Neuropsychological Assessment

In recent years, we have seen a progressive ageing of the population, which has affected most European countries, including Italy [1,2]. Structural changes, the structure of society and people’s quality of life have combined with medical knowledge, a decrease in infant mortality, lower birth rates and longer life expectancy with an ageing population [3] The proportion of older people over 65 is set to increase in the coming years. The Istat, has examined the economic and social situation in Italy in the year 2021 and in the first months of 2022, and found that the percentage of elderly people with 65 years or more is equal to 23.8% of the total population, and it is estimated that will reach 34% in 2042. In Italy, the over-80 age group exceeds 4.5 million, while the number of centenarians is more than 20 thousand, and this figure will triple in the next twenty years. The average age at 65 is 19.4 for men and 22.4 for women. Ageing brings with it physical and sensory changes, making older people more vulnerable to disease.

Neurodegenerative diseases are among the major causes of disability in ageing, with over 50 million people currently estimated to suffer from dementia, This number is growing compared to 38 million people in 2009 and will continue to grow, involving some 152 million people in 2050 [4].These quantitative estimates also covered the etiopatogenesis of the forms of neurocognitive disorder, highlighting that the most widespread disease is Alzheimer’s type, with decreasing frequency for types with vascular origin, frontotemporal and Lewy bodies [5]. Due to this rapid spread, the World Health Organization (WHO) and Alzheimer’s Disease International (ADI) have declared dementia a global public health priority. According to the World Health Organization, Alzheimer’s disease and other forms of neurocognitive disorder are the seventh leading cause of death for people over 65 years old. In Italy, data from the Ministry of Health [6] show that 8% of elderly people over 65 and 20% of those over 80 live with a form of dementia and 60-70% of them are affected by Alzheimer’s disease. The main risk factor for being diagnosed with dementia is age, and as the population continues to age, it is inevitable that the number of people suffering from dementia will continue to increase in the years ahead [7].

The emergency that has been created with the increase in cases of DNC, has been addressed through two different connotations. The first approach is pharmacological, which is used to counter the evolution of the disease through the use of active ingredients (anticholinesterases), which have proved effective only in managing symptoms and slowing the progression of the disease without preventing its course [8], a new molecule has recently been identified (Aducanumab), but its efficacy and tolerability are the subject of much controversy [9].

The second approach stems from considerations of the limits of the other and knowledge of the mechanisms of plasticity, which allow the brain to change and reorganize itself throughout life [10]. For this reason, many researchers have devised non-pharmacological interventions of cognitive stimulation, with similar objectives to those of chemicals, but which have the advantage of minimizing adverse effects. Thus, a large number of interventions with different objectives have been proposed that may concern different aspects in the evolution of the disease and aimed at supporting the cognitive state, mood tone, functional and behavioural state and improving the quality of life. Some of these treatments have been subject to rigorous tests that have demonstrated their effectiveness, others, also very popular, have not reached the required qualitative and quantitative standards, so that only the first have been included in the guidelines of many countries [11].

This review offers a careful analysis of the literature, for the aspects related to cognitive changes in normal and pathological aging, with particular attention to the modifications linked to DNC Maggiore. The starting point is a vision of ageing not only as an inexorable and generalized decline, but also as a period of life, assessed according to a multidimensional and multidirectional perspective. The following will be illustrated, scales and assessment batteries suitable for detecting cognitive, emotional, behavioural and functional deficits of DNC in order to specify their diagnosis.

Population aging and major neurocognitive disorder

Ageing is a global phenomenon, and at the same time it is a process that involves the whole life of a person, with consequent physical, sensory, emotional and cognitive changes [3]. Ageing is influenced by negative stereotypes of the way we perceive older people and sometimes they result in forms of discrimination, one must distinguish physiological ageing from disease [12]. Increasing age is an inevitable cause of universal and irreversible changes, but this does not mean that they are of an invalidating type, aging is a multidimensional and multidirectional process with high interindividual and intraindividual variability [12-14]. As the years go by, cognitive abilities follow different paths, there are skills that suffer a worsening throughout life (life-long decline), others that only decline in late age (late-life decline) and still others that remain stable throughout life (life-long stability). In this regard, the cognitive functions that undergo life-long decline we have the speed of information processing, working memory and the ability to store new information in episodic memory. The breadth of vocabulary and semantic knowledge, and short-term memory, instead result in a late-life decline. Other skills, such as Theory of Mind (ToM), autobiographical memory and automatic information processing mechanisms, remain stable even in old age.

Cattel [15] with his bifactorial model of intelligence, proposed a theory to explain the differentiated deterioration of cognitive abilities in development, according to his assumption, there is a fluid component of intelligence (Gf) and a Crystallized One (Gc). The first, dependent on biological factors, concerns the ability to reason and infer from information, of a spatial or verbal nature, present in the environment to arrive at the solution of problems and adapt to new situations. Crystallized intelligence is based on information learned within one’s own cultural context, and is the result of the process imparted by education and life experiences. To evaluate the fluid component of intelligence, reasoning tests are used, the most common ones are the Raven’s Matrices, while the crystallized component is evaluated with vocabulary tests.

According to Cattel [15], the two components follow different development trajectories: Gf seems to decline with age while Gc seems to remain stable or in some cases even improve. Many authors have confirmed the results of Cattel [16,17], it was also found that fluid intelligence reaches a plateau of performance around 20-30 years, and that the ontogenetic pathway is not stable after 60 years, and that but it even seems to improve in old age. Baltes [10], takes up the model of Cattel, the author in his theory of the life span, resumes the concept that development is not only concerned with the young age, but is a continuous process, influenced by biological and cultural variables.

Baltes also distinguishes between basic mental operations (mechanics of cognition) and aspects related to culture (pragmatics of cognition). The former include memory, abstract thinking, reasoning, perceptual speed and spatial orientation, all of which are influenced by neurobiological processes that cause their early decline. The latter include verbal and numerical skills which, being the product of cultural learning, may even increase up to 60-70 years, then begin to decline at a very advanced age [3].

To better understand the extent of cognitive changes that aging brings with it, it is essential to start from changes in the efficiency of basic cognitive mechanisms (information processing speed, attention and inhibition, working memory) which are the most compromised as we age. In particular, the speed of information processing, defined as the speed at which a person can complete basic cognitive operations, was studied [3], within the processes of development and aging is now considered one of the factors that most affect cognition [18,19], explaining the better cognitive performance of young people compared to older. Salthouse studies [20] found that older people have much slower execution times than younger people, and this affects more complex skills such as working memory, episodic memory and reasoning. According to the author, the slowness in processing parts of a task would not leave enough time to complete the next ones (limited time mechanism), thus damaging the final performance.

Numerous studies have shown the correlation between processing speed and cognitive decline in the elderly [21], especially slow reaction times seem to be early signs of Alzheimer’s disease [22-24]. Another function explored in the elderly is attention, a multicomponent cognitive function [25] that allows to select some stimuli at the expense of others, what would be compromised in the elderly is inhibitory control, the ability to select and maintain attention on relevant information and prevent distracting stimuli from interfering with activities being performed [26]. Inhibitory control is essential in working memory tests [27] because, since it must temporarily store information for another task, interference must be resisted, in order not to impair performance by allowing irrelevant material to consume available resources. However, the literature on changes in the ability to inhibit ageing has produced mixed results. Verhaeghen & De Meersman [28], found that the difficulties reported by them were greatly reduced by controlling certain factors such as processing speed and psychometric characteristics of the test. These results suggest that inhibitory control is not a unitary function, but rather that different levels of inhibition are activated according to the demands of the task [29]. This would imply that older people do not have deficient inhibitory mechanisms but are more susceptible to interference with irrelevant information. A 2008 study by Borella, Carretti & De Beni [30] showed the non-linear trend of inhibition over life: the effectiveness of this mechanism decreases from the sixth decade and, more clearly, in people aged over 70 years.

Working Memory (or WM) refers to the ability to hold momentarily relevant information in order to use it for a subsequent task [27]. Although the conceptualization of WM varies considerably depending on the theoretical model used, there are some common features. These include the importance of careful data retention to complete the task, and control processes, essential for monitoring and updating WM content continuously, as well as to inhibit the entry of irrelevant information [3]. In fact, the tasks of working memory involve careful processes necessary for the processing of previously retained material, a particularity that distinguishes it from simple short-term memory. In the literature, age-related differences between young and old have been widely reported in working memory tasks [31-33], evidence not found in simple short-term memory tasks, such as digit span [34].

Despite these data, it is still unclear which mechanism is responsible for age-related deficits in working memory performance [33]. Some speculate that the cause is a general slowdown in information processing speed [20] others a general decline in attentive resources [35], while still others believe it is due to a deficit of inhibitory control [26]. What is clear is that WM predicts performance in more complex cognitive tasks, including text comprehension, learning, reasoning, problem solving and therefore fluid intelligence skills in general [3,26]. This, together with evidence of lower working memory performance in the elderly compared to the young [32,33,36], confirms the hypothesis that WM is a basic cognitive mechanism able to explain cognitive changes in advanced age. In conclusion, studying the changes that underlie basic cognitive mechanisms over life, and particularly in late life, is important not only to distinguish between normal and pathological ageing, but especially to plan cognitive enhancement interventions [3].

Major neurocognitive disorder: Etiology

The increase in the average age and the progressive aging of the population have inevitably caused an increase in related age pathologies, not only organic but also neurodegenerative, for which the main risk factor is precisely age. Dementia is one of the major causes of disability in the population over 65 (2) Istituto Superiore di Sanità, ISS). The generic term dementia is a progressive and generally irreversible syndrome (that is, a set of symptoms) which causes an alteration in certain cognitive functions (3), in particular, the loss of memory is the most known symptom is also present the deterioration of other cognitive domains (attention, reasoning, language, orientation, practical and recognition skills), as well as personality and behavioural changes.

With the new edition of DSM-5 (2013) was introduced the concept of Neurocognitive Disorder (NCD) Major to indicate that pathological process characterized by progressive loss of cognitive processes; to make a diagnosis, the deterioration must affect one or more domains of cognition, be of such severity as to constitute a change in relation to a pre-morbid level of functioning and cause serious impediments in daily life [37,38]. Based on the severity of the symptoms and the level of impairment, three stages of progression of DNC Major have been defined: Mild, stage of the disease in which the patient has difficulty with instrumental activities of daily life (money management, housework, etc.), Moderate, where difficulties arise even in the basic activities of daily life (feeding, dressing, etc.) and Severe, final stage where the person is completely dependent and requires continuous assistance. The classification of Major Neurocognitive Disorder is based on the nature of the etiological process in place, from which it is possible to distinguish between two types of dementia: degenerative and non-degenerative.

Secondary dementia to infectious diseases and pseudodementia and secondary dementia to depression. Alzheimer’s Disease (AD) is the most common form of dementia and accounts for about 60-70% of all cases. The main symptom of the disease is episodic memory deficit, usually present at onset, followed by progressive impairment of other cognitive domains that worsen to compromise the individual’s autonomy in daily life [3]. It is a disease with insidious beginning since the patient can spend many years in an asymptomatic phase, during which the neuropathological process is already in place but the symptoms are almost imperceptible [3].

The underlying pathological mechanisms are the accumulation of beta-amyloid protein in the extracellular space, which inhibits synaptic transmission and therefore the effectiveness of information transfer between neurons, and the intracellular accumulation of tau protein, which forms neurofibrillary tangles and interferes with the transport of molecules essential to the functioning of neurons. The accumulation of these proteins causes irreversible and irreparable damage that causes death of nerve cells, the traces of tau and betaamyloid proteins at the brain level are considered biomarkers of Alzheimer’s disease. The first brain areas to be affected by the disease are those that have superior cognitive functions, so the symptoms evident at the beginning concern memory, language and abstract reasoning. Alzheimer’s dementia, in its classical form, progresses gradually following a continuum that allows the distinction of three stages of disease: mild, moderate and severe, based on the severity of symptoms.

The duration and course of disease stages vary from individual to individual, and are influenced by variables such as age, sex and genetic factors [39]. In the mild stage of illness, people experience early memory problems but are able to be independent, however, they may need assistance with some Instrumental Activities of Daily Life (IADL), such as paying bills or managing money, and require more time for basic Activities of Daily Living (ADL), in this phase also the first changes of personality occur, with the loss of interests, lack of motivation, apathy, and accentuation of previous traits [3].

In the moderate phase, deficits become marked and are dependent on memory, language and orientation, therefore requiring continuous assistance. As the memory and orientation deficit worsen, the patient usually manifests confusion and suspicion that is managed with episodes of aggressiveness. Another aspect is the difficulty in recognizing their loved ones. The terminal phase, also called afasico aloic-aprasica, the patient is no longer able to communicate and loses completely its autonomy in elementary functions. The involvement of the areas affected by movement forces the patient to be lulled, which makes him vulnerable to serious physical complications. Finally, the disease extends to regions of the brain that control vital functions and death occurs. Cognitive and especially behavioural disorders, as well as the loss of autonomy in daily life activities, are a cause of institutionalisation [40].

The impact in social, health and welfare terms has led to an increasing research effort aimed at identifying risk factors and protection related to AD. The scientific community believes that, like other chronic diseases, AD is the result of the interaction of several factors, only some of them would be modifiable. The main factors most closely related to the onset of symptoms are age, genetic variables and familiarity with the disease. Among the many genes involved that increase the risk of developing Alzheimer’s dementia, APOE-e4 is the most important [39]. A case of AD in the family is not in itself a sine qua non for the development of the disease, having a first-degree relative suffering from this form of dementia increases the probability of receiving the diagnosis at an advanced age. In 2017, the Lancet Commission released a report identifying the role of nine variables in predicting the onset of Alzheimer’s disease, these were: low levels of education, hearing impairment, hypertension, smoking, obesity, depression, Lack of physical activity, diabetes and poor social contacts [41].

In 2020, the same organisation added three more elements: alcohol consumption, air pollution and having suffered a traumatic brain injury in life [41]. According to data provided by the Lancet Commission, controlling the factors mentioned can reduce or delay the risk of developing Alzheimer’s dementia by 40%.

Frontotemporal Dementia (FTD) refers to a group of neurodegenerative diseases characterized by atrophy of the frontal and/or temporal lobes caused by intraneuronal accumulation of tau and/or TAR proteins [42].

Clinically, two forms of FTD can be distinguished, one frontal and one temporal. These two forms may also present different characteristics depending on the type of variant involved, which may involve for example the personality of the individual and/or the scope of social relations, or, language, as in the case of Primary Progressive Aphasia (PPA), This is further decomposable into three subtypes, depending on the language domain compromised: Semantic Variant (PPA-S), non-fluent or Agrammatic Aphasia (PPA-G) And Logopenic Aphasia (LBP) [43].

Despite the characteristics that make different subtypes of FTD unique, it is noteworthy that in clinical practice there is an overlap of symptomatological manifestations, which are highly heterogeneous in presentation [42]. Although the behavioral and linguistic deficits may affect all variants in different ways, for the diagnosis of PPA (primary progressive aphasia) the communication difficulties must represent the main factor of disability for at least two years [37]. The characteristics of different types of frontotemporal dementia are examined:

The Behavioral Variant (FTD; bvFTD), compared to other forms of dementia that are typical for aging, has an early onset: usually symptoms occur before 65 years and the average age of onset is 58, This subtype, which occurs in the front, is characterized by changes in personality traits and ability to relate to others, of which the patient usually has no awareness, but which are a source of stress for the caregiver [44].The most common behavioral symptoms are: apathy, disinhibition, lack of empathy, mental rigidity, stereotyped speech, hyperorality and hypersexuality. From the neuropsychological point of view, these patients show deficits in executive functions, but visual spatial abilities and episodic memory are relatively spared.

In the PPA primary progressive aphasia, semantic variant PPA, at temporal onset, the main symptom is the progressive deterioration of the semantic memory (that part of memory where linguistic or general knowledge about the world is stored). The clinical picture is characterized initially by fluency, but over time the number of gyrus and anomies increase and the understanding of the content worsens. In the advanced stages, the patient is no longer able to recognize or use objects of common use and the typical behavioral symptoms of bvFTD occur [45]. The non-fluent agrammatic variant of primary progressive aphasia is a disorder of motor language programming that causes production deficit. In this clinical picture, non-fluent language is characterized by agrammatism, frequent pauses, alterations of the prosody and articulatory errors that make it difficult to repeat words [42].

In the logopenic variant of PPA, deficient mechanisms are understanding and repetition of words and phrases due to deficits in short-term auditory memory. The speech of patients with this variant is not fluent and is characterized by frequent breaks, which are different from those of PPA-G, difficulties in recovering shortterm auditory memory track [42]. Logopenic PPA has more similar behavioral symptoms to those usually found in AD: depression, anxiety, apathy and irritability [46]. Lewy Body Dementia (LBD) is a clinical picture characterized by cognitive deficits, psychotic symptoms and motor dysfunction [3] that would be present in the range of 4-8% in people with Neurocognitive Disorder [47].

Advanced age is the main risk factor for LBD diagnosis: patients are usually aged 70-85 years, with a higher prevalence among men [48]. Lewy body dementia is a disease characterized by an alteration of the alpha-synuclein protein (as occurs in Parkinson’s disease) which, accumulating in the cytoplasm of neurons in the form of agglomerates (Lewy bodies) Causes major dysfunctions in the dopamine and cholinergic systems. Lewy bodies are located in the neocortex, limbic system and olfactory bulb [49]. The cognitive symptoms found in LBD are mainly fluctuations in attention levels, difficulties in tasks involving executive functions and visual-spatial skills [3]. The patient presents with psychotic symptoms, which manifest themselves in the form of vivid visual hallucinations, as the disease progresses, the motor signs typical of Parkinson’s Disease (PD) appear with a prevalence of stiffness and bradicinesia [50], in addition to the disturbance of the sleep behavior rem, decreased olfactory sensitivity and constipation [51].

There are also cases where the patient may have short-term memory deficits, but these differ from those typical of AD (which concern encoding processes) because they involve the retrieval of memory traces and can therefore be controlled by providing cues [52]. This is useful for differentiating Lewy body dementia from Alzheimer’s disease, which can be further supported by PET or SPECT [3]. Another important differential diagnosis is between LBD and the dementia observed in Parkinson’s disease, which have very similar clinical pictures and also share the etiopathogenic mechanisms at the base, what changes is the different course of the symptoms, in Levy Body Dementia, cognitive and psychotic symptoms precede the appearance of motor symptoms, whereas the diagnosis of dementia in Parkinson’s disease is made when cognitive deficits emerge in a clear picture of Parkinson’s Disease [53,54].

Parkinson’s Disease (PD) is a neurodegenerative disease caused by the dysfunction of dopamine neurons within a brain structure called substantia nigra [55]. The symptoms of the disease are motor (bradykinesia, stiffness, tremor at rest and postural instability), accompanied by other non-motor (hyposmia, sleep disorders, cognitive deficits, alterations of the gastrointestinal and genitourinary tract). The disease progresses slowly, during the prodromal phase appear non-motor symptoms, often overlooked for many years, until the appearance of motor symptoms, which coincides with the diagnosis. Although cognitive deficits are relatively common in PD, a clear picture of dementia emerges only in the disease phases where advanced age is a risk factor for deterioration, affecting 30-40% of patients aged 60-80 years [56].

Cognitive symptoms in PD include memory deficits (especially episodic and procedural components), executive functions, attention, processing speed, visual-spatial skills and language. Also present, neuropsychiatric symptoms, the most common for prevalence are anxiety and apathy, followed by depression [57]. Patients report hallucinations and paranoid delusions that may be side effects of medication, while if they occur before the drug intervention, suggest diagnosis of Lewy body dementia [58].

Treatment for Parkinson’s disease involves the therapy with Levodopa, which stimulates the production of dopamine within nerve cells and allows to relieve symptoms. In recent years, a procedure that is rapidly spreading for patients who report side effects from Levodopa therapy is the Deep Brain Stimulation (Deep Brain Stimulation - DBS), which allows the reduction of the dosage of drugs with consequent positive effects on motor symptoms, while neither approach seems to slow down nor act on the progression of cognitive deficits [59].

Vascular Dementia (VaD) is a non-degenerative form of neurocognitive disorder, whose cognitive impairment results from vascular accidents of various nature and magnitude [59]. The prevalence of this disease is around 15-20%, and seems to affect more frequently men, who have a higher risk of stroke than women. In many cases, Vascular Dementia occurs concurrently with a neurocognitive disorder of different etiology, for example Alzheimer’s disease, from which the term “mixed dementia” derives. It is not possible to define a typical clinical picture of this form of dementia, as the symptoms with which it presents reflect the portion of brain affected by vascular injury, which can be ischemic or hemorrhagic. As a result, the type of onset and course of the AoR also vary considerably [3].

In clinical practice, the cognitive deficits most attributable to vascular dementia concern executive functions and, in particular, deficits of attention, information processing, in the execution of complex actions, as well as the presence of disorganized thought content and behavior [59] Santos et al. (2018) in a study, confirmed that the most common psychological symptoms are depression and apathy. Due to the heterogeneity of clinical manifestations of ADVs, the criteria for diagnosis have been revisited over the years. At present, the criteria for diagnosing DNC, it is necessary that instrumental tests detect the presence of cerebrovascular damage (stroke) following which, after 3-6 months, there are signs indicating dementia.

Neuropsychological assessment and differential diagnosis

Neuropsychological assessment is a methodological procedure that, through the collection of anamnestic, signs and symptoms of the patient, determines the integrity or impairment of his cognitive and behavioral functioning with the aim of arriving at a diagnosis [60], it allows to distinguish between normal and pathological aging, compare the performance of the person with a reference sample of equal age and schooling to determine the degree of impairment, Understand the nature of the pathological process observed and make a differential diagnosis, which will allow treatment planning and a series of follow-up assessments aimed at providing adequate prognoses on the progression of the disease [61,62].

It is essential to make a differential diagnosis, for the correct identification of the pathology on the basis of specific diagnostic criteria and the exclusion of other demented syndromes with similar symptomatological pictures, making diagnosis, allows the patient to plan treatments (pharmacological and non-pharmacological) specific to the type of dementia and achieve a better level of patient care [3]. The neuropsychologist, in the evaluation has the tools to conduct the assessment: observation, interview, neuropsychological tests, scales of evaluation, questionnaires, and information found through the caregiver, which can be of assistance, even during the anamnestic collection. The assessment should be carried out in a multidimensional way, taking into account aspects that contribute to the functioning of a person as well as intra- and inter-individual differences which characterize the elderly population in particular.

Below, we will review the main tools used in clinical practice for the neuropsychological evaluation of the elderly with DNC Major. The analysis is not exhaustive in itself but describes the tests and scales of evaluation most frequently used in Italy. In the literature, the most commonly used tools for assessing the cognitive state of elderly patients are the following. The Mini Mental State Examination (MMSE (62) is one of the most common screening tools used for screening, for an initial assessment of the cognitive functioning of the elderly. The test, through items that investigate spatio-temporal orientation, memory, attention, language and praxis, returns a global cognitive picture of the patient. Scores below 24 (range 0-30) indicate cognitive impairment, the test does not provide the necessary elements to make a diagnosis, and according to a recent literature review presented by the Cochrane Library [63], should only be used to outline an initial diagnostic hypothesis. Over the years, there has been a lot of criticism about the use of MMSE in clinical practice, whether it can be conceived as a valid tool for measuring general cognitive deficit or as a diagnostic tool. Among the factors that make it a favourable tool is the fact that it contains only items of a verbal nature, such as orientation and language, but this has a disadvantage for people with low level of education, although corrective strategies are planned. Research has shown a bias in favour of the highly educated elderly, whose scores would remain high despite clinical signs of dementia [64]. A meta-analysis by Mitchell [65], reveals that the MMSE is more accurate in quantifying an already evident cognitive deficit, rather than discriminating between healthy subjects, people with mild cognitive impairment and individuals with BMD. A Cochrane review [66] has established that the MMSE is to be considered as a useful tool to be used during the screening phase of the disease, for an initial assessment of the patient’s cognitive state, that it should not be used as the only means of diagnosing.

The Montreal Cognitive Assessment (MoCA; [67] is a shortadministration screening test, investigating the following domains of cognition: attention, Orientation, memory, language, executive functions, abstraction, computational and spatial skills. In a range of 0-30, scores below 26 indicate cognitive impairment. There is some consensus in the literature that MoCa is more sensitive than MMSE for detecting mild stage Major DNC [68]. The Short Portable Mental Status Questionnaire (SPMSQ) [69] Pfeiffer, 1975), is a short screening test that investigates the general cognitive functioning of the patient through ten item errors related to: spacetime orientation, short- and long-term memory and numeracy skills. The score ranges from a minimum of zero (total absence of cognitive impairment) to a maximum of ten points. In the original article by Pfeiffer [69] four possible levels of cognitive functioning are highlighted based on the errors committed by the patient: 0-2 errors indicate performance in the norm and therefore no deterioration, 3-4 errors show a slight deterioration, 5-7 errors show a moderate deterioration and 8-10 errors show a severe deterioration. The administration takes 5-10 minutes and can also be done at the patient’s bed.

The Milan Overall Dementia Assessment (MODA); [70] is an initial screening tool for cognitive functions, also useful for repeated control assessments. The instrument consists of three sections: the first investigates the orientation (spatial, personal, family), the second the level of autonomy, the third includes part of the tests contained in the manual “Italian standardization and calibration of neuropsychological tests” [71] This study examines the standardisation of cognitive domino tests in the elderly population. Given the variety of tests available, it is considered a sensitive test for detection of mild and moderate DNC [72].

The Short Neuropsychological Examination - 2 (ENB-2; [73] is a screening tool that returns both an overall picture of the individual’s cognitive state and detailed information on the functioning of each function. The domains investigated are: shortand long-term memory, working memory, attention, visual-spatial skills, comprehension and language production, practical skills, executive functions, logical reasoning and abstraction. Three stages are planned for the administration of ENB- 2: neuropsychological anamnesis, clinical interview with patient and family members, administration of the testicular battery. The Mental Deterioration Battery (MDB; [74] is a useful battery for differential diagnosis of initial forms of dementia, as it investigates the overall cognitive efficiency through 7 tests divided into verbal tests and visualspatial tests. The first group includes the immediate and deferred recollection of Rey’s 15 words, phonological verbal fluency and sentence construction: to the second the progressive Raven Matrices in the color version, the task of visual immediate memory, the copy of a freehand drawing and the one with programming elements. The mood tone in the elderly population is investigated mainly through two scales.

The Frontal Assessment Battery (FAB; [75] is the most widely used tool for fast screening of executive functions. It investigates the presence and severity of symptoms resulting from frontal lobe lesions and is useful for detecting DNC major, in particular for a differential diagnosis between Alzheimer’s disease and frontotemporal dementia [76]. The items investigate abstract reasoning, mental flexibility, motor programming, sensitivity to interference, inhibitory control and environmental autonomy. Other tools for the specific evaluation of executive functions are the Wisconsin Card Sorting Test [77] and the Stroop Test (1935). The first, structured as a card game with wins and losses, evaluates the cognitive flexibility component of executive functions: the patient must identify a strategy and modify it based on the feedback received. The second evaluates the patient’s ability to inhibit the predominant responses.

The Alzheimer Disease Assessment Scale [78] ADAS; useful for an evaluation of the progression of cognitive decay, consists of two scales: a cognitive (ADAS-cog) and a non-cognitive (ADASnoncog). The first allows to verify the integrity of the main cognitive functions, compromised in particular in Alzheimer’s disease, while the second can assess mood, delusions, hallucinations, motor and eating behavior. ADAS-cog is considered both an accurate tool for assessing cognitive impairment in patients with DNC and the gold standard for measuring the effectiveness of psychosocial treatments on cognitive disorders [79]. The Clinical Dementia Rating Scale [80] CDR is a useful tool to assess dementia as it investigates not only the cognitive sphere, but also the behavioral and functional ones (through items that concern autonomy in everyday life skills). The overall CDR score is obtained by separately evaluating six domains: memory, orientation, judgement and problem solving, community life, home and hobbies, personal care. It is currently one of the most widely used tools in science because it is considered reliable and sensitive to differentiate the stages of dementia along a continuum from normal aging to terminal pathology [81]. The Geriatric Depression Scale (GDS; [82] is a tool used for screening depressive symptoms in elderly patients. Through 30 items (or 15, 10 or 5 in the reduced forms) it evaluates the cognitive, affective and behavioral aspects related to depression.

The Cornell Scale for Depression in Dementia (CSDD; [83] investigates depressive symptoms in elderly people with cognitive decline, through the exploration of five domains: mood tone, depressive ideas, daily life activities, behavioral and eating disorders. The examiner assesses CSDD items based on the answers provided by a caregiver and the patient. The Quality of Life in Alzheimer’s Disease (QoL-AD; [84] is used to assess the elderly person’s quality of life, which often reflects their emotional experience in relation to physical and cognitive changes resulting from the aging process. This is a self-report scale that provides a measure about the perception of well-being in elderly people diagnosed with Alzheimer’s disease whose items investigate: physical health, mood, interpersonal relationships, participation in activities, financial situation.

In the management of patients with dementia, it is very important to evaluate the presence of behavioral and psychological symptoms, as they are the main predictors of the use of psycho drugs [85]. The Neuropsychiatric Inventory NPI [86]; is the tool of excellence for the detection of neuropsychiatric symptoms in patients suffering from neurodegenerative pathologies. It is administered to the patient’s caregivers and consists of two scales: the first evaluates the frequency and severity of neuropsychiatric symptoms and the second the emotional and psychological stress perceived by the caregiver. Similarly, the Behavioral Pathology in Alzheimer’s Disease Rating Scale [87,88] investigates the following symptoms: delusions, hallucinations, aggressiveness, circadian disorders, affective disorders, anxiety and phobias [88]. Finally, the functional status of the patient is assessed using scales for assessing daily life skills.

Another tool, which allows to assess comorbidities in forms of dementia, assessed by the doctor with a severity rating is the Cumulative Illness Rating Scale [89] CIRS: In advanced stages of dementia, many of the scales for assessing cognitive and behavioral functions in dementia lose sensitivity to identifying further pathological developments. The Bedford Alzheimer Nursing [90] Severity Scale (BANSS was developed to assess the degree of cognitive or functional impairment and the presence of pathological symptoms. The scale is compiled based on information from the care staff and the patient’s physical examination. Another useful tool for assessing quality of life in dementia is the Caregiver Burden Inventory [91], which assesses the burden and effort required to care for a patient with dementia. The interview allows to obtain a profile of the caregiver’s load in different areas (evolutionary, physical, social, emotional), and is also useful to evaluate the changes in the load over time.

Activity of Daily Living [92] (ADL) evaluates the patient’s ability to perform basic actions of daily life (eating and dressing independently, moving around in their home, managing personal hygiene), while Instrumental Activities of Daily Living [93] It looks at more complex tasks such as money management, cleaning, using the telephone, taking medicines on their own. Barthel Index [94] evaluates functional and motor disability through ten domains similar to the previous ones. The scales mentioned have been at least partially surpassed by the latest knowledge on functional symptoms related to dementia. For this reason, some researchers have constructed and standardized a more complex scale that takes better account of the peculiarities of the functional deficits peculiar to this group of diseases: Activities of Daily Living Inventory (ADCSADL) [95] This scale is administered to the caregiver, asking them to report their responses to the previous 4 months, and deepening the level of independence of the patient in the examined activities. The tools are a useful aid both to accompany with psychometric instruments instrumental diagnostic examinations aimed at the diagnosis of dementia and the specification of the different forms of it, to support the exploitation of remaining resources and the rehabilitation - as far as possible - of those lacking, in order to counter or to prevent progressive deterioration and maintain the best quality of life corresponding to the patient’s clinical situation.

Pharmacological and non-pharmacological interventions

The global increase in people with DNC Major, makes it necessary to identify treatments for people with dementia, not just to ensure they get the care they need, but also to relieve the care burden that inevitably falls on caregivers. Interventions for patients with dementia can be divided into two classes: drug-based and non-drug-based treatments. Drug treatment for dementia is rather limited as, to date, only a few drugs are authorised on the market and all of them are designed to act on brain changes typical of Alzheimer’s disease [96]; no drugs for the treatment of other forms of dementia have been developed at this time. In Italy, the drugs available are Donepezil, Rivastigmina, Galantamine and Memantine, which act by raising or lowering the levels of some neurotransmitters present in the brain, but they are not able to stop the neuropathological mechanisms in action or alter the course of the pathology Donepezil, Rivastigmina and Galantamine are acetylcholinesterase inhibitory drugs and are approved for mild and moderate forms of Alzheimer’s: act on the pathology by inhibiting the enzyme that breaks down acetylcholine, the neurotransmitter mainly deficient in patients with AD. These three molecules, while sharing the general mechanism of action, have different characteristics and formulations that make it possible to personalise therapy [96].

Patients taking these drugs reported modest overall benefits on cognitive functions (tested through ADAS-Cog), especially attention levels, and daily life activities [97]. The most common side effects are related to excess acetylcholine and affect the patient’s vascular and gastrointestinal health. Memantine acts on the levels of glutamate in the brain by limiting its excessive activity, which seems to be what makes the synaptic transmission less functional, contributing to the neurodegeneration typical of AD; this drug is approved for moderate and severe forms. There is a possibility to plan a treatment by combining an acetylcholinesterase inhibitor with memantine, but there is no clear evidence of efficacy yet. Two elements to be taken into account are that not all patients respond to pharmacological therapy and that the latter acts to relieve for a limited time the cognitive symptoms, but then the pathology resumes its characteristic progression [96].

In addition to drug treatment for dementia, other classes of drugs are often prescribed, used to contain the Behavioral and Psychological Symptoms of Dementia (BPSD). The BPSD, defined during the 1996 Consensus Conference of the International Psychogeriatric Association as “alterations in perception, thought content, mood or behaviour, which are frequently observed in people with dementia” can be marked by signs of affective (depression, anxiety, irritability, euphoria), psychotic (delusions and hallucinations), neurovegetative (sleep rhythm, food) or conduct (vagrancy, worry, aggression, restlessness, inhibition). Psychological and behavioural symptoms, as well as being the main cause of caregiver stress and institutionalisation [98], are what push for a pharmacological treatment with antipsychotics, mood stabilizers and antidepressants. Several meta-analyses have, however, highlighted the many side effects of these classes of drugs, particularly antipsychotic drugs, concluding that this treatment should be limited to cases where the severity of BPSD is such as to endanger the patient or those around him [99]. Based on this last consideration, in recent years a lot is being invested in the design of non-pharmacological evidenced-based interventions with the aim of slowing down the course of the Major Neurocognitive Disorder.

Non-pharmacological treatment means any type of intervention, based on sound theoretical principles, aimed at promoting the well-being and health of a person, which does not involve the use of medicinal products. In the case of dementia, these interventions are usually conducted in institutional settings and involve patients’ active involvement in stimulating activities, whose ultimate goal is to promote clinically relevant improvement. Non-pharmacological treatments are based on the phenomenon of plasticity and brain redundancy [100] and aim to stimulate the cognitive resources and residual skills of the patient, acting on his cognitive reserve [3].

The concept of brain plasticity refers to the ability of neurons to assume functions different from those they were originally assigned to, in situations of need related to cell loss caused by pathologies of different types [101]. Brain redundancy refers to the presence in the brain of a greater number of neurons than the actual needs. These two assumptions form the basis of any stimulation intervention as they explain the ability of neurons to reorganize and cope with age-related changes. The concept of cognitive reserve, on the other hand, was first introduced by Stern [102] in 2002 and refers to qualitative differences in how people manage their mental resources to cope with cognitive damage of different nature. In particular, this construct is born from the observation that there is often no direct correspondence between the extent of brain damage and the symptoms shown by the patient: faced with changes in brain function, caused by aging or a pathology, People react differently, using existing resources or compensation mechanisms [3]. Cognitive reserve capacity is influenced by early school and work experiences, as well as involvement in leisure activities that stimulate the individual from a physical, cognitive and social point of view [102].

The cognitive reserve therefore assumes an active role by the individual throughout life and also takes on relevance in aging, especially in the case of degenerative diseases. Non-drug treatments, in addition to assuming active involvement of the individual, are based on a “person-cantered care” model, first introduced by Kitwood [103] in 1997. He expresses the need to go beyond the mere symptomatology of the disease, defining the output of DNC not only as the manifestation of a neurological damage, but as the interaction between this and other factors affecting the individual, including personality characteristics, biography, physical health and living environment. According to this principle, this means that the individual cannot be identified only by the symptoms of his disease, but must be considered in its entirety, bearing in mind all the elements that make him unique.

The approach to care of Kitwood [103] was subsequently taken up by Spector and Orrell [104], who, within their biopsychosocial model, highlight the need to take into account biological, psychological and social factors in the management of patients with dementia. The two authors extend the previous model by postulating the influence of more elements in determining how dementia manifests itself. Additional factors contributing to symptomatology may be through the interaction between neurological Damage (NF), Mental Stimulation (MS), Social Psychology (SP), Personality (P), Sensory Stimulation (SS), Environment (E), Physical Health (PH), Life Events (LE) and Mood (M). The authors contrast this model with that of traditional medicine (which focuses only on symptoms and their treatment by means of equal drug therapy for all), proposing an individualized intervention tailored to each individual patient, that takes into account all the variables that make up the formula [104].

Compared to drug therapy, psychosocial interventions require a greater effort in planning activities based on the characteristics of each patient and require the collaboration of its entire social network, by caregivers, family members and health care personnel [3]. In the light of the above considerations, it can be concluded that pharmacological and non-pharmacological interventions are not in conflict with each other but that, for a good management of the patient suffering from dementia, it is necessary to integrate them [105].

Alzheimer’s disease is the most common form of dementia and being typical of old age, it involves a condition or rather, a neurodegenerative syndrome, which causes a gradual and irreversible loss of cognitive functions, associated with progressive behavioural and neuropsychiatric symptoms. Empirical evidence reports different statistics related to the development of the disease, finding that about one in ten adults over 65 years old and almost 50% of people over 85 years old develop AD. This relationship inevitably has an impact on the impact that the disease has on public health, including the incidence and prevalence, mortality rates, costs of care and the overall effect on health care workers and society, determining the disease as a kind of “challenge”. The above data, therefore, continue to point us to a phenomenon in continuous growth, before which we must not be unprepared. For this reason, it is necessary to concentrate empirical work on dementia, and especially on AD, so that the possibilities of disseminating information relating to a correct diagnosis of the same are always available to the team, the patient and the caregiver.

All this allows us to face the disease taking into account a new perspective such as that of the Biopsychosocial Model, which allows us to adopt a type of care totally different from that implemented in the past: the psychophysical consequences of the disease involve a potentially stressful and painful life that needs much more attention given the breakdown in a previous balance. Consequently, the keyword which reflects this perspective could be associated with the so-called “multidisciplinary care”, that is to say a set of professional figures working together in different modes of performance but for the same objective, as the achievement of the highest quality of life for both patients and their families, focusing on different needs, such as medical and psychosocial, promoting a highly meaningful approach. This work, has proposed an overview of dementia from a diagnostic point of view, with the help of neuropsychological evaluation, also theoretical and practical aspects were examined, with the aim of paying attention to the need to implement multidisciplinary programmes that provide for the improvement of the coordination of the therapeutic diagnostic process at the patient’s expense and which are of assistance to the caregiver, who is aware of the diagnosis of his family. Managing the disease means adopting a biopsychosocial approach that allows updating of clinical implications related to prevention, evaluation, monitoring and support.

The approach to care and assistance in such patients should be based on a multidisciplinary approach, not only addressing noncognitive symptoms but also the relationship and environmental context, if this concept is not clear and shared by the multidisciplinary team (general practitioner, neurologist, psychologist) with the involvement of the main caregiver and the family, the patient will become a subject of care and no longer a subject of care [106]. It is therefore strongly stated that all professionals in the field have an ethical and solidarity duty towards these patients. Only the analysis of real needs allows, in fact, to face the many ethical dilemmas that are highlighted during the course of the disease, respecting the principles of autonomy-self-determination, charity and social justice. It is often the temptation, on the part of today’s cultural world, to believe that dignity in the subject with dementia no longer exists. Man, as a “person”, has his original dignity, in every stage of his existence, and to reinforce the concept that the patient with dementia is still a “person”, in any relationship with him, it is necessary to recognize this dignity [106].

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