Neuropsychological Tools for Dementia: Differential Diagnosis and Treatment

Preface

During the past decades, the entry of clinical and cognitive neuropsychology into the neurological departments at hospitals has contributed to the differential diagnosis of neurodegenerative diseases leading to dementia. Meanwhile, clinical neuropsychologists are regular members of neurologic, psychiatric, and geriatric departments and are involved in testing patients to objectify subtle cognitive deficits or to help find a probable diagnosis. Symposia concerning neurodegenerative diseases are common at neuropsychological conferences and research regarding neurodegenerative diseases has entered the psychological departments at the university. At the same time, the call for more specific and earlier diagnosis of patients suffering from neurodegenerative diseases is getting louder. Thirty years ago, the task for neuropsychology was limited to argue that there are memory deficits on the side of the patient and therefore the patient suffers from Alzheimer’s disease. Differential diagnosis did not play a major role, then. Meanwhile the spectrum of neurodegenerative diseases exploded during the following years. For example, Alzheimer’s disease has been divided into one typical variant and three atypical variants. The former frontotemporal lobe dementia or Pick’s disease developed into those starting primarily with aphasia and one starting with behavioral problems. This differentiation of phenotypes (clinical syndromes) serves to identify specific neuropathological causes and subsequently discover specific treatments. For most of the neurodegenerative diseases, there are no clear-cut biomarkers that would enable a simple and fast diagnosis. As long as such biomarkers are lacking, the clinical assessment is important, and neuropsychology is an essential part of it.

Many neuropsychological studies focus on cognitive deficits characteristic for single neurodegenerative diseases to increase the certainty of a differentiation. In clinical and translational terms, they concern the question of differential diagnosis. Due to these scientific studies, it is now well-known that patients with Alzheimer’s disease suffer from a deficit in recollection and often use familiarity to compensate for that deficit. However, this insight has not reached clinical routine assessment, yet. Memory testing is often still based on neuropsychological tests that does not allow for a separation of recollection and familiarity. Another example concerns typical and atypical Parkinson’s disease. Assessment of these patients is often based on the assumption that both suffer from executive or frontal functions deficits. However, results from recent studies pose the question, if typical and atypical Parkinson’s disease patients differ in visuoperceptive impairments. However, testing for specific visuoperceptive impairment is still underrepresented in the assessment of this patient group. Thus it seems that the results of a growing number of studies on cognitive deficits in neurodegenerative disease have not already reached the clinical routine practice.

A further question that is still outside the focus of clinical neuropsychological routine practice is that of treating the patients. At first sight, this may appear somewhat curious: treatment of neurodegenerative disease that are progressive and cannot be cured? Does that make any sense at all? It is the firm conviction of the author that treatment questions should gain much more importance in neuropsychological research on neurodegenerative diseases. At the end of the day, avoiding or at least delaying the cognitive decline is the major goal of the patients (and not just getting a correct diagnosis). And benefitting the patients is the major goal of the health system. Neuropsychologists should be prepared to contribute to this goal. Rehabilitation and functional training already play a crucial role, for example, for the treatment of patients with Parkinson’s disease, where physiotherapy forms an essential part. Motor and cognitive functions both rely on processes of the same brain. There is no radical difference between them. Thus there is no reason that only motor functions should show enough neuroplasticity for being a target of rehabilitative effort. Cognitive training and cognitive intervention might also be helpful in patients suffering from neurodegenerative diseases. Fortunately there is an increasing number of studies documenting an effect of such treatments, and it will be the task of neuropsychologist is to establish them for more and more patients.

However, the role of neuropsychology is not limited to differential diagnosis and cognitive rehabilitation. Educating the patients about lifestyle changes and how to cope with the increasing impairments by adapting the environment is another important topic of clinical work. Education also involves information about the functional independence of the patients and helps find an optimal time-point for the decision to move into a nursery home. Such decisions are often accompanied by strong emotions on the side of the relatives and professional information about the behavior of other families may diminish self-reproaches. Unfortunately research regarding this important question is still very limited. However, some information is already available. Additionally, research on the progression of the disease delaying life-style changes has already reached some global consensus.

This book is written to synthesize the existing knowledge on assessing patients for differential diagnosis, for treating them, and for psychoeducation or counseling. Its goal is to inform clinical neuropsychologists (and colleagues from other disciplines) working in hospitals and to help teach students by preparing them for such a working place. Therefore each chapter of the book entails a case example and different summaries regarding how to proceed with the process of diagnosing and envisioning treatment. To increase the practical value of the book, a guideline is added for the assessment answering question like: Which aspect should be part of the anamnesis for different neurodegenerative diseases? What are clinical aspects in the behavior of the patients one should look for? Which tests should be added to a core battery for the suspected disease? Which features contradict a specific clinical diagnosis and should lead to a reconsideration? Another guideline answers question concerning psychoeducation and the treatment of the patients, which is most important for the patient. It is the hope of the author that the chapters and the guidelines are helpful for students and newcomers in the field. In the best case scenario, this book also helps to slightly improve the fate of the patients suffering not only from a severe disease that cannot be cured but also from uncertainties concerning how to delay the progress and how to prepare for a future with increasing loss of functional independence.

Not all parts of the book are written for clinical practical purposes. There are some sections that have a more scientific claim. During the past two decades, neuropsychology diverged into two major branches—research oriented and clinically oriented. At universities, neuropsychology progressively became a part of neuroscience, whereby the main focus of the research concerned functional brain imaging and its different techniques. Clinically oriented colleagues joined cognitive behavioral therapy and looked for adaptation of the patients or the environment to increase the assimilation to the consequence of brain damage. The traditional core of neuropsychology, that is, diagrams explaining cognitive processes and developing cognitive models, has lost its meaning. There is no doubt that the new brain imaging tools enable the collection of new and important information about the implementation of cognitive and physiological processes in the brain that clinical neuropsychology is unable to offer. On the other hand, clinical neuropsychology is concerned with patients suffering from specific disease or brain lesions (and not with brains or brain areas). Understanding the problems of the patients and treating them presupposes a clinical level of research, which was the strength of classical neuropsychology. Therefore the last section of each chapter is dedicated to questions of cognitive neuropsychology, the level of thinking, which permits the integration of neuroscientific and clinical knowledge to serve diagnosis and treatment on the patient’s level.

This book is based on years of clinical routine practice with patients as well as on years of teaching students and clinical colleagues in cognitive neuropsychology of the dementias. This interplay dominated the motivation and the outline of the book.

Various colleagues read specific chapters and provided comments and valuable feedback. Therefore I would collectively like to extend my gratitude and appreciation to them for their support and cooperation.

However, there are two persons to whom I express my gratitude individually:

Paul Eling commented on all chapters and forced me to rethink a lot of my writings, especially regarding cognitive models and explaining the behavior of the patients by diagrams.

Elfriede Diestel did a marvelous job translating my poor writing skills and English knowledge into a fluent text. Her work was a really painful job and I admire her patience.

Chapter 1

Introduction: neuropsychology and the assessment of patients with dementia

Abstract

The number of patients with dementia is increasing because of increasing life expectancy. Dementia is a clinical syndrome, not a cause of disease. Up to now, there are no valid biomarkers for most kinds of dementia. Therefore the differential diagnosis is based on the clinical assessment, whereby neuropsychology plays a major role. Neuropsychological testing has two goals: to increase the correctness of the differential diagnosis and to predict the psychosocial consequence of mild cognitive impairment and dementia (the ability to live at home and the need for external help). Hopefully soon, there will be a third goal: to inform about the best functional treatment. Screening for dementia is helpful for grading and following up. Raw scores in screening tests are influenced by the background of the patients, that is, education, gender, and age. Patients with a mini mental status examination score less than 21 start to develop impairments of instrumental activities of daily living (IADL). However, basic ADL only decline after further disease progression. Stating that the diagnosis relies on the anamnesis, which should encompass cognitive deficits as well as autonomous functioning, walking, fine-motor control, mood, and relevant diseases of the patient and their relatives. The Consortium to Establish a Registry for Alzheimer’s Disease, Neuropsychological Assessment Battery (CERAD-NAB) is a standardized test battery, which is recommended as part of a core set of tests. Together with results from other tests of the core set, a hypothesis for the differential diagnosis should be developed. This hypothesis must be tested through tests sensitive for the different kinds of dementia. The core test set should be used in patients older than 60 years, and in younger patients it might be too easy. For such patients the assessment should rely on harder tests. Effective treatment for dementia relies on early diagnosis because in later stages the neurodegenerative process already caused irreversible atrophy. During later phases of dementia, delaying its progression will be the most important concern.

Keywords

Dementia as clinical syndrome; biomarkers; neuropsychological differential diagnosis; neuropsychological functional diagnosis; CERAD-NAB; core set for assessing dementia; anamnesis; cognitive screening; early treatment

General summary

The number of patients with dementia is increasing because of increasing life expectancy. Dementia is a clinical syndrome, not a cause of disease. Up to now, there are no valid biomarkers for most kinds of dementia. Therefore the differential diagnosis is based on the clinical assessment, whereby neuropsychology plays a major role. Neuropsychological testing has two goals: to increase the correctness of the differential diagnosis and to predict the psychosocial consequence of mild cognitive impairment and dementia (the ability to live at home and the need for external help). Hopefully soon, there will be a third goal: to inform about the best functional treatment.

Screening for dementia is helpful for grading and following up. Raw scores in screening tests are influenced by the background of the patients, that is, education, gender, and age. Patients with a mini mental status examination (MMSE) score less than 21 start to develop impairments of instrumental activities of daily living (IADL). However, basic ADL only decline after further disease progression.

Stating that the diagnosis relies on the anamnesis, which should encompass cognitive deficits as well as autonomous functioning, walking, fine-motor control, mood, and relevant diseases of the patient and their relatives. The Consortium to Establish a Registry for Alzheimer’s Disease, Neuropsychological Assessment Battery (CERAD-NAB) is a standardized test battery, which is recommended as part of a core set of tests. Together with results from other tests of the core set, a hypothesis for the differential diagnosis should be developed. This hypothesis must be tested through tests sensitive for the different kinds of dementia. The core test set should be used in patients older than 60 years, in younger patients it might be too easy. For such patients the assessment should rely on harder tests.

Effective treatment for dementia relies on early diagnosis because in later stages the neurodegenerative process already caused irreversible atrophy. During later phases of dementia, delaying its progression will be the most important concern.

1.1 Some epidemiological background information

The 10th International Classification of Disease (ICD-10) defines dementia as a significant cognitive decline that lasts (or progresses) for at least 6 months. This decline might be due to an acute or a subtly increasing damage to the brain and must be independent of an acute or temporary cognitive impairment. If the cognitive impairment is rather temporary, the ICD provides the diagnosis of a delirium, defined as a short-term severe cognitive disorder. Furthermore the cognitive decline must comprise different cognitive functions. This is important because isolated cognitive disorders may be classified under other specific headings like organic amnesia (F04 or R41.0), neglect (R29.5), aphasia (R47.0), or attentional impairment (R46.4). Only a combination of different cognitive disorders allows the use of the term dementia. These impairments also must be severe enough to diminishing social functioning at work or the ability to live independently. The last important aspect, which plays a role in the diagnosis of dementia, is that the cognitive decline has to be leading. In other words, it must be excluded that the decline is due to an affective disorder like psychosis or depression. This does not mean that patients with dementia may not also suffer from depression, it only means that the affective state is not a sufficient explanation for the cognitive decline.

It is well known that the number of patients with dementia is increasing. An increase in life expectancy automatically leads (more or less automatically) to a higher number of patients with dementia (Reischies et al., 1997XXX). In Germany it has been estimated that around the year 2000 approximately 1.61% of all inhabitants older than 65 years suffered from dementia. That would mean that approximately 150,000 people developed dementia (not including patients with vascular dementia) each year. Because vascular dementia embraces approximately 30% of all dementias, another 45,000 cases of dementia must be added to the yearly figure. Around the year 2000 there were about one million people older than 65 years living with a dementia diagnosis in Germany. Fifteen years later this number has increased to 1.6 million patients and it is estimated that in 2050 this number will rise to three million (www.alzheimer-europe.org/EN/Research/European-Collaboration-on-Dementia/Prevalence-of-dementia/Prevalence-of-dementia-in-Europe). Out of these estimated figures, about one-half of these patients will develop Alzheimer’s dementia (AD), 10% a variant of frontotemporal lobe dementia and 10% Lewy body dementia or Parkinson’s disease dementia. One should be aware that these estimations do not reflect the real picture because dementia is often not additionally diagnosed in patients where the organic cause is evident (e.g., stroke or Parkinson’s disease patients). From the age of 70–90 years, the frequency of dementia doubles every 5 years (Fig. 1.1).

Figure 1.1 Relative risk for dementia according to older age groups (standardized for age group 70–74 years).

Prevalence of dementia (according to the DSM IIIR criteria) for six different age groups subdivided for mild, moderate, and severe dementia and subclinical dementia, that is, patients who might suffer from dementia without fulfilling all DSM IIIR criteria. The data are corrected for gender differences, because females are more overrepresented in older age group. From Reischies, F. M., Geiselmann, B., Gessner, R., Kanowski, S., Wagner, M., Wernicke, F., Helmchen, H. (1997). Dementia in the very elderly. Results of the Berlin Aging Study. Nervenarzt, 68(9), 719–729.

Taking care of patients with dementia is a considerable burden for relatives, and this burden increases as the disease progresses. Most patients with mild dementia live at home, outside of inpatient care. During this phase, the nursing costs are paid by relatives that fill the (unpaid) caregiver role. Thirty five percentage of caregivers for individuals with dementia report that their health has gotten worse due to the demands of their care responsibilities. However, only 19% of caregivers for patients without dementia report such a decrease in health. As the disease progresses to later stages of moderate and severe dementia, the public costs raise rapidly. A Canadian investigation by Hux et al. (1998) calculated annual costs for patients with AD. They found that the costs averaged $9451 (CAD) in the mild stage and rising to $36,794 in the severe stage (Fig. 1.2). As in Fig. 1.2, costs in the early stages are primarily comprised of unpaid caregiver work that is carried out by relatives. These costs remain high when the moderate stage is reached and start to fall only in the severe stage. It has been estimated that in 2017, the total cost of taking care of dementia patients in the United States was $259 million. By 2050, this figure is expected to increase to $1.1 billion (USD).

Figure 1.2 Estimated annual costs for Alzheimer’s disease per patient.

Mild, mini-mental state examination (MMSE) score 21–26; mild to moderate, MMSE score 15–20; moderate, MMSE score 10–14; severe, MMSE score <10. Differences between severity groups for each component of care were significant at P<.001, except for unpaid net supervision time (time after subtracting direct care time (P=.64). From Hux, M. J., O'Brien, B. J., Iskedjian, M., Goeree, R., Gagnon, M., Gauthier, S. (1998). Relation between severity of Alzheimer’s disease and costs of caring. CMAJ, 159(5), 457–465.

The assessment and diagnosis of dementia is often a frightening experience for many patients and their families. In addition to fear, a diagnosis of Alzheimer’s dementia is accompanied by enormous stress for both parties. Unfortunately, the public debate on dementia almost always focuses exclusively on the late state of the disease and often on living in sheltered nursing homes. Knowledge about the natural cause of the different types of dementia is rare in the general population. Moreover, there are also only a few longitudinal studies with a long duration that can provide evidence to the patients and their relatives about the possible development of the disease. There is a consensus that patients with Alzheimer’s disease (AD) show a disease progression related cognitive decline that varies between 1.8 and 4 points per year in the MMSE. Since a total score of 24 in the MMSE is considered the starting point for a clinically relevant impairment that indicates a state of dementia, it would take between 6 and 12 years before a patient reaches a state in which very simple cognitive tasks can no longer be completed. However, this statement does not represent the entire picture. Tschanz et al. (2011) conducted an interesting study in which they followed patients diagnosed with Alzheimer’s dementia for 8–12 years (Fig. 1.3).

Figure 1.3 Cognitive decline in patients with AD. AD, Alzheimer’s disease dementia; MMSE, mini-mental state examination. From Tschanz, J. T., Corcoran, C. D., Schwartz, S., Treiber, K., Green, R. C., Norton, M. C., et al. (2011). Progression of cognitive, functional, and neuropsychiatric symptom domains in a population cohort with Alzheimer dementia: the Cache County Dementia Progression study. American Journal of Geriatric Psychiatry, 19(6), 532–542. https://doi.org/10.1097/JGP.0b013e3181faec23.

The results of Tschanz et al. (2011) insinuate that there is a fairly large group of patients that reach the lowest score in the MMSE after 6–8 years. On the other hand, there is also a smaller group of patients that show a slow progression of cognitive decline that lasts over more than 10 years. Unfortunately, the exact factors that could explain which trajectory a single patient will follow currently remain unknown. An obvious course of action in telling the patients the diagnosis is to explain that we do not know to which group he or she belongs to and that there is a fair chance that they will experience slower disease progression (still, patients should also be informed that the risk of suffering from a usual decline of maximum 3–4 MMSE scores per year is a realistic possibility). Furthermore it should be mentioned that there are some interventions that might be able to slow the progression of the disease. These interventions will be discussed later in more detail. Informing patients about both possibilities might improve their ability to emotionally cope with the diagnosis.

1.2 Dementia is a syndromic and not a causal diagnosis

Dementia is not a causing diagnosis, but rather a term that refers to a cognitive syndrome. The significance of the term dementia is often confused not only by laymen but also by professionals who are new to the field. Dementia means that patients possess a specific combination of cognitive impairments and that these impairments are severe enough to have significant consequences for one’s ability to work or live independently. Dementia does not cause the cognitive deficits, it is simply a common heading for them. In terms of causation, the loss of independence in everyday functioning is the only thing that ensues once the label dementia has been assigned to a person. More strictly speaking, it is not the diagnosis of dementia that implies any causation. Instead, it is the cognitive decline that is associated with it: Patients with mild dementia may still be able to live at home, sometimes with some help even alone, whereas patients with moderate or severe dementia will not be able to do so (or will need considerable nursing assistance). To estimate the already present (but ignored) or the soon to be present psychosocial consequences based on the severity of the cognitive impairment is an important task of neuropsychological assessment. At the same time, this task differs, in many respects, from the task of using neuropsychological test results for a differential diagnosis, that is, determining the kind of dementia the patient is developing. Therefore there are two aspects of the meaning of the term dementia. The first meaning is syndromic and concerns a specific combination of cognitive deficits that can be used to differentiate between different possible causes of the state of dementia. The other meaning concerns the severity of the cognitive decline and how the degree of severity relates to the ability of the patient to live independently. Both aims of neuropsychological testing should not be confused as they partly require the use of different assessment measures.

In the following section we will mainly focus on the first meaning, which concerns the cognitive pattern of deficits. The theoretical assumption is that the cognitive impairment pattern is related to the specific organic disease. Neuropsychological assessment is, in this respect, very similar to neuroradiological or neurophysiological assessment. It measures the results of a pathogenetic cause, but not the cause itself. Further neuropsychological assessment tries to diagnosis which pathogen could have caused the specific pattern of decline. Thus the accuracy of neuropsychological assessment depends on two aspects. The first aspect is the validity of the tests used during the assessment to measure the specific deficits. In the early stage of a disease, one might fail to recognize cognitive decline if the neuropsychological tests that are used are not appropriate for the neurodegenerative disease of the patient. The second aspect concerns whether the spread of the organic cause in the brain is specific enough to allow a differential diagnosis based on a distinct cognitive pattern of decline. There are some diseases that lead to dementia where it is unclear if the analysis of the pattern of cognitive deficits will allow for a differential diagnosis. Take vascular dementias, for example. The patterns of stroke-induced brain lesions can affect various structures of the brain with various focal impairments; however, a large group of these patients suffer from vascular dementia. There is a type of vascular dementia that is explicitly caused by a widespread pattern of subcortical arteriosclerotic encephalopathy. Therefore the chance of defining a specific impairment pattern for this kind of dementia is low as any kind of cognitive impairments might be present (ranging from memory deficits after thalamic strokes to diffuse cognitive slowing after widespread microangiopathic changes). For example, the amount of subcortical arteriosclerotic encephalopathy is often rated by the Fazekas scale score (Fig. 1.4). In an unpublished paper, we analyzed the relation between the Fazekas scale score and neuropsychological test performance in a group of approximately 90 patients. There were only a few differences present when comparing groups with different Fazekas grades. Patients with higher grades performed more intratrial errors in spatial working memory tasks and were slower in the Trail Making Test A and B (TMT-A and TMT-B). The significant difference concerned the comparison between grades 0 and 3. Patients with grades 1 and 2 performed similarly to patients with grade 0. One can conclude that a loss of psychomotor speed might be a significant impairment following severe white matter lesions (at least in the tests we used for our analysis, which included the CERAD-NAB as well as tests for verbal and spatial working memory and language comprehension). However, at the same time, higher grades in the Fazekas scale correlated with higher age, which limits any interpretation of differences between the groups.

Figure 1.4 Examples of the Fazekas score to quantify vascular white matter lesion load. The lesions are randomly distributed over the white matter which makes it difficult to define a specific pattern of functional impairment. Without a specific pattern of impairment, it is impossible to establish a differential diagnosis of dementia relying on neuropsychological tests. https://radiopaedia.org/articles/fazekas-scale-for-white-matter-lesions. Case courtesy of Dr Bruno Di Muzio, Radiopaedia.org, rID: 36927.

Two different consequences can be drawn from this example. One is that better cognitive models are needed to develop valid measures of subcortical white matter lesions and to improve the differential power of neuropsychological testing for this group of demented patients. The other consequence could be that neuropsychology is unable to contribute to the differential diagnoses for patients with vascular dementia. For the following chapters we decided to follow the second consequence. Thus this book does not entail a section on vascular dementia. Still neuropsychological testing may be helpful in predicting the psychosocial consequences related to the severity of the cognitive decline, which concerns the second task of neuropsychological assessment defined earlier.

When it comes to finding causes for diseases in the clinical routine practice, the ultimate goal of the diagnostic process does not end with the identification of a lesion (e.g., a thalamic lesion or widespread white matter lesions corresponding to grade 3 on the Fazekas scale). Rather the real task is to find the causes that contribute to the development of these kinds of lesions (high blood pressure, diabetes, embolic vs stenosis as cause for a stroke, etc.). Only at this level can the pathogenetic process be stopped and prevented. The same holds true for neurodegenerative diseases such as Alzheimer’s dementia or frontotemporal lobe dementia. The goal is to find a specific neuropathological process that causes the cognitive decline, not to identify a specific brain structure that is related to the cognitive process. Alzheimer’s disease may result in clinically divergent impairments. For example, there is the typical variant of AD, in which patients suffer from severe memory impairment that dominates the clinical picture. However, there is also the atypical logopenic variant, which begins with language disorders, and the postcentral cortical atrophy variant of AD, which begins visual perceptive deficits. These three variants show different symptoms, which are caused by the same pathological process, that is, Alzheimer’s disease. The same problem of different neuropathology that lead to similar functional consequence and vice versa is true for frontotemporal lobe dementia. Although different symptoms, for example, in language impairment, may map out different pathological processes (e.g., tauopathy vs TDP-43 pathology), there will be many patients that share symptoms with other patients who suffer from aberrant variants of dementia. Therefore it is an enduring task to develop assessment tools and testing algorithms (combination of tests) to improve the differential diagnostic power in the examination of the patients.

A large group of patients showed impairments on neuropsychological tests and in ADL, which are not severe enough to qualify for the diagnosis of dementia. Instead, these patients received the clinical diagnosis of a mild cognitive impairment (MMSE>24) (Kurz, Diehl, Riemenschneider, Perneczky, & Lautenschlager, 2004). Mild cognitive impairment (MCI) has the ICD code F06.7. Defining features of MCI can be found in Table 1.1. In conjunction with this diagnosis, it is common to indicate whether the impairment also concerns memory function (mild cognitive impairment, amnestic subtype) or not (nonamnestic subtype) because patients with the amnestic subtype are at a higher risk of developing Alzheimer’s dementia. Another distinction is whether the impairment only concerns one cognitive function (single-domain) or whether it concerns at least two different functions (multidomain mild cognitive impairment). The risk of cognitive decline is higher for patients with multidomain MCI. It should be mentioned that focal (isolated) cognitive impairments resulting from a stroke or other acute brain injuries must not be coded with the ICD-10 as MCI (F06.7) but can be also coded by using its R chapter. There you will find codes for memory impairment (R41.0), aphasia (R47.0), apraxia (R48), etc.

Table 1.1

Unfortunately, there are currently no cures for the classical neurodegenerative diseases. Should cures be found, they will be especially helpful if initiated early in the disease process. This highlights the importance of developing neuropsychological tests that are sensitive enough to detect the early, preclinical (MCI) stages of Alzheimer’s dementia. Increasing the sensitivity of neuropsychological testing to predict conversion from MCI (presence of cognitive impairments) to dementia is also important from the patient’s perspective: they want to know how their cognitive impairment may develop over time. Therefore both a diagnosis of dementia and mild cognitive impairment, require a professional neuropsychological assessment. To quote the German S3 Guideline for dementia: In the case of a mild dementia, doubtful dementia, or differential diagnosis, detailed neuropsychological tests should be conducted. The selection of appropriate methods should be chosen concerning the clinical question, the stage of the disease and the experience of the examiner. Influential variables like educational status and sociocultural background or language abilities have to be considered. Cognitive areas like learning and memory, orientation, alertness, praxis, language and action planning should be examined using standardized instruments performing a neuropsychological assessment in patients early in their disease process and for differential diagnostic questions. (https://www.awmf.org/uploads/tx_szleitlinien/038-013l_S3-Demenzen-2016-07.pdf).

1.3 International classification of disease diagnosis codes for dementia—still more than noticing abnormal biomarkers

The diagnosis of dementia is represented through different levels in the ICD-10. There are so-called F diagnoses, which cover the spectrum from F00.0 to F03. Important classifications for neurodegenerative dementias are as follows: Alzheimer’s Dementia (F00.0–F00.9), vascular dementia (F01), frontotemporal dementia including Pick’s disease (F02.0), Parkinson’s disease dementia (F.02.3), Lewy-body dementia (F02.8), and dementia with unclear etiology (F03). Additionally, you will find the same diseases listed in other chapters of the ICD-10 (often in chapter G for neurological diseases, where Alzheimer’s disease has the G30.x code). This diversification reiterates that the ultimate goal of a diagnosis is to find the common physiological cause of the impairment, but different causes may lead to similar impairments and psychosocial consequences. Because there are clinical syndromes without any sufficient biological explanation, the ICD-10 allows for some multidimensional coding.

In this respect, it is important to state that most of the consensual statements about neurodegenerative diseases provide different levels of certainty for the diagnosis: definite, probable, and possible. To start with the last level, neuropsychological testing is part of formulating a possible diagnosis. This means that the patient should show the specific clinical signs defining the diagnosis and that there are no other obvious causes that may explain these signs. Neuropsychological testing is not able to provide a probable or a definite diagnosis because it does not provide a causal link between the symptoms and the biological causes of the disease. In this respect, it is important to mention that most of the clinical diagnoses for specific types of dementia cannot be verified as long as the patient is still living (which makes the development of specific pharmacological interventions very hard). Only the postmortem analysis of the brain allows for a definite diagnosis. The goal of developing valid biomarkers for differential diagnoses, to deliver a definite diagnosis during the patient’s life-time, has made only moderate progress during the last years. Still, there are no unambiguous early biomarkers for the group of frontotemporal dementias and patients with different kinds of Parkinson’s syndrome. Furthermore there is no definite relationship between patients with suggested vascular dementia between subcortical encephalopathy and cognitive impairment as already mentioned earlier. The existent biomarkers for Alzheimer’s disease are often incomplete and even contradictory. One example of this can be seen in the two cerebrospinal fluid (CSF) proteins beta-amyloid (1–42) and phosphor-tau, which are often used to diagnose AD (Rivero-Santana et al., 2017XXX). Fig. 1.5 documents the concentration of beta-amyloid (1–42) and phosphor-tau in 275 patients. These patients were assessed because of subjective or objective cognitive impairments. The figure shows that there is a negative correlation between phosphor-tau levels and beta-amyloid (1–42); however, this correlation is not very strong. In other words, there are many patients with low beta-amyloid (1–42) scores and low phosphor-tau levels or high beta-amyloid and high phosphor-tau levels. In these patients the CSF biomarkers point in different directions. Therefore the possibility of basing the diagnosis on them is restricted.

Figure 1.5 Correlation of phosphor-tau and beta-amyloid (1–42) in patients with suspected cognitive impairment or dementia.

Due to the moderate correlation between beta-amyloid(1–42) and phosphor-tau, it has been proposed to use the ratio between tau or phosphor-tau and beta-amyloid (1–42) as a bio-marker for AD (Weissberger et al., 2017XXX). The total tau/beta-amyloid (1–42) ratio (Tapiola et al., 2009) for defining two groups, with AD-like CSF scores and without CSF-like AD scores, in our patient sample can be found in Fig. 1.6. Although the cut-off value for this ratio clearly improves the classification of the patients into those with and without AD, there is still a considerable number of patients for whom the diagnosis remains somewhat unclear (Hildebrandt, Kastrup, & Eling, 2020XXX). This can be seen through the overlap between the two groups on the y-axis, which shows the concentration of beta-amyloid (1–42) in the patients.

Figure 1.6 CSF-based [total tau to beta-amyloid (1–42)] classification of the patients into Alzheimer’s positive and Alzheimer’s negative in relation to their CSF phosphor-tau and beta-amyloid (1–42) concentration (same as Fig. 1.5; blue circles represent patients with normal tau/beta ratio; green circles, patients with tau/beta ratio pointing to AD). AD, Alzheimer’s dementia; CSF, cerebrospinal fluid.

In the clinical routine, patients often show unimpaired levels of phosphor-tau and beta-amyloid or impaired levels of either phosphor-tau or beta-amyloid. It is rare that patients display impaired levels of both beta-amyloid and phosphor-tau. Proteins that have more recently gained attention for their usefulness in conducting a differential diagnosis are either unspecific for the cause but specific for the severity of the disease process (e.g., neurofilament) or show no better accuracy than beta-amyloid and phosphor-tau. Moreover, a recent study revealed that the new techniques using PET scans sensitive to beta-amyloid plaques do not increase the diagnostic precision compared to CSF analysis (Palmqvist, Mattsson, Hansson, & Alzheimer’s Disease Neuroimaging Initiative, 2016XXX). As a result, in the majority of cases the clinical diagnosis of dementia is still based on the combination of the clinical picture of the patient and the status of the biomarkers.

Coming back to the three different levels of certainty in diagnosing neurodegenerative diseases, the combination of a possible diagnosis (the patient shows the specific clinical features of that disease) and the presence of one specific biomarker allows a probable diagnosis to be made. There are often additional restrictions for denoting a diagnosis as probable, for example, if there are other causes which may induce a similar possible diagnosis. Because the clinical picture of the patients concerns their cognitive abilities and deficits, neuropsychological assessment belongs to the core process of finding a correct diagnosis.

1.3.1 Summary

The prevalence and incidence of patients with dementia in the population is increasing because of the increasing life expectancies. Dementia is a clinical syndrome not a cause of disease. Neuropsychological testing in dementia has two goals: to increase the correctness of the differential diagnosis concerning the neuropathological cause and to help predict the psychosocial consequence of mild cognitive impairment and dementia (the ability to live at home and the need for external help). The first goal is based on the assumption that a specific neuropathological cause will also have a specific functional consequence. In reality, however, this assumption will not always be valid since some kinds of dementia have specific functional consequences and others have unspecific or varying impairments. Neuropsychology can only be of help for the first group of diseases by providing a possible diagnosis. However, for both groups neuropsychological assessment can help to measure the handicaps and to estimate whether the patients are still able to live independently. Up to now, there are no valid biomarkers for most kinds of dementia. Therefore the differential diagnosis is based on the clinical assessment, whereby neuropsychology plays a major