Differential diagnosis of behavioral variant of fronto-temporal dementia (bvFTD)

Background

Diagnosis of Fronto-temporal dementia (FTD) requires – beside brain-imagining – a careful evaluation of genetic and neuropathological, cognitive processes disorders, and behaviour problems. The complexity of the symptoms observed after frontal lobe damage creates the necessity for a very careful neuropsychological examination [1,2]. Gustafson and Nielsen [3] already in the last century proposed a way of evaluating the behaviour of patients with frontal dementia enabling a differentiation of Pick’s and Alzheimer Disease. The Manchester group evaluated also the symptoms of FTD in retrospective studies in order to compare the clinical diagnosis with post mortem examination [4,5]. This made possible a differential diagnosis of Dementia and of Alzheimer Type (DAT) [6]. Lopez et al. [7] stated more symptoms of depression, anxiety, irritability, mood lability, disinhibition, inertia as well as social withdrawal in FTD patients in comparison to DAT patients, in whom paranoic symptoms were more often observed. Gregory and Hodges [8] conducted a review of psychotic symptoms in FTD patients with at least 5 basic diagnostic features. In a half of the patients a diagnosis of FTD already established, 1/3 had been diagnosed with schizophrenia, psychosis, depression with obsessive-compulsive traits, alcohol addiction, and psychogenic memory disorders.

The course of illness in FTD is similar to DAT and it includes three stages. The nature of the stages including disorders of cognitive, emotional processes as well as disorders of behaviour were described in many works [9]. Lebert [10] applied an Inventory of Symptoms to discriminate FTD, Alzheimer disease, and vascular dementia. The inventory took into account the following disorders:

Miller et al. [11] performed a retrospective evaluation of occurrence and the lack of symptoms of the Lund-Manchester scale in 30 patients with FTD. Patients were selected on the basis of a SPECT examination. The following differences between patients with FTD and were noted:

Kertesz et al. [12] developed a Frontal Behavioural Inventory (FBInv) in order to delineate specific behaviours, which would make possible a reliable diagnosis of frontal dementia. The inventory may be used both for the purpose of an introductory evaluation and to perform retrospective diagnosis. The items of the inventory were selected from the elementary diagnostic of the Lund-Manchester group and out of the most common syndromes of FTD observed in the patients examined by Kertesz et. al. [13]. The test was administered to 12 FTD patients, 16 DAT patients at the early stage of illness, and 11 patients with dementia caused by depression diagnosed by a psychiatrist and the Beck Depression Test during a pilot study. DAT patients were found to meet the criteria of NINCDS-ADRD. The depth of dementia was defined on the basis of scores gained on the Mattis Dementia Rating Scale (MDRS). FTD patients were selected taking into account clear cut behavioural symptoms, yet several developed logopenia at the later state of illness, and a typical Motor Neuron Disorder (MND) was stated in one of them. Frontal lobes atrophy was observed in 10 of those 12 patients with neuroimaging techniques. Pick disease was confirmed in 3 patients post-mortem, while in one cortico-basal symptoms were noted, while in two tau-negative ubiquitin inclusions as well as clinical symptoms of MND were stated. Results of the pilot study revealed that patients with frontal lobe lesions obtained much higher scores in the FBInventory than did the two control groups, something which was confirmed with ANOVA. No significant differences between the scores of patients with Alzheimer dementia and dementia following depression were noted. Patients with Alzheimer dementia were older, than patients with FTD and depression with one exception – all FTD patients were 65 years old at the onset of illness (which is a common time for falling ill in such cases). An analysis of the mean scores gained at FBInv revealed that the most common behavior disorders were: lack of insight, thinking rigidity, concreteness, personal neglect, inappropriate remarks due to disinhibition. A significant difference, however, was stated between the scores of FTD patients, and the control groups. The results made it possible to define a cutting point, and to operationalize the behavioural diagnosis of FTD. The point consists of 27 out of 72 points, which can be gained in FBInv, and includes all the FTD patients. Only one patient from amongst those with depressive dementia behaviour disorders was observed. Symptoms of depression were confirmed by vegetative symptoms as well as by scores recorded on the Beck Depression Inventory. All DAT patients, and most depressive patients scored below 24 points. Kertesz [14] notes, that the cutting points of FBInv may enable a grouping of the patients in order to perform a further examination. There are many inventories of behaviour evaluation that aim at screening deviant behaviours in geriatric, psychiatric or dementive patients [15–22]. Geriatric scales frequently combine cognition, behaviour, and everyday activities in order to measure global functional deterioration but they do not discriminate particular behavioural syndromes. Psychiatric behavioural scales also do not discriminate frontal and psychiatric symptoms. A direct evaluation of behaviour of FTD patients takes into account items measuring motor or cognitive perseverations, verbal inclusions, disinhibition, aspontaneity, and utilization behaviours. There were attempts to make the evaluation of symptoms of frontal lobe injuries more formal with the use of executive interviews [23]. Such direct tests often are a part of neurological examination and supplement FBInv. Logopenia appears at the later stages of FTD, and is sometimes connected with verbal and oral apraxia. Frequent hesitations in speech, prozodic disorders, the leaving out of initial consonants, and stuttering was also noted. Yet the scores of items evaluating those disorders were as a rule lower as they appear at a later stage of the illness in FTD patients. Those symptoms used to be called a Primary Progressive Aphasia (PPA) [24]. At the later phases of PPA personality disorders are quite common [26].

Some modification including new items were introduced to FBInv with time. The new version consists of a series of 24 items enabling an evaluation of social behaviour disorders as well as motor behaviours and the syndrome of alien hand. The last 5 items apply to behaviours appearing at the late stage of FTD. They create a lot of anxiety in family members who are reluctant to speak about them. The author believe that the inventory discussed may be of use in the case of PPA if administered along with specific language tests.

The aim of our research was to show the diagnostic value of FBInv [12–14, in distinguishing FTD from such syndromes as VAD or depression as well as in evaluating the efficacy of neurotherapy.

Material and Method

PROCEDURE:

The inventory was given to a patient caregiver, and the examiner provided explanations of the meaning of particular questions in the case of such a need.

Results

EVALUATION OF COGNITIVE FUNCTIONS:

The screening of cognitive functions taking into account intellectual abilities, memory, visual functions, language functions, and general features of dementia in individual groups is presented in Table 2.

INTELLECTUAL FUNCTIONS:

An analysis of WAIS-R scores shows that the lowest global I.Q. was noted in patients with Alzheimer dementia, fvFTD patients, and PPA patients. Therefore, it does not discriminate the examined groups. Yet, it may be observed that the distribution of results in nonverbal I.Q. and verbal I.Q. is different in the groups. Thus, patients with Alzheimer dementia gained significantly lower scores in nonverbal I.Q. when compared with their verbal I.Q. On the other hand, the proportions are reversed in fvFTD and PPA patients as their nonverbal I.Q. is much higher than nonverbal I.Q.

The above is most probably connected with the different profile of disorders in Alzheimer dementia, in which visual-spatial deficits connected with a performance part of WAIS-R are more pronounced, while language disorders dominate in PPA and FTD patients (five patients with Semantic Dementia – SD were included in that group, and this might have influenced the results).

MEMORY:

WMS-III test revealed disorders of logical memory in all examined patients, yet the depth of those disorders is different. Most severely impaired were DAT patients, less PPA and VAD patients, and the least DD patients. All of them presented difficulties in performing tasks with delay. It should be noted that DAT patients, as might be expected, exhibit more clear cut impairments in visual memory than other groups. In fact they practically do not accomplish any delay tasks whatsoever. On the other hand, FTD and PPA patients score much worse in auditory memory than in the visual memory. On reproduction with delay they score worse but they are able to remember considerable amounts of information.

VISUAL-SPATIAL FUNCTIONS:

The most pronounced disorders of visual-spatial functions occurred as was expected for DAT patients both in the Benton Test as well as in the Face Recognition Test, the disorders were less pronounced in VAD patients. FTD and PPA patients revealed non-significant disorders, while DD patients stayed within a norm. Those results can be explained due to the observation of patients performance. It can be noticed that FTD and PPA patients tend to abandon the tasks, which may be the cause of a lower scoring. Visual-spatial dysfunctions may be also connected with deficits in memory selectivity, as the patients spare much less time to individual tasks.

LANGUAGE FUNCTIONS:

Western Aphasia Battery (WAB) showed the occurrence of aphasic disorder in all examined patients with the exception of patients with depression. As expected most pronounced disorders were observed in PPA patients – with Aphasia Quotient =64.3, slightly lower in AD patients – with AQ=87.3, and in FTD patients – with AQ=85.1. The least pronounced disorders were stated in VAD patients – with AQ=92.7. Depressive patients were on the borderline of the norm.

Slightly surprising are the profiles of the cortical quotients as they show the reverse tendency. The worst scores were gained by DAT patients – with a Cortical Quotient =68.6. It was probably due to the fact that Picture recognition scores are included in the CQ, and as we know this is frequently impaired in Alzheimer dementia.

GENERAL TRAITS OF DEMENTIA:

Comparison of the scores of the examined groups in the MMSE Test did not reveal statistically significant differences among the examined groups. The lowest mean, however, was gained by patients with DAT, and the lowest patients with depression and PPA, which was in agreement with expectations.

BEHAVIOURAL CHANGES:

The FBInv scores of patients with various types of dementia are presented in Table 3. It may be observed that the highest scores (much above the cutting point) were obtained by FTD patients. The scores of PPA patients were higher than in the control groups, but not as high as in the case of patients with FTD. The scores of VAD patients were similar to the scores of FTD patients. It confirms the observations of other authors that the so called frontal type occurs within VAD – which must be connected with dissociation of the frontal subcortical structures taking place in VAD [33,34]. It was stated that disinhibition symptoms, which prevail over apathy and withdrawal, are helpful in distinguishing FTD patients from VAD or DD patients [35].

Frequency of the occurrence of individual frontal lobe symptoms in 18 patients with bvFTD, correlated with the data gathered from the structured interview is shown in Table 4. This will enable the reader to better see the spectrum of behaviour disorders that appear in bvFTD patients.

In our study bvFTD patients were given a half-a-year neuropsychotherapy aimed at a reduction of frontal symptoms in accordance with a program elaborated by Pąchalska [36]. The patients behaviour was then evaluated with FBInv. The results of the study are shown in Table 5, and in Figure 1A, B. It may be observed that rehabilitation resulted in an improvement of some deviant behaviours. Thus, a significant decrease of indifference and emotional flatness as well as of apathy was observed. Yet, some disorders, mainly the behaviours connected with disinhibition did increase along with the progression of the illness despite neurotherapy. Those behaviours such as impulsivity, restlessness, aggressiveness, and excessive jocularity. Behaviours resulting from difficulties in passing from an idea to action as well as apathy also increased. Those were apraxia of speech, concreteness, disorganization, and inattention. As might have been expected alien hand symptoms as well as incontinence also increased.

Mean scores of patients with bvFTD in I i II examination in the first 12 traits of the inventory, i.e. negative behaviours resulting from difficulty in passing from an idea to action as well as apathy is shown in Figure 1A.

Mean scores of bvFTD patients in I and II examination in the other 12 trait of the inventory, which measure positive behaviours connected with disinhibition are shown in Figure 1B.

To sum up, it is worth pointing out that the above results are in agreement with the results obtained in the studies of other authors that, however, were performed much later than our study [34].

Discussion

HOW CAN THIS BE EXPLAINED?:

Naturally, the limbic structures, which play an essential role in basic drives and their affective correlates, may not be damaged at the early stage of FTD. The lesions may be noted after cutting of the ways leading from the frontal lobes to the limbic system or if that system is destroyed as a consequence of neurodegenerative changes.

Ablation of the frontal part of the temporal lobe connected with the bilateral ablation of the amygdalia body in animals is followed by dramatic changes in sexual and aggressive behaviours [30]. Klüver-Bucy syndrome, including hypersexuality, lack of fear reaction and visual agnosia, show how dramatic the results of lesions of the limbic structures for emotional-motivational functions can be. FTD patients often exhibit Klüver-Bucy Syndrome. They exhibit various deviant social behaviors, such as disinhibition, verbal or physical aggression, and executive functions disorders connected with apathy [36]. Lesions leading to the above mentioned pathological behaviours are difficult to grasp. Dysfunctions observed in those patients remind one of the behaviours of animals with lesions disrupting the activity of the limbic system. Microgenetic theory of a symptom [74] developed on the basis of an evolutionary, four-dimensional model of brain work [75] may be of help in understanding those disorders. Damage to the limbic system or of one of its connections with other brain structure including the frontal lobes (Figure 2) disrupts the normal activity of the brain, and due to that basic limbic-cortical dysfunction many patients with dementia exhibit difficulties with “adult” or “civilized” behaviours [36,75].

Behaviour disorders are often the first symptom of an illness, which may enable putting an early by a well trained evaluator [36]. The microgenetic model of brain work makes us aware that in Fronto-Temporal Dementia the whole of the brain systems become disrupted and not only specific cognitive functions as in the case of local brain injuries. The function of those systems are at first disorganized only in part, but then undergo global disruption, after the destabilization reaches a level, which causes a loss of integrity. It needs to be stressed that even in the case of the linguistic variant of FTD (lvFTD), neither the course nor the nature of the disorders observed, speech and language disorders, recalls aphasia [9,76,77]. There is a difference in reaction of the dynamic system that receives one strong and localized blow as is the case in a brain stroke; and of the system, which loses its energy and undergoes entropy as in the case of dementia. In such case the changes are vertical: the upper levels of complex brain processes lose energy, become disorganized, and finally disintegrate, in contradistinction to the “horizontal” effects of focal lesions, when one part of the system is damaged, and others remain untouched.

As cortical dementia traits grow, which occurs both in Alzheimer disease as well as in FTD, the process of neurodegeneration runs counter to microgenesis, that is: from the upper areas to the lower (deeper) areas of the brain. The deeper the neurodegenerative changes in the brain are, the less specific will be the symptoms. And after the illness assaults the lowest level (brain stem and midbrain), basic life functions will also undergo entropy: will lose energy and disintegrate, which results in decease. Therefore, at the final stage of any neurogenerative dementive disease differences in the clinical picture, which might be clear at the very beginning, become difficult to distinguish [78,79]. In other words, each dementia:

Conclusions

To sum up, it should be stressed that the scores of the present study enable differentiation due to the specific behavioural profiles of the various dementive syndromes and are of significance for the course of therapy. At the same time they enable evaluation of the efficacy of neurotherapy, and hence they make possible a raising in the quality of life of persons with various types of dementia.

The results obtained in the present study confirmed the diagnostic value of FBInv in the differential diagnosis of various types of FTD and in the evaluation of neurotherapy efficacy.