Disrupted sleep and circadian patterns in frontotemporal dementia

Background:  A study of the pattern of Sleep/Wake disturbance in frontotemporal dementia (FTD).
Methods:  Sleep diaries and prolonged actigraphy were used to record the activity, sleep and wake of 13 patients with a clinical diagnosis of FTD. These were compared with diaries and actigraphy from normal age/sex matched controls and also to a population with probable Alzheimer's disease (AD).
Results:  There was significant sleep/wake disturbance in FTD. This occurred throughout the course of the illness and the nature of the sleep disturbance was different to patients with AD. FTD subjects showed increased nocturnal activity and decreased morning activity compared with controls, suggesting possible phase delay. Sleep diary data confirmed decreased sleep efficiency and decreased total sleep in all FTD patients.
Conclusions:  We describe significant sleep disturbance in non-institutionalized patients with FTD and suggest that early sleep disturbance may help differentiate between FTD and AD.     

Neuropsychiatric symptoms of dementia: cross-sectional analysis from a prospective, longitudinal Belgian study

OBJECTIVE: Given the rather limited knowledge on profiles of neuropsychiatric symptoms (behavioural and psychological signs and symptoms of dementia, BPSD) in several degenerative dementias, we designed a prospective study of which we here present the baseline data. METHODS: Diagnosed according to strictly applied clinical diagnostic criteria, patients with probable Alzheimer's disease (AD) (n = 205), frontotemporal dementia (FTD) (n = 29), mixed dementia (MXD) (n = 39) and dementia with Lewy bodies (DLB) (n = 23) were included. All patients underwent a neuropsychological examination and behavioural assessment by means of a battery of scales (Middelheim Frontality Score (MFS), Behave-AD, Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia). RESULTS: In AD and MXD, activity disturbances and aggressiveness occurred in more than 80% of the patients. With a prevalence of 70%, apathy was very common whereas delusions and hallucinations were rare in FTD patients. Frequently used behavioural assessment scales like the Behave-AD systematically underestimated BPSD in FTD whereas the MFS displayed high sensitivity for frontal lobe symptoms. Hallucinations discriminated DLB patients from other dementias. A high prevalence of disinhibition (65%) in DLB pointed to frontal lobe involvement. CONCLUSIONS: Behavioural assessment may help differentiating between different forms of dementia, further stressing the need for the development of new and more sensitive behavioural assessment scales. By means of the MFS, frontal lobe involvement was frequently observed in DLB. As 70% of FTD patients displayed apathy, prevalence was about two times higher compared to the other disease groups, meanwhile indicating that apathy is frequently observed in dementia, irrespective of its etiology.     

Different TMS patterns of intracortical inhibition in early onset Alzheimer dementia and frontotemporal dementia.

OBJECTIVE: To investigate putative changes in cortical excitability of patients affected by early-onset mild dementia by means of transcranial magnetic stimulation (TMS) and to verify whether a peculiar neurophysiological profile may contribute to characterise Alzheimer's disease (AD) vs frontotemporal dementia (FTD). METHODS: Motor threshold and intracortical inhibition (ICI) and facilitation (ICF) after paired-pulse TMS (inter-stimulus intervals from 1 to 20 ms) were studied in two groups of early-onset demented patients with a neuropsychological profile suggestive of AD (n = 12) and FTD (n = 8). Twelve age-matched healthy subjects were considered as control group. In both patient groups, recordings were performed before and after a single oral dose of 4 mg galantamine. RESULTS: No significant difference in motor threshold was observed among the three studied groups. On the contrary, early-onset AD showed a significant reduction of ICI compared to control group, no changes were detected in FTD patients. No significant changes in ICF were found between both patient groups and healthy subjects. The acute administration of galantamine reversed the modified ICI in AD group. CONCLUSIONS: The differential pattern of ICI exhibited by early-onset AD vs FTD in the early stage of disease may represent a non-invasive, reproducible electrophysiological tool, which may contribute to early differential diagnosis and, possibly, to monitor therapeutic effectiveness. SIGNIFICANCE: The present results support the possibility that subtle, early modifications in intracortical circuitry features AD, but not FTD patients.     

Frontotemporal dementia: patient characteristics,cognition, and behaviour

OBJECTIVES: To describe sociodemographic data of patients with frontotemporal dementia (FTD), to compare the cognitive profile of patients with FTD with that of severity-matched patients with Alzheimer's disease using the CERAD neuropsychological battery (CERAD-NP), to investigate the frequency of behavioural disturbances, and to examine the relation between FTD-specific non-cognitive behavioural symptoms of patients with FTD with age and sex. METHODS: Fifty outpatients were diagnosed with FTD according to the Lund-Manchester consensus criteria. Cognitive impairment was assessed in 30 patients using the CERAD-NP. Severity of dementia was rated on the Clinical Dementia Rating (CDR). Eleven non-cognitive symptoms were rated by severity. To compare CERAD-NP results between patients with FTD and AD, 30 patients with AD were matched for age, sex, and global severity of cognitive performance. RESULTS: The average age at onset of first symptoms was 57.8 years. Eighteen patients (36%) had a positive family history of dementia. On the CERAD-NP patients with FTD performed significantly better than patients with AD on word list learning, delayed verbal recall and visuoconstruction (p < 0.05). There were no significant differences between FTD and AD on naming and verbal fluency tasks. The most frequent non-cognitive behavioural symptoms in FTD were loss of insight, speech abnormality, and apathy. Non-cognitive behavioural symptoms were more frequent in younger and in male than in older patients and in female patients. CONCLUSIONS: The CERAD-NP is a valuable clinical instrument for the cognitive evaluation of patients with suspected FTD. Complementary short tests of attention and executive function may be recommended. To enhance diagnostic sensitivity informant interviews should focus on non-cognitive behavioural changes, taking advantage of standardised questionnaires.     

Diagnostic patterns of regional atrophy on MRI and regional cerebral blood flow change on SPECT in young onset patients with Alzheimer's disease, frontotemporal dementia and vascular dementia

OBJECTIVES: Alzheimer's disease (AD), frontotemporal dementia (FTD) and vascular dementia (VaD) are the three most common causes of young onset dementias. Most neuroimaging studies of these disorders have involved comparisons with normal controls. The aims of this study were to examine the clinical diagnostic value of magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) (in combination and in isolation) in the differentiation of one form of dementia from another from amongst a group of AD, FTD and VaD. METHODS: T1 weighted MRI images and 99mTc-HMPAO SPECT images were obtained from consecutive patients with FTD (n=21), AD (n=23) and VaD (n=20) and rated visually by experienced neuroradiologists and nuclear medicine physicians. RESULTS: Asymmetrical atrophy was seen only in FTD. Frontotemporal dementia patients were the most atrophic whereas severe atrophy was rarely observed in VaD. Severe frontal atrophy (unilaterally or bilaterally) and/or asymmetrical atrophy on MRI is highly diagnostic (sensitivity 0.71, specificity 0.93, LR 10.24) of FTD from within a group of FTD and non-FTD (AD, VaD) patients. Mild or severe parietal atrophy with severe reduction in parietal regional cerebral blood flow on SPECT is diagnostic (sensitivity 0.71, specificity 0.76, LR 3.02) of AD from within a group of AD and non-AD (VaD, FTD) patients. CONCLUSION: Anatomical (MRI) and functional (SPECT) imaging provide different information and a combination of these modalities improves diagnostic specificity.     

A brief cognitive test battery to differentiate Alzheimer's disease and frontotemporal dementia

OBJECTIVES: To validate a simple bedside test battery designed to detect mild dementia and differentiate AD from frontotemporal dementia (FTD). METHODS: Addenbrooke's Cognitive Examination (ACE) is a 100-point test battery that assesses six cognitive domains. Of 210 new patients attending a memory clinic, 139 fulfilled inclusion criteria and comprised dementia (n = 115) and nondementia (n = 24) groups. The composite and the component scores on the ACE for the two groups were compared with those of 127 age- and education-matched controls. Norms and the probability of diagnosing dementia at different prevalence rates were calculated. To evaluate the ACE's ability to differentiate early AD from FTD, scores of the cases diagnosed with dementia with a Clinical Dementia Rating < or = 1 (AD = 56, FTD = 24, others = 20) were compared. RESULTS: Two cut-off values for the ACE composite score (88 and 83) were of optimal utility depending on the target population. The ACE had high reliability, construct validity, and sensitivity (93%, using 88 as cut-off). Using the lower cut-off of 83, the ACE had a higher sensitivity (82%) and predictive value than the Mini-Mental State Examination for a wide range of dementia prevalence. The ACE differentiated AD from FTD, and the VLOM ratio (derived using component scores: [verbal fluency + language]/[orientation + memory]) of <2.2 for FTD and >3.2 for AD was highly discriminating. CONCLUSION: The ACE is a brief and reliable bedside instrument for early detection of dementia, and offers a simple objective index to differentiate AD and FTD in mildly demented patients.     

A short neuropsychologic and cognitive evaluation of frontotemporal dementia

Objective

To elaborate a brief but efficient neuropsychological assessment of frontotemporal dementia (FTD), selecting the most specific and sensitive cognitive and behavioural items for distinguish between AD and FTD in the earlier dementia stages.

Methods

Retrospective study with three groups, 35 patients with FTD, 46 with AD and 36 normal subjects, were administered the MMSE, FAB, Tower of London and Stoop's test along with a 98 items behavioural and cognitive questionnaire. The most sensitive items were selected and validated internally for diagnosis by lineal discriminant analysis.

Results

From the 98 items in the questionnaire, 29 showed significant discriminatory power. Non-cognitive symptoms with higher odd-ratio for FTD compared to AD were impairment in social behaviour (disinhibition, aggressiveness), loss of insight and inappropriate acts. Language disorders, such as echolalia, verbal apraxia or aggramatism, dominate in the cognitive profile of FTD. FAB was confirmed as the best cognitive instrument to differentiate FTD and AD. A linear discriminant function with the combination of the FAB score and the items from our questionnaire with higher OR for FTD accurately classified 97% of individuals.

Conclusions

The neuropsychological tests allow the differentiation between FTD and AD. The combination of FAB test with the assessment of key behavioural and cognitive symptoms appears helpful in this distinction.     

Distinct behavioural profiles in frontotemporal dementia and semantic dementia

OBJECTIVE: To test predictions that frontotemporal dementia and semantic dementia give rise to distinct patterns of behavioural change. METHODS: An informant based semistructured behavioural interview, covering the domains of basic and social emotions, social and personal behaviour, sensory behaviour, eating and oral behaviour, repetitive behaviours, rituals, and compulsions, was administered to carers of 41 patients with semantic dementia and with apathetic (FTD-A) and disinhibited (FTD-D) forms of frontotemporal dementia. RESULTS: Consistent with prediction, emotional changes differentiated FTD from semantic dementia. Whereas lack of emotional response was pervasive in FTD, it was more selective in semantic dementia, affecting particularly the capacity to show fear. Social avoidance occurred more often in FTD and social seeking in semantic dementia. Patients with FTD showed reduced response to pain, whereas patients with semantic dementia more often showed exaggerated reactions to sensory stimuli. Gluttony and indiscriminate eating were characteristic of FTD, whereas patients with semantic dementia were more likely to exhibit food fads. Hyperorality, involving inedible objects, was unrelated to gluttony, indicating different underlying mechanisms. Repetitive behaviours were common in both FTD and semantic dementia, but had a more compulsive quality in semantic dementia. Behavioural differences were greater between semantic dementia and FTD-A than FTD-D. A logistic regression analysis indicated that emotional and repetitive, compulsive behaviours discriminated FTD from semantic dementia with 97% accuracy. CONCLUSION: The findings confirm predictions regarding behavioural differences in frontotemporal and semantic dementia and point to differential roles of the frontal and temporal lobes in affect, social functioning, eating, and compulsive behaviour.     

Stereotypical movements and frontotemporal dementia.

Stereotypical movements are characteristic of autism or mental retardation but can also occur in patients with dementia, particularly frontotemporal dementia (FTD). In this study, we administered the Abnormal Involuntary Movement Scale (AIMS) to 18 patients with FTD and to 18 patients with the most common form of dementia, Alzheimer's disease (AD). The AIMS scores were gathered at the initial presentation of patients who had not received antipsychotic medications. Compared to the AD patients, the FTD patients had significantly more stereotypical movements, including frequent rubbing behaviors and some self-injurious acts. All the FTD patients with stereotypical movements had compulsive-like behaviors, suggesting a similar pathophysiologic cause, and most had a decrease in their stereotypical movements with the administration of sertraline, a serotonin selective reuptake inhibitor.     

A review of the literature on neuroimaging of serotoninergic function in Alzheimer’s disease and related disorders

Summary Behavioural and psychological disorders are frequent not only in frontotemporal dementia (FTD), but also in Alzheimer’s disease (AD), and many of them are related to serotoninergic dysfunction. In vitro biochemical measurements on brain samples show both pre- and post-synaptic impaired brain serotoninergic function in degenerative dementia, sometimes related to hyperactivity or aggressive behaviour. To date, few studies have explored in vivo 5HT2A and 5HT1A brain receptors in AD and FTD. They suggest that brain cells are lost in the associative cortices (5HT2A) and hippocampus (5HT1A) of AD patients, and in the medial prefrontal and orbitofrontal cortices of FTD subjects (5HT2A). Apart from reflecting a loss of local neurons, the meaning of the decrease in 5HT receptors is not yet clear and larger populations are required to establish relationships with clinical symptoms such as dementia severity and search for possible consequences for patients’ behavioural and affective status.     

Support to family carers of patients with frontotemporal dementia

Objectives: To examine the provision of support to patients with frontotemporal dementia (FTD) and their family carers compared with patients with early onset Alzheimer's dementia (AD) and their carers, and the carers' satisfaction with the support. Method: Data came from 60 dyads of patients with dementia and their principal family carers, 23 subjects with frontotemporal dementia and their 23 carers, and 37 subjects with early onset Alzheimer's disease and their 37 carers. Results: Patients with a frontotemporal dementia diagnosis were significantly more frequently offered stays in nursing homes (p = 0.04). Carers of patients with frontotemporal dementia were significantly less satisfied with the provision of information about the disease compared with carers of early onset Alzheimer's disease patients (p = 0.05) and were significantly less satisfied with counseling and follow-up advice (p = 0.05). Conclusion: Changes of personality in patients with frontotemporal dementia may be the major reason why they were offered more stays in institutions. These family carers tend to be less satisfied with the provision of support they received from the specialist health service compared to carers of Alzheimer's disease patients, and are in need of more, and other forms of support.     

Frontal Behavioural Inventory in the differential diagnosis of dementia

Objective –  To evaluate diagnostic properties of the Frontal Behavioural Inventory (FBI) in patients suffering from different forms of dementia.
Methods –  The FBI was administered with other psychometric tests investigating cognitive performances and behavioral scales to the caregivers of 35 patients with the frontal variant of frontotemporal dementia (fv-FTD), 22 patients with Alzheimer's disease (AD) and 15 with vascular dementia (VaD). All patients were comparable for degree of dementia severity and level of executive impairment.
Results –  The FBI showed high concurrent validity, internal consistency and good inter-rater and test–retest reliability. The discriminant validity was also very high. A new FBI cut-off score of 23 gave 97% sensitivity and 95% specificity in distinguishing fv-FTD from non-FTD patients. Conversely, the Neuropsychiatic Inventory (NPI) score was unable to differentiate fv-FTD from AD.
Conclusions –  The FBI is a neurobehavioral tool suitable to distinguish fv-FTD from other forms of dementia also when data from cognitive testing or other behavioral scales fail to support the differential diagnosis.     

Evaluation of the NINCDS-ADRDA criteria in the differentiation of Alzheimer's disease and frontotemporal dementia

OBJECTIVES: The diagnosis of Alzheimer's disease (AD) is now reliant on the use of NINCDS-ADRDA criteria. Other diseases causing dementia are being increasingly recognised--for example, frontotemporal dementia (FTD). Historically, these disorders have not been clearly demarcated from AD. This study assesses the capability of the NINCDS-ADRDA criteria to accurately distinguish AD from FTD in a series of pathologically proved cases. METHODS: The case records of 56 patients (30 with AD, 26 with FTD) who had undergone neuropsychological evaluation, brain imaging, and ultimately postmortem, were assessed in terms of whether at initial diagnosis the NINCDS-ADRDA criteria were successful in diagnosing those patients who had AD and excluding those who did not. RESULTS: (1) The overall sensitivity of the NINCDS-ADRDA criteria in diagnosing "probable" AD from 56 patients with cortical dementia (AD and FTD) was 0.93. However, the specificity was only 0.23; most patients with FTD also fulfilled NINCDS-ADRDA criteria for AD. (2) Cognitive deficits in the realms of orientation and praxis significantly increased the odds of a patient having AD compared with FTD, whereas deficits in problem solving significantly decreased the odds. Neuropsychological impairments in the domains of attention, language, perception, and memory as defined in the NINCDS-ADRDA statement did not contribute to the clinical differentiation of AD and FTD. CONCLUSION: NINCDS-ADRDA criteria fail accurately to differentiate AD from FTD. Suggestions to improve the diagnostic specificity of the current criteria are made.     

Psychiatric symptoms and their psychosocial consequences in frontotemporal dementia

Based on a retrospective study of 19 neuropathologically verified cases with frontotemporal dementia (FTD), neuropsychiatric symptoms related to behavioral disturbances and their psychosocial consequences were studied. The results indicate that frontotemporal dementia is often misdiagnosed early in the clinical course. Behavioural features with impaired social interactions, impaired personal regulation, and loss of insight were seen in all patients. The psychosocial consequences reported in this paper challenge future research in frontotemporal dementia.     

Changes in dietary or eating behavior in frontotemporal dementia versus Alzheimer's disease

BACKGROUND: Changes in dietary or eating behavior are common in dementia and may help distinguish between different dementing illnesses. Objective: To evaluate and characterize differences in dietary and eating behavior among patients with early frontotemporal dementia (FTD) versus Alzheimer's disease (AD). METHODS: This study administered the Food-Related Problems Questionnaire (FRPQ) to caregivers of 16 patients with FTD and 16 comparable patients with AD. The FRPQ was evaluated at initial presentation when patients presented for a diagnostic evaluation. RESULTS: Compared with the AD patients, the FTD patients had significantly more changes on the FRPQ. Subscale analysis indicated that the FTD patients showed impairment of observed satiety, improper taking of food, and inappropriate responses when food was not available. CONCLUSIONS: The use of food-related questionnaires, such as the FRPQ, can help distinguish FTD patients, early in their course, from those with AD and can further characterize the altered dietary and eating behavior.     

Quantitative and qualitative analyses of clock drawing in frontotemporal dementia and Alzheimer's disease.

The clock drawing test (CDT) is a widely used cognitive screening test. It is useful in identifying focal lesions and cognitive deficits in dementia groups. Lately, several studies attempted its use to differentiate between dementia subtypes. Although many studies have examined the CDT in dementia populations, research into the use of clock drawing in frontotemporal dementia (FTD) is limited. We examined quantitative (global) and qualitative (specific error type) differences on the CDT between FTD (n = 36) and Alzheimer's disease (AD; n = 25) patients and controls without dementia (n = 25). Results showed significantly lower overall scores in the dementia groups compared to the control group, whereas FTD patients scored significantly higher than the AD group. On qualitative analysis, the FTD group had fewer stimulus bound responses, conceptual deficits, and spatial or planning errors compared to the AD group. In conclusion, both global and error analysis of the CDT helped discriminate the FTD group from controls and AD patients.     

Confabulation, but not executive dysfunction discriminate AD from frontotemporal dementia

We examined confabulation and performance on frontal/executive tasks in Alzheimer's disease (AD) patients and patients with a diagnosis of probable frontotemporal dementia (FTD). Twenty-two patients with probable AD, 10 patients with probable FTD and 32 normal control subjects entered the study. Executive functions were assessed with the Modified Card Sorting test; a verbal fluency test; the Cognitive Estimation test; and the Stroop test. Confabulations were assessed with a modified version of the Confabulation Battery. The Confabulation Battery included 10 questions tapping each of the following domains: Episodic Memory (memories of personal past episodes), Semantic Memory (knowledge of famous facts and famous people), and Personal Future (personal plans). The results revealed that both AD patients and FTD patients were clearly and equally impaired on tests of executive functions. Both patients' groups confabulated across the three tasks of the Confabulation Battery, but FTD patients confabulated significantly more than AD patients on Episodic Memory and Personal Future. The results failed to provide any evidence of a correlation between the performance on frontal/executive tasks and the tendency to produce confabulatory reports. According to our results, confabulation, more than a deficit of frontal/executive functions, discriminate between AD and FTD. Therefore, screening for confabulation and, possibly, for other types of memory distortions may constitute a useful additional clinical tool in order to discriminate AD from FTD.     

Frontal assessment battery and differential diagnosis of frontotemporal dementia and Alzheimer disease

BACKGROUND: The different distribution of pathologic features in frontotemporal dementia (FTD) and Alzheimer disease (AD) predicts a predominant dysexecutive syndrome in FTD. The Frontal Assessment Battery (FAB) has previously been validated in diseases associated with a frontal lobe dysfunction. OBJECTIVE: To evaluate the sensitivity of the FAB to differentiate FTD and AD. DESIGN: Comparison study. SETTING: Memory Clinic of the Salpêtrière Hospital, Paris, France. PATIENTS: Twenty-six patients with FTD and 64 patients with AD. MAIN OUTCOME MEASURES: Comparison of FAB and Mini-Mental State Examination (MMSE) scores between patients with FTD and those with AD. RESULTS: The mean +/- SD FAB scores significantly differed between patients with FTD (7.6 +/- 4.2) and those with AD (12.6 +/- 3.7) (P<.001), but not MMSE scores. The FAB correctly identified 78.9% of the patients. These results were maintained in a subgroup of mildly demented patients (MMSE score, > or =24). In these patients, a cutoff score of 12 on the FAB was optimal to differentiate both disorders (sensitivity, 77%; specificity, 87%). CONCLUSIONS: The FAB takes less than 10 minutes to administer and provides an objective measure to distinguish FTD from AD in mildly demented patients.     

Neuropsychiatric symptoms in dementia-frequency, relationship to dementia severity and comparison in Alzheimer's disease, vascular dementia and frontotemporal dementia

Noncognitive behavioral and psychiatric disturbances are common in dementia and help in the clinical differentiation of the various subtypes. We studied the frequency of neuropsychiatric disturbances, their relationship to dementia severity and compared these disturbances in Alzheimer's disease (AD), vascular dementia (VaD) and frontotemporal dementia (FTD) using the 12-item Neuropsychiatric Inventory (NPI). A total of 98 patients (AD-44, VaD-31, FTD-23) were evaluated. All subjects were community dwelling at the time of evaluation. The three groups were comparable on global dementia severity and functional ability. All patients had clinically significant scores on the NPI with apathy, irritability and agitation being very common (>90% of patients). AD and VaD patients in Clinical Dementia Rating (CDR) stage 2 had significantly higher scores on the total NPI, agitation and disinhibition subscales compared to those in CDR stage 1. Mean scores in the domains of aberrant motor behavior, disinhibition and appetite/eating behavior differentiated FTD from AD and VaD. Neuropsychiatric disturbances in dementia appear to be universal with agitation, disinhibition and irritability being more frequent in the later stages. In this cohort disinhibition, aberrant motor behavior and appetite/eating disturbances could reliably differentiate AD and VaD from FTD. There were no significant differences between the neuropsychiatric profiles of AD and VaD.     

Comparison of polysomnographic variables and their relationship to cognitive impairment in patients with Alzheimer's disease and frontotemporal dementia

Polysomnograhic (PSG) studies in Alzheimer’s disease (AD) show REM sleep abnormalities, which may be indicative for the deterioration of cholinergic pathways and probably closely linked to declarative memory impairment. To clarify the specificity of the association between sleep and cognitive impairment in dementia, we compared AD patients with patients suffering from frontotemporal dementia (FTD) with regard to PSG and neuropsychological variables. 15 AD and 6 FTD patients underwent polysomonography and a neuropsychological battery (CERAD-NB). Group differences (age: AD > FTD; education level: AD < FTD) were considered as covariates. Polysomnography revealed a trend towards increased REM latency and reduced REM sleep in AD, as well as a decrease of stage 2 sleep, however, at least partly due to effects of age. Declarative memory was more impaired in AD than in FTD, but this difference disappeared when adjusted for covariates. While no relationship was found between REM sleep and CERAD-NB parameters, strong positive correlations between stage 2 sleep and declarative memory measures were observed, which were also detectable when analyzing both groups separately. Based on these results we conclude that REM sleep alterations may be specific for AD, distinguishable from other dementia diagnoses, whereas NonREM stage 2 sleep may be related to declarative memory formation in dementia independent of subtype.