Changes in appetite,food preference,and eating habits in frontotemporal dementia and Alzheimer's disease

BACKGROUND: Despite numerous reports of changes in satiety, food preference, and eating habits in patients with frontotemporal dementia, there have been few systematic studies. OBJECTIVES: To investigate the frequency of changes in eating behaviours and the sequence of development of eating behaviours in frontotemporal dementia and Alzheimer's disease, using a caregiver questionnaire. METHODS: Three groups of patients were studied: frontal variant frontotemporal dementia (fv-FTD) (n = 23), semantic dementia (n = 25), and Alzheimer's disease (n = 43). Level of education and dementia severity was similar in the three groups. The questionnaire consisted of 36 questions investigating five domains: swallowing problems, appetite change, food preference, eating habits, and other oral behaviours. RESULTS: The frequencies of symptoms in all five domains, except swallowing problems, were higher in fv-FTD than in Alzheimer's disease, and changes in food preference and eating habits were greater in semantic dementia than in Alzheimer's disease. In semantic dementia, the developmental pattern was very clear: a change in food preference developed initially, followed by appetite increase and altered eating habits, other oral behaviours, and finally swallowing problems. In fv-FTD, the first symptom was altered eating habits or appetite increase. In Alzheimer's disease, the pattern was not clear although swallowing problems developed in relatively early stages. CONCLUSIONS: Change in eating behaviour was significantly more common in both of the frontotemporal dementia groups than in Alzheimer's disease. It is likely that the changing in eating behaviours reflects the involvement of a common network in both variants of frontotemporal dementia-namely, the ventral (orbitobasal) frontal lobe, temporal pole, and amygdala.     

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.     

Frontotemporal lobar degeneration – tau as a pied piper?

Frontotemporal lobar degeneration (FTLD) is the second most-common form of cortical dementia in the presenium after Alzheimer disease. Clinically three disease entities can be distinguished: frontotemporal dementia, semantic dementia, and primary progressive aphasia. The underlying neuropathology can be classified into disorders with tau pathology (including Pick disease, corticobasal degeneration, progressive supranuclear palsy, and familial frontotemporal dementia with parkinsonism linked to chromosome 17 – FTDP-17), and into disorders that lack tau abnormalities (including dementia lacking distinctive histology and motor neuron disease inclusion dementia). The recent discovery of tau gene mutations in FTDP-17 brought tau to the center stage, but led to the erroneous trend of collectively grouping all forms of FTLD as tauopathies. However, clinicopathological and genetic studies strongly suggest that the majority of sporadic and familial FTLD cases are not associated with tau pathology and/or tau gene mutations. Furthermore, recent studies have linked several autosomal dominantly inherited familial frontotemporal dementia cases to a variety of gene loci on different chromosomes. Thus, this review is intended to summarize our current knowledge about the sporadic and familial FTLD disorders that lack tau pathology, and shall further strengthen the view that FTLD is heterogeneous, both in terms of clinicopathological phenotypes as well as genetic backgrounds. Electronic Publication     

Dysphagia and videofluoroscopic examination of swallowing in patients with severe motor and intellectual disabilities, and the results of dysphagia rehabilitation for these patients

A dysphagia rehabilitation team at National Ehime Hospital treated fifty-seven patients with severe motor and intellectual disabilities suspected of having dysphagia. The rehabilitation team graded the degree of dysphagia by observing the patients at mealtimes. The grades were compared with the videofluoroscopic examination of swallowing results. There was some correlation with the dysphagia grades and videofluoroscopic examination of swallowing results (solid food:p = - 0.434, n =54, p < 0.0001, liquid:p = - 0.482, n = 54, p = 0.005). There were cases in which manifestations of severe dysphagia such as retention of solid food in the pharynx could only be detected on videofluoroscopic examination of swallowing. Dietary manipulation allowed shortening of the time taken at mealtimes for some patients. The dysphagia rehabilitation was useful in many cases in decreasing the number of days with fever, and improving the eating functional level, but the results as a whole were not statistically significant.     

EEG abnormalities in frontotemporal lobar degeneration

The EEG appearances in patients with frontotemporal lobar degeneration (FTLD) were compared with those in patients with Alzheimer disease (AD). EEG abnormalities were found in 61% of FTLD patients, with the degree of EEG abnormality increasing with dementia severity. There was no significant difference in the severity of EEG abnormality between the FTLD and AD patient groups. These data suggest a need for reappraisal of the role of the EEG in the diagnostic differentiation of FTLD from AD.     

Stereotyped behaviors and compulsive complaints of pain improved by fluvoxamine in two cases of frontotemporal dementia]

There have been no systematic efforts to manage and treat patients with frontotemporal dementia (FTD), but Perry described pharmacologic interventions for some behavioral syndromes in 2001. In Perry's report, selective serotonin reuptake inhibitors (SSRI) were recommended as first choice drugs because they were well tolerated and might have an effect on some symptoms such as compulsive symptoms and eating abnormalities. Some reports were presented concerning Japanese FTD patients which showed the effect of SSRI on stereotyped behaviors and eating abnormalities by Nishikawa, et al. (2001), Ikeda, et al. (2004), and others. We describe two FTD patients with compulsive complaints of pain, one mainly on abdomen and the other on lumbar region. Fluvoxamine markedly improved their complaints of pain as well as stereotyped symptoms. Fluvoxamine might be effective for behavioral disturbances due to improvement of serotoninergic dysfunction in frontal medial and cingulated cortices, as previously described. Moreover, it has been reported that an altered response to pain stimuli, either via a loss of awareness of pain or exaggerated reaction to pain, is a specific feature of FTD, but there have been only a few reports on this feature. Fluvoxamine might be effective for compulsive complaints of pain due to improvements of compulsive symptoms and exaggerated reactions to pain in FTD, or due to the analgesic effect of SSRI. SSRI may improve compulsive complaints of pain in FTD patients.     

Frontotemporal dementia: clinicopathological correlations

OBJECTIVE: Frontotemporal lobar degeneration (FTLD) is characterized by impairments in social, behavioral, and/or language function, but postmortem studies indicate that multiple neuropathological entities lead to FTLD. This study assessed whether specific clinical features predict the underlying pathology. METHODS: A clinicopathological correlation was performed on 90 consecutive patients with a pathological diagnosis of frontotemporal dementia and was compared with an additional 24 cases accrued during the same time period with a clinical diagnosis of FTLD, but with pathology not typically associated with frontotemporal dementia. RESULTS: Postmortem examination showed multiple pathologies including tauopathies (46%), FTLD with ubiquitin-positive inclusions (29%), and Alzheimer's disease (17%). The pathological groups manifested some distinct demographic, clinical, and neuropsychological features, although these attributes showed only a statistical association with the underlying pathology. FTLD with ubiquitin-positive inclusions was more likely to present with both social and language dysfunction, and motor neuron disease was more likely to emerge in these patients. Tauopathies were more commonly associated with an extrapyramidal disorder. Alzheimer's disease was associated with relatively greater deficits in memory and executive function. INTERPRETATION: Clinical and neuropsychological features contribute to delineating the spectrum of pathology underlying a patient diagnosed with FTLD, but biomarkers are needed that, together with the clinical phenotype, can predict the underlying neuropathology.     

Unusual clinical presentation and neuropathology in two subjects with fused‐in sarcoma (FUS) positive inclusions

We report two unusual autopsy cases with frontotemporal lobar degeneration (FTLD) that were hyperphosphorylated‐tau‐ and TAR DNA binding protein 43 (TDP‐43)‐ negative. The behavioral symptoms in both cases were compatible with frontotemporal dementia, but they exhibited more prominent speech and language related symptoms than previously reported. Moreover, they displayed a short duration of the disease; the male case had a disease onset age of 45 years, and duration of 5 years, and the female case suffered even shorter disease duration and a later onset of the symptoms, at the age of 67 years. Moreover, the motor functions had deteriorated in different ways in these cases. The male patient showed progressive motor symptoms, weakness of extremities and bulbar muscles suggesting motor neuron disease with a muscle biopsy supporting neurogenic deficits, whereas the female patient exhibited dyskinesias and tremor with progressive swallowing disorders. The father of the male case displayed dementia of similar type at the age of 68 years. In both cases, neuropathological examination showed fused‐in sarcoma (FUS)‐positive pathology. The male patient had intensely FUS‐positive cytoplasmic and intranuclear inclusions that resembled the characteristics previously reported in FTLD FUS, whereas the female patient did not exhibit any cytoplasmic inclusions but had roundish, dense FUS‐positive intranuclear inclusions. She also displayed a plethora of other pathologies including α‐synuclein, hyperphosphorylated‐tau, β‐amyloid aggregation and some neuronal polyglutamine aggregation (1C2) but no well‐demarcated inclusions were observed. We conclude that clinical phenotypes of FUS pathologies also include elderly patients and are more variable with motor and speech disorders than previously reported.     

The FTLD‐modified Clinical Dementia Rating scale is a reliable tool for defining disease severity in Frontotemporal Lobar Degeneration: evidence from a brain SPECT study

Background: Frontotemporal Lobar Degeneration (FTLD) is a heterogeneous disorder characterized by impairment in executive functions, behavioural disturbance and language deficit. Reliable scales of global impairment are under evaluation. A consortium of Mayo Clinic and University of California FTLD Centers has recently developed the FTLD‐modified Clinical Dementia Rating (CDR) scale to assess FTLD severity. Objective: To evaluate whether FTLD‐modified CDR scores correlate with the pattern and degree of brain SPECT hypoperfusion in patients with FTLD. Methods: Ninety‐nine patients with FTLD entered the study. Patients underwent a clinical evaluation and a wide standardized neuropsychological assessment, including mini‐mental state examination (MMSE) and FTLD‐modified CDR. A brain SPECT perfusion imaging study was carried out in each patient. A linear correlation analysis between frontotemporal dementia‐modified CDR or neuropsychological tests scores and perfusion data was performed. Results: There was a significant relationship between higher FTLD‐modified CDR score and lower global regional cerebral blood flow in the frontal and temporal lobes, bilaterally. No significant correlation between MMSE and brain frontotemporal hypoperfusion was found. The correlation between brain hypoperfusion pattern and neuropsychological test scores tapping different cognitive domains fitted with previously published data. Conclusions: The recently introduced FTLD‐modified CDR scale correlates with the degree of frontotemporal hypoperfusion in patients with FTLD. This study confirms and further supports the usefulness of FTLD‐modified CDR in future clinical trials to monitor disease progression.     

Hippocampal atrophy on MRI in frontotemporal lobar degeneration and Alzheimer's disease

BACKGROUND: Hippocampal atrophy on magnetic resonance imaging (MRI) is an early characteristic of Alzheimer's disease. However, hippocampal atrophy may also occur in other dementias, such as frontotemporal lobar degeneration (FTLD). OBJECTIVE: To investigate hippocampal atrophy on MRI in FTLD and its three clinical subtypes, in comparison with Alzheimer's disease, using volumetry and a visual rating scale. METHODS: 42 patients with FTLD (17 frontotemporal dementia, 13 semantic dementia, and 12 progressive non-fluent aphasia), 103 patients with Alzheimer's disease, and 73 controls were included. Hippocampal volumetry and the easily applicable medial temporal lobe atrophy (MTA) rating scale were applied to assess hippocampal atrophy. RESULTS: Multivariate analysis of variance for repeated measures showed an effect of diagnostic group on hippocampal volume. There was a significant diagnosis by side (left v right) interaction. Both FTLD and Alzheimer's disease showed hippocampal atrophy compared with controls. Results of the visual MTA rating scale confirmed these findings. Within the FTLD subtypes there were marked differences in hippocampal atrophy. Frontotemporal dementia and semantic dementia showed bilateral hippocampal atrophy, and in semantic dementia the left hippocampus was smaller than in Alzheimer's disease. No significant hippocampal atrophy was detected in non-fluent progressive aphasia. CONCLUSIONS: Hippocampal atrophy is not only a characteristic of Alzheimer's disease but also occurs in FTLD. The three clinical subtypes of FTLD show different patterns of hippocampal atrophy.     

Utility of clinical criteria in differentiating frontotemporal lobar degeneration (FTLD) from AD

OBJECTIVE: To assess the ability of the current diagnostic criteria for frontotemporal lobar degeneration (FTLD) to differentiate FTLD from AD. METHODS: Thirty cases with autopsy-proven FTLD and 30 cases of AD, matched for Mini-Mental State Examination score, were identified from the clinical databases of three dementia subspecialty centers, and their charts were reviewed for the presence of clinical features described in the current criteria for FTLD. The proportion of patients with each clinical feature at the first clinical presentation was compared across groups. RESULTS: A significantly larger proportion of patients with FTLD showed behavioral abnormalities, particularly social and personal conduct disorders and emotional blunting, than patients with AD. Few differences in language features were seen between the groups, and many of the language features detailed in the criteria were found in only a small proportion of patients. In both groups, many patients showed neuropsychological abnormalities, except for perceptual difficulties, which were present in many patients with AD but only in a few patients with FTLD. Extrapyramidal motor symptoms were more likely to be present in FTLD. Logistic regression revealed that five features-social conduct disorders, hyperorality, akinesia, absence of amnesia, and the absence of a perceptual disorder-correctly classified 93% of patients with FTLD and 97% of patients with AD. CONCLUSION: A combination of behavioral, neuropsychological, and physical findings is most useful in distinguishing FTLD from AD. Future studies should be directed at establishing more objective methods of identifying these clinical features.     

You stole my food! Eating alterations in frontotemporal dementia

ABSTRACT

Patients with different types of dementia may exhibit pathological eating habits, including food fads, hyperphagia, or even ingestion of inanimate objects. Several findings reveal that such eating alterations are more common in patients with frontotemporal dementia (FTD) than other types of dementia. Moreover, eating alterations may differ between the two variants of the disease, namely the behavioral variant and semantic dementia (SD). In this review, we summarized evidences regarding four areas: eating and body weight alterations in FTD, the most common assessment methods, anatomical correlates of eating disorders, and finally, proposed underlying mechanisms. An increasing understanding of the factors that contribute to eating abnormalities may allow first, a better comprehension of the clinical features of the disease and second, shed light on the mechanism underlying eating behaviors in the normal population.     

Epidemiology of frontotemporal lobar degeneration

A few epidemiologic studies have dealt with the prevalence of frontotemporal lobar degeneration (FTLD), including Pick's disease. The aim of this study was to review the epidemiologic studies of FTLD in western countries and to compare them with those in Japan. A community-based study of early-onset dementia in London revealed that 12% of cases with frontotemporal dementia (FTD) fulfilled the Lund-Manchester criteria in contrast to 34% of cases with Alzheimer's disease (AD) in a sample of 185 cases. The Cambridge Group has recently examined the prevalence of early-onset dementia in a community-based study. Of 108 cases, 15.7% had FTLD and 25% had AD. FTLD included 13 FTD cases, and 2 each with semantic dementia (SD) and nonfluent progressive aphasia (PA). Almost one third of cases with FTLD (29%) had a positive family history. Of our consecutive 330 outpatients with dementia (hospital setting without age limitation), 42 (12.7%) had FTLD and 215 (65.1%) had AD. In our series of patients, 22 FTD, 15 SD and 5 PA cases were identified. There was no family history in all subtypes of FTLD. Epidemiologic studies, both community-based and hospital-based, demonstrate that FTLD is a more common cause of early-onset dementia than previously recognized. Regarding the subtypes of FTLD, in Japan, compared with the data from the UK, FTD is less common, SD may be more common and PA is equally common. The reason for this discrepancy is supposed to be mainly based on the role of heredity.     

Serum leptin levels are higher in females affected by frontotemporal lobar degeneration than Alzheimer's disease

Frontotemporal lobar degeneration (FTLD) includes different heterogeneous conditions, mainly characterised by personality changes, along with cognitive deficits in language and executive functions. Movement disorders are variably represented. Behavioural disturbances constitute the core feature of FTLD, and eating disorders represent one of the most distinguishing symptoms between FTLD and Alzheimer's disease (AD). The biochemical correlates of such dysfunctions remain to be defined. The adipocyte derived hormone leptin is known to play a foundamental role in food intake and energy balance. To understand whether leptin could be involved in FTLD eating abnormalities, we measured serum leptin levels in 59 patients with FTLD compared with 25 with AD. Serum leptin levels in patients with FTLD were comparable with those in patients with AD. Nevertheless, females with FTLD showed significantly higher leptin levels compared with females with AD. No difference was found between FTDL and AD males or within the spectrum of patients with FTLD. Hyperphagic FTLD females showed higher circulating leptin levels in comparison with those without eating abnormalities; no differences were found between males with FTLD with respect to serum leptin and food intake disturbances. The present study showed a selective gender difference in leptin levels between females with FTLD and AD, which may suggest specific cognitive and behavioural networks need to be investigated.     

Screening for the LRRK2 G2019S and codon-1441 mutations in a pathological series of parkinsonian syndromes and frontotemporal lobar degeneration

BACKGROUND: The neuropathology associated with LRRK2 mutations is heterogeneous but Lewy body (LB) type pathology is the most common substrate encountered. While the prevalence of LRRK2 mutations has been extensively studied in Parkinson's disease (PD), limited information is available on the frequency of LRRK2 mutations in dementia with Lewy bodies (DLB) and in other pathological conditions associated with these mutations, such as non-specific nigral degeneration without LB, tau-immunopositive neurofibrillary tangle pathology, and ubiquitin-positive neuronal inclusions resembling those observed in a subtype of frontotemporal lobar degeneration (FTLD-U). OBJECTIVE: To further investigate the neuropathology associated with LRRK2 mutations. METHODS: We have screened for the LRRK2 G2019S and codon-1441 (R1441G/C/H) mutations in 110 cases from a Spanish Brain Bank, which include: 66 synucleinopathies (33 PD, 25 DLB and 8 multiple system atrophy cases), 29 tauopathies (21 progressive supranuclear palsy, 3 corticobasal degeneration and 5 tau-positive FTLD cases), 3 cases of non-specific nigral degeneration and 12 tau-negative FTLD (9 FTLD-U and 3 dementia lacking distinctive histology cases). RESULTS: The G2019S mutation was found in two cases: One case had a clinical and pathological diagnosis of PD and the other suffered from typical PD and on neuropathological examination had non-specific nigral degeneration without LB. A synonymous variant (R1441R; c.4323C>T) was detected in another PD case. CONCLUSIONS: In this brain bank-based series, LRRK2 G2019S mutation occurred in patients with parkinsonism associated with either typical brainstem LB pathology or non-specific nigral degeneration. LRRK2 mutations were not encountered in other neurodegenerative disorders associated with synuclein and tau deposition.     

Dysphagia in multiple sclerosis - prevalence and prognostic factors

The aim of the study was to analyse swallowing function and to identify reliable prognostic factors associated with dysphagia in a consecutive series of patients with multiple sclerosis (MS). Swallowing examination was performed by means of indirect and direct methods (fiberendoscopic evaluation) in 143 consecutive patients with primary and secondary progressive MS. Dysphagia was found in 49 patients (34.3%). A close relationship with dysphagia was found in the patients with severe brainstem impairment (OR=3.24; 95% CI 1.44-7.31) as compared to the patients without. There was also a significant correlation with pronounced severity of illness (OR=2.99; CI 1.36-6.59). Compensatory strategies were sufficient to resolve the dysphagia in 46 cases (93.8%). The potential risk of aspiration and malnutrition and the high efficacy of swallowing rehabilitation suggests that all MS patients should have a careful evaluation of deglutition functionality, especially those with brainstem impairment and a high grade of disability level.     

Comparison of family histories in FTLD subtypes and related tauopathies

Pedigrees from 269 patients with frontotemporal lobar degeneration (FTLD), including frontotemporal dementia (FTD), FTD with ALS (FTD/ALS), progressive nonfluent aphasia, semantic dementia (SD), corticobasal degeneration, and progressive supranuclear palsy were analyzed to determine the degree of heritability of these disorders. FTD/ALS was the most and SD the least heritable subtype. FTLD syndromes appear to have different etiologies and recurrence risks.     

Hippocampal shape analysis in Alzheimer's disease and frontotemporal lobar degeneration subtypes

Hippocampal pathology is central to Alzheimer's disease (AD) and other forms of dementia such as frontotemporal lobar degeneration (FTLD). Autopsy studies have shown that certain hippocampal subfields are more vulnerable than others to AD and FTLD pathology, in particular the subiculum and cornu ammonis 1 (CA1). We conducted shape analysis of hippocampi segmented from structural T1 MRI images on clinically diagnosed dementia patients and controls. The subjects included 19 AD and 35 FTLD patients [13 frontotemporal dementia (FTD), 13 semantic dementia (SD), and 9 progressive nonfluent aphasia (PNFA)] and 21 controls. Compared to controls, SD displayed severe atrophy of the whole left hippocampus. PNFA and FTD also displayed atrophy on the left side, restricted to the hippocampal head in FTD. Finally, AD displayed most atrophy in left hippocampal body with relative sparing of the hippocampal head. Consistent with neuropathological studies, most atrophic deformation was found in CA1 and subiculum areas in FTLD and AD.     

Semantic dementia with lower motor neuron disease showing FTLD‐TDP type 3 pathology (sensu Mackenzie)

We describe a case of frontotemporal lobar degeneration with semantic dementia and lower motor neuron disease. A 63‐year‐old man presented with the full clinical picture of semantic dementia, including semantic anomia, surface alexia, lexical agraphia, associative agnosia, prosopagnosia and phonagnosia. Flaccid dysarthria, bulbar dysphagia and fasciculations developed 7 years after onset, followed by death within a year. The neuropathological examination showed heavy neuronal loss in the anterior temporal lobe cortex, dorsal vagal and hypoglossal nuclei and anterior horns of the spinal cord. Ubiquitin‐ and TDP‐43‐positive cytoplasmic inclusions were abundant in layer II of affected cortices and in granular cells of the hippocampal dentate gyrus, whereas dystrophic neurites were sparse and intranuclear inclusions absent. It is concluded that FTLD‐TDP type 3 can be associated with semantic dementia and lower motor neuron disease in combination.     

Frontotemporal lobar degeneration: new understanding brings new approaches

Frontotemporal dementia (FTD) describes a group of clinical syndromes united by underlying frontotemporal lobar degeneration (FTLD) pathology. The clinical syndromes associated with FTLD are heterogeneous and are based on whether the patients present with behavioral, language, or motor impairments. FTLD is at the center of a paradigm shift in neurodegenerative diseases, with thought being given at diagnosis of underlying disease. There is pathologic heterogeneity of certain clinical syndromes such as behavioral variant FTD. Differentiation between the proteinopathies will become imperative as protein-specific treatments become available. This review provides an overview of FTLD, with an update of recent discoveries.