The Stereotypy Rating Inventory for frontotemporal lobar degeneration

A many behavioral disturbances, Stereotypic behaviors are among the best discriminators of Frontotemporal Lobar Degeneration (FTLD). A recent preliminary report suggests many of the behavioral symptoms, including stereotypic behaviors in FTLD patients, respond to medication with selective serotonin re-uptake inhibitors. However, there is no scale that evaluates stereotypic behaviors comprehensively. To assess the wide range of stereotypic behaviors encountered in FTLD, we developed a new instrument, the Stereotypy Rating Inventory (SRI). The SRI assesses five distinctive stereotypic behavioral disturbances often seen in patients with FTLD: eating and cooking behaviors, roaming, speaking, movements, and daily rhythm. The SRI uses the same technique as the Neuropsychiatric Inventory (NPI) in that both the frequency and the severity of each behavior are determined. The studies reported here demonstrate the content and concurrent validity, as well as inter-rater and test-retest reliability, of the instrument. Scores of FTLD patients (n=26) on the SRI were much higher than those of patients with Alzheimer's disease (n=46), patients with vascular dementia (n=26), and normal control subjects (n=40). The SRI appears to be a useful instrument for detecting stereotypic behaviors and monitoring of therapies in FTLD patients.     

TDP-43 in Alzheimer’s disease is not associated with clinical FTLD or Parkinsonism

Widespread deposition of TAR DNA-binding protein of 43 kDa (TDP-43), a major protein inclusion commonly found in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) can also be seen in a subset of cases with Alzheimer’s disease (AD). Some of these AD cases have TDP-43 immunoreactivity in basal ganglia (BG) and substantia nigra (SN), regions that when affected can be associated with parkinsonian signs or symptoms, or even features suggestive of frontotemporal dementia. Here, we examined the presence of clinical features of FTLD, parkinsonian signs and symptoms, and BG atrophy on MRI, in 51 pathologically confirmed AD cases (Braak neurofibrillary tangle stage IV–VI) with widespread TDP-43 deposition, with and without BG and SN involvement. All 51 cases had presented with progressive cognitive impairment with prominent memory deficits. None of the patients demonstrated early behavioral disinhibition, apathy, loss of empathy, stereotyped behavior, hyperorality, and/or executive deficits. Furthermore, TDP-43 deposition in BG or SN had no significant association with tremor (p = 0.80), rigidity (p = 0.19), bradykinesia (p = 0.19), and gait/postural instability (p = 0.39). Volumes of the BG structures were not associated with TDP-43 deposition in the BG. The present study demonstrates that TDP-43 deposition in pathologically confirmed AD cases is not associated with a clinical manifestation suggestive of FTLD, or parkinsonian features.     

Effects of prescribed medications on cognition and behavior in frontotemporal lobar degeneration

A retrospective chart review of 21 patients meeting core clinical criteria for behavioral or aphasic variants of frontotemporal lobar degeneration (FTLD) was conducted. Data recorded included Folstein Mini-Mental State Examination (MMSE) scores, medications prescribed, and subjective reports of behavioral symptoms from each visit. Behaviors were graded on a scale from 1 to 3 and totaled for each visit. Changes in MMSE and behavior scores between visits 1 month and 6 months apart where a new medication was started were analyzed using a paired t test and were compared between medication classes using an unpaired t test. Acetylcholinesterase inhibitors (AChEIs) were associated with a decrease in MMSE scores by 1.6 (P = .02) and an increase in total behavior scores by 1.0 (P = .03). Mean MMSE and behavior scores were statistically more improved by selective serotonin reuptake inhibitors than AChEIs (P = .04). This data suggest a potential worsening of objective measures of cognitive and behavioral symptoms in FTLD with AChEI treatment.     

Difficulties in detecting behavioral symptoms of frontotemporal lobar degeneration across cultures

Cross-cultural studies of neurodegenerative disorders are especially important when the disease in question is difficult to diagnose, particularly if symptoms of the illness include behavioral disturbances that may be interpreted differently in different cultures. One such disease is frontotemporal lobar degeneration (FTLD), an early-age-of-onset dementia that disproportionately affects social behavior. We report the demographic and neuropsychologic characteristics of more than 300 patients diagnosed with FTLD in the United States, Greece, and Turkey. We find that patients with the frontal variant of frontotemporal dementia (FTD) are diagnosed at an earlier age and report earlier symptom onset in the United States than in Greece or Turkey. Furthermore, neuropsychologic measures indicate that at diagnosis, FTD patients in the United States are less impaired than patients in Greece and Turkey. Patients with FTD in Greece and Turkey are diagnosed later in the disease, presumably because their behavioral symptoms are not easily detected by the medical system in these countries. Our study underscores the need to create culturally appropriate indices of the behavioral symptoms of FTLD, so that patients may be diagnosed and treated at an earlier stage.     

Behavioral variant of frontotemporal dementia: Fundamental clinical issues associated with prediction of pathological bases

Behavioral variant of frontotemporal dementia (bvFTD) is a clinical syndrome characterized mainly by behavioral symptoms due to frontal dysfunction. Major neurodegenerative bases of bvFTD include Pick's disease, frontotemporal lobar degeneration with trans‐activation response DNA protein 43‐positive inclusions, corticobasal degeneration, and progressive supranuclear palsy. Early disinhibition characterized by socially inappropriate behaviors, loss of manners, and impulsive, rash and careless actions is the most important clinical feature of bvFTD. On the other hand, it was reported that clinical presentations of some Alzheimer's disease cases and patients with psychiatric disorders (e.g., addictive disorders, gambling disorder and kleptomania) often resemble that of bvFTD. Although clinical differentiation of ‘true’ bvFTD cases with frontotemporal lobar degeneration (FTLD) pathology from mimicking cases without it is not always easy, evaluation of the following features, which were noted in autopsy‐confirmed FTLD cases and/or clinical bvFTD cases with circumscribed lobar atrophy, may often provide clues for the diagnosis. (i) The initial symptoms frequently develop at 65 years or younger, and (ii) ‘socially inappropriate behaviors’ can be frequently interpreted as contextually inappropriate behaviors prompted by environmental visual and auditory stimuli. Taking a detailed history usually reveals various kinds of such behaviors in various situations in everyday life rather than the repetition of a single kind of behavior (e.g., repeated shoplifting). (iii) A correlation between the distribution of cerebral atrophy and neurological and behavioral symptoms is usually observed, and the proportion of FTLD cases with right side‐predominant cerebral atrophy may be higher in a psychiatric setting than a neurological setting. Finally, (iv) whether the previous course and the combination of symptoms observed at the first medical visit can be explained by major evolution patterns of clinical syndromes in pathologically confirmed FTLD cases should be considered. These views may provide clues to differentiate FTLD from Alzheimer's disease and to predict a subsequent clinical course and therapeutic interventions needed in the future.     

Different patterns of magnetic resonance imaging atrophy for frontotemporal lobar degeneration syndromes

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is an uncommon degenerative dementia that presents with focal cognitive and behavioral deficits. OBJECTIVE: To determine the correlation of the different presentations of FTLD with structural neuroimaging findings. DESIGN AND PATIENTS: In a blinded study, we retrospectively evaluated the clinical presentations and magnetic resonance imaging (MRI) patterns of atrophy in 59 patients with FTLD and 26 patients with probable Alzheimer disease at a memory disorders clinic. RESULTS: Analysis of variance revealed a significant difference in the patterns of atrophy in the FTLD and Alzheimer disease groups. Patients with FTLD presenting with altered personal conduct had significant bifrontal atrophy, whereas patients presenting with semantic dementia had significant left temporal and bifrontal atrophy compared with other groups. Disinhibited behavior and hyperphagia correlated with right frontal atrophy, and fluent, anomic aphasia correlated with left temporal atrophy. CONCLUSIONS: We found that the type of clinical presentation of FTLD correlates with specific areas of atrophy. Our method of analysis may be useful to elicit further anatomic-behavioral relationships in degenerative brain disorders.     

Initial symptoms, survival and causes of death in 115 patients with frontotemporal lobar degeneration

The early and differential diagnosis of the clinical phenotypes of frontotemporal lobar degeneration (FTLD), including frontotemporal dementia (FTD), semantic dementia (SD) and non-fluent progressive aphasia (NFPA), can be challenging. It may be difficult not only to differentiate these conditions from normal aging, psychiatric disorders, and other dementias, but also to distinguish between them. For early diagnosis, information on the initial and presenting symptoms of the FTLD phenotypes is essential. In the present study caregivers of 78 patients with FTD, 20 patients with SD and 17 patients with PA were interviewed about initial symptoms. In patients with FTD, the most frequent initial symptoms were alterations of personality, followed by forgetfulness and word finding difficulty. Patients with SD presented with word finding difficulty and behavioral disturbances. Almost all patients with PA developed word finding difficulty as the first manifestation of their disorder. Diagnostic latency - the time from disease onset to diagnosis was 4.1 years in FTD, 4.2 years in SD and 3.1 years in PA. Caregivers, and in some cases also patients, should be educated about the likely course and mortality of FTLD. To obtain information about survival time and cause of death associated with FTLD we analyzed follow-up data on 106 patients of whom 25 had died. The median survival time from the occurrence of first symptoms was 14 years. Mortality risk was significantly higher in patients with an early disease onset. Causes of death were varied, but pneumonia and sudden unexplained deaths were particularly frequent.     

Behavioral effects of chronic phencyclidine in monkeys.

Phencyclidine (PCP) and other NMDA receptor antagonists such as ketamine induce psychotic symptoms that are difficult to reverse with current medications and which closely resemble those of schizophrenia. This study investigated the behavioral effects of continuous PCP administration in six socially-housed Cebus apella monkeys. Chronic treatment was associated with a sustained decrease in stereotyped locomotion (pacing) and a sustained increase in scanning behavior. Treatment was also associated with a modest decrease in self- and environment-directed behavior and goal-directed locomotion and an increase in affiliative behavior at lower doses. Four animals had one or more episodes of extreme motoric and physiological responses precipitated by stressful events. The results indicate that behavioral effects of chronic PCP in primates differ from those seen following acute treatments and represent an appropriate model system for new antipsychotic drug development.     

额颞叶变性的临床及生物学标记物特点

目的探讨额颞叶变性(FTLD)患者的临床、影像以及生物学标记物的特点。方法回顾性分析入组的43例FTLD患者的临床资料,包括一般资料、临床特点、行为-认知量表评分[如蒙特利尔认知评估量表(MoCA)、简易精神状态检查量表(MMSE)、日常活动能力量表(ADL)、额叶行为量表(FBI)、神经精神量表(NPI)和汉密尔顿抑郁量表(HAMD)评分]、头MRI、血APOEε4、尿液Alzheimer相关神经丝蛋白(AD7c-NTP)以及FDG-PET检查结果。结果 FTLD患者早期主要表现为执行功能障碍、行为去抑制;头颅MRI检查结果表现为单/双侧对称(或)不对称性额颞叶萎缩,可伴或不伴海马萎缩;FDG-PET检查结果显示大脑半球前部对称/不对称性葡萄糖低代谢改变;FTLD患者APOEε4等位基因的表达频率为15.12%,尿液AD7c-NTP平均值(3.23±1.78)ng/mL,高于正常值范围(0~1.5ng/mL);P300波的潜伏期不同程度延长,波幅均降低。结论FTLD患者早期临床表现以行为、执行功能障碍多见,也可出现记忆障碍。行为-认知量表和FDG-PET检查可能有助于FTLD诊断。FTLD患者P300波的潜伏期和波幅也可出现变化,可能有助于发现患者记忆、推理功能障碍。FTLD患者也可以出现APOEε4等位基因表达以及尿AD7c-NTP表达的变化。     

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.     

Initial complaints in frontotemporal lobar degeneration

AIMS: Frontotemporal lobar degeneration (FTLD) is probably underrecognized. The goal of this study was to investigate initial complaints of both patients and their caregivers at first specialist referral. Also, we tried to assess whether misrecognition of symptoms contributed to diagnostic delay. METHODS: The case notes of all patients diagnosed with FTLD at the VU University Medical Center, Alzheimer Center of Amsterdam, The Netherlands, since 1998 were retrospectively reviewed. Only patients of whom detailed information of first specialist referral was available were included. The diagnosis of FTLD was based on the clinical diagnostic criteria of Neary and Snowden, supported by ancillary investigations. RESULTS: Forty-six patients with FTLD were included. Twenty-one patients had frontotemporal dementia (FTD), 17 semantic dementia (SD) and 8 progressive nonfluent aphasia (PA). The majority of the FTD patients presented without complaints or with somatic complaints and nearly a quarter of them expressed memory complaints. The presenting complaints of most of their caregivers differed from the patients' complaints and often consisted of cognitive complaints. In SD and PA, language problems but also forgetfulness were presented. Misrecognition of the initial symptoms in some cases seemed to have contributed to diagnostic delay. CONCLUSION: Presenting complaints in FTLD can be misleading. In our cohort, memory complaints occurred relatively often. A multidisciplinary approach, including a structured behavioral interview, is important to recognize symptoms of FTLD.     

Cognitive and behavioral profile in a case of right anterior temporal lobe neurodegeneration

Semantic dementia (SD) is a clinical variant of frontotemporal lobar degeneration (FTLD) characterized by progressive deterioration of semantic memory with relative sparing of other cognitive functions. It is associated with mainly left anterior temporal atrophy, and is also referred to as “left-temporal lobe variant” of FTLD. Recently, patients with mainly right-sided atrophy, or “right-temporal lobe variant”(RTLV), have been described. While some authors have reported that the initial and most significant deficit in these right-sided cases is a difficulty in recognizing famous people, others have observed that major behavioral abnormalities are the presenting symptoms. Here we report a detailed neuropsychological, language, behavioral and neuroimaging assessment of JT, a case of right temporal lobe variant of FTLD. JT showed early and prominent behavioral changes accompanied by a severe impairment in recognizing foods by their look, flavor or name. Later she also developed a difficulty in recognizing familiar people and objects. Standardized caregiver questionnaires of JT's pre- and post-morbid personality and interpersonal functioning showed that she went from being a flexible, dominant, extraverted, person to showing rigid, submissive and introverted behaviors. Her levels of neuroticism significantly increased, while her scores on agreeableness and cognitive and emotional empathy dropped. Voxel-based morphometry (VBM) showed most significant atrophy in the right amygdala/anterior hippocampal complex and collateral sulcus, extending to the right insula. We discuss the atypical cognitive and behavioral features of this case of RTLV of FTLD and stress the importance of behavioral changes and atypical semantic deficits for early diagnosis.     

New therapeutic strategies for behavioral and psychological symptoms of dementia]

Interventional studies, with the aim of reducing the burden of care through drug or non-drug therapies of behavioral and psychological symptoms of dementia (BPSD), have been scarce. However, we are now able to do pharmacological management for BPSD with new drugs such as atypical neuroleptics, SSRIs, and cholinesterase inhibitors. Delusions of theft are one of the most frequently observed BPSD in patients with AD. In addition, the delusions and ensuing aggression and anxiety are major factors that increase the burden of caregivers. Delusions of theft in patients with AD were eliminated or reduced with low-dose atypical neuroleptics (risperidone). This significantly reduced the burden of care overall for caregivers. New therapeutic strategies such as cholinesterase inhibitors for visual hallucinations in DLB and SSRIs for overeating and stereotyped behavior in FTLD might also remarkably reduce the burden of care for these patients. For many dementia patients, there are still no drugs that offer a principal cure. It is, therefore, important to evaluate their BPSD correctly at the earliest possible time, so that the burden of caring can be reduced through appropriate drug treatment. This reduction is critical for the continuation of satisfactory at-home care and might contribute to the health economics.     

Frontotemporal dementias: clinical features and management

This 2-part review of the frontotemporal lobar degeneration (FTLD) begins with an outline of clinical features, which differentiate FTLD from Alzheimer's disease, the more common cause of dementia. The second part describes interventions for FTLD. Although there is currently no disease-modifying therapeutic agent, symptomatic pharmacotherapy helps to control the marked mood and behavioral disturbances that may distinguish this syndrome from other causes of dementia.     

A case study of an emerging visual artist with frontotemporal lobar degeneration and amyotrophic lateral sclerosis

Patients presenting with left-sided FTLD syndromes sometimes develop a new preoccupation with art, greater attention to visual stimuli, and increased visual creativity. We describe the case of a 53-year-old, right-handed man with a history of bipolar disorder who presented with language and behavior impairments characteristic of FTLD, then developed motor symptoms consistent with a second diagnosis of amyotrophic lateral sclerosis. Though the patient had never created visual art before, he developed a compulsion for painting beginning at the earliest stages of his disease, and continued producing art daily until he could no longer lift a paintbrush because of his motor deficits. Upon autopsy, he was found to have ubiquitin and TDP43-positive inclusions with MND pathology. This case study details the patient's longitudinal neuropsychological, emotional, behavioral, and motor symptoms, along with structural imaging, neurologic, and neuropathologic findings. Multiple examples of the patient's art are depicted throughout all stages of his illness, and the possible cognitive, behavioral, and neurologic correlates of his new-onset visual artistry are discussed.     

Enhancing Effects of Sound on Methamphetamine-Induced Behavioral Aberrations in the Rat: A Model of Relapse of Schizophrenia-Like Symptoms

Abstract: Conditioning of methamphetamine (MAP)-induced behavioral aberrations, hyperactivity (HA), stereotyped (SB) and bizarre behavior (BB) in rats were examined using Pavlovian conditioning methods. A speaker-sound (SS) was used as the conditioning stimulus (CS) and MAP-induced behavior as the unconditioned stimulus (UCS). The rats belonging to the Sound Group were repeatedly administered with MAP or saline paired with SS in an observation room and those in the Soundless Group with MAP only in the housing room.
After chronic administration with MAP, conditioned behavioral responses (CBR) such as HA, SB, and BB were observed more intensely in the Sound Group than in the Soundless Group while being subjected to SS. CBR were greatest on the 30th day after the last MAP administration and they did not disappear for 120 days.
CBR were considered as analogous to the spontaneous relapse of schizophrenia-like symptoms.
Furthermore, as a certain behavior which had been conditioned could easily be observed as CBR with both specific (SS) and nonspecific environmental cues (handling), it is difficult to distinguish the withdrawal behavioral effects of MAP that lacks those of CBR.     

MRI signatures of the frontotemporal lobar degeneration continuum

Objective. To identify overlapping and unique grey (GM) and white matter (WM) signatures within the frontotemporal lobar degeneration (FTLD) continuum, and discriminate likely FTLD‐TAU and FTLD‐TDP patients using structural and diffusion tensor (DT) magnetic resonance imaging (MRI). Methods. T1‐weighted and DT MRI were collected from 121 subjects: 35 motor neuron disease (MND), 14 behavioral variant of frontotemporal dementia, 12 semantic and 11 nonfluent primary progressive aphasia, 21 progressive supranuclear palsy syndrome patients, and 28 healthy controls. Patterns of GM atrophy were established using voxel‐based morphometry. Tract‐based spatial statistics was used to perform a WM voxelwise analysis of mean diffusivity and fractional anisotropy. Results. In all clinical FTLD phenotypes, the pattern of WM damage was more distributed than that of GM atrophy. All patient groups, with the exception of MND cases with a pure motor syndrome, shared a focal GM atrophy centered around the dorsolateral and medial frontal cortex and a largely overlapping pattern of WM damage involving the genu and body of the corpus callosum and ventral frontotemporal and dorsal frontoparietal WM pathways. Surrounding this common area, phenotype (symptom)‐specific GM and WM regions of damage were found in each group. Conclusions. In the FTLD spectrum, WM disruption is more severe than GM damage. Frontal cortex and WM pathways represent the common target of neurodegeneration in these conditions. The topographic pattern of damage supports a “prion‐like” protein propagation through WM connections as underlying mechanism of the stereotyped progression of FTLD. Hum Brain Mapp 36:2602–2614, 2015. © 2015 Wiley Periodicals, Inc.     

Enhancing effects of sound on methamphetamine-induced behavioral aberrations in the rat: a model of relapse of schizophrenia-like symptoms

Conditioning of methamphetamine (MAP)-induced behavioral aberrations, hyperactivity (HA), stereotyped (SB) and bizarre behavior (BB) in rats were examined using Pavlovian conditioning methods. A speaker-sound (SS) was used as the conditioning stimulus (CS) and MAP-induced behavior as the unconditioned stimulus (UCS). The rats belonging to the Sound Group were repeatedly administered with MAP or saline paired with SS in an observation room and those in the Soundless Group with MAP only in the housing room. After chronic administration with MAP, conditioned behavioral responses (CBR) such as HA, SB, and BB were observed more intensely in the Sound Group than in the Soundless Group while being subjected to SS. CBR were greatest on the 30th day after the last MAP administration and they did not disappear for 120 days. CBR were considered as analogous to the spontaneous relapse of schizophrenia-like symptoms. Furthermore, as a certain behavior which had been conditioned could easily be observed as CBR with both specific (SS) and nonspecific environmental cues (handling), it is difficult to distinguish the withdrawal behavioral effects of MAP that lacks those of CBR.     

Frontotemporal lobar degeneration: current knowledge and future challenges

Frontotemporal lobar degeneration (FTLD) is one of the most frequent neurodegenerative disorders with a presenile onset. It presents with a spectrum of clinical manifestations, ranging from behavioral and executive impairment to language disorders and motor dysfunction. New diagnostic criteria identified two main cognitive syndromes: behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia. Regarding bvFTD, new criteria include the use of biomarkers. According to them, bvFTD can be classified in “possible” (clinical features only), “probable” (inclusion of imaging biomarkers) and “definite” (in the presence of a known causal mutation or at autopsy). Familial aggregation is frequently reported in FTLD, and about 10?% of cases have an autosomal dominant transmission. Microtubule-associated protein tau gene mutations have been the first ones identified, and are generally associated with early onset (40–50?years) and with the bvFTD phenotype. More recently, progranulin gene mutations were recognized in association with the familial form of FTLD and a hexanucleotide repetition in C9ORF72 has been shown to be responsible for familial FTLD and amyotrophic lateral sclerosis. In addition, other genes are linked to rare cases of familiar FTLD. Lastly, a number of genetic risk factors for sporadic forms have also been identified.