Behavioral changes in frontotemporal dementia with Parkinsonism.
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Aphasia↗
Biomedical subjects
Bruce L Miller
Publications and source records attributed to Bruce L Miller.
Neurologic signs and mobility limitations: a neglected link in the elderly.
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Aged↗
When sporadic disease is not sporadic: the potential for genetic etiology.
BACKGROUND: Approximately 2% of Alzheimer disease cases and 10% to 15% of prion disease cases are due to mutations in autosomal dominant genes. Mutations have been found in patients without family histories of neurological disease. OBJECTIVES: To emphasize the need for consideration of a genetic etiology of prion disease and early-onset Alzheimer disease, regardless of the absence of a significant family history, as well as the need for pretest genetic counseling of all patients or their families. DESIGN: Three case reports. PATIENTS AND RESULTS: Patient 1, a 53-year-old man with possible Creutzfeldt-Jakob disease, was enrolled in a research study that included sequencing of the prion protein gene. Although there was no family history of neurological disease, an E200K mutation was found. This unexpected result caused the family significant distress. Patient 2, a 55-year-old woman with biopsy-proven Creutzfeldt-Jakob disease, participated in a prion disease research study. Her family was counseled about the possibility of hereditary Creutzfeldt-Jakob disease, despite the lack of family history. After assessing the ramifications, the family decided not to learn about the patient's genetic test results. Patient 3 was a 54-year-old man with a 6-year history of memory loss. A diagnosis of probable Alzheimer disease was given, and the patient and his family were counseled on the availability of presenilin 1 testing, although there was no known family history of dementia. The family agreed to testing, and a presenilin 1 mutation was identified. CONCLUSIONS: Certain neurodegenerative diseases may have a genetic etiology, despite the lack of a positive family history. Revealing a newly discovered hereditary cause of Creutzfeldt-Jakob disease or Alzheimer disease can have a profound effect on families. Pretest counseling on genetic issues is essential to better prepare families and to allow them to make an informed choice about learning genetic test results.
Alzheimer Disease↗
17q-linked frontotemporal dementia-amyotrophic lateral sclerosis without tau mutations with tau and alpha-synuclein inclusions.
BACKGROUND: Frontotemporal dementia (FTD) is a clinically heterogeneous condition that can be associated with clinical manifestations of an extrapyramidal disorder or motor neuron disease. A range of histologic patterns has been described in patients with FTD. The most common familial form of this condition is caused by mutations in the microtubule-associated protein tau gene (MAP tau) and is associated with neuronal or glial tau inclusions. OBJECTIVES: To determine the clinical, anatomic, and pathological features of San Francisco family A and to map the mutation responsible for disease in this family. DESIGN: A systematic clinical, neuropsychologic, neuroimaging, and chromosome segregation analysis of San Francisco family A was performed. A pathological and biochemical assessment of a family member was made. SETTING: Family study. PATIENTS: San Francisco family A, with FTD, variable extrapyramidal symptoms, and prominent motor neuron disease. Afflicted family members do not have a MAP tau coding or splice regulatory sequence mutation, and the MAP tau is genetically excluded. MAIN OUTCOME MEASURES: Comparison of clinical, neuropsychologic, neuroimaging, and linkage findings of San Francisco family A with other familial forms of FTD and amyotrophic lateral sclerosis (ALS). RESULTS: The most probable location for the mutation responsible for this condition is on chromosome arm 17q, distal to the MAP tau. All previously identified susceptibility loci for FTD and ALS are excluded. Autopsy findings from an afflicted family member show distinctive tau and alpha-synuclein inclusions. Another unique feature is that the insoluble tau protein consists predominantly of the 4R/0N isoform. CONCLUSION: The condition affecting members of San Francisco family A is clinically, pathologically, and genetically distinct from previous familial forms of FTD and ALS.
Adult↗
Portraits of artists: emergence of visual creativity in dementia.
As a uniquely human talent that has evolved from prehistoric cave paintings, art draws on many brain areas responsible for various cognitive processes. The pattern of degeneration in dementia leads to predictable changes in art. The visuospatial deficits in Alzheimer disease lead to less precision and attention to spatial relationships. In some cases of frontotemporal dementia, artistic creativity appears anew as the disease develops. The artwork is approached in a compulsive manner and is often realistic or surrealistic in style. Art in the context of dementia provides a unique window into the cognitive processes of various brain regions and an opportunity for rehabilitation.
Creativity↗
Cognition and anatomy in three variants of primary progressive aphasia.
We performed a comprehensive cognitive, neuroimaging, and genetic study of 31 patients with primary progressive aphasia (PPA), a decline in language functions that remains isolated for at least 2 years. Detailed speech and language evaluation was used to identify three different clinical variants: nonfluent progressive aphasia (NFPA; n = 11), semantic dementia (SD; n = 10), and a third variant termed logopenic progressive aphasia (LPA; n = 10). Voxel-based morphometry (VBM) on MRIs showed that, when all 31 PPA patients were analyzed together, the left perisylvian region and the anterior temporal lobes were atrophied. However, when each clinical variant was considered separately, distinctive patterns emerged: (1) NFPA, characterized by apraxia of speech and deficits in processing complex syntax, was associated with left inferior frontal and insular atrophy; (2) SD, characterized by fluent speech and semantic memory deficits, was associated with anterior temporal damage; and (3) LPA, characterized by slow speech and impaired syntactic comprehension and naming, showed atrophy in the left posterior temporal cortex and inferior parietal lobule. Apolipoprotein E epsilon4 haplotype frequency was 20% in NFPA, 0% in SD, and 67% in LPA. Cognitive, genetic, and anatomical features indicate that different PPA clinical variants may correspond to different underlying pathological processes.
Aged↗
Hippocampal volume and retention in Alzheimer's disease.
This study tested the hypothesis that the hippocampus has a relatively specific role in retaining information over delays. Thirty-seven subjects with probable Alzheimer's disease were evaluated with a verbal memory task and structural MRI. Cortical gray matter but not hippocampal volume predicted immediate free recall. In contrast, hippocampal volume was the best predictor of how well information was retained over a delay, even after controlling for levels of immediate recall. Results suggest that the role of the hippocampus is relatively specific to the consolidation of new memories.
Aged↗
Relational integration and executive function in Alzheimer's disease.
Executive functions depend on the ability to represent relations between objects and events, and the prefrontal cortex provides the neural substrate for this capacity. Patients with probable Alzheimer's disease (AD) and control participants were administered measures of working memory and reasoning that varied systematically in their relational complexity. AD patients showed impairment on reasoning measures that required the online integration of relations but performed as well as control participants on nonrelational items and items requiring the processing of only single relations. When AD patients were divided into subgroups based on their performance on relational reasoning measures, the subgroup that showed significant impairment on relational integration measures exhibited a neuropsychological profile consistent with prefrontal cortical dysfunction.
Aged↗
Clinical, cognitive and anatomical evolution from nonfluent progressive aphasia to corticobasal syndrome: a case report.
Recent clinical and pathological studies have suggested that frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS) show clinical and pathological overlap. We present four years of longitudinal clinical, cognitive and anatomical data in the case of a 56-year-old woman, AS, whose clinical picture evolved from FTLD to CBS. For the first three years, AS showed a progressive speech and language disorder compatible with a diagnosis of the nonfluent aphasia variant of FTLD. At year four, 10 years after her first symptom, AS developed the classical clinical signs of CBS, including alien limb phenomenon and dystonia. Voxel-based morphometry (VBM) applied to AS's four annual scans showed progression of atrophy from the inferior posterior frontal gyrus, to the left insula and finally to the medial frontal lobe. This case demonstrates the clinical overlap between FTLD and CBS and shows that the two can appear in the same patient at different stages of the disease in relation to the progression of anatomical damage.
Aphasia, Broca↗
Forgetting in dementia with and without subcortical lacunes.
Alzheimer's disease (AD) and subcortical ischemic vascular disease (SIVD) are common causes of dementia, often co-occur, and can present quite similarly, making differential diagnosis clinically challenging. This study tested the hypothesis that patients with SIVD retain information better than AD patients. Participants were 35 dementia patients with subcortical lacunes (SIVD group), 27 dementia patients without lacunar infarction (AD group), and 56 normal controls. Results indicated that despite comparable levels of initial acquisition, AD patients showed more rapid forgetting. Further analysis indicated that memory patterns within the SIVD group were heterogeneous, with some participants exhibiting rapid forgetting and some exhibiting good retention. SIVD participants with good retention showed a trend for greater executive impairments relative to SIVD participants with rapid forgetting and AD participants. Results suggest that rapid forgetting in SIVD may imply concomitant AD, whereas the dementia in patients with good retention may be purely vascular in origin. Three SIVD patients with rapid forgetting followed to autopsy all had AD pathology, further supporting the link between memory patterns and AD.
Aged↗
Frontotemporal dementia: genetics and genetic counseling dilemmas.
BACKGROUND: Frontotemporal dementia (FTD) is a neurodegenerative disease with early symptoms of personality change and/or language disorder. Approximately 40% of individuals with FTD have a family history of dementia; however, in our experience, less than 10% have clear autosomal dominant inheritance. Mutations in the microtubule-associated protein tau (MAPT) gene have been reported in up to 50% of hereditary cases, but are unusual except in families with more than 3 individuals with FTD. The genetics of FTD is complicated by clinical heterogeneity, variable expression, phenocopies, misdiagnoses, and lost family histories. The objective of this paper is to enable physicians to recognize hereditary patterns and genetic concerns of FTD families and to understand genetic counseling strategies. REVIEW SUMMARY: The complexity of FTD genetics and genetic counseling are illustrated using 4 case histories. Case 1 demonstrates the difficulty obtaining a reliable FTD family history. Case 2 illustrates how psychiatric phenocopies can make family linkage studies difficult. The lack of genotype and phenotype correlation and issues of predictive genetic testing within FTD families are the subject of case 3, and case 4 shows how normal aging language difficulties and cognitive changes can be misinterpreted when a family history of dementia is present. CONCLUSIONS: Physicians seeing patients with possible FTD should be aware of the risk of a genetic etiology. A 3-generation family history should be obtained with attention to neurologic, psychiatric, and behavioral symptoms. Variable expression and phenocopies are confounding factors when assessing a possible genetic etiology. Referral of the patient and family for genetic counseling is recommended.
Dementia↗
Recognition of emotion in the frontal and temporal variants of frontotemporal dementia.
Recent studies have suggested that the frontal and temporal variants of frontotemporal dementia (fvFTD and tvFTD) are both associated with impairments in emotional processing. However, the degree and type of emotional processing deficits in the two syndromes have not been previously compared. We used the Florida Affect Battery to examine recognition of facial expressions of emotion in fvFTD and tvFTD patients who have no evidence of visual perceptual difficulties for faces. In general, both groups were impaired at recognizing emotions compared with age-matched controls. In tvFTD, this deficit was limited to emotions with a negative valence (sadness, anger, fear), while fvFTD patients showed impairment for positive valence (happiness) as well. These results suggest that damage to frontal lobe regions in FTD may lead to more profound impairment in recognition of emotion than when damage is more limited to the temporal lobe.
Aged↗
Right and left medial orbitofrontal volumes show an opposite relationship to agreeableness in FTD.
Recent investigations of the neuroanatomy of complex social behaviors suggest that the underlying brain circuits involve multiple cortical and subcortical structures. The neuroanatomic origins of agreeableness have not yet been clearly elucidated. However, frontotemporal dementia (FTD) patients can evidence dramatic alterations in agreeableness arising from frontal and temporal lobe damage. Based on previous research, we hypothesized that agreeableness would be negatively correlated with left medial orbitofrontal cortex size and positively correlated with right amygdala volume. First-degree relatives of 27 FTD patients (diagnosed according to the Lund-Manchester criteria) were asked to fill out the NEO-Five Factor Inventory to assess the patients' current level of agreeableness, a construct comprised of the facets trust, straightforwardness, altruism, compliance, modesty, and tender-mindedness. These patients underwent T(1)-weighted MRI imaging, and gray matter volumes for right and left orbitofrontal lobes and amygdalas were derived via segmentation and region of interest tracing, normalizing for total intracranial volume. Regression analysis revealed that 38% of the variance in the NEO agreeableness score was predicted by a model in which right orbitofrontal volume (beta = 0.731) was positively correlated with agreeableness, and left orbitofrontal lobe volume (beta = -0.638) was negatively correlated with agreeableness (p < 0.01). Contrary to our hypothesis, amygdala volume did not significantly predict agreeableness. This finding partly replicates a previous study that used a different measure of social functioning, the Interpersonal Adjective Scale, to delineate a left frontal-right amygdala circuit for agreeableness. These data support the hypothesis that regulation of agreeableness arises from a balanced, mutually inhibitory circuit involving both hemispheres.
Aged↗
A neurocomputational model of analogical reasoning and its breakdown in frontotemporal lobar degeneration.
Analogy is important for learning and discovery and is considered a core component of intelligence. We present a computational account of analogical reasoning that is compatible with data we have collected from patients with cortical degeneration of either their frontal or anterior temporal cortices due to frontotemporal lobar degeneration (FTLD). These two patient groups showed different deficits in picture and verbal analogies: frontal lobe FTLD patients tended to make errors due to impairments in working memory and inhibitory abilities, whereas temporal lobe FTLD patients tended to make errors due to semantic memory loss. Using the "Learning and Inference with Schemas and Analogies" model, we provide a specific account of how such deficits may arise within neural networks supporting analogical problem solving.
Aged↗
Non-Alzheimer's disease dementias: anatomic, clinical, and molecular correlates.
OBJECTIVE: To review the clinical and molecular features of non-Alzheimer's disease (non-AD) dementias, focusing on disorders associated with tau pathology (that is, frontotemporal lobar degeneration [FTLD], corticobasal ganglionic degeneration [CBD], and progressive supranuclear palsy [PSP]) or on disorders with synuclein pathology (that is, dementia with Lewy bodies [DLB] and multisystem atrophy [MSA]). We also discuss the pharmacologic treatment of these disorders. METHODS: We report a selective review of the literature on FTLD, CBD, PSP, DLB, and MSA. RESULTS: The non-AD dementias can present with a wide variety of cognitive and behavioural symptoms. Through common clinical features and shared molecular etiologies, neurodegenerative disorders previously thought to be distinct are now classified into tauopathies and synucleinopathies. CONCLUSIONS: The unique cognitive and behavioural manifestations of the non-AD dementias can be mistaken for psychiatric disorders. Improved detection of tauopathies and synucleinopathies and their differentiation from AD is possible.
Alzheimer Disease↗
Art and the brain: the influence of frontotemporal dementia on an accomplished artist.
A talented artist developed a progressive aphasia syndrome associated with frontotemporal dementia (FTD). As her disease progressed, language and executive skills declined, but her paintings became freer and more original. She demonstrates that artistic development can occur in the setting of language-dominant types of FTD. The study of artistic development in the setting of FTD suggests that language is not required for, and may even inhibit, certain types of visual creativity.
Aphasia↗
Double dissociation of social functioning in frontotemporal dementia.
BACKGROUND: Efforts to characterize changes in social functioning in frontotemporal dementia (FTD) have failed to elicit clear dissociation between frontal and temporal variants of the disease based on behavioral measures. METHODS: This study obtained premorbid and current first-degree relative ratings using an established measure of interpersonal functioning, the Interpersonal Adjectives Scales, to measure personality change in 16 patients with frontal variant (FLV) and 13 with temporal variant (TLV) FTD, and in a control group of 16 patients with AD. RESULTS: All three groups showed significant change over time in multiple domains, including increased introversion (FG) and submissiveness (HI). However, patients with both FTD subtypes evidenced significantly greater increases in overall interpersonal pathology vector length [VL] than did patients with AD, who remained within the normal range on all scores. Patients with FLV showed a 2 SD increase in submissiveness (HI), but their cold-heartedness (DE) change scores were not significantly different from those of patients with AD. Conversely, the TLV cold-heartedness (DE) score increased 2 SD compared to minimal change for the AD and FLV groups, yet change in submissiveness (HI) did not differentiate between AD and TLV groups. CONCLUSIONS: The Interpersonal Adjectives Scales differentiated both FTD groups from patients with AD on the basis of both degree and direction of personality change. Also, the two subtypes of FTD showed distinctly different patterns of change in social functioning: patients with temporal variant shifted toward severe interpersonal coldness with mild loss of dominance, whereas patients with frontal variant showed the opposite pattern.
Alzheimer Disease↗
Novel tau polymorphisms, tau haplotypes, and splicing in familial and sporadic frontotemporal dementia.
BACKGROUND: A subset of familial cases (FTDP-17) of frontotemporal dementia (FTD) are caused by mutations in the tau gene. The role of tau gene mutations and haplotypes in sporadic FTD and the functional consequences of tau polymorphisms are unknown. OBJECTIVES: To investigate (1) the frequency of known FTDP-17 mutations in familial and sporadic FTD and compare these results with previous studies; (2) whether the tau H1 haplotype is associated with FTD; and (3) the functional effect of intronic tau sequence variations. PATIENTS AND METHODS: Patients with familial and sporadic FTD were screened for mutations in the microtubule-binding region of tau. The frequencies of tau haplotypes and genotypes were compared between patients with FTD and control subjects. We analyzed the splicing effect of novel intronic polymorphisms associated with FTD. RESULTS: The P301L mutation was detected in 11% of familial FTD cases. The H1 haplotype was not overrepresented in patients with FTD, but the P301L mutation appeared on the background of the H2 tau haplotype. We identified 4 novel single nucleotide polymorphisms in intron 9 and a 9-base pair deletion in intron 4A. A C-to-T transition 177 base pairs upstream from exon 10 was significantly increased in patients with FTD compared with controls. Direct analysis of brain tissue from a patient with this variant showed an increase in exon 10-containing tau transcripts. CONCLUSIONS: Sequence variations in intronic or regulatory regions of tau may have previously unrecognized consequences leading to tau dysfunction and neurodegeneration.
Adult↗