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Demencia frontotemporal
... El mayor costo de esta enfermedad es el que se da a nivel humano. De acuerdo con Iragorri (2007), Llibre y Gutiérrez (2014), Méndez (2010) y Ostrosky y Lozano (2012), las familias y cuidadores son quienes sufren las consecuencias psicológicas, físicas, sociales y financieras. Este panorama se presenta especialmente en países en vías de desarrollo. ...
... A partir de esta revisión, se espera proyectar un panorama general acerca de factores que se tienen en cuenta durante las investigaciones de demencia DTA y DFT y cuidadores e identificar el papel que se le ha dado a la cognición social en las investigaciones. Ruiz et al. (2010) y Gil y Martín (2006), la demencia tipo Alzheimer, así como la demencia fronto-temporal, han sido reconocidas como los tipos primarios de demencia degenerativa primaria -de predominio cortical-en donde la primera es responsable de aproximadamente el 50% del total de casos de demencias, mientras la DFT ocupa un 10% entre las demencias; sin embargo, es necesario reconocerla debido a las alteraciones a nivel comportamental que impactan directamente al cuidador (Diehl et al., 2013;Iragorri, 2007;Mioshi et al., 2013). En cuanto a la prevalencia por rango de edad, la DTA es la segunda causa degenerativa de demencias en pacientes de menos de 65 años, mientras la edad media de pacientes con DFT se encuentra entre los 70 a 79 años. ...
... Adicionalmente, de acuerdo con ADI (2016), Llibre (2012), Méndez (2010), Ministerio de Salud (MinSalud, 2017) y Ostrosky y Lozano (2012) este incremento sugiere aumentos en los costos para la salud pública, relacionados con cuidados informales, costos sociales, tratamientos y cuidados médicos; sin embargo, el mayor costo es el que se da a nivel humano, específicamente desde las familias y cuidadores, que son quienes sufren las consecuencias psicológicas, físicas, sociales y financieras. Estas consecuencias incluyen, entre otras, problemas de ansiedad, estrés y la depresión (Iragorri, 2007;Mioshi et al., 2013y Diehl et al., 2013. Informes Psicológicos Vol. ...
La demencia tipo Alzheimer (DTA) y la demencia fronto-temporal (DFT), desde una perspectiva psicosocial, coinciden, debido a sus características, en el impacto directo y significativo sobre los integrantes del entorno social de quien las vivencia. Objetivo: Identificar y describir a partir de la información disponible en la literatura, el papel de las redes de apoyo social, enfatizando en el cuidador, considerando en éste, los procesos de la cognición social, unicamente a partir del análisis conceptual y de evidencias empíricas disponibles, procedentes de investigaciones en torno a estos dos tipos de demencias. Método: Revisión documental y sistemática de investigaciones procedentes de bases de datos especializadas. Resultados: se evidenciaron diferencias en el nivel de impacto que ambos tipos de demencias tienen sobre la red de apoyo social, incluido el cuidador1, dependiendo del tipo de demencia, y en función de la disponibilidad de recursos por parte de la red. Así mismo, se observó que existe un vacío documental en el análisis acerca de la participación de la cognición social en la relación entre los integrantes de la red y aquellas personas con alguna de estas demencias. De esta investigación surgen interrogantes encaminados que sugieren profundizar más allá en la descripción de estos tipos de demencia.
... Las manifestaciones clínicas iniciales de la demencia frontotemporal se relacionan con un déficit en las funciones ejecutivas, con dificultades en la organización del espacio y la planificación, unido a alteraciones en la personalidad y el afecto (Jameson et al., 2020). Los síntomas iniciales se relacionan con las funciones ejecutivas, la memoria de trabajo y afectan ampliamente a varios aspectos del lenguaje, manteniéndose intacto el dominio visuoconstructivo, lo que la diferencia de la EA (Iragorri, 2007). ...
... Se describen dos formas clínicas de la DFT de variante frontal que oscilan entre el comportamiento apático y el desinhibido. No obstante, se mantienen preservadas, en las primeras fases, las funciones visuoespaciales, el lenguaje y las actividades instrumentales (Iragorri, 2007). ...
Tal y como constata la Organización Mundial de la Salud, las demencias se consideran una prioridad de salud pública. Se reconoce un aumento de 10 millones de casos por año situándose entre las diez principales causas de muerte en el mundo. La conceptualización psicológica de las demencias se beneficia del análisis integral, desde diferentes perspectivas, para mejorar su comprensión y abordaje. En este trabajo se presenta un análisis de la literatura científica con el objetivo de comparar, desde un prisma psiconeurobiológico, las tres principales demencias corticales: la Enfermedad de Alzheimer, la Demencia Frontotemporal y la Demencia por cuerpos de Lewy. En primer lugar se presentan los síntomas psicológicos y conductuales que se producen en cada cuadro demencial. Posteriormente,se destacacómo los estudios realizados através de técnicas de neuro imagen nos permiten conocer las repercusiones estructurales y funcionales de las alteraciones, a lo largo de la progresión del deterioro, relacionándolas con sus bases neuroanatómicas. Finalmente, se plantea la presencia diferentes alteraciones proteínicas, que permiten diferenciar estas demencias en función de sus biomarcadores patológicos.
... Las neuronas afectadas presentan una sustancia denominada cuerpos de Pick que contienen una forma anormal de proteína Tau. Sólo un 10% de los casos es hereditario, con alteraciones en el cromosoma 17 y mutaciones de la presenilina 1, lo cual provoca demencia frontotemporal aún en ausencia de placa amiloide como en la EA (Iragorri, 2007). ...
... Sus síntomas generales son cambios de personalidad y comportamiento, con deterioro de la memoria, la inteligencia y del lenguaje, acompañado de apatía y euforía, los demás síntomas son específicos de la variante del trastorno (Peña, Rodríguez y Casas, 2001). Existen tres tipos de demencia frontotemporal (Iragorri, 2007): a) Variante frontal: se produce por lesiones de la corteza orbitofrontal bilateral, atrofia del cíngulo y de la ínsula anterior, presentándose cambios de comportamiento y personalidad. Este trastorno es más frecuente en varones con una proporción de 2:1, siendo la variante con evolución más rápida, con una muerte a los 3-4 años del diagnóstico. ...
El presente texto contiene la información más relevante sobre las características del sistema nervioso y los trastornos más comunes que abarca la neuropsicobiología. Para los estudiantes de pedagogía resulta fundamental conocer las estructuras y funciones cerebrales que subyacen a los procesos cognitivos más importantes en el ser humano, funciones como la atención, memoria, planificación, control de impulsos, lenguaje, etc., todos elementos fundamentales para el proceso de aprendizaje de sus futuros estudiantes. Este libro contiene información sobre la etiología y tratamientos de diferentes problemas del sistema nervioso surgido por lesiones ya sea cerebrovasculares, infecciosas, tumores, traumáticas, etc. con un énfasis especial en la evaluación de los síntomas mediante pruebas neuropsicológicas.
Pesticides are chemicals used in agricultural fields for the prevention or destruction of pests. Inappropriate use of these substances, as well as handling them without using personal protective equipment, may result in serious health problems such as neurodegenerative diseases and mental disorders. Previous studies have demonstrated the adverse effects of pesticides on brain function. However, some researchers have associated pesticide poisoning with the development of disorders such as dissociative amnesia, multiple personality disorders, and depersonalization disorder. The objective of this work was to perform a bibliographic review of the relationship between pesticide poisoning and the development of dissociative disorders. Previous studies suggest that the duration of pesticide exposure is a major determinant in the development of dissociative diseases and disorders. The information obtained in this review suggests that there is no specific relationship between dissociative disorders and pesticide poisoning. However, these results point to associating the most representative symptoms of dissociative disorder (such as amnesia and memory loss) with pesticide exposure. Based on the bibliographic search, possible mechanisms of action were suggested in an attempt to explain a possible association between exposure to pesticides and the appearance of dissociative disorders.
El tema de la inteligencia es hasta el día de hoy, motivo de polémicas y controversias, constituyéndose como el ejemplo clásico de naturaleza v/s entorno ¿la inteligencia es innata y heredable o por el contrario depende de los ambientes culturales y educativos pudiendo mejorarse? La historia de la definición de la inteligencia es la historia de esta lucha en base a modelos teóricos e instrumentos para medirla, lo cuales explícita o implícitamente se adscriben a una de estas dos posturas.
Si bien el interés por estudiar esta capacidad se remonta a tiempos antiguos, es recién a fines del siglo XIX y principios del XX que toma un carácter científico, cuando se elaboran teorías que tratan de explicar el increíble intelecto humano, construyendo diversas pruebas psicométricas para intentar evaluar cuantitativa y objetivamente este constructo.
Durante el siglo pasado proliferaron los modelos que hablaban de un elemento central a todas las habilidades y que daba cuenta de una inteligencia única, en tanto otros modelos se inclinaban por la
existencia de varias inteligencias, independientes entre sí y que explicaban la enorme variabilidad del intelecto entre las personas. Por otro lado, los recientes descubrimientos biológicos han entregado algunas pistas sobre la naturaleza de la inteligencia, entregando las bases cerebrales que la sustentan.
Los estudios sobre los tras-tornos de la inteligencia, por un lado, y de los niños talentosos y superdotados, por el otro, entregan información valiosa para ayudar a comprender este fenómeno. De igual forma el desarrollo de la inteligencia artificial (o al menos lo que hoy en día se desarrolla bajo ese concepto) representan importantes esfuerzos en este camino de conocimiento de una de las capacidades más sobresalientes de nuestra especie.
El presente texto navega a través de la evolución de las di-versas teorías de la inteligencia durante el siglo pasado y muestra perspectivas nuevas y que han visto la luz en los albores del siglo XXI, entregando una amplia mirada del estado actual de la discusión sobre el fenómeno del intelecto
For a long time amyotrophic lateral sclerosis was seen as an exclusively motor disease, however, a lot of investigations have proved the existence of cognitive symptoms similar to frontotemporal dementia that could precede, coexist or appear after the motor symptoms. We report the case of a 69 years old hispanic man who consults about progressive swallowing impairments. In the speech languagepathologist assessment, we detected cognitive impairments that made necessary to complete the workout with specific test. The results of the assessment, shown disturbance in swallowing with suggestive symptomatology of motor neuron disease, besides cognitive impairments in executive functions, visuospatial abilities, memory, language and behaviors and conductual abnormalities. A few months after speech language pathologist assessment, the diagnosis of amyotrophic lateral sclerosis was given. This case emphasize in the importance of a exhaustive anamnesis and clinical assessment, as well as early diagnosis focused on opportune interventions. Additionally, it’s important to note the need for professionals with update knowledge in neuropsychology, to support interventions.
We have previously reported a large Danish pedigree with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 3 (FTD3). Here we identify a mutation in CHMP2B, encoding a component of the endosomal ESCRTIII complex, and show that it results in aberrant mRNA splicing in tissue samples from affected members of this family. We also describe an additional missense mutation in an unrelated individual with FTD. Aberration in the endosomal ESCRTIII complex may result in FTD and neurodegenerative disease.
We report five patients with a stereotyped clinical syndrome characterized by fluent dysphasia with severe anomia, reduced vocabulary and prominent impairment of single-word comprehension, progressing to a stage of virtually complete dissolution of the semantic components of language. A marked reduction in the ability to generate exemplars from restricted semantic categories (e.g. animals, vehicles, etc.) was a consistent and early feature. Tests of semantic memory demonstrated a radically impoverished knowledge about a range of living and man-made items. In contrast, phonology and grammar of spoken language were largely preserved, as was comprehension of complex syntactic commands. Reading showed a pattern of surface dyslexia. Autobiographical and day-to-day (episodic) memory were relatively retained. Non-verbal memory, perceptual and visuospatial abilities were also strikingly preserved. In some cases, behavioural and personality changes may supervene; one patient developed features of the Kluver-Bucy Syndrome. Radiological investigations have shown marked focal temporal atrophy in all five patients, and functional imaging by single positron emission tomography and positron emission tomography (one case) have implicated the dominant temporal lobe in all five. In the older literature, such cases would have been subsumed under the rubric of Pick's disease. Others have been included in series with progressive aphasia. We propose the term semantic dementia, first coined by Snowden et al. (1989), to designate this clinical syndrome.
The cortical anatomy of 6 patients with semantic dementia (the temporal lobe variant of frontotemporal dementia) was contrasted with that of a group of age-matched normal subjects by using voxel-based morphometry, a technique that identifies changes in gray matter volume on a voxel-by-voxel basis. Among the circumscribed regions of neuronal loss, the left temporal pole (Brodmann area 38) was the most significantly and consistently affected region. Cortical atrophy in the left hemisphere also involved the inferolateral temporal lobe (Brodmann area 20/21) and fusiform gyrus. In addition, the right temporal pole (Brodmann area 38), the ventromedial frontal cortex (Brodmann area 11/32) bilaterally, and the amygdaloid complex were affected, but no significant atrophy was measured in the hippocampus, entorhinal, or caudal perirhinal cortex. The degree of semantic memory impairment across the 6 cases correlated significantly with the extent of atrophy of the left anterior temporal lobe but not with atrophy in the adjacent ventromedial frontal cortex. These results confirm that the anterior temporal lobe is critically involved in semantic processing, and dissociate its function from that of the adjacent frontal region.
Despite numerous reports of changes in satiety, food preference, and eating habits in patients with frontotemporal dementia, there have been few systematic studies.
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.
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.
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.
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.
To discern behavioral problems that co-occur in frontotemporal dementia (FTD) patients, and to investigate the relation between behavioral clusters and the burden for caregivers.
Baseline data of 63 FTD patients and their respective caregivers were used to detect the behavioral clusters in the Neuropsychiatric Inventory (NPI) and the accompanying distress evoked in caregivers. To detect the clusters in behavior of the FTD patients, we performed multidimensional scaling (procedure: PROXSCAL). Multiple regression analysis was used to determine the association between behavior of patients and the distress experienced by caregivers.
This was the first study that found behavioral clusters for FTD. Two behavioral clusters were found: agitation/psychosis (comprising delusions, hallucinations, irritability and agitation) and mood (made up of anxiety and depression). The remaining NPI domains (euphoria, disinhibition, aberrant motor behavior and apathy were found to be autonomous. After controlling for relevant confounding factors, caregiver distress was strongest related to agitation/psychosis, followed by mood. Disinhibition and aberrant motor behavior were mildly related to caregiver distress. Euphoria and apathy were not significantly related to distress. Caregivers of patients living at home were more distressed by the behavioral problems of the FTD patients than caregivers of hospitalized patients.
The high prevalence of psychopathology in FTD patients and the associated caregiver distress was confirmed in this study. Clustering behavioral symptoms allows investigation of the relationship between structural or functional cerebral deficits and neuropsychiatric symptoms.
CERAD-NAB (Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery) data were compared between 51 patients with frontotemporal dementia, 13 with semantic dementia, and 69 with Alzheimer's disease. There were statistically significant differences between the 3 groups. Compared with patients with Alzheimer's disease, patients with frontotemporal dementia were more impaired on Animal Fluency but not on any other CERAD-NAB subtest. Patients with semantic dementia performed worse in Animal Fluency and Boston Naming Test compared with frontotemporal dementia and Alzheimer's disease. Multiple logistic regression analysis revealed that in the differentiation between frontotemporal dementia and Alzheimer's disease, the combination of Animal Fluency and Boston Naming Test correctly classified 90.5% of patients. In segregating semantic dementia and Alzheimer's disease, the combination of Boston Naming Test and Mini Mental State Examination resulted in a correct classification of 96.3%. These findings demonstrate that the Mini Mental State Examination and the language subtests of the CERAD-NAB are valuable clinical instruments for the differential diagnosis between early frontotemporal dementia, semantic dementia, and Alzheimer's disease.
Neurodegenerative diseases are associated with profound changes in social and emotional function. The emergence of increasingly sophisticated methods for measuring brain volume has facilitated correlation of local changes in tissue content with cognitive and behavioural changes in neurodegenerative disease. The current study examined neuroanatomical correlates of behavioural abnormalities, as measured by the Neuropsychiatric Inventory, in 148 patients with dementia using voxel-based morphometry. Of 12 behaviours examined, 4 correlated with tissue loss: apathy, disinhibition, eating disorders and aberrant motor behaviour. Increasing severity across these four behaviours was associated with tissue loss in the ventral portion of the right anterior cingulate cortex (vACC) and adjacent ventromedial superior frontal gyrus (vmSFG), the right ventromedial prefrontal cortex (VMPC) more posteriorly, the right lateral middle frontal gyrus, the right caudate head, the right orbitofrontal cortex and the right anterior insula. In addition, apathy was independently associated with tissue loss in the right vmSFG, disinhibition with tissue loss in the right subgenual cingulate gyrus in the VMPC, and aberrant motor behaviour with tissue loss in the right dorsal ACC and left premotor cortex. These data strongly support the involvement of the right hemisphere in mediating social and emotional behaviour and highlight the importance of distinct regions on the medial wall of the right frontal lobe in regulating different behaviours. Furthermore, the findings underscore the utility of studying patients with dementia for understanding the neuroanatomical basis of social and emotional functions.
Frontotemporal dementia with parkinsonism, chromosome 17 type (FTDP-17), a recently defined disease entity, is clinically characterized by personality changes sometimes associated with psychosis, hyperorality, and diminished speech output, disturbed executive function and nonfluent aphasia, and rigidity. Neuropathological changes include frontotemporal atrophy often associated with atrophy of the basal ganglia, substantia nigra, and amygdala. Neurofibrillary tangles (NFTs) are seen in some but not all families. Inheritance is autosomal dominant and the gene has been regionally localized to 17q21-22 in a 2- to 4-centimorgan (cM) region flanked by markers D17S800 and D17S791. The gene for tau, the primary component of NFTs, is located in the same region of chromosome 17. Tau was evaluated as a candidate gene. Physical mapping studies place tau within 2 megabases or less of D17S791, but it is probably outside the D17S800-D17S791 FTDP-17 interval. DNA sequence analysis of tau coding regions in affected subjects from two FTDP-17 families revealed nine DNA sequence variants, eight of which were also identified controls and are thus polymorphisms. A ninth variant (Val279Met) was found in one FTDP-17 family but not in the second FTDP-17 family. Three lines of evidence indicate that the Val279Met change is an FTDP-17 causative mutation. First, the mutation site is highly conserved, and normal valine is found at this position in all three tau interrepeat sequences and in other microtubule associated protein tau homologues. Second, the mutation co-segregates with the disease in family A. Third, the mutation is not found in normal controls.
Familial forms of frontotemporal dementia (FTD) with tauopathy are mostly caused by mutations in the gene encoding the microtubule-associated protein tau (MAPT). However, rare forms of familial tauopathy without MAPT mutations have been reported, suggesting other tauopathy-related genetic defects. Interestingly, two presenilin 1 (PS1) mutations (Leu113Pro and insArg352) recently have been associated with familial FTD albeit without neuropathological confirmation. We report here a novel PS1 mutation in a patient with Pick-type tauopathy in the absence of extracellular β-amyloid deposits. The mutation is predicted to substitute Gly→Val at codon position 183 (Gly183Val) and to affect the splice signal at the junction of the sixth exon and intron. Further clinical-genetic investigation showed a positive family history of FTD-like dementia and suggested that Gly183Val is associated with a phenotypically heterogeneous neurodegenerative disorder. Our results suggest PS1 as a candidate gene for Pick-type tauopathy without MAPT mutations.
Primary progressive aphasia (PPA) is a focal dementia characterized by an isolated and gradual dissolution of language function. The disease starts with word-finding disturbances (anomia) and frequently proceeds to impair the grammatical structure (syntax) and comprehension (semantics) of language. The speech output in PPA can be fluent or nonfluent. Memory, visual processing, and personality remain relatively well-preserved until the advanced stages and help to distiguish PPA from frontal lobe dementia and the typical forms of Alzheimer's disease. The term “semantic dementia” was originally introduced to designate a different group of patients with a combination of verbal and visual processing deficits. In practice, however, this diagnosis is also being used in a variant sense to denote a subtype of PPA with fluent speech and impaired comprehension, even in the absence of visual processing deficits. Insofar as the diagnosis of semantic dementia can have these two different meanings, it is important to specify whether it is being used in the original sense or to denote a subtype of PPA. Structural and physiological neuroimaging confirms the selective predilection of PPA for the left hemisphere, especially for its language-related cortices. A few patients with PPA display the neuropathological markers of Alzheimer's disease, but in an unusual distribution. The majority of the autopsies in PPA have shown either Pick's disease or lobar atrophy without distinctive histopathology. The suggestion has been made that PPA and frontal lobe dementia constitute phenotypical variations of a unitary disease process within the “Pick-lobar atrophy” spectrum. Recent advances in chromosome 17-linked dementias justify a rigorous search for tau polymorphisms and tauopathy in sporadic PPA. An informed approach to this syndrome will increase the effectiveness with which clinicians can address the unique challenges associated with the diagnosis and care of PPA. Ann Neurol 2001;49:425–432
ick's disease has been relabeled recently as frontotemporal dementia (FTD) and the ep- onymic term restricted to the autopsy finding of typical inclusion bodies. Frontotempo- ral dementia is being used as a technical term in journals, while relatives of patients, the lay public, and many practitioners find Pick's disease (PiD), similar to Alzheimer's dis- ease (AD), more acceptable. Furthermore, FTD commonly denotes the behavioral disorder, hin- dering the aphasic and extrapyramidal manifestations from being recognized as part of the syn- drome. Recent advances in histochemistry suggest further fractionation, but the discovery of chromosome 17 localization of the familial forms of the disease suggests the cohesiveness of the clinical and biological entity.
Sixteen patients with progressive language disorder have been studied longitudinally. Anomia was a prominent presenting characteristic and mutism ultimately occurred. Patients, however, were clinically heterogeneous. Some exhibited nonfluent, agrammatic features, whereas others demonstrated a fluent aphasia, with profound loss of word meaning. Although language disorder remained the sole symptom in a minority of patients, in others an associative agnosia or personality and behavioral changes, or both, emerged. Findings on computed tomography and single photon emission tomography mirrored the areas of dysfunction suggested by the neuropsychological profiles and demonstrated abnormalities restricted to the left hemisphere or involving bilateral frontotemporal cortices. Brains of 3 patients, with distinctive clinical pictures, have been examined at autopsy. Each revealed a focal distribution of atrophy, gliosis and spongiform change, and an absence of senile plaques and neurofibrillary tangles. There was clinical and pathological overlap with frontal lobe dementia. We argue that progressive language disorder is clinically heterogeneous and forms part of a spectrum of clinical presentations of non-Alzheimer lobar atrophy.
Choline acetyltransferase and acetylcholinesterase activities as well as serotonin and imipramine binding were determined in the hypothalamus, nucleus basalis of Meynert, and frontal and temporal poles of subjects with Pick's disease. Choline acetyltransferase activity was decreased in the hypothalamus and nucleus basalis of Meynert, and acetylcholinesterase activity was decreased in the nucleus basalis of Meynert only. Serotonin binding was decreased in all sites but the nucleus basalis of Meynert, and imipramine binding was altered only in the frontal pole. Comparison with previous reports of Alzheimer's disease indicates that with respect to these synaptic markers, Alzheimer's disease and Pick's disease are not similar.
Four patients with the clinical syndrome of primary progressive aphasia and a nonfluent aphasia profile were followed up over a period of 3 to 5 years. Extensive neuropsychological data for three patients revealed a progressive, quantitative decline of language with relative stability of memory, visuospatial skills, and reasoning. Comportment and most activities of daily living were preserved even when speech was unintelligible. Although several aphasia types may be associated with primary progressive aphasia, a nonfluent aphasia profile and phonemic paraphasic errors are most useful in differentiating it from the much more common clinical syndrome, "probable Alzheimer's disease." The clinicopathological correlates of probable Alzheimer's disease differ from those associated with primary progressive aphasia. Therefore, the clinical distinction between the two syndromes may be important for predicting the underlying pathophysiologic changes during the life of the patient.
The authors review the accumulating evidence from preclinical, clinical and postmortem studies suggesting that abnormality in serotonin systems may be associated with both attempts at suicide and aggression towards others and inanimate objects. Although these behaviors are multidetermined they often involve poor impulse control, which may reflect low central serotonin turnover. The need for further studies of possible peripheral biological markers for suicidal and impulsive behavior is discussed.
Three patients are described presenting with a slowly progressive aphasic disorder associated with degenerative cortical disease. The symptoms began in the presenium and the length of illness was 4 to 5 years. The language disorder corresponded in all patients to a severe form of amnesic aphasia but a moderate to marked semantic breakdown was also found. Formal language examination was complemented by extensive neuropsychological testing. This revealed a severe deficit in language-dependent cognitive tasks. The patients were given a follow-up language and neuropsychological examination. In addition to the deterioration of language functions, a significant decline was observed in nonverbal intelligence tasks even though their level of performance still remained within the normal range. Follow-up with standardized intelligence tests might detect a trend towards generalized dementia in similar cases. This would mean that these patients should be considered as presenting with slowly progressive aphasia preceding generalized dementia.
A retrospective chart review of clinical symptoms was done for 20 consecutive patients in whom postmortem examination had revealed senile plaques and neurofibrillary tangles in a distribution consistent with Alzheimer's disease. All patients had met clinical diagnostic criteria for probable Alzheimer's disease. On initial examination, 1 to 14 years beyond putative onset of the dementia, all patients displayed at least some memory impairment. In 16 patients, disturbances of attention or recent memory were among the most salient features. In two patients, language disturbances, and in two others, visuospatial deficits, were more prominent than difficulties with memory and attention. On initial examination, 17 of the 20 patients displayed word-finding difficulties, characteristically in the context of a fluent, anomic aphasia. All of the 12 reexamined patients demonstrated progressive, although variable, deterioration. In general, the initial salient deficit remained salient during much of the disease course. Language comprehension was spared in the earlier stages but eventually deteriorated. Severe deficits emerged in all major cognitive domains as the disease reached the terminal stages. Nonfluent aphasias (eg, Broca's aphasia) were not observed even in the advanced stages of the disease.
Frontal lobe degeneration of non-Alzheimer type (FLD) is the second most common primary degenerative dementia in southern Sweden. Clinical findings in 30 FLD cases with postmortem-verified diagnoses are described. FLD starts in the presenium with a mean disease duration of 7.5 years (range 3-17 years). Clinical onset is insidious and slow and the early stage is dominated by personality changes with lack of insight and judgement and signs of disinhibition. A typical feature is progressive loss of expressive speech with stereotyped phrases, late mutism and amimia. Restlessness, changes of oral/dietary behavior and utilization behavior are prevalent as also psychotic features. Temporal and spatial orientation are usually preserved for a long time in contrast to Alzheimer's disease. Dementia in FLD is similar to that of Pick's disease and ALS with dementia. Early recognition of FLD seems possible based on standardized clinical evaluation supported by neuropsychological tests, measurement of regional cerebral blood flow and other types of brain imaging. The etiology of FLD is unknown but a positive heredity was reported in 60%.
Several drugs are apparently effective in treating pathologic anger and aggression. Because many of the studies on aggressive populations allowed the use of concomitant medications, it is unclear whether the efficacy of each drug in a particular population is dependent on the presence of other medications, such as antipsychotic agents. Finally, one needs to be circumspect in inferring efficacy of a particular drug in aggressive patients with neuropsychiatric conditions other than the ones in which some efficacy has been established. Lithium appears to be an effective treatment of aggression among nonepileptic prison inmates, mentally retarded and handicapped patients, and among conduct-disordered children with explosive behavior. Certainly, lithium would be the treatment of choice in bipolar patients with excessive irritability and anger outbursts, and it has been shown to be effective in this population. Anticonvulsant medications are the treatment of choice for patients with outbursts of rage and abnormal EEG findings. The efficacy of these drugs in patients without a seizure disorder, however, remains to be established, with the exception perhaps of valproate and carbamazepine. In fact, dyphenylhydantoin did not appear to be effective in treating aggressive behavior in children with temper tantrums and was found to be effective in only a prison population. There is some evidence for the efficacy of carbamazepine and valproate in treating pathologic aggression in patients with dementia, organic brain syndrome, psychosis, and personality disorders. As Yudofsky et al point out in their review of the literature, although traditional antipsychotic drugs have been used widely to treat aggression, there is little evidence for their effectiveness in treating aggression beyond their sedative effect in agitated patients or their antiaggressive effect among patients whose aggression is related to active psychosis. Antipsychotic agents appear to be effective in treating psychotic aggressive patients, conduct-disordered children, and mentally retarded patients, with only modest effects in the management of pathologic aggression in patients with dementia. Furthermore, at least in one study, these drugs were found to be associated with increased aggressiveness in mentally retarded subjects. On the other hand, atypical antipsychotic agents (i.e., clozapine, risperidone, and olanzapine) may be more effective than traditional antipsychotic drugs in aggressive and violent populations, as they have shown efficacy in patients with dementia, brain injury, mental retardation, and personality disorders. Similarly, benzodiazepines can reduce agitation and irritability in elderly and demented populations, but they also can induce behavioral disinhibition. Therefore, one should be careful in using this class of drugs in patients with pathologic aggression. Beta-blockers appear to be effective in many different neuropsychiatric conditions. These drugs seem effective in reducing violent and assaultive behavior in patients with dementia, brain injury, schizophrenia, mental retardation, and organic brain syndrome. As pointed out by Campbell et al in their review of the literature, however, systematic research is lacking, and little is known about the efficacy and safety of beta-blockers in children and adolescents with pathologic aggression. Although widely used in the management of pathologic aggression, the use of this class of drugs has been limited partially by marked hypotension and bradycardia, which are side effects common at the higher doses. The usefulness of the antihypertensive drug clonidine in the treatment of pathologic aggression has not been assessed adequately, and only marginal benefits were observed with this drug in irritable autistic and conduct disorder children. Psychostimulants seem to be effective in reducing aggressiveness in brain-injured patients as well as in violent adolescents with oppositional or conduct disorders, particu
We obtained apolipoprotein E genotyping in a population of 12 consecutive patients who fulfilled rigorous criteria for the clinical diagnosis of primary progressive aphasia (PPA). The allele frequencies were 4% for E2, 83% for E3, and 13% for E4. This pattern of allele distribution was significantly different from the pattern seen in groups of patients either with the clinical diagnosis of probable Alzheimer's disease (PRAD) or the histopathologic diagnosis of Alzheimer's disease (AD). The E4 allele frequency in the group of patients with PPA was in the range seen in control populations and was much lower than the one reported in populations of patients with PRAD or AD. The E4 allele is therefore not a significant risk factor for developing PPA. These results provide neurobiological support for the syndromic distinction of PPA from PRAD and are in keeping with neuropathologic evidence showing that the vast majority of patients with PPA do not have the histopathology of AD. Although we do not yet have neuropathologic information on our patients, these results indicate that the clinical diagnosis of PPA has biological validity in that it identifies a population that is genetically different from the population of patients with a clinical diagnosis of PRAD.
Frontotemporal dementia (FTD) is the most common early-onset non-Alzheimer's dementia (non-AD). Although the role of the epsilon4 allele of apolipoprotein E (ApoE) has been well established in AD, studies of ApoE allele distribution in patients with FTD have produced variable results. We studied 33 rigorously diagnosed FTD patients, including several who were pathologically confirmed, and compared the frequency of the epsilon4 allele in patients with FTD with the frequency in those with early-onset AD (EOAD), in those with late-onset AD (LOAD), and in non-demented elderly controls. The frequency of ApoE epsilon4 was 21% in patients with FTD, significantly less than the ApoE epsilon4 frequency in those patients with EOAD (38%) and those with LOAD (40%), but not significantly different from the ApoE epsilon4 frequency in elderly controls (13%).
To improve clinical recognition and provide research diagnostic criteria for three clinical syndromes associated with frontotemporal lobar degeneration.
Consensus criteria for the three prototypic syndromes-frontotemporal dementia, progressive nonfluent aphasia, and semantic dementia-were developed by members of an international workshop on frontotemporal lobar degeneration. These criteria build on earlier published clinical diagnostic guidelines for frontotemporal dementia produced by some of the workshop members.
The consensus criteria specify core and supportive features for each of the three prototypic clinical syndromes and provide broad inclusion and exclusion criteria for the generic entity of frontotemporal lobar degeneration. The criteria are presented in lists, and operational definitions for features are provided in the text.
The criteria ought to provide the foundation for research work into the neuropsychology, neuropathology, genetics, molecular biology, and epidemiology of these important clinical disorders that account for a substantial proportion of cases of primary degenerative dementia occurring before the age of 65 years.
The authors compared age-matched groups of patients with the frontal and temporal lobe variants of frontotemporal dementia (FTD; dementia of frontal type [DFT] and semantic dementia), early Alzheimer's disease (AD), and normal controls (n = 9 per group) on a comprehensive neuropsychological battery. A distinct profile emerged for each group: Those with AD showed a severe deficit in episodic memory with more subtle, but significant, impairments in semantic memory and visuospatial skills; patients with semantic dementia showed the previously documented picture of isolated, but profound, semantic memory breakdown with anomia and surface dyslexia but were indistinguishable from the AD group on a test of story recall; and the DFT group were the least impaired and showed mild deficits in episodic memory and verbal fluency but normal semantic memory. The frontal and temporal presentations of FTD are clearly separable from each other and from early AD.
Familial forms of frontotemporal dementias are associated with mutations in the tau gene. A kindred affected by progressive subcortical gliosis (PSG), a rare form of presenile dementia, has genetic linkage to chromosome 17q21-22. This kindred (PSG-1) is included in the 'frontotemporal dementias and Parkinsonism linked to chromosome 17' group along with kindreds affected by apparently different forms of atypical dementias. Some of these kindreds have mutations in the tau gene. We report here that PSG-1 has a tau mutation at position +16 of the intron after exon 10. The mutation destabilizes a predicted stem-loop structure and leads to an over-representation of the soluble four-repeat tau isoforms, which assemble into wide, twisted, ribbon-like filaments and ultimately result in abundant neuronal and glial tau pathology. The mutations associated with PSG and other atypical dementias can be subdivided into three groups according to their tau gene locations and effects on tau. The existence of tau mutations with distinct pathogenetic mechanisms may explain the phenotypic heterogeneity of atypical dementias that previously led to their classification into separate disease entities.
Frontotemporal dementia (FTD) is often misdiagnosed as Alzheimer's disease (AD). We hypothesized that the first symptoms associated with FTD would be different from those seen in AD and that the first symptoms in FTD would reflect loss of function in the frontal region with the greatest degree of degeneration. The objective of the study was to compare the earliest symptoms in patients with FTD and AD, and to delineate the symptoms that were associated with right, left or bilateral frontotemporal degeneration in FTD. The first symptoms in 52 FTD and 101 AD patients were determined in retrospect. Based on functional imaging studies, the FTD patients were divided into those with predominantly bilateral (n = 15), left-sided (n = 19) and right-sided (n = 18) patterns of atrophy. The results showed that disinhibition, social awkwardness, passivity and loss of executive function were more common in FTD, while memory loss was more common in AD. Disinhibition was greatest in the asymmetric right-sided group, language dysfunction was commonest in the asymmetric left-sided group and loss of executive function was most frequent in the bilateral group. In summary, different first symptoms appeared in FTD and AD, which may help distinguish between the diseases. The anatomic site for FTD largely determined the kind of first symptoms.
To provide evidence for the hypothesis that the corticobasal degeneration syndrome (CBDs) overlaps significantly with primary progressive aphasia and frontotemporal dementia, and that CBDs is part of the Pick complex.
Corticobasal degeneration has been mainly described as a movement disorder, but cognitive impairment is also increasingly noted.
Thirty-five cases of clinically diagnosed CBDs were followed-up with clinical, neuropsychological, and neuroimaging investigations. Twenty-nine patients were seen prospectively in movement disorder and cognitive neurology clinics; five of these came to autopsy. Six other autopsied cases that fulfilled the clinical criteria of CBDs were added with retrospective review of records.
All 15 patients presenting with movement disorders developed behavioral, cognitive, or language deficits shortly after onset or after several years. Patients presenting with cognitive problems (n = 20), progressive aphasia (n = 13), or frontotemporal dementia (n = 7) developed the movement disorder subsequently. Eleven cases with autopsy had CBD or other forms of the Pick complex.
There is a clinical overlap between CBD, frontotemporal dementia, and primary progressive aphasia. There is also a pathologic overlap between these clinical syndromes. The recognition of this overlap will facilitate the diagnosis and avoid consideration of CBD as "heterogenous."
Familial dementia with swollen achromatic neurons and corticobasal inclusion bodies is a neurodegenerative disease that resembles corticobasal degeneration. It is characterized by the presence of abundant neuronal and glial tau protein deposits. Here we describe a novel silent mutation in exon 10 of tau (N296N) in this familial dementia. By exon trapping, the mutation produced an increase in the splicing in of exon 10, indicating that it probably causes disease through an overproduction of four-repeat tau.
To characterize and quantify the patterns of temporal lobe atrophy in AD vs semantic dementia and to relate the findings to the cognitive profiles. Medial temporal lobe atrophy is well described in AD. In temporal variant frontotemporal dementia (semantic dementia), clinical studies suggest polar and inferolateral temporal atrophy with hippocampal sparing, but quantification is largely lacking.
A volumetric method for quantifying multiple temporal structures was applied to 26 patients with probable AD, 18 patients with semantic dementia, and 21 matched control subjects.
The authors confirmed the expected bilateral hippocampal atrophy in AD relative to controls, with involvement of the amygdala bilaterally and the right parahippocampal gyrus. Contrary to expectations, patients with semantic dementia had asymmetric hippocampal atrophy, more extensive than AD on the left. As predicted, the semantic dementia group showed more severe involvement of the temporal pole bilaterally and the left amygdala, parahippocampal gyrus (including the entorhinal cortex), fusiform gyrus, and the inferior and middle temporal gyri. Performance on semantic association tasks correlated with the size of the left fusiform gyrus, whereas naming appeared to depend upon a wider left temporal network. Episodic memory measures, with the exception of recognition memory for faces, did not correlate with temporal measures.
Hippocampal atrophy is not specific for AD but is also seen in semantic dementia. Distinguishing the patients with semantic dementia was the severe global but asymmetric (left > right) atrophy of the amygdala, temporal pole, and fusiform and inferolateral temporal gyri. These findings have implications for diagnosis and understanding of the cognitive deficits in AD and semantic dementia.
An international group of clinical and basic scientists participated in the Frontotemporal Dementia and Pick's Disease Criteria Conference at the National Institutes of Health in Bethesda, Md, on July 7, 2000, to reassess clinical and neuropathological criteria for the diagnosis of frontotemporal dementia (FTD). Previous criteria for FTD have primarily been designed for research purposes. The goal of this meeting was to propose guidelines that would enable clinicians (particularly neurologists, psychiatrists, and neuropsychologists) to recognize patients with FTD and, if appropriate, to expedite their referral to a diagnostic center. In addition, recommendations for the neuropathological criteria of FTD were reviewed, relative to classical neuropathology and modern molecular biology.
To identify and compare the patterns of cerebral atrophy associated with two clinical variants of frontotemporal lobar degeneration (FTLD): frontotemporal dementia (FTD) and semantic dementia (SemD).
Twenty patients with FTLD were classified as having FTD (N = 8) or SemD (N = 12) based on current clinical criteria. Both groups showed a similar spectrum of behavioral abnormalities, as indicated by the neuropsychiatric inventory. T1-weighted MRI was obtained for each patient and 20 control subjects. The regions of focal gray matter tissue loss associated with both FTD and SemD, as well as those differing between the two groups were examined using voxel-based morphometry.
Regions of significant atrophy seen in both groups were located in the ventromedial frontal cortex, the posterior orbital frontal regions bilaterally, the insula bilaterally, and the left anterior cingulate cortex. The FTD, but not the SemD, group showed atrophy in the right dorsolateral frontal cortex and the left premotor cortex. The SemD, but not the FTD, group showed tissue loss in the anterior temporal cortex and the amygdala/anterior hippocampal region bilaterally.
Although FTD and SemD are associated with different overall patterns of brain atrophy, regions of gray matter tissue loss in the orbital frontal, insular, and anterior cingulate regions are present in both groups. The authors suggest that pathology in the areas of atrophy associated with both FTD and SemD may underlie some the behavioral symptoms seen in the two disorders.
Patients with ALS are often told that the disease spares cognition; however, recent evidence suggests deficits in frontal executive skills occur in a sizable minority of ALS patients. In many instances, the frontal executive deficits represent the co-occurrence of frontotemporal lobar dementia (FTLD) and ALS.
Word generation, a simple frontal task that takes <2 minutes, was tested in 100 consecutive patients with ALS seen in the authors' multidisciplinary clinic. Any patient with a prior dementia diagnosis was excluded from the study. A subset of 44 patients agreed to undergo further neuropsychological testing and clinical interview to confirm or deny a diagnosis of dementia.
Diminished word generation was found in one-third. Of the patients with abnormal word generation who agreed to further evaluation, nearly all were shown to meet research criteria for FTLD. In addition, one-quarter of the patients with normal word generation who agreed to further evaluation met research criteria for FTLD; these patients had new-onset personality changes.
This study suggests that frontal executive deficits are present in half of ALS patients, many of whom meet strict research criteria for FTLD. Word generation tests are a useful screening tool in this cohort.
Primary progressive aphasia (PPA) is a neurodegenerative disease presenting with isolated, progressive, language dysfunction. After at least 2 years, dementia may develop, but the aphasia predominates. Few families with hereditary PPA have been reported; some have autosomal dominance. A chromosome 17 mutation in tau exon 13 has been found in one family, and a few have linkage to chromosome 17. However, early appearance of prominent memory, behavior, and motor impairments differentiates these patients from typical PPA. The objective was to report clinical features, pathology, and genetic analysis of a family with typical PPA. We report three siblings with the typical clinical syndrome of PPA. Each presented with word-finding difficulties and early anomia. Ages at onset were 60, 61, and 65 years. Aphasia was the only symptom for at least 2 years. A nonaffected brother is 75 years of age. Family history review found no other affected relatives. Neuropathology in one patient demonstrated "dementia lacking distinctive histopathology" with ubiquitin-positive cortical neurons. DNA analysis of the proband did not detect any known mutation in tau exons 1-5, 7, or 9-13. To our knowledge, this is the first family presenting with hereditary aphasia in which typical PPA occurs in all affected members.
To compare frontal cortex activation in patients with early frontotemporal dementia (FTD) with that in patients with early AD.
Seven patients with FTD and seven patients with AD were studied (Clinical Dementia Rating: four patients with FTD 0.5, three patients with FTD 1, all patients with AD 1; mean Mini-Mental State Examination score: FTD 28.0 +/- 2.1, AD 23.1 +/- 2.7). Cerebral atrophy on MRI was mild, with no differences between FTD and AD. A parametric working memory task was applied to assess frontal activation as a function of working memory load.
The activated working memory network in FTD and AD included frontal and parietal lobe and thalamus. In frontal and parietal cortex, brain activation was significantly decreased in FTD. Frontal regions in patients with FTD showed less linear activation increase with working memory load than in AD. Possibly as a compensation mechanism, the cerebellum showed a stronger increasing response in FTD.
These data on regional functional loss in the frontal cortex in early FTD suggest that fMRI can identify FTD when results on structural MRI are normal.
Primary progressive aphasia is an atypical dementia in which language abilities deteriorate while memory is relatively preserved. For many years, the principal signs and symptoms may be confined to the area of language. Patients may come to medical attention because of the onset of word-finding difficulties, abnormal speech patterns, or prominent errors in spelling. Neuropsychological testing can help establish the correct diagnosis.
Progressive nonfluent aphasia (PA) is a slow deterioration of language that remains relatively isolated from other cognitive or behavioral deficits for at least 2 years. The differentiation of PA from early Alzheimer's disease (AD) is important, given the presence of early language changes in AD.
A language assessment was administered to 15 patients who met established criteria for PA, 15 patients with clinically probable AD and mild dementia, and 15 normal control subjects. The language battery included verbal fluency, the Boston Naming Test with cuing and recognition, and an aphasia test battery with a motor speech exam.
Pronounced literal paraphasic errors distinguished the PA patients from the AD patients. The PA group had anomia, decreased letter fluency, neologisms, difficulty on phrase repetition, decreased phrase length, and a decreased rate of verbal output. Interference from paraphasic anomia accounted for much of their decreased fluency.
Many patients with PA have a primary defect in accessing sound-based representation of speech (phonemes), similar to conduction aphasia, possibly as a consequence of disturbed white matter tracts in the left superior temporal region.
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.
The temporal variant of frontotemporal dementia (tvFTD) features asymmetric anterior temporal/amygdala degeneration as well as ventromedial frontal, insular, and inferoposterior temporal involvement. Left temporal atrophy has been linked to loss of semantic knowledge, whereas behavioral symptoms dominate the right temporal variant.
To investigate the first symptoms and the timing of subsequent symptoms in patients with left versus right tvFTD.
Twenty-six patients with tvFTD were identified. Six had right > left temporal atrophy (right temporal lobe variant [RTLV]) and were matched with six having comparable left > right temporal atrophy (left temporal lobe variant [LTLV]). Clinical records were reviewed to generate individualized symptom chronologies.
In all patients, first symptoms involved semantics (4/6 LTLV, 1/6 RTLV), behavior (4/6 RTLV, 1/6 LTLV), or both (1 LTLV, 1 RTLV). Semantic loss began with anomia, word-finding difficulties, and repetitive speech, whereas the early behavioral syndrome was characterized by emotional distance, irritability, and disruption of physiologic drives (sleep, appetite, libido). After an average of 3 years, patients developed whichever of the two initial syndromes--semantic or behavioral--that they lacked at onset. A third stage, 5 to 7 years from onset, saw the emergence of disinhibition, compulsions, impaired face recognition, altered food preference, and weight gain. Compulsions in LTLV were directed toward visual, nonverbal stimuli, whereas patients with RTLV were drawn to games with words and symbols.
The temporal variant of frontotemporal dementia follows a characteristic cognitive and behavioral progression that suggests early spread from one anterior temporal lobe to the other. Later symptoms implicate ventromedial frontal, insular, and inferoposterior temporal regions, but their precise anatomic correlates await confirmation.
To compare the behavioral features and to investigate the neuroanatomic correlates of behavioral dysfunction in anatomically defined temporal and frontal variants of frontotemporal dementia (tvFTD and fvFTD).
Volumetric measurements of the frontal, anterior temporal, ventromedial frontal cortical (VMFC), and amygdala regions were made in 51 patients with FTD and 20 normal control subjects, as well as 22 patients with Alzheimer disease (AD) who were used as dementia controls. FTD patients were classified as fvFTD or tvFTD based on the relative degree of frontal and anterior temporal volume loss compared with controls. Behavioral symptoms, cerebral volumes, and the relationship between them were examined across groups.
Both variants of FTD showed significant increases in rates of elation, disinhibition, and aberrant motor behavior compared with AD. The fvFTD group also showed more anxiety, apathy, and eating disorders, and tvFTD showed a higher prevalence of sleep disturbances than AD. The only behaviors that differed significantly between fvFTD and tvFTD were apathy, greater in fvFTD, and sleep disorders, more frequent in tvFTD. FvFTD was associated with greater frontal atrophy and tvFTD was associated with more temporal and amygdala atrophy compared with AD, but both groups showed significant atrophy in the VMFC compared with AD, which was not associated with VMFC atrophy. In FTD, the presence of many of the behavioral disorders was associated with decreased volume in right-hemispheric regions.
FvFTD and tvFTD show many similarities in behavior, which appear to be associated with damage to right frontal and temporal structures.
Until recently, frontotemporal lobar degeneration (FTLD) was considered a rare neurodegenerative disorder that was difficult to diagnose. The publication of consensus criteria for FTLD, however, prompted systematic studies. The criteria categorize FTLD into 3 subgroups: frontotemporal dementia, semantic dementia, and progressive nonfluent aphasia.
To compare demographic characteristics of patients in the 3 FTLD subgroups.
We compared diagnostic breakdown, age at onset, sex, Mini-Mental State Examination score at first visit, education, and neuropathological diagnoses in a large sample of FTLD patients from 3 different university dementia clinics, including 2 neurologic clinics in the United States and 1 psychiatric clinic in Germany.
The frontotemporal dementia subgroup represented approximately half of all FTLD diagnoses. Patients diagnosed as having frontotemporal dementia (mean age, 57.5 years) and semantic dementia (mean age, 59.3 years) had an earlier age at onset than patients diagnosed as having progressive nonfluent aphasia (mean age, 63.0 years). There were significantly more men diagnosed as having frontotemporal dementia (63.5%) and semantic dementia (66.7%) when compared with progressive nonfluent aphasia (39.1%) (P = .005 for frontotemporal dementia vs progressive nonfluent aphasia and P = .002 for semantic dementia vs progressive nonfluent aphasia). Generally, the demographic features and diagnostic categories of the patient populations across the 3 sites were comparable. There were 68 deaths and 37 autopsies. Frontotemporal lobar degeneration with ubiquitin-positive tau-negative inclusions (48.5%), dementia lacking distinctive histopathological features (18.2%), and Pick disease (15.2%) were the most common neuropathological diagnoses.
These findings show that cohorts of patients can be combined using new research criteria for FTLD and demonstrate striking demographic differences among FTLD subgroups. The sex and age-at-onset differences suggest that there may be biological differences among FTLD subgroups. In this sample, FTLD with ubiquitin-positive inclusions accounted for half of all neuropathological diagnoses.
Frontotemporal lobar degeneration (FTLD) is a common cause of non-Alzheimer dementia, but its natural history and the factors related to mortality in affected patients are not well understood.
This retrospective, longitudinal study compared survival in FTLD (n = 177) with Alzheimer disease (AD; n = 395). Hazards analysis investigated the contribution of various demographic, neuropsychiatric, and neuropsychological variables and associated neurologic and neuropathologic findings.
The frontotemporal dementia (FTD) subtype of FTLD progressed faster than AD (median survival from retrospectively determined symptom onset, 8.7 +/- 1.2 vs 11.8 +/- 0.6 years, p < 0.0001; median survival from initial clinic presentation, 3.0 +/- 0.5 vs 5.7 +/- 0.1 years, p < 0.0001). Survival was similarly reduced in the related conditions corticobasal degeneration and progressive supranuclear palsy. Survival in the semantic dementia subtype of FTLD (11.9 +/- 0.2 years from onset and 5.3 +/- 0.4 years from presentation), however, was significantly longer than in FTD and did not differ from AD. Hazards analysis to determine factors affecting survival in FTLD showed no effect of age at onset, sex, education, family history, or neuropsychiatric profile. Among neuropsychological measures examined, impaired letter fluency had a significant association with reduced survival. Associated ALS significantly reduced survival in FTLD. The presence of tau-positive inclusions was associated with the slowest progression.
Frontotemporal lobar degeneration progresses more rapidly than Alzheimer disease, and the fastest-progressing cases are those with the frontotemporal dementia clinical subtype, coexisting motor neuron disease, or tau-negative neuropathology.
The pathologic substrates of frontotemporal dementia (FTD) are difficult to predict in vivo.
To determine whether different pathologic substrates of FTD have distinct patterns of regional atrophy on magnetic resonance imaging (MRI).
Retrospective case study.
The Institute of Neurology, University College London, and the Institute of Psychiatry, King's College London. Patients Twenty-one cases of FTD selected on pathologic grounds (9 with ubiquitin-positive [tau- and alpha-synuclein-negative] inclusions [FTD-U], 7 with Pick disease [PiD], and 5 with familial FTD with tau exon 10+16 mutations [tau exon 10+16]) and 20 healthy controls were studied.
Patterns of gray matter atrophy in each group as assessed by voxel-based morphometry (VBM) and a blinded visual assessment of each MRI study.
All pathologic substrates were associated with atrophy that involved the inferior and medial temporal and inferior frontal lobes. Additionally, specific VBM signatures were identified for each subgroup: FTD-U was associated with asymmetric (left > right) temporal lobe atrophy, PiD was associated with severe dorsolateral bifrontal atrophy, and tau exon 10+16 was associated with asymmetric (right > left) medial temporal lobe atrophy. The VBM findings were supported by blinded visual assessment.
These findings suggest that MRI patterns of regional gray matter atrophy constitute signatures of tissue pathology in FTD.
To test if arterial spin labeling (ASL) MRI could detect a pattern of hypoperfusion in frontotemporal dementia (FTD) vs cognitively normal (CN) control subjects; to determine the regional difference of perfusion between FTD and Alzheimer disease (AD); and to determine whether hypoperfusion in FTD correlates with cognitive impairment.
We included 21 patients with FTD, 24 patients with AD, and 25 CN subjects in this cross-sectional MRI study. All subjects had MRI scans including T1-weighted structural images and ASL-MR images.
ASL-MRI detected a pattern of hypoperfusion in right frontal regions in patients with FTD vs CN subjects, similar to PET and SPECT. FTD had higher perfusion than AD in the parietal regions and posterior cingulate. Frontal hypoperfusion in FTD correlated with deficits in judgment and problem solving. Adding frontal perfusion to gray matter (GM) atrophy significantly improved the classification of FTD from normal aging to 74%, and adding parietal perfusion to GM atrophy significantly improved the classification of FTD from AD to 75%. Combining frontal and parietal lobe perfusion further improved the classification of FTD from AD to 87%.
Frontotemporal dementia and Alzheimer disease display different spatial distributions of hypoperfusion on arterial spin labeling MRI. With further development and evaluation, arterial spin labeling MRI could contribute to the differential diagnosis between frontotemporal dementia and Alzheimer disease.
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.