Frontal deficits differentiate progressive supranuclear palsy from Parkinson's disease

The clinical differentiation of progressive supranuclear palsy from Parkinson's disease can be challenging, due to overlapping clinical features and a lack of diagnostic markers. Abnormalities in cognitive function form part of the clinical spectrums of these diseases and distinctive cognitive profiles may be helpful in differentiating these diseases in the diagnostic period. A comprehensive neuropsychological test battery was administered to 12 patients with clinically diagnosed progressive supranuclear palsy and 12 patients with Parkinson's disease matched for age and disease duration. Effect size (Cohen's d) was calculated for cognitive tests that were significantly different between groups. Patients with progressive supranuclear palsy performed significantly worse than those with Parkinson's disease on measures of processing speed, verbal fluency, planning, verbal abstract reasoning, verbal memory, and made more perseverative responses on a set shifting task. Measures of executive function, manual dexterity and processing speed were most diagnostically useful (Cohen's d > 2.0) in differentiating between progressive supranuclear palsy and Parkinson's disease. These findings suggest that more severe and prominent ‘frontal’ cognitive deficits in patients with progressive parkinsonism would be helpful in predicting progressive supranuclear palsy rather than Parkinson's disease and these findings may contribute to the development of diagnostic criteria.     

Changing perspectives on frontotemporal dementia: A review

This article examines the evolution in understanding of frontotemporal dementia (FTD) during the last four decades. A central theme is the recognition of heterogeneity. Originally construed as a disorder of behaviour and executive impairment, FTD is now known also to be associated with alterations in language, conceptual knowledge and praxis. An absence of neurological signs is the hallmark of many FTD patients, but there is also an established association with motor neurone disease (MND), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). FTD is commonly defined as an early onset dementia, yet about a quarter of patients present after the age of 65. The underlying pathological protein is tau, TDP-43 or more rarely fused-in-sarcoma (FUS). Distinct genetic mutations have been identified in familial FTD. There are predictable relationships between clinical phenotype, pathological substrate and genetic mutation. For example, a circumscribed semantic disorder predicts TDP-43 pathology, and speech or limb apraxia tau pathology. The co-occurrence of MND predicts TDP-43 pathology, and PSP and CBD tau pathology. FUS pathology is associated with very youthful onset, stereotyped behaviours and caudate atrophy. Non-fluent aphasia is linked to progranulin (GRN) mutations and MND and psychosis to repeat expansions in the C9orf72 gene. Despite striking worldwide consensus in findings there remain some issues of contention, largely related to the classification of FTD and its sub-variants. Understanding the diverse nature of FTD is crucial for effective diagnosis, management and the development of targeted therapies.     

Sound naming in neurodegenerative disease

Modern cognitive neuroscientific theories and empirical evidence suggest that brain structures involved in movement may be related to action-related semantic knowledge. To test this hypothesis, we examined the naming of environmental sounds in patients with corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), two neurodegenerative diseases associated with cognitive and motor deficits. Subjects were presented with 56 environmental sounds: 28 sounds were of objects that required manipulation when producing the sound, and 28 sounds were of objects that required no manipulation. Subjects were asked to provide the name of the object that produced the sound and also complete a sound-picture matching condition. Subjects included 33 individuals from four groups: CBD/PSP, Alzheimer disease, frontotemporal dementia, and normal controls. We hypothesized that CBD/PSP patients would exhibit impaired naming performance compared with controls, but the impairment would be most apparent when naming sounds associated with actions. We also explored neural correlates of naming environmental sounds using voxel-based morphometry (VBM) of brain MRI. As expected, CBD/PSP patients scored lower on environmental sounds naming (p < 0.007) compared with the controls. In particular, the CBD/PSP patients scored the lowest when naming sounds of manipulable objects (p < 0.05), but did not show deficits in naming sounds of non-manipulable objects. VBM analysis across all groups showed that performance in naming sounds of manipulable objects correlated with atrophy in the left pre-motor region, extending from area six to the middle and superior frontal gyrus. These results indicate an association between impairment in the retrieval of action-related names and the motor system, and suggest that difficulty in naming manipulable sounds may be related to atrophy in the pre-motor cortex. Our results support the hypothesis that retrieval of action-related semantic knowledge involves motor regions in the brain.     

Too much to count on: impaired very small numbers in corticobasal degeneration

Patients with corticobasal degeneration (CBD) have calculation impairments. This study examined whether impaired number knowledge depends on verbal mediation. We focused particularly on knowledge of very small numbers, where there is a precise relationship between a cardinality and its number concept, but little hypothesized role for verbal mediation. We evaluated accuracy and reaction time (RT) for matching dot arrays and Arabic numerals involving smaller (2-4) and larger (5-9) cardinalities in non-aphasic patients with CBD (n=16), frontotemporal dementia (FTD; n=23), and healthy controls (n=15). CBD were less accurate and slowed at judging smaller Arabic numeral-dot array stimuli compared to FTD patients and controls. Moreover, only CBD showed longer RTs judging successively larger number-dot array pairs among the smaller cardinalities. Difficulty judging very small numbers is impaired in CBD, suggesting degraded representation of precise number knowledge that does not depend on language functioning.     

Progressive agraphia can be a harbinger of degenerative dementia

By investigating three patients with progressive agraphia, we explored the possibility that this entity is an early sign of degenerative dementia. Initially, these patients complained primarily of difficulties writing Kanji (Japanese morphograms) while other language and cognitive impairments were relatively milder. Impairments in writing Kana (Japanese syllabograms), verbal language, executive function, visuo- and visuospatial cognition and memory were identified by neuropsychological testing. The agraphia was compatible with a peripheral type, based on deficits at the interface between the central letter selection and the graphemic motor execution (Patient 1) or at the stage of central letter selection as well (Patients 2 and 3). Agraphia was generally more prominent, although not exclusive, for Kanji probably because of later acquisition and larger total number of Kanji letters leading to lower frequency of use and familiarity per letter. Concurrent or subsequent emergence of non-fluent aphasia, ideomotor apraxia, executive dysfunction and asymmetric akinetic-rigid syndrome in two patients suggested degenerative processes involving the parietal-occipital-temporal regions, basal ganglia and striato-frontal projections. We propose that progressive agraphia may be one of the early symptoms of degenerative dementia such as corticobasal degeneration.     

Disturbance of Emotion Processing in Frontotemporal Dementia: A Synthesis of Cognitive and Neuroimaging Findings

Accurate processing of emotional information is a critical component of appropriate social interactions and interpersonal relationships. Disturbance of emotion processing is present in frontotemporal dementia (FTD) and is a clinical feature in two of the three subtypes: behavioural-variant FTD and semantic dementia. Emotion processing in progressive nonfluent aphasia, the third FTD subtype, is thought to be mostly preserved, although current evidence is scant. This paper reviews the literature on emotion recognition, reactivity and expression in FTD subtypes, although most studies focus on emotion recognition. The relationship between patterns of emotion processing deficits and patterns of neural atrophy are considered, by integrating evidence from recent neuroimaging studies. The review findings are discussed in the context of three contemporary theories of emotion processing: the limbic system model, the right hemisphere model and a multimodal system of emotion. Results across subtypes of FTD are most consistent with the multimodal system model, and support the presence of somewhat dissociable neural correlates for basic emotions, with strongest evidence for the emotions anger and sadness. Poor emotion processing is evident in all three subtypes, although deficits are more widespread than what would be predicted based on studies in healthy cohorts. Studies that include behavioural and imaging data are limited. Future investigations combining these approaches will help improve the understanding of the neural network underlying emotion processing. Presently, longitudinal investigations of emotion processing in FTD are lacking, and studies investigating emotion processing over time are critical to understand the clinical manifestations of disease progression in FTD.     

Primary Progressive Aphasias and Their Contribution to the Contemporary Knowledge About the Brain-Language Relationship

Primary progressive aphasia (PPA), typically resulting from a neurodegenerative disease such as frontotemporal dementia/Pick Complex or Alzheimer’s disease, is a heterogeneous clinical condition characterized by a progressive loss of specific language functions with initial sparing of other cognitive domains. Based on the constellation of symptoms, PPA has been classified into a nonfluent, semantic, or logopenic variant. This review of the literature aims to characterize the speech and language impairment, cognition, neuroimaging, pathology, genetics, and epidemiology associated with each of these variants. Some therapeutic recommendations, theoretical implications, and directions for future research have been also provided.     

Quantifier comprehension in corticobasal degeneration

In this study, we investigated patients with focal neurodegenerative diseases to examine a formal linguistic distinction between classes of generalized quantifiers, like "some X" and "less than half of X." Our model of quantifier comprehension proposes that number knowledge is required to understand both first-order and higher-order quantifiers. The present results demonstrate that corticobasal degeneration (CBD) patients, who have number knowledge impairments but little evidence for a deficit understanding other aspects of language, are impaired in their comprehension of quantifiers relative to healthy seniors, Alzheimer's disease (AD) and frontotemporal dementia (FTD) patients [F(3,77)=4.98; p<.005]. Moreover, our model attempts to honor a distinction in complexity between classes of quantifiers such that working memory is required to comprehend higher-order quantifiers. Our results support this distinction by demonstrating that FTD and AD patients, who have working memory limitations, have greater difficulty understanding higher-order quantifiers relative to first-order quantifiers [F(1,77)=124.29; p<.001]. An important implication of these findings is that the meaning of generalized quantifiers appears to involve two dissociable components, number knowledge and working memory, which are supported by distinct brain regions.     

An overview on Primary Progressive Aphasia and its variants

We present a review of the literature on Primary Progressive Aphasia (PPA) together with the analysis of neuropschychological and neuroradiologic profiles of 42 PPA patients. Mesulam originally defined PPA as a progressive degenerative disorder characterized by isolated language impairment for at least two years. The most common variants of PPA are: 1) Progressive nonfluent aphasia (PNFA), 2) semantic dementia (SD), 3) logopenic progressive aphasia (LPA). PNFA is characterized by labored speech, agrammatism in production, and/or comprehension. In some cases the syndrome begins with isolated deficits in speech. SD patients typically present with loss of word and object meaning and surface dyslexia. LPA patients have word-finding difficulties, syntactically simple but accurate language output and impaired sentence comprehension. The neuropsychological data demonstrated that SD patients show the most characteristic pattern of impairment, while PNFA and LPA overlap within many cognitive domains. The neuroimaging analysis showed left perisylvian region involvement. A comprehensive cognitive, neuroimaging and pathological approach is necessary to identify the clinical and pathogenetic features of different PPA variants.     

Neuropsychological Differences Between Frontotemporal Dementia and Alzheimer's Disease: A Review

This paper surveys the similarities and differences between frontotemporal dementia (FTD) and Alzheimer's disease (AD). The review covers findings primarily from neuropsychological studies on memory, language, attention/executive function, and visuospatial abilities. However, neuropsychiatric and neuroimaging data are also briefly discussed. Distinguishing features of both FTD and AD are described in order to present a comprehensive clinical picture of these dementing diseases, which is essential for the process of differential diagnosis. The cause of specific cognitive deficits is also considered. Our comprehensive review of the empirical literature reveals that AD is characterized by early memory loss and visuospatial problems, while among the main features of FTD are behavioral abnormalities and executive dysfunctions.     

Schizophrenia: Disease,Syndrome, or Dimensions?

Schizophrenia has the status of a clinical syndrome and may comprise a number of specific disease entities. This construct is similar to dementia, in which several diseases have been defined within the syndrome. Alternatively, schizophrenia may be a single disease entity with quite variable manifestations across cases. Kraepelin proposed dementia praecox as a disease entity, and Bleuler proposed dissociative pathology as fundamental to each case, thus substantiating the single disease entity concept. More recently, the nuclear schizophrenia construct defined the disease entity using specific criteria proposed by Schneider and Langfeldt. This view has been challenged by a series of studies during the past three decades. These investigations are summarized in this report. Implications for clinical work with families are considered.     

Neuropsychological assessment could distinguish among different clinical phenotypes of progressive supranuclear palsy: A Machine Learning approach

Progressive supranuclear palsy (PSP) is a rare, rapidly progressive neurodegenerative disease. Richardson’s syndrome (PSP-RS) and predominant parkinsonism (PSP-P) are characterized by wide range of cognitive and behavioural disturbances, but these variants show similar cognitive pattern of alterations, leading difficult differential diagnosis. For this reason, we explored with an Artificial Intelligence approach, whether cognitive impairment could differentiate the phenotypes. Forty Parkinson's disease (PD) patients, 25 PSP-P, 40 PSP-RS, and 34 controls were enrolled following the consensus criteria diagnosis. Participants were evaluated with neuropsychological battery for cognitive domains. Random Forest models were used for exploring the discriminant power of the cognitive tests in distinguishing among the four groups. The classifiers for distinguishing diseases from controls reached high accuracies (86% for PD, 95% for PSP-P, 99% for PSP-RS). Regarding the differential diagnosis, PD was discriminated from PSP-P with 91% (important variables: HAMA, MMSE, JLO, RAVLT_I, BDI-II) and from PSP-RS with 92% (important variables: COWAT, JLO, FAB). PSP-P was distinguished from PSP-RS with 84% (important variables: JLO, WCFST, RAVLT_I, Digit span_F). This study revealed that PSP-P, PSP-RS and PD had peculiar cognitive deficits compared with healthy subjects, from which they were discriminated with optimal accuracies. Moreover, high accuracies were reached also in differential diagnosis. Most importantly, Machine Learning resulted to be useful to the clinical neuropsychologist in choosing the most appropriate neuropsychological tests for the cognitive evaluation of PSP patients.     

Decision making cognition in primary progressive aphasia

We sought to investigate the decision making profile of Primary Progressive Aphasia (PPA) by assessing patients diagnosed with this disease (n = 10), patients diagnosed with behavioral variant frontotemporal dementia (bvFTD, n = 35), and matched controls (n = 14) using the Iowa Gambling Task, a widely used test that mimics real-life decision making. Participants were also evaluated with a complete neuropsychological battery. Patients with PPA were unable to adopt an advantageous strategy on the IGT, which resulted in a flat performance, different to that exhibited by both controls (who showed advantageous decision making) and bvFTD patients (who showed risk-appetitive behavior). The decision making profile of PPA patients was not associated with performance on language tasks and did not differ between sub-variants of the disease (namely, semantic dementia and progressive nonfluent aphasia). Investigating decision making in PPA is crucial both from a theoretical perspective, as it can shed light about the way in which language interacts with other cognitive functions, as well as a clinical standpoint, as it could lead to a more objective detection of impairments of decision making deficits in this condition.     

Phonological and articulatory impairment in Alzheimer's disease: a case series

We demonstrate that phonological and articulatory impairments may occur at presentation or early in the course of Alzheimer's disease, contrary to claims that these aspects of language production are relatively preserved until the final stages of this disease. Six patients with pathologically confirmed Alzheimer's disease (AD) and four patients with clinically diagnosed dementia of the Alzheimer's type (DAT) presented with one of five different clinical profiles: nonfluent progressive aphasia, mixed progressive aphasia, progressive aphasia diagnosed as DAT from neuropsychological assessment, initial amnestic syndrome with prominent phonological errors, and biparietal syndrome. Analysis of their conversational speech, single-word production, and performance of highly familiar series speech tasks such as counting revealed false start errors, phonological paraphasias, and/or articulatory difficulty. Neuropathological changes were located in left perisylvian regions consistent with speech and language impairment but atypical for Alzheimer's disease.     

Insight in frontotemporal dementia: conceptual analysis and empirical evaluation of the consensus criterion "loss of insight" in frontotemporal dementia

The objective of this study was to suggest a new formulation of the core research diagnostic consensus criterion "loss of insight" in frontotemporal dementia (FTD). Eight patients with FTD (diagnoses made by interviews, medical and neuropsychological examination, CT scan, and regional cerebral glucose metabolism measured by positron emission tomography (PET) participated in the study). The results indicated that insight was present in three out of eight patients, and that insight appears to be a heterogeneous concept. Two types of insight emerged: Emotional insight associated with frontotemporal functions, and cognitive insight, related to posterior cognitive functions. These results suggest that loss of insight should not serve as a core criterion on FTD, but serves well as a supportive criterion of the disease.     

Naming of grammatical classes in frontotemporal dementias: linguistic and non linguistic factors contribute to noun-verb dissociation

We studied noun and verb naming in three main variants of frontotemporal dementia: the frontal variant(Fv-FTD), primary progressive aphasia (PPA) and semantic dementia (SD). We further distinguished PPA in nonfluent and fluent forms and restricted diagnosis of SD to subjects with progressive semantic breakdown leading to agnosia for words and objects. Fv-FTD and nonfluent-PPA named objects better than actions, SD showed an inverse dissociation and no specific pattern emerged in fluent-PPA. In this last group, in spite of the broad definition of fluent aphasia, quite heterogeneous patterns of language disorders and word class dissociation emerged when single-subject analyses were performed. In fv-FTD correlations between executive tasks and action naming were stronger than between executive tasks and object naming. We conclude that both linguistic and non linguistic factors, in particular an executive deficit, contribute to grammatical class dissociation. We also suggest that the fluent vs. nonfluent distinction does not reflect the complexity of primary aphasia.     

The role of behavior analysis in the rehabilitation of persons with dementia

With the rapidly aging population, it is expected that increases in cases of dementia will double over the next 20 years. Currently, there is no cure for diseases such as Alzheimer's disease or frontotemporal dementia (FTD) that cause progressive dementia, and only a few pharmacological interventions that slow the progression of the decline exist. Given that there is no cure available, a rehabilitation approach that emphasizes maintaining existing abilities and removing excess disability (as opposed to emphasizing cure or recovery) for as long as possible is warranted. The current paper proposes that nonpharmacological rehabilitation efforts need to target 5 broad areas/targets: memory enhancement, altering social contingencies and communication styles, improving self-care skills, the arrangement of physical environments to maintain and improve functioning, and increasing physical fitness/physical activity. The purpose of this paper is to review specific behaviorally oriented interventions that target these 5 areas and show promise for inclusion in comprehensive rehabilitation efforts for individuals with dementia.     

Genetic Counseling Dilemmas for a Patient with Sporadic Amyotrophic Lateral Sclerosis,Frontotemporal Degeneration &amp; Parkinson’s Disease

Amyotrophic lateral sclerosis (ALS), frontotemporal degeneration and Parkinson’s disease may be different expressions of the same neurodegenerative disease. However, association between ALS and parkinsonism-dementia complex (ALS-PDC) has only rarely been reported apart from the cluster detected in Guam. We report a patient presenting with ALS-PDC in whom pathological mutations/expansions were investigated. No other family members were reported to have any symptoms of a neurological condition. Our case demonstrates that ALS-PDC can occur as a sporadic disorder, even though the coexistence of the three clinical features in one patient suggests a single underlying genetic cause. It is known that genetic testing should be preferentially offered to patients with ALS who have affected first or second-degree relatives. However, this case illustrates the importance of genetic counseling for family members of patients with sporadic ALC-PDC in order to provide education on the low recurrence risk. Here, we dicuss the ethical, psychological and practical consequences for patients and their relatives.     

Structural and Functional Meta-analytic Evidence for Fronto-subcortical System Deficit in Progressive Supranuclear Palsy

Meta-analytic methods were used to determine the most sensitive indexes to fronto-subcortical deficit in progressive supranuclear palsy (PSP) and to further characterize the neurocognitive and related features of PSP that can provide a basis of comparison to other disorders with prominent subcortical brain lesions. Studies dating back to 1984 were gathered and calibrated to compare the neuropsychological, neuroimaging, and neurophysiological test results from 229 patients with PSP, and 357 healthy controls. The tests most sensitive to fronto-subcortical deficit in PSP were mostly neuropsychological measures that include such tests as the Stroop Task, Trail Making Test Part A, and Purdue pegboard performance. We conclude that although neuropsychological measures may be most sensitive to deficits in PSP, they are also less specific and valid indicators of fronto-subcortical brain system integrity.