A cognitive marker for Alzheimer disease pathology in primary progressive aphasia? A validation study in the clinical setting.

We validated in the clinical setting a putative clinical marker for a biological diagnosis of primary progressive aphasia (PPA) due to amyloid previously identified in an autopsy cohort and including impaired (score ≤4) digit span (DS) as index of phonological loop dysfunction and broadened criteria for logopenic PPA. In 29 PPA patients with an amyloid-positive (A+) biomarker and 28 PPA patients with an amyloid-negative (A-) biomarker, Receiver Operating Characteristics (ROC) curve analysis showed moderate specificity (71%) but insufficient sensitivity (41%) for the proposed marker. Specificity was particularly poor (58%) for the discrimination between A+ PPA and the A- subgroup with nonfluent PPA. DS may be compromised in both logopenic and nonfluent PPA, whose loci of neurodegeneration lie at the 2 ends of the left fronto-parieto-temporal system that underpins phonology. An Statistical Parametric Mapping (SPM) correlation analysis between DS score and metabolism on brain 18-fluoro-deoxy-glucose positron emission tomography also showed a major contribution of the left frontal cortex to impaired span.

Pure Prosodic Type of Primary Progressive Apraxia of Speech Mimicking Nonfluent Aphasia and Later Progressing to Corticobasal Syndrome.

Primary progressive apraxia of speech (PPAOS), a rare neurodedegenerative disorder, can be subdivided into predominant phonetic or prosodic type. Pure prosodic type of PPAOS as an isolated disorder has been hardly found. We present 2 cases of patients with pure prosodic PPAOS who initially were misdiagnosed as nonfluent variant of primary progressive aphasia and later turned out to be corticobasal syndrome. A 65-year-old woman and a 72-year-old man were referred to our speech-language clinic under the clinical impression of nonfluent variant of primary progressive aphasia. The neurological examinations revealed no definite abnormalities except for slow and effortful speech with the production of simple sentences. However, their receptive and expressive language abilities were normal. Their brain magnetic resonance imaging was unremarkable. We initially entertained the diagnosis of pure prosodic type of PPAOS. During several years of follow up, they gradually developed extrapyramidal symptoms which are compatible with corticobasal syndrome. The characteristics of the patients and the results of neuroimaging studies are discussed.

Automatic Subtyping of Individuals with Primary Progressive Aphasia.

BACKGROUND: The classification of patients with primary progressive aphasia (PPA) into variants is time-consuming, costly, and requires combined expertise by clinical neurologists, neuropsychologists, speech pathologists, and radiologists. OBJECTIVE: The aim of the present study is to determine whether acoustic and linguistic variables provide accurate classification of PPA patients into one of three variants: nonfluent PPA, semantic PPA, and logopenic PPA. METHODS: In this paper, we present a machine learning model based on deep neural networks (DNN) for the subtyping of patients with PPA into three main variants, using combined acoustic and linguistic information elicited automatically via acoustic and linguistic analysis. The performance of the DNN was compared to the classification accuracy of Random Forests, Support Vector Machines, and Decision Trees, as well as to expert clinicians' classifications. RESULTS: The DNN model outperformed the other machine learning models as well as expert clinicians' classifications with 80% classification accuracy. Importantly, 90% of patients with nfvPPA and 95% of patients with lvPPA was identified correctly, providing reliable subtyping of these patients into their corresponding PPA variants. CONCLUSION: We show that the combined speech and language markers from connected speech productions can inform variant subtyping in patients with PPA. The end-to-end automated machine learning approach we present can enable clinicians and researchers to provide an easy, quick, and inexpensive classification of patients with PPA.

Distinguishing logopenic from semantic & nonfluent variant primary progressive aphasia: Patterns of linguistic and behavioral correlations.

While language characteristics of logopenic variant primary progressive aphasia (lvPPA) are well-defined, behavioral characteristics are less understood. We investigated correlations between language and behavioral scores across three variants of primary progressive aphasia (PPA) and found language performance and behavioral disturbances are correlated in lvPPA, but not other PPA subtypes. Results suggest that unlike other PPA variants, patients diagnosed with lvPPA do not develop negative behaviors until language deficits are severe. This is consistent with the underlying neuropathology of lvPPA, Alzheimer's Disease. Such findings are crucial to clinical prognosis, especially when considering the progressive nature of this disease.

Frontotemporal Dementia: A Clinical Review.

Frontotemporal dementias are a clinically, neuroanatomically, and pathologically diverse group of diseases that collectively constitute an important cause of young-onset dementia. Clinically, frontotemporal dementias characteristically strike capacities that define us as individuals, presenting broadly as disorders of social behavior or language. Neurobiologically, these diseases can be regarded as "molecular nexopathies," a paradigm for selective targeting and destruction of brain networks by pathogenic proteins. Mutations in three major genes collectively account for a substantial proportion of behavioral presentations, with far-reaching implications for the lives of families but also potential opportunities for presymptomatic diagnosis and intervention. Predicting molecular pathology from clinical and radiological phenotypes remains challenging; however, certain patterns have been identified, and genetically mediated forms of frontotemporal dementia have spearheaded this enterprise. Here we present a clinical roadmap for diagnosis and assessment of the frontotemporal dementias, motivated by our emerging understanding of the mechanisms by which pathogenic protein effects at the cellular level translate to abnormal neural network physiology and ultimately, complex clinical symptoms. We conclude by outlining principles of management and prospects for disease modification.

Hereditary primary lateral sclerosis and progressive nonfluent aphasia.

OBJECTIVE: To report a kindred with an association between hereditary primary lateral sclerosis (PLS) and progressive nonfluent aphasia. PATIENTS AND METHODS: Six members from a kindred with 15 affected individuals spanning three generations, suffered from spasticity without muscle atrophy or fasciculation, starting in the lower limbs and spreading to the upper limbs and bulbar musculature, followed by effortful speech, nonfluent language and dementia, in 5 deceased members. Disease onset was during the sixth decade of life, or later. Cerebellar ataxia was the inaugural manifestation in two patients, and parkinsonism, in another. RESULTS: Neuropathological examination in two patients demonstrated degeneration of lateral corticospinal tracts in the spinal cord, without loss of spinal, brainstem, or cerebral motor neurons. Greater loss of corticospinal fibers at sacral and lumbar, rather than at cervical or medullary levels was demonstrated, supporting a central axonal dying-back pathogenic mechanism. Marked reduction of myelin and nerve fibers in the frontal lobes was also present. Argyrophilic grain disease and primary age-related tauopathy were found in one case each, and considered incidental findings. Genetic testing, including exome sequencing aimed at PLS, ataxia, hereditary spastic paraplegia, and frontotemporal lobe dementia, triplet-repeated primed polymerase chain reaction aimed at dominant spinocerebellar ataxias, and massive sequencing of the human genome, yielded negative results. CONCLUSION: A central distal axonopathy affecting the corticospinal tract, exerted a pathogenic role in the dominantly inherited PLS-progressive nonfluent aphasia association, described herein. Further molecular studies are needed to identify the causative mutation in this disease.

Emergence of artistic talent in progressive nonfluent aphasia: a case report.

Some patients with frontotemporal lobar degeneration have developed artistic skills after the onset mainly in painting and music. Most of these cases have semantic dementia (SD), one of the frontotemporal lobar degeneration subtypes. In previously reported cases, the paintings made by patients with SD were usually hyper realistic, without a significant symbolic or abstract component. Here, we report on a patient with progressive nonfluent aphasia (PNFA), another frontotemporal lobar degeneration subtype, who started making creative bamboo crafts after PNFA onset. His techniques were completely his original; he devised the shapes of the crafts and made them without samples. His work did not become an obsessive preoccupation. The artistic style expressed by patients with PNFA differs from that expressed by patients with SD. Therefore, the underlying mechanisms for the emergence of artistic talent might differ between SD and PNFA.

A case of progressive non-fluent aphasia as onset of amyotrophic lateral sclerosis with frontotemporal dementia.

The association between Amyotrophic Lateral Sclerosis (ASL) and FrontoTemporal Dementia (FTD) is well known. Most of reports describing ASL-FTD cases show a strong association between ALS and the behavioural form of FTD. Conversely, the association between ALS and pure Semantic Dementia or Progressive Non-Fluent Aphasia (PNFA) is extremely rare, ranging from 1 to 3%. A clinical phenotype characterized by a rapidly progressive aphasic dementia and motoneuron disease (MND) has been described in few case reports; since the updating of PNFA diagnostic criteria in 2011, no clinical report has been related. We want to describe a case of patient presented, at the onset, as PNFA who developed, one year later, ALS with bulbar onset. The patient was screened for the main genes causing or associated with MND and/or dementia but no variants with a pathogenetic effect were observed.

Sentence composition ability in two patients with non-fluent/agrammatic variant primary progressive aphasia.

Agrammatism is one of the core clinical features of non-fluent/agrammatic variant primary progressive aphasia, and it has traditionally been considered the hallmark of non-fluent aphasia in Western countries. However, agrammatic speech may remain undetected in Japanese patients because of the agglutinative structure of the language and high flexibility in word order. In the present study, we aimed to analyze agrammatism in the speech production of Japanese patients with aphasia due to neurodegenerative disease using an anagram test generated by our laboratory. Four patients were recruited from the dementia clinic at Tohoku University Hospital between December 2014 and August 2015: two patients with non-fluent/agrammatic variant primary progressive aphasia, one with semantic variant primary progressive aphasia, and one with probable Alzheimer's disease experiencing episodic memory impairment accompanied by transcortical sensory aphasia. All patients underwent thorough neurological and neuropsychological testing before performing a Japanese anagram task based on the Northwestern Anagram Test. Our findings indicated that the two patients with non-fluent/agrammatic variant primary progressive aphasia exhibited poorer performance on the anagram task than the remaining two patients. Therefore, the anagram test used in the present study may aid in detecting output aspects of agrammatism in Japanese patients with aphasia, although future studies are required to develop a standardized version of test.

Afasia progresiva primaria: aspectos clínicos y diagnósticos / No disponible

La Degeneración Lobar Frontotemporal (DLFT) es una entidad neurodegenerativa heterogénea que abarca varios síndromes clínicos diferenciados según su fenotipo, el cual viene determinado por la distribución neuropatológica inicial (frontal o bien temporal), y en los que una alteración progresiva del lenguaje es un hallazgo fundamental. Esto es así especialmente en la variante temporal de la DLFT que también se conoce como Afasia Progresiva Primaria (APP), y que tiende a presentar neuropatología de complejo Pick/Demencia Frontotemporal, o bien de enfermedad de Alzheimer. La APP se caracteriza por debutar con una alteración progresiva del lenguaje que causa un trastorno de la funcionalidad, y con una conservación inicial de otras funciones cognitivas. Aunque los pacientes con APP suelen ser derivados a neurólogos, es importante que los psicogeriatras, y especialmente aquéllos que trabajan con pacientes con demencia, estén familiarizados con este síndrome y que sepan valorar de forma adecuada el lenguaje como función cognitiva. Los pacientes con APP suelen también presentar trastornos de naturaleza neuroconductual y psiquiátrica, y por esta razón, el rol del psicogeriatra será fundamental en su valoración y su tratamiento

Complaints about poor memory and cognitive function found not to be due to dementia are common in the general population, and they are a reason for consultation in primary care and of referrals to specialist services. This could increase the risk of overdiagnosing dementia in a proportion of patients. Various clinical entities that present with mild to moderate memory dysfunction and their possible pathophysiological mechanisms are reviewed in this paper, with the aim to assist the clinician in the differential diagnosis, the consideration of their risk of conversion to dementia, and in deciding on their best possible management

The midbrain-to-pons ratio distinguishes progressive supranuclear palsy from non-fluent primary progressive aphasias.

BACKGROUND AND PURPOSE: To determine the clinical utility of the midbrain-to-pons (M/P) ratio as a clinical biomarker of progressive supranuclear palsy (PSP) in patients with non-fluent primary progressive aphasia syndromes. METHODS: Patients with PSP, progressive non-fluent aphasia (PNFA) and logopenic progressive aphasia (LPA) were recruited. Patients were diagnosed clinically, but pathological confirmation was available in a proportion of patients. Midbrain and pons areas were measured using Osirix Lite, a free DICOM viewer. The M/P ratio and Magnetic Resonance Parkinsonism Index were calculated and their diagnostic utility compared. RESULTS: A total of 72 participants were included (16 PSP, 18 PNFA, 16 LPA and 22 controls). Patients with PSP had motor features typical of the syndrome. Both the M/P ratio and Magnetic Resonance Parkinsonism Index differed significantly in PSP compared with controls. The M/P ratio was disproportionately reduced in PSP compared with PNFA and LPA (PSP, 0.182 ± 0.043; PNFA, 0.255 ± 0.034; LPA, 0.258 ± 0.033; controls, 0.292 ± 0.031; P < 0.001). An M/P ratio of ≤0.215 produced a positive predictive value of 77.8% for the diagnosis of PSP syndrome. Pathological examination revealed Alzheimer's disease in three cases (all LPA), pathological PSP in two cases (one clinical PSP and one PNFA) and corticobasal degeneration in one case (PNFA). The M/P ratio was ≤0.215 in both pathological cases of PSP. CONCLUSIONS: The M/P ratio was disproportionately reduced in PSP, suggesting its potential as a clinical marker of the PSP syndrome. Larger studies of pathologically confirmed cases are needed to establish the M/P ratio as a biomarker of PSP pathology.

Behavioural and neuropsychiatric disturbance in three clinical subtypes of frontotemporal dementia: A Clinical Research Center for Dementia of South Korea-FTD Study.

OBJECTIVES: To characterise the behavioural and neuropsychiatric disturbances of patients with three clinical subtypes of frontotemporal dementia (FTD): behavioural variant FTD (bvFTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA). METHODS: Consecutive series of 66 patients with bvFTD, 58 patients with SD and 21 patients with PNFA were compared using the Frontal Behavioural Inventory (FBI) and the Neuropsychiatric Inventory (NPI). RESULTS: Patients with bvFTD had more behavioural and neuropsychiatric disturbances than patients with PNFA based on the total scores of FBI and NPI. When comparing subtotal and item scores of FBI and NPI, there were some significant differences among three clinical subtypes of FTD. CONCLUSION: There are some distinct patterns of behavioural and neuropsychiatric disturbance among three clinical subtypes of FTD.

[Frontotemporal dementia].

Frontotemporal dementia (FTD) refers to the clinical syndromes caused by various neurodegenerative diseases in the frontal and temporal lobes. Advances in the knowledge and understanding of these diseases have resulted in changes in the clinical as well as the genetic and pathological classification. This is a short review of the current classification and understanding of FTD.

Temporal acoustic measures distinguish primary progressive apraxia of speech from primary progressive aphasia.

The purpose of this study was to determine if acoustic measures of duration and syllable rate during word and sentence repetition, and a measure of within-word lexical stress, distinguish speakers with primary progressive apraxia of speech (PPAOS) from nonapraxic speakers with the agrammatic or logopenic variants of primary progressive aphasia (PPA), and control speakers. Results revealed that the PPAOS group had longer durations and reduced rate of syllable production for most words and sentences, and the measure of lexical stress. Sensitivity and specificity indices for the PPAOS versus the other groups were highest for longer multisyllabic words and sentences. For the PPAOS group, correlations between acoustic measures and perceptual ratings of AOS were moderately high to high. Several temporal measures used in this study may aid differential diagnosis and help quantify features of PPAOS that are distinct from those associated with PPA in which AOS is not present.

Afasia progresiva logopénica asociada a enfermedad de Parkinson idiopática / Logopenic progressive aphasia associated with idiopathic Parkinson's disease

No disponible

A multimodal neuroimaging study of a case of crossed nonfluent/agrammatic primary progressive aphasia.

Crossed aphasia has been reported mainly as post-stroke aphasia resulting from brain damage ipsilateral to the dominant right hand. Here, we described a case of a crossed nonfluent/agrammatic primary progressive aphasia (nfvPPA), who developed a corticobasal syndrome (CBS). We collected clinical, cognitive, and neuroimaging data for four consecutive years from a 55-year-old right-handed lady (JV) presenting with speech disturbances. 18-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) and DaT-scan with (123)I-Ioflupane were obtained. Functional MRI (fMRI) during a verb naming task was acquired to characterize patterns of language lateralization. Diffusion tensor MRI was used to evaluate white matter damage within the language network. At onset, JV presented with prominent speech output impairment and right frontal atrophy. After 3 years, language deficits worsened, with the occurrence of a mild agrammatism. The patient also developed a left-sided mild extrapyramidal bradykinetic-rigid syndrome. The clinical picture was suggestive of nfvPPA with mild left-sided extrapyramidal syndrome. At this time, voxel-wise SPM analyses of (18)F-FDG PET and structural MRI showed right greater than left frontal hypometabolism and damage, which included the Broca's area. DaT-scan showed a reduced uptake in the right striatum. FMRI during naming task demonstrated bilateral language activations, and tractography showed right superior longitudinal fasciculus (SLF) involvement. Over the following year, JV became mute and developed frank left-sided motor signs and symptoms, evolving into a CBS clinical picture. Brain atrophy worsened in frontal areas bilaterally, and extended to temporo-parietal regions, still with a right-sided asymmetry. Tractography showed an extension of damage to the left SLF and right inferior longitudinal fasciculus. We report a case of crossed nfvPPA followed longitudinally and studied with advanced neuroimaging techniques. The results highlight a complex interaction between individual premorbid developmental differences and the clinical phenotype.

Frontotemporal dementia: diagnosis, deficits and management.

Frontotemporal dementia (FTD) is a progressive neurologic syndrome with diverse clinical presentations and attendant underlying pathologies. Psychiatric prodrome, neuropsychiatric symptoms and language difficulties are common in FTD, but the diversity of presentation raises unique diagnostic challenges that can significantly impact patient care and counsel for caregivers regarding clinical status and prognosis. While neuropsychiatric symptom measures are helpful, more sensitive assessments delineating the specific behavioral and linguistic deficits accompanying FTD are needed. Comprehensive clinical assessment in combination with evaluation of language, socio-emotional functioning, cognition and neuroimaging aid in accurate and early diagnosis and treatment planning. In what follows, we review each of the FTD syndromes, highlight current research investigating the cognitive, behavioral and socio-emotional deficits observed with this disease, address common diagnostic challenges and summarize best practices associated with management of FTD.