Progressive nonfluent aphasia and its characteristic motor speech deficits

Progressive nonfluent aphasia (PNFA) is a clinical syndrome characterized by motor speech impairment and agrammatism, with relative sparing of single word comprehension and semantic memory. PNFA has been associated with the characteristic pattern of left anterior insular and posterior frontal atrophy, including the motor and premotor regions and Broca's area. Postmortem histopathologic evidence has shown that PNFA is usually associated with tau pathology, although focal Alzheimer disease pathology and tau-negative, ubiquitin-TDP-43 inclusions also have been reported in association with this clinical syndrome. We performed a detailed analysis of motor speech errors in 18 patients with PNFA and investigated their neural correlates using voxel-based morphometry on magnetic resonance imaging scans. Seven patients demonstrated only apraxia of speech (AOS) errors, whereas 11 showed AOS along with dysarthria. Slow rate of speech, effortful articulation with groping, and consonant distortions were the most common AOS errors. Hypernasality was the most represented dysarthric feature and dysarthria was most often classified as spastic, hypokinetic, or mixed spastic-hypokinetic. Neuroimaging results demonstrated that patients with AOS-only and AOS plus dysarthria showed atrophy in the left posterior frontal, anterior insular, and basal ganglia regions when compared with controls. Patients with AOS plus dysarthria showed greater damage than patients with AOS-only in the left face portion of primary motor cortex and left caudate. PNFA is a distinct frontotemporal lobar degeneration clinical syndrome associated with characteristic clinical, neuroimaging, and pathologic features. The clinical features are driven by the severity of left frontal and caudate damage.     

Primary Progressive Aphasia and Alzheimer’s Disease: Brief History, Recent Evidence

Primary progressive aphasia (PPA) has been recognized as a syndrome distinct from the usual pattern of language deterioration in Alzheimer??s disease and typically more related to the pathology of frontotemporal dementia (FTD). In recent years, however, the syndromes of primary progressive aphasia have become more complex, divided into the three subtypes of progressive nonfluent aphasia (PNFA), semantic dementia (SD), and logopenic/phonological progressive aphasia (LPA). These syndromes have not only made the linguistic analysis more complex, but the associated pathologies have also become more variable. In particular, PNFA is usually, but not always, associated with FTD pathology and often evidence of a tau mutation, but rarely AD; SD is usually associated with FTD of the ubiquitin staining or progranulin (TAR-DNA) mutation type, but, again, occasionally AD; LPA is typically associated with AD pathology. Patterns of atrophy on magnetic resonance imaging (MRI) generally conform to these subtypes, with PNFA associated with left frontal and insular atophy, SD associated with bilateral temporal atrophy, and LPA associated with L superior-posterior temporal and parietal atrophy. These patterns can also be seen on positron emission (PET) scanning with fluorodeoxyglucose. The newer amyloid binding ligand PET technologies are less useful for detecting regional atrophy patterns but more useful for indication of the underlying pathology. We can thus speak of syndromes of PPA or underlying pathological bases of PPA.     

Clinical features of frontotemporal dementia

What was once called Pick's disease has three major anatomic variants. With all three, frontotemporal brain is selectively injured whereas posterior cortical regions are spared. These three clinical patterns include a bifrontal, slightly asymmetric subtype with more involvement of the right frontotemporal region called frontotemporal dementia or the frontal variant of FTD (fvFTD), a temporal-predominant subtype called the temporal variant of FTD or semantic dementia (SD), and a left frontal-predominant subtype called progressive nonfluent aphasia (PNFA). The three anatomic groups help to classify distinctive clinical syndromes with unique features. Careful study of these subtypes of frontotemporal dementia, using combinations of new quantitative neuroimaging, behavioral and physiological measures are yielding important information about the functioning of the brain's frontal and temporal regions. As we come to better understand the biologic basis for the three FTD clinical syndromes, new classification schemas may emerge, but our current clinical criteria serve as a strong guide to the diagnosis and separation of FTD from Alzheimer disease and other dementias.     

Confrontation naming and morphometric analyses of structural MRI in frontotemporal dementia

We studied the neural basis for confrontation naming difficulty in 29 patients with frontotemporal dementia (FTD) by correlating naming with voxel-based morphometric analyses of gray matter volume in structural MRI. We found that naming is significantly impaired in FTD, including patients with semantic dementia (SD), progressive nonfluent aphasia (PNFA), and nonaphasic patients (NON-APH) with a disorder of social and executive functioning. Significant cortical atrophy was found in the left anterior temporal cortex in all three FTD subgroups relative to healthy seniors. We also found significant cortical atrophy in unique anatomic distributions in each FTD subgroup. This included: lateral, ventral, and parahippocampal regions of the left temporal lobe in SD; inferior, orbital, dorsolateral, and premotor regions of the left frontal lobe in PNFA, and bilateral frontal regions in NON-APH. Direct correlations between confrontation naming and gray matter volume revealed distinct patterns in each FTD subgroup. SD patients showed a significant correlation in the left lateral temporal cortex, PNFA patients in several left frontal regions, and NON-APH patients in the right dorsolateral prefrontal cortex. These findings suggest that confrontation naming is supported by a large-scale neural network, and that naming is compromised in FTD due to interruption of the network in several different ways.     

原发性进行性失语的临床、影像及语言特征

目的 探讨原发性进行性失语（PPA）的临床、影像及语言特征.方法 PPA患者7例,其中语义性痴呆（SD）6例,进行性非流利性失语（PNFA）1例,收集患者的人口学资料、病史,进行头MRI检查,采用汉语失语成套测验进行语言评估.结果 患者平均发病年龄56岁,均缓慢起病,以语言表达、命名障碍为首发症状.MRI示左侧颞极萎缩为主,病程长的患者左侧额叶和顶叶、右侧颞叶也明显萎缩.语言评估发现所有患者的自发语言、复述、命名、听理解、阅读和书写均不同程度损害.SD患者言语流利,复述、朗读能力下降相对较轻,命名、复杂语句的理解能力损害突出.PNFA言语顿挫吃力,患者列名能力明显下降,但命名相对保存完好.结论 PPA多为老年前期发病,语言障碍为最早、最突出的症状.MRI特征性的改变为额叶和颞极萎缩,左侧为著.其中SD表现为命名性失语和经皮质感觉性失语,PNFA表现为经皮质运动性失语的特征.     

Frontotemporal lobar degeneration: clinical and pathological relationships

Frontotemporal lobar degeneration (FTLD) encompasses a heterogeneous group of clinical syndromes that include frontotemporal dementia (FTD), frontotemporal dementia with motor neurone disease (FTD/MND), progressive non-fluent aphasia (PNFA), semantic dementia (SD) and progressive apraxia (PAX). Clinical phenotype is often assumed to be a poor predictor of underlying histopathology. Advances in immunohistochemistry provide the opportunity to re-examine this assumption. We classified pathological material from 79 FTLD brains, blind to clinical diagnosis, according to topography of brain atrophy and immunohistochemical characteristics. There were highly significant relationships to clinical syndrome. Atrophy was predominantly frontal and anterior temporal in FTD, frontal in FTD/MND, markedly asymmetric perisylvian in PNFA, asymmetric bitemporal in SD and premotor, parietal in PAX. Tau pathology was found in half of FTD and all PAX cases but in no FTD/MND or SD cases and only rarely in PNFA. FTD/MND, SD and PNFA cases were ubiquitin and TDP-43 positive. SD cases were associated with dystrophic neurites without neuronal cytoplasmic or intranuclear inclusions (FTLD-U, type 1), FTD/MND with numerous neuronal cytoplasmic inclusions (FTLD-U, type 2 ) and PNFA with neuronal cytoplasmic inclusions, dystrophic neurites and neuronal intranuclear inclusions (FTLD-U, type 3). MAPT mutations were linked to FTD and PGRN mutations to FTD and PNFA. The findings demonstrate predictable relationships between clinical phenotype and both topographical distribution of brain atrophy and immunohistochemical characteristics. The findings emphasise the importance of refined delineation of both clinical and pathological phenotype in furthering understanding of FTLD and its molecular substrate.     

Clinicopathological and genetic correlates of frontotemporal lobar degeneration and corticobasal degeneration

Objective To correlate clinical diagnosis and genetic features with different pathological substrates in patients with frontotemporal lobar degeneration (FTLD) and corticobasal degeneration (CBD). Methods 32 cases with pathological proven FTLD or CBD were selected. Patients were classified clinically as frontotemporal dementia (FTD), progressive nonfluent aphasia (PNFA), semantic dementia (SD), CBD or FLTD with motor neuron disease (FLTDMND). Coding exons 1 and 9–13 of MAPT and exons 0–12 of the PGRN gene were screened by direct sequencing. Regarding the neuropathological findings, cases were classified as tau-positive, ubiquitinpositive tau-negative (FTLD-U), neuronal intermediate filaments inclusions disease (NIFID), dementia lacking distinctive histology (DLDH) or CBD. Results 17 patients were clinically diagnosed with FTD. Ten showed tau pathology, 3 FTLD-U, 1 NIFID and 3 DLDH. All patients clinically classified as FTLD-MND (6 patients) or SD (3 patients) were FTLD-U. Tau-positive pathology was the substrate of the three patients with PNFA. All three patients classified clinically as CBD presented neuropathologic features of CBD. The three individuals with familial history of early onset FTD and tau-positive pathology carried the P301L mutation in the MAPT gene. One out of 3 cases with FTLD-U and intranuclear inclusions carried a mutation in the PGRN gene. Conclusions We found that pathology underlying sporadic FTD is heterogeneous and not predictable. MAPT mutations and clinical diagnosis of PNFA and CBD were associated with tau-positive pathology. The presence of signs of lower MND and SD correlated with FTLD-U.A genetic study of MAPT is only recommended when familial history of early onset DFT is present. * Other members of the Catalan collaborative Study Group for FTLD are listed in the Appendix.     

Anatomical correlates of early mutism in progressive nonfluent aphasia

Patients with progressive nonfluent aphasia (PNFA) can become mute early in the course of the disease. Voxel-based morphometry showed that PNFA is associated with left anterior insula and inferior frontal atrophy. In PNFA with early mutism, volume loss was more prominent in the pars opercularis and extended into the left basal ganglia. Damage to the network of brain regions involved in both coordination and execution of speech causes mutism in PNFA.     

Hippocampal shape analysis in Alzheimer's disease and frontotemporal lobar degeneration subtypes

Hippocampal pathology is central to Alzheimer's disease (AD) and other forms of dementia such as frontotemporal lobar degeneration (FTLD). Autopsy studies have shown that certain hippocampal subfields are more vulnerable than others to AD and FTLD pathology, in particular the subiculum and cornu ammonis 1 (CA1). We conducted shape analysis of hippocampi segmented from structural T1 MRI images on clinically diagnosed dementia patients and controls. The subjects included 19 AD and 35 FTLD patients [13 frontotemporal dementia (FTD), 13 semantic dementia (SD), and 9 progressive nonfluent aphasia (PNFA)] and 21 controls. Compared to controls, SD displayed severe atrophy of the whole left hippocampus. PNFA and FTD also displayed atrophy on the left side, restricted to the hippocampal head in FTD. Finally, AD displayed most atrophy in left hippocampal body with relative sparing of the hippocampal head. Consistent with neuropathological studies, most atrophic deformation was found in CA1 and subiculum areas in FTLD and AD.     

Rates of hemispheric and lobar atrophy in the language variants of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder which presents with either behavioral or language impairment. The two language syndromes are known as progressive nonfluent aphasia (PNFA) and semantic dementia (SEMD). While cross-sectional imaging patterns of brain atrophy are well-described in FTLD, fewer studies have investigated longitudinal imaging changes. We measured longitudinal hemispheric and lobar atrophy rates using serial MRI in a cohort of 18 patients with PNFA and 17 patients with SEMD as well as 14 cognitively-normal control subjects. We subsequently calculated sample size estimates for clinical trials. Rates of left hemisphere atrophy were greater than rates of right hemisphere atrophy in both PNFA and SEMD with no significant differences between the groups. The disease groups showed asymmetrical atrophy (more severe on the left) at baseline with significantly increasing asymmetry over time. Within a hemisphere, the fastest rate of atrophy varied between lobes: in SEMD temporal > frontal > parietal > occipital, while in PNFA frontal > temporal/parietal > occipital. In SEMD, using temporal lobe measures of atrophy in clinical trials would provide the lowest sample sizes necessary, while in PNFA left hemisphere atrophy measures provided the lowest sample size. These patterns provide information about disease evolution in the FTLD language variants that is of both clinical and neurobiological relevance.     

Familial progressive aphasia: its relationship to other forms of lobar atrophy.

Two brothers presented with slowly progressive aphasia. One brother, who became behaviourally disturbed only at the end of his illness, was found at necropsy to have predominant left frontotemporal atrophy. The other brother developed severe behavioural disturbances shortly after the onset of language impairment. His brain revealed bilateral frontotemporal atrophy. In both there was non-Alzheimer's disease pathology with the histological features of loss of large cortical nerve cells, spongiform change and mild gliosis. The differential anatomical atrophy supports the view that clinical manifestations of lobar atrophy are dictated by the topographical distribution of a common underlying pathology, linking the syndromes of progressive aphasia to dementia of frontal lobe type (DFT) and DFT with motor neuron disease.     

Semantic dementia and primary progressive aphasia: a problem of categorization?

The relationship between semantic dementia (SD) and primary progressive aphasia (PPA) has been the subject of debate ever since the syndromes were first described, in converging streams of research from the neuropsychological and neurologic communities. The most salient clinical features of SD are anomia with circumlocution and semantic paraphasia, single-word comprehension deficit, and reduced category fluency. Of critical importance is the fact that patients also show deficits on non-verbal tasks using visual, auditory, and other modalities, suggesting that the key impairment in SD is a breakdown in conceptual knowledge rather than a specific problem with language. The finding of item consistency between the various tests supports this view. The order in which the features appear can be explained by the variable degree of redundancy in access to semantic knowledge from the different perceptual modalities. Atrophy is seen in the anterior and inferior temporal lobe rather than in classic language areas, further distancing SD from aphasic syndromes. Semantic dementia and progressive non-fluent aphasia (PNFA) share some clinical and pathologic characteristics with frontal variant frontotemporal dementia, but there are also clear differences between the three syndromes. We believe that many patients described as having fluent primary progressive aphasia in fact have early SD. Semantic dementia is a well-defined syndrome, distinct from PNFA but related to it within the spectrum of frontotemporal lobar degeneration syndromes.     

Neuroimaging in Frontotemporal Dementia: Heterogeneity and Relationships with Underlying Neuropathology

Frontotemporal dementia encompasses a group of clinical syndromes defined pathologically by degeneration of the frontal and temporal lobes. Historically, these syndromes have been challenging to diagnose, with an average of about three years between the time of symptom onset and the initial evaluation and diagnosis. Research in the field of neuroimaging has revealed numerous biomarkers of the various frontotemporal dementia syndromes, which has provided clinicians with a method of narrowing the differential diagnosis and improving diagnostic accuracy. As such, neuroimaging is considered a core investigative tool in the evaluation of neurodegenerative disorders. Furthermore, patterns of neurodegeneration correlate with the underlying neuropathological substrates of the frontotemporal dementia syndromes, which can aid clinicians in determining the underlying etiology and improve prognostication. This review explores the advancements in neuroimaging and discusses the phenotypic and pathologic features of behavioral variant frontotemporal dementia, semantic variant primary progressive aphasia, and nonfluent variant primary progressive aphasia, as seen on structural magnetic resonance imaging and positron emission tomography.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01101-x.     

Progressive nonfluent aphasia: A rare clinical subtype of FTLD‐TDP in Japan

Progressive nonfluent aphasia (PNFA) is a clinical subtype of frontotemporal lobar degeneration (FTLD). FTLD with tau accumulation (FTLD‐tau) and FTLD with TDP‐43 accumulation (FTLD‐TDP) both cause PNFA. We reviewed clinical records of 29 FTLD‐TDP cases in the brain archive of our institute and found only one case of PNFA. The patient was an 81‐year‐old male at death. There was no family history of dementia or aphasia. He presented with slow, labored and nonfluent speech at age 75. Behavioral abnormality and movement disorders were absent. MRI at age 76 demonstrated atrophy of the perisylvian regions, including the inferior frontal gyrus, insular gyrus and superior temporal gyrus. The atrophy was more severe in the left hemisphere than the right. On post mortem examinations, neuronal loss was evident in these regions as well as in the substantia nigra. There were abundant TDP‐43‐immunoreactive neuronal cytoplasmic inclusions and round or irregular‐shaped structures in the affected cerebral cortices. A few dystrophic neurites and neuronal intranuclear inclusions were also seen. FTLD‐TDP showing PNFA seems to be rare but does exist in Japan, similar to that in other countries.     

Progressive aphasic syndromes: clinical and theoretical advances

PURPOSE OF REVIEW: Knowledge of the neural basis for language and related aspects of cognition has been advanced through detailed studies of patients with primary progressive aphasia. This brief review highlights some recent work. RECENT FINDINGS: The impairment of semantic knowledge in patients with semantic dementia appears to influence performance in a wide variety of linguistic and cognitive domains, including morphological agreements such as the irregular past tense. Computational studies modeling the deficits of these patients have advanced interpretations of the impairments in semantic dementia. Imaging analyses have confirmed the presence of temporal atrophy cross-sectionally and longitudinally in these patients. In patients with semantic dementia, it appears that both the left temporal and right temporal regions contribute in different proportions to naming and comprehension, although the nature of the process underlying the consolidation of knowledge in semantic memory continues to be actively debated. In patients with progressive non-fluent aphasia, recent work has emphasized an impairment with verbs. Functional neuroimaging work with progressive non-fluent aphasics, compared directly to non-aphasic patients with frontotemporal dementia, has demonstrated a dissociation for grammatical and working memory aspects of sentence processing within the left frontal cortex. SUMMARY: These findings will improve diagnostic accuracy, prognostic ability, and therapeutic potential in patients with progressive aphasia.     

Behavioral Variant Frontotemporal Dementia with Corticobasal Degeneration Pathology: Phenotypic Comparison to bvFTD with Pick’s Disease

Patients with corticobasal degeneration (CBD) pathology present with diverse clinical syndromes also associated with other neuropathologies, including corticobasal syndrome, progressive nonfluent aphasia, and an Alzheimer's-type dementia. Some present with behavioral variant frontotemporal dementia (bvFTD), though this subtype still requires more detailed clinical characterization. All patients with CBD pathology and clinical assessment were reviewed (N?=?17) and selected if they initially met criteria for bvFTD [bvFTD(CBD), N?=?5]. Available bvFTD patients with Pick's [bvFTD(Pick's), N?=?5] were selected as controls. Patients were also compared to healthy older controls [N?=?53] on neuropsychological and neuroimaging measures. At initial presentation, bvFTD(CBD) showed few neuropsychological or motor differences from bvFTD(Pick's). Neuropsychiatrically, they were predominantly apathetic with less florid social disinhibition and eating disturbances, and were more anxious than bvFTD(Pick's) patients. Voxel-based morphometry revealed similar patterns of predominantly frontal atrophy between bvFTD groups, though overall degree of atrophy was less severe in bvFTD(CBD), who also showed comparative preservation of the frontoinsular rim, with dorsal?>?ventral frontal atrophy, and sparing of temporal and parietal structures relative to bvFTD(Pick's) patients. Despite a remarkable overlap between the two patient types, bvFTD patients with underlying CBD pathology show subtle clinical features that may distinguish them from patients with Pick's disease neuropathology.     

A 62-year-old woman presenting with progressive nonfluent aphasia, apraxia of eyelid opening, supranuclear gaze palsy, and asymmetric rigidity

A 62-year-old woman presented with difficulty in speaking and difficulty in opening her eyes. A neurological examination revealed progressive nonfluent aphasia (PNFA), apraxia of eyelid opening, supranuclear vertical gaze palsy, and mild asymmetric rigidity. The diagnosis was difficult to establish because of unusual clinical features, and progressive supranuclear palsy (PSP) was considered. The results from recent studies suggest a positive association between PNFA and a diagnosis of corticobasal degeneration (CBD) or PSP, even in mild parkinsonism cases. The overlapping clinical, genetic, and pathological features of CBD and PSP have also been recently recognized. However, in Japan, there have been few reports evaluating the clinical features of CBD or PSP accompanied by primary progressive aphasia. We report the case of our patient and compare the clinical features of our patient with those of Japanese patients with CBD or PSP accompanied by primary progressive aphasia; moreover we discuss clues that can lead to the correct clinical diagnosis of patients with primary progressive aphasia and parkinsonism comorbidities.     

Cognition and anatomy in three variants of primary progressive aphasia

We performed a comprehensive cognitive, neuroimaging, and genetic study of 31 patients with primary progressive aphasia (PPA), a decline in language functions that remains isolated for at least 2 years. Detailed speech and language evaluation was used to identify three different clinical variants: nonfluent progressive aphasia (NFPA; n = 11), semantic dementia (SD; n = 10), and a third variant termed logopenic progressive aphasia (LPA; n = 10). Voxel-based morphometry (VBM) on MRIs showed that, when all 31 PPA patients were analyzed together, the left perisylvian region and the anterior temporal lobes were atrophied. However, when each clinical variant was considered separately, distinctive patterns emerged: (1) NFPA, characterized by apraxia of speech and deficits in processing complex syntax, was associated with left inferior frontal and insular atrophy; (2) SD, characterized by fluent speech and semantic memory deficits, was associated with anterior temporal damage; and (3) LPA, characterized by slow speech and impaired syntactic comprehension and naming, showed atrophy in the left posterior temporal cortex and inferior parietal lobule. Apolipoprotein E epsilon4 haplotype frequency was 20% in NFPA, 0% in SD, and 67% in LPA. Cognitive, genetic, and anatomical features indicate that different PPA clinical variants may correspond to different underlying pathological processes.     

Abstracts Presented at the British Neuropsychological Society Autumn Meeting,October/November 2006

Classifying primary progressive aphasia (PPA) into variants that may predict the underlying pathology is important. However, some PPA patients cannot be classified. A 78-year-old woman had unclassifiable PPA characterized by anomia, dysarthria, and apraxia of speech without agrammatism. Magnetic resonance imaging revealed left mesial temporal atrophy and 18-flourodeoxy-glucose positron emission tomography showed left anterior temporal and posterior frontal (premotor) hypometabolism. Autopsy revealed a mixed tauopathy (argyrophilic grain disease) and transactive response-DNA-binding-protein-43 proteinopathy. Dual pathologies may explain the difficulty classifying some PPA patients and recognizing this will be important as new imaging techniques (particularly tau-positron emission tomography) are introduced and patients begin enrollment in clinical trials targeting the underlying proteinopathy.     

Dementia with Lewy bodies presenting as Logopenic variant primary progressive Aphasia

ABSTRACT

We report a patient presenting with clinical features of logopenic variant primary progressive aphasia (lvPPA) who was later diagnosed with probable dementia with Lewy bodies. LvPPA is a neurodegenerative disease that is characterized by anomia, word-finding difficulty, impaired comprehension, and phonological errors. The most common underlying pathology for lvPPA is Alzheimer’s disease. However, our patient with clinical features of logopenic progressive aphasia was later diagnosed with probable dementia with Lewy bodies. This case demonstrates that lvPPA can also be an initial manifestation of a phenotype of dementia with Lewy bodies.