Forms Of Primary Progressive Aphasia Research Articles

Differential patterns of lysosomal dysfunction are seen in the clinicopathological forms of primary progressive aphasia.

Increasing evidence implicates endo-lysosomal dysfunction in frontotemporal dementia (FTD). 18 proteins were quantified using a mass spectrometry assay panel in the cerebrospinal fluid of 36 people with the language variant of FTD, primary progressive aphasia (PPA) (including 13 with non-fluent variant (nfvPPA), 11 with semantic variant (svPPA), and 12 with logopenic variant (lvPPA)) and 19 healthy controls. The concentrations of the cathepsins (B, D, F, L1, and Z) as well as AP-2 complex subunit beta, ganglioside GM2 activator, beta-hexosaminidase subunit beta, tissue alpha L-fucosidase, and ubiquitin were decreased in nfvPPA compared with controls. In contrast, the concentrations of amyloid beta A4 protein, cathepsin Z, and dipeptidyl peptidase 2 were decreased in svPPA compared with controls. No proteins were abnormal in lvPPA. These results indicate a differential alteration of lysosomal proteins in the PPA variants, suggesting those with non-Alzheimer's pathologies are more likely to show abnormal lysosomal function.

Genetic forms of primary progressive aphasia within the GENetic Frontotemporal dementia Initiative (GENFI) cohort: comparison with sporadic primary progressive aphasia.

Primary progressive aphasia is most commonly a sporadic disorder, but in some cases, it can be genetic. This study aimed to understand the clinical, cognitive and imaging phenotype of the genetic forms of primary progressive aphasia in comparison to the canonical nonfluent, semantic and logopenic subtypes seen in sporadic disease. Participants with genetic primary progressive aphasia were recruited from the international multicentre GENetic Frontotemporal dementia Initiative study and compared with healthy controls as well as a cohort of people with sporadic primary progressive aphasia. Symptoms were assessed using the GENetic Frontotemporal dementia Initiative language, behavioural, neuropsychiatric and motor scales. Participants also underwent a cognitive assessment and 3 T volumetric T1-weighted MRI. One C9orf72 (2%), 1 MAPT (6%) and 17 GRN (44%) symptomatic mutation carriers had a diagnosis of primary progressive aphasia. In the GRN cohort, 47% had a diagnosis of nonfluent variant primary progressive aphasia, and 53% had a primary progressive aphasia syndrome that did not fit diagnostic criteria for any of the three subtypes, called primary progressive aphasia-not otherwise specified here. The phenotype of the genetic nonfluent variant primary progressive aphasia group largely overlapped with that of sporadic nonfluent variant primary progressive aphasia, although the presence of an associated atypical parkinsonian syndrome was characteristic of sporadic and not genetic disease. The primary progressive aphasia -not otherwise specified group however was distinct from the sporadic subtypes with impaired grammar/syntax in the presence of relatively intact articulation, alongside other linguistic deficits. The pattern of atrophy seen on MRI in the genetic nonfluent variant primary progressive aphasia group overlapped with that of the sporadic nonfluent variant primary progressive aphasia cohort, although with more posterior cortical involvement, whilst the primary progressive aphasia-not otherwise specified group was strikingly asymmetrical with involvement particularly of the insula and dorsolateral prefrontal cortex but also atrophy of the orbitofrontal cortex and the medial temporal lobes. Whilst there are overlapping symptoms between genetic and sporadic primary progressive aphasia syndromes, there are also distinct features. Future iterations of the primary progressive aphasia consensus criteria should encompass such information with further research needed to understand the earliest features of these disorders, particularly during the prodromal period of genetic disease.

Hesitations in Primary Progressive Aphasia

Hesitations are often used by speakers in spontaneous speech not only to organise and prepare their speech but also to address any obstacles that may arise during delivery. Given the relationship between hesitation phenomena and motor and/or cognitive–linguistic control deficits, characterising the form of hesitation could be potentially useful in diagnosing specific speech and language disorders, such as primary progressive aphasia (PPA). This work aims to analyse the features of hesitations in patients with PPA compared to healthy speakers, with hesitations understood here as those related to speech planning, that is, silent or empty pauses, filled pauses, and lengthened syllables. Forty-three adults took part in this experiment, of whom thirty-two suffered from some form of PPA: thirteen from logopenic PPA (lvPPA), ten from nonfluent PPA (nfvPPA), and nine from semantic PPA (svPPA). The remaining 11 were healthy speakers who served as a control group. An analysis of audio data recorded when participants produced spontaneous speech for a picture description task showed that the frequency of silent pauses, especially those classified as long (>1000 ms) was particularly useful to distinguish PPA participants from healthy controls and also to differentiate among PPA types. This was also true, albeit to a lesser extent, of the frequency of filled pauses and lengthened syllables.

Temporopolar regions of the human brain.

Following prolonged neglect during the formative decades of behavioural neurology, the temporopolar region has become a site of vibrant research on the neurobiology of cognition and conduct. This turnaround can be attributed to increasing recognition of neurodegenerative diseases that target temporopolar regions for peak destruction. The resultant syndromes include behavioural dementia, associative agnosia, semantic forms of primary progressive aphasia and semantic dementia. Clinicopathological correlations show that object naming and word comprehension are critically dependent on the language-dominant (usually left) temporopolar region, whereas behavioural control and non-verbal object recognition display a more bilateral representation with a rightward bias. Neuroanatomical experiments in macaques and neuroimaging in humans show that the temporoparietal region sits at the confluence of auditory, visual and limbic streams of processing at the downstream (deep) pole of the 'what' pathway. The functional neuroanatomy of this region revolves around three axes, an anterograde horizontal axis from unimodal to heteromodal and paralimbic cortex; a radial axis where visual (ventral), auditory (dorsal) and paralimbic (medial) territories encircle temporopolar cortex and display hemispheric asymmetry; and a vertical depth-of-processing axis for the associative elaboration of words, objects and interoceptive states. One function of this neural matrix is to support the transformation of object and word representations from unimodal percepts to multimodal concepts. The underlying process is likely to start at canonical gateways that successively lead to generic (superordinate), specific (basic) and unique levels of recognition. A first sign of left temporopolar dysfunction takes the form of taxonomic blurring where boundaries among categories are preserved but not boundaries among exemplars of a category. Semantic paraphasias and coordinate errors in word-picture verification tests are consequences of this phenomenon. Eventually, boundaries among categories are also blurred and comprehension impairments become more profound. The medial temporopolar region belongs to the amygdalocentric component of the limbic system and stands to integrate exteroceptive information with interoceptive states underlying social interactions. Review of the pertinent literature shows that word comprehension and conduct impairments caused by temporopolar strokes and temporal lobectomy are far less severe than those seen in temporopolar atrophies. One explanation for this unexpected discrepancy invokes the miswiring of residual temporopolar neurons during the many years of indolently progressive neurodegeneration. According to this hypothesis, the temporopolar regions become not only dysfunctional but also sources of aberrant outputs that interfere with the function of areas elsewhere in the language and paralimbic networks, a juxtaposition not seen in lobectomy or stroke.

Abstract- Poster

INTRODUCTION.§ Frontotemporal dementia (FTD) refers to a group of dementias characterized by degeneration in the frontal and temporal lobes of the brain. Rates of early-onset FTD are high with 13% of individuals with FTD being under the age of 50.§ Younger cases of FTD tend to exhibit frequent abrupt mood changes, increased aggression, behavioral disinhibition, lack of empathy, and deficits in working memory.There are three clinical presentations of FTD: behavioral variant (bvFTD) and two forms of primary progressive aphasia.Here we report a a 37 yr Old married man was brought with complaints of a progressive history of changes in behaviour and personality.The patient was in good baseline health until age 35 years, when his family noticed an increase in change in behavior with history of cannabis smoking for 2 yrs, H/O multiple extra marital affairs for 2 yrs,with H/O restlessness,dull and withdrawn, sleep disturbance,poor self care, refusing to eat properly, slowly not speaking to anyone, poor work performance for the past 6 months. He was diagnosed as a case of substance induced psychosis with catatonic features and treated. Again after three months pt presented to psychiatric opd with complaints of restlessness, speech difficulty forgetting things, inappropriate laugh,disinterest in daily activities, walking in the house all the time, disinhibited behaviour,weight loss,excessive craving for tobacco,putting inedible things at mouth all these symptoms for one month.On Mse O/E he was alert,ambulant,kempt,yawning frequently during interview, not cooperative, sits in chair and gets up frequently, no Spontaneous speech. He did not attempt to initiate conversation, answering questions with short, terse responses. relevant replies. He often gazed with a prolonged, fixed stare and exhibited motor stereotypies such as clapping his thighs or tapping his feet vigorously.— There were no upper or lower motor neurone signs, frontal release signs positive, and no parkinsonism or limb apraxia. His gait was normal. He scored only 55 out of 100 on the Addenbrooke’s Cognitive Examination-III, with impairments across domains but with particularly poor executive function (naming only two words beginning with P in a minute, and only 10 animals over a minute, leading to a very low verbal fluency score of 4 out of 14). Attention (score 12 out of 18), language (19 out of 26), memory (9 out of 26) and visuospatial (11 out of 16) abilities were also affected.— Further neuropsychological testing identified a global reduction in general intellectual function, with severe executive function deficits as well as poor verbal working— Neurology opinion obtained as a case of young onset FTD— MRI scan of the brain showed substantial bilateral, symmetrical frontal atrophy, with no evidence of white matter changes that would be typical of a vascular, vasculitic or inflammatory cause (figure 1). In addition, autoimmune encephalitis was negative; and HIV and syphilis serology were all normal or negative. Cerebrospinal fluid (CSF) contained no white cells or abnormal cells and therefore no evidence of an active inflammatory, infective or malignant process; the CSF protein concentration was also normal. PET scan suggestive of FTDReference 1. Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011;134:2456?77.2. Lebert F, Stekke W, Hasenbroekx C, et al. Frontotemporal dementia: a randomised, controlled trial with trazodone. Dement Geriatr Cogn Disord 2004;17:355?9.3. Warren JD, Rohrer JD, Rossor MN. Clinical review. Frontotemporal dementia. BMJ 2013;347:f4827.4. Neumann M, Mackenzie IRA. Review: Neuropathology of non-tau frontotemporal lobar degeneration. Neuropathol Appl Neurobiol 2019;45:19?40.5. Mann DMA, Snowden JS. Frontotemporal lobar degeneration: pathogenesis, pathology and pathways to phenotype. Brain Pathol 2017;27:723?36. Ct brain showed bilateral frontoparietotemporal Subdural HYGROMA.Neurologist opinion obtained. There was no focal neurological defecit and conservative management suggested. Patient was treated with tab risperidone 2mg 1-0-1 tab sodium valproate 200 mg 1-1-1, tab diazepam 5mg 0-0-1, her symptom improved with treatment (ymrs-12.)

Primary progressive aphasias: clinical and genetic heterogeneity and diagnostic difficulties

This systematic review describes primary progressive aphasia (PPA) variants and includes the authors' own clinical observations. Over 20 genes have now been identified, with mutations that are directly involved in the development of the behavioural variant of frontotemporal dementia, as well as other forms of PPA. Pathomorphological markers of Alzheimer's disease were identified in 76% of cases of logopenic PPA, while signs of frontotemporal dementia associated with TDP-43 were identified in 80% of cases of the semantic variant, and those associated with TDP-43/tau were identified in 64% of cases of agrammatic PPA. The clinical diagnosis of PPA is based on a history of long-term, progressive speech disturbances and identifying a particular variant: agrammatic, semantic or logopenic. The primary variant of the speech disorder cannot be identified in approximately 30% of cases. The focus should be on the main and additional clinical signs (presence of agrammatism, object naming, word comprehension, preserved repetition), as well as neuroimaging (presence of asymmetrical frontal and/or temporal lobe atrophy).
 The article also provides key aspects of differential diagnosis of the PPA variants, and puts forth a stepwise diagnostic algorithm. It examines features of PPA progression, with possible development of corticobasal syndrome, illustrated by a clinical case. A dissociation between neuroimaging findings and clinical disease variant is also demonstrated to be possible. Different neuropsychological assessments of patients with aphasia and methods of determining the severity of speech dysfunction are presented. Standardized aphasia assessment tools and the adapted PPA severity scale are provided.

Functional Disabilities and Psychiatric Symptoms in Primary Progressive Aphasia

Introduction Frontotemporal dementia (FTD) compromises a group of clinically and pathologically heterogeneous neurodegenerative syndromes including two forms of primary progressive aphasia (PPA) – nonfluent aphasia and semantic dementia (SD). While language impairments are the most prominent and impairing initial symptom, over time additional disabilities accumulate as these illnesses progress, eroding quality of life and increasing the burden of care. Little is known about the chronology of acquiring non-language functional disabilities in PPA. The primary aim of this study is to describe the chronology of functional disabilities in PPA, and to examine temporal associations between psychiatric comorbidities and specific disabilities. Methods Data are from subjects enrolled in the National Alzheimer's Coordinating Center (NACC) database between June 2005 and May 2019. We included subjects whose recent diagnosis was PPA. Functional status was coded as a binary variable for the following functions: ambulation (gait and falls), transaction skills (shopping, taxes, and bills), verbal communication, meal preparation, and self-care. Descriptive statistics and cox proportional hazard analyses were used to characterize the emergence of disabilities and their association with medical and psychiatric comorbidities. Results We enrolled 1,944 subjects, comprising 91 with a CDR score of zero at baseline who were used in our analysis. Mean age of this population at baseline was 68.8 years and 43.5% were males. At the onset of the study, no individuals had impairments in self-care, while 7% had impairments in the transactions domain, 3% in ambulation, and 2% in meal preparation. Ninety-three percent had language impairments at the onset of the study, and all by 4 years. By 5 years, 41% of patients had impairments in ambulation and in self-care, 49% were impaired with respect to meal preparation and 70% had impairment in transactions. The presence of psychosis was associated with an increased risk for self-care impairment (HR 5.0, CI [2.4-10.6], p Conclusions We provide a preliminary estimation in a large sample of the year-by-year frequency of functional disability in PPA patients. Impairment in communication skills appear early, followed closely by impairment in transactions. Ambulation, self-care and meal preparation impairments occur later. A number of psychiatric symptoms were significantly associated with functional disability progression, suggesting the potential of forestalling disability progression by treating psychiatric symptoms. These findings, when fully developed, can be expected to provide clinicians with practical guidance for forecasting disabilities in their patients, providing a rational basis for targeted interventions, individualized programs of care, and care giver education and training. Funding The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P30 AG062428-01 (PI James Leverenz, MD) P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P50 AG047266 (PI Todd Golde, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P30 AG062421-01 (PI Bradley Hyman, MD, PhD), P30 AG062422-01 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Thomas Wisniewski, MD), P30 AG013854 (PI Robert Vassar, PhD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P50 AG047366 (PI Victor Henderson, MD, MS), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P30 AG062429-01(PI James Brewer, MD, PhD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG053760 (PI Henry Paulson, MD, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P30 AG049638 (PI Suzanne Craft, PhD), P50 AG005136 (PI Thomas Grabowski, MD), P30 AG062715-01 (PI Sanjay Asthana, MD, FRCP), P50 AG005681 (PI John Morris, MD), P50 AG047270 (PI Stephen Strittmatter, MD, PhD).

Quantitative EEG Differences in Subtypes of Frontotemporal Dementia

Frontotemporal dementia (FTD) is the second most common group of neurodegenerative disorder following Alzheimer’s Disease (AD); and characterized by degeneration of frontal and/or temporal lobes. FTD can be classified as behavioral variant FTD (bvFTD) and primary progressive aphasia (PPA). The aim of this study is to investigate electrophysiological differences in bvFTD and nonfluent/agrammatic PPA (naPPA), one of three forms of PPA. Twelve patients with bvFTD and 15 patients with naPPA were included in the study. EEG was recorded from 19 electrode sites based on international 10-20 system. Each participant's data were averaged across the recording epochs for each electrode, and the mean absolute power values were computed for delta, theta, beta and alpha frequency bands. For all frequency bands, inter-hemispheric and intrahemispheric coherence was calculated. In absolute power; decreased theta power at all regions was found in bvFTD group as compared to naPPA group. Regarding coherence; increased beta coherence at left centoparietal region and increased alpha coherence at inter-hemispheric frontal region was found in bvFTD as compared to naPPA group. Our findings suggests that subtypes of FTD vary in resting-state EEG especially indexed by the decreased theta power reflecting bvFTD.

Diagnostic utility of FDG-PET in the differential diagnosis between different forms of primary progressive aphasia

PurposeA joint effort of the European Association of Nuclear Medicine (EANM) and the European Academy of Neurology (EAN) aims at clinical guidance for the use of FDG-PET in neurodegenerative diseases. This paper addresses the diagnostic utility of FDG-PET over clinical/neuropsychological assessment in the differentiation of the three forms of primary progressive aphasia (PPA).MethodsSeven panelists were appointed by the EANM and EAN and a literature search was performed by using harmonized PICO (Population, Intervention, Comparison, Outcome) question keywords. The studies were screened for eligibility, and data extracted to assess their methodological quality. Critical outcomes were accuracy indices in differentiating different PPA clinical forms. Subsequently Delphi rounds were held with the extracted data and quality assessment to reach a consensus based on both literature and expert opinion.ResultsCritical outcomes for this PICO were available in four of the examined papers. The level of formal evidence supporting clinical utility of FDG-PET in differentiating among PPA variants was considered as poor. However, the consensual recommendation was defined on Delphi round I, with six out of seven panelists supporting clinical use.ConclusionsQuantitative evidence demonstrating utility or lack thereof is still missing. Panelists decided consistently to provide interim support for clinical use based on the fact that a typical atrophy or metabolic pattern is needed for PPA according to the diagnostic criteria, and the synaptic failure detected by FDG-PET is an earlier phenomenon than atrophy. Also, a normal FDG-PET points to a non-neurodegenerative cause.

The neural correlates of auditory and visuospatial span in logopenic progressive aphasia and Alzheimer's disease

IntroductionLogopenic progressive aphasia (lv-PPA) is a form of primary progressive aphasia and is predominantly associated with Alzheimer's disease (AD) pathology. The neuropsychological profiles of lv-PPA and typical clinical AD are, however, distinct. In particular, these two syndromes differ on attention span measures, where auditory attention span is more impaired in lv-PPA than in AD and visuospatial span appears more impaired in AD than in lv-PPA. The neural basis of these span profiles, however, remains unclear. MethodSixteen lv-PPA and 21 AD matched patients, and 15 education-matched healthy controls were recruited. All participants were assessed by a neurologist and completed a neuropsychological assessment that included the Wechsler Memory Scale–III Digit and Spatial Span tasks, and underwent a high-resolution structural brain MRI to conduct cortical thickness analyses. ResultsPatient groups were impaired on all span tasks compared to Controls. In addition, performance on Digit Span Forward (DSF) was significantly lower in the lv-PPA than the AD group, while Spatial Span Forward (SSF) was significantly lower in the AD than the lv-PPA group. No differences were found between patient groups on the Digit or Spatial Span Backward tasks. Neuroimaging analyses revealed that reduced DSF performance correlated to thinning of the left superior temporal gyrus in the lv-PPA group, whereas reduced SSF performance was related to bilateral precentral sulcus and parieto-occipital thinning in the AD group. Analyses of the backward span tasks revealed that reduced Spatial Span Backward (SSB) performance in the lv-PPA group related to cortical thinning of the left superior parietal lobule. ConclusionsThis study demonstrates that while lv-PPA and AD commonly share the same underlying neuropathology, their span profiles are distinct and are mediated by divergent patterns of cortical degeneration.

John Richard van Loo, born 19 October 1947, died 14 December 2013, aged 66.

John Richard van Loo, born 19 October 1947, died 14 December 2013, aged 66.

Primary progressive aphasia

Primary progressive aphasia (PPA) is a progressive loss of specific language functions with relative sparing of other cognitive domains at least for the first few years of the illness. Based on the constellation of symptoms, PPA has been recently classified into a nonfluent, semantic, or logopenic variant. Nonfluent variant PPA is characterized by dysfluent and effortful speech, often combined with agrammatism. Also, some patients have initially predominant apraxia of speech. The neuroimaging findings in nfvPPA are in most cases progressive atrophy within the left inferior, opercular, and insular regions. Pathology is a tauopathy (FTLD-T), most often Pick's disease or CBD. Semantic variant PPA, on the other hand is characterized by fluent, but circumlocutory speech, then severe anomia and word-finding difficulties, all being associated with a progressive loss of lexical-semantic knowledge. As the disease progresses, the semantic impairment typically becomes multimodal. The clinical picture of svPPA is often associated with atrophy of the anterior regions of the temporal lobes, usually more prominent on the left side. The majority of these patients have TDP-43 pathology. The third, most recently described form of PPA is the logopenic variant characterized by decreased spontaneous speech output with frequent word-finding pauses, phonologic parahpasias, and repetition deficits. It resembles aphasia in Alzheimer's disease. Imaging abnormalities in lvPPA have been predominantly found in the left temporo-parietal junction area, and the pathological changes have been often those of AD.

Speech deterioration in an English-Shanghainese Speaker with Logopenic Variant Primary Progressive Aphasia

Speech deterioration in an English-Shanghainese Speaker with Logopenic Variant Primary Progressive Aphasia

Differentiating primary progressive aphasias in a brief sample of connected speech

A brief speech expression protocol that can be administered and scored without special training would aid in the differential diagnosis of the 3 principal forms of primary progressive aphasia (PPA): nonfluent/agrammatic PPA, logopenic variant PPA, and semantic variant PPA. We used a picture-description task to elicit a short speech sample, and we evaluated impairments in speech-sound production, speech rate, lexical retrieval, and grammaticality. We compared the results with those obtained by a longer, previously validated protocol and further validated performance with multimodal imaging to assess the neuroanatomical basis of the deficits. We found different patterns of impaired grammar in each PPA variant, and additional language production features were impaired in each: nonfluent/agrammatic PPA was characterized by speech-sound errors; logopenic variant PPA by dysfluencies (false starts and hesitations); and semantic variant PPA by poor retrieval of nouns. Strong correlations were found between this brief speech sample and a lengthier narrative speech sample. A composite measure of grammaticality and other measures of speech production were correlated with distinct regions of gray matter atrophy and reduced white matter fractional anisotropy in each PPA variant. These findings provide evidence that large-scale networks are required for fluent, grammatical expression; that these networks can be selectively disrupted in PPA syndromes; and that quantitative analysis of a brief speech sample can reveal the corresponding distinct speech characteristics.

The effects of initiation, termination and inhibition impairments on speech rate in a case of progressive nonfluent aphasia with progressive apraxia of speech with frontotemporal degeneration

Recent research into nonfluent forms of primary progressive aphasia and progressive apraxia of speech has highlighted the importance of speech rate as a diagnostic feature. We describe detailed investigation and comparison of speech rate (latencies and utterance length in single word/nonword production and speech rate in connected speech) on a range of experimental tasks in a man with progressive speech deterioration of 10 years duration from Pick's Disease. C.S. had a progressive nonfluent aphasia (PNFA) together with progressive apraxia of speech (pAOS) with an absence of significant interlectual, phonological or semantic impairment. C.S. showed increased latencies but reduced word length compared to matched controls on single word and nonword repetition and reading, an absence of a syllabic length effect in either single word/nonword tasks or connected speech tasks. Further investigation suggested that underlying his speech production impairments were problems with speech initiation, termination and inhibition. Most impairments worsened with progression over a 12-month period. Results provide support for the view that progressive apraxia of speech presents differently to apraxia of speech following stroke and, especially at advanced stages, involves deterioration in more central and supportive cognitive processes.

Verbal and Visuospatial Span in Logopenic Progressive Aphasia and Alzheimer's Disease

Logopenic progressive aphasia (LPA) is a form of primary progressive aphasia (PPA) characterized by hesitant speech with marked impairment in naming and repetition. LPA is associated with brain atrophy in the left temporal and inferior parietal cortices and is predominantly associated with Alzheimer’s disease (AD) pathology. In contrast to LPA, ‘‘typical’’ AD is commonly associated with episodic memory disturbance and bilateral medial temporal lobe atrophy. Recent evidence suggests verbal short-term memory is more impaired than visuospatial short-term memory in LPA. This study investigated verbal and visuospatial short-term memory in 12 LPA and 12 AD patients matched for disease severity, and in 12 age- and education-matched healthy controls. Overall, both patient groups showed significantly reduced verbal and visuospatial spans compared with controls. In addition, LPA patients performed significantly worse than AD patients on both forward and backward conditions of the Digit Span task. In contrast, no difference was present between patient groups on either version of the Spatial Span task. Importantly, LPA patients showed better visuospatial than verbal span whereas AD patients and controls did not differ across modality. This study demonstrates the specificity of the short-term memory disturbance in LPA, which arises from a breakdown of the phonological system.

Multimodal predictors for Alzheimer disease in nonfluent primary progressive aphasia.

Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) are hypothesized to cause clinically distinct forms of primary progressive aphasia (PPA) that predominantly affect expressive speech. AD is thought to cause logopenic progressive aphasia (LPA), and FTLD may cause progressive nonfluent aphasia (PNFA). We sought to determine the value of clinical characterization, neuropsychological analysis, and MRI atrophy in predicting pathology of LPA and PNFA. Patients with LPA (n = 19) and patients with PNFA (n = 19) were evaluated with neuropsychological assessments, structural MRI, CSF analysis, and neuropathologic examination. Twelve of 19 patients with LPA (63%) and 6 of 19 patients with PNFA (32%) had neuropathologic findings or CSF biomarkers consistent with AD. Neuropsychological testing showed that naming was more impaired in patients with AD, and letter-guided fluency was more affected in patients with a non-AD disorder. Voxel-based morphometry analysis revealed that in patients with AD, patients with LPA and PNFA had significant posterior-superior temporal atrophy; in patients with non-AD, patients with LPA had peri-Sylvian atrophy and patients with PNFA had dorsolateral prefrontal and insular atrophy. Receiver operator characteristic curve analysis showed that combining neuropsychological testing with MRI atrophy pattern had 90% specificity for pathology or CSF biomarkers consistent with AD, and combining clinical features with neuropsychological analysis had 100% sensitivity for pathology or CSF biomarkers consistent with AD. Neither PPA phenotyping nor imaging alone is a reliable predictor of pathology. Multimodal predictors, such as combining neuropsychological testing with MRI analysis, can improve noninvasive prediction of underlying pathology in nonfluent forms of PPA.

The neuropathology and clinical phenotype of FTD with progranulin mutations

Mutations in the progranulin gene (PGRN), on chromosome 17q21, have recently been identified as a major cause of familial frontotemporal dementia (FTD). These cases have a characteristic pattern of neuropathology that is a distinct subtype of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), with lentiform neuronal intranuclear inclusions being a consistent feature. There is no abnormal accumulation of PGRN protein in the brain and immunohistochemical and biochemical analysis indicates that the ubiquitinated pathological protein is TDP-43. In these families, FTD is inherited in an autosomal dominant fashion with high penetrance. The clinical phenotype is usually a combination of behavioural abnormality and language disturbance that is most often a form of primary progressive aphasia. Mild parkinsonism is common but motor neuron disease is notably rare. Marked variation in the disease course and clinical features are common, not only between families with different mutations, but also within individual families. This degree of clinical variability makes it difficult to predict which cases of familial FTD will turn out to have a PGRN mutation.

Semantic dementia and fluent primary progressive aphasia: two sides of the same coin?

Considerable controversy exists regarding the relationship between semantic dementia (SD) and progressive aphasia. SD patients present with anomia and impaired word comprehension. The widely used consensus criteria also include the need for patients to exhibit associative agnosia and/or prosopagnosia: many authors have used the label SD for patients with non-verbal, as well as verbal, semantic deficits on formal testing even if they recognize the objects and people encountered in everyday life; others interpret the criterion of agnosia to require pervasive recognition impairments affecting daily life. According to this latter view, SD patients have pathology that disrupts both a bilateral ventrotemporal-fusiform network (resulting in agnosia) and the left hemisphere language network (resulting in profound aphasia). These authors suggest that this profile is different to that seen in the fluent form of primary progressive aphasia (fPPA), a neurodegenerative disease primarily affecting language function. We present data on seven patients who met the diagnostic criteria for fPPA. All seven showed deficits relative to matched controls on both verbal and non-verbal measures of semantic memory, and these deficits were modulated by degree of anomia, concept familiarity and item typicality. Voxel-based morphometry revealed reduced grey matter density in the temporal lobes bilaterally (more widespread on the left), with the severity of atrophy in the left inferior temporal lobe being significantly related to performance on both the verbal and non-verbal measures. Together these findings suggest that patients who meet the diagnostic criteria for fPPA, can also meet the diagnostic criteria for early-stage SD provided that the impact of concept familiarity and typicality is taken into account. In addition, these findings support a claim that the patients' deficits on both verbal and non-verbal tasks reflect progressive deterioration of an amodal integrative semantic memory system critically involving the rostral temporal lobes, rather than a combination of atrophy in the left language network and a separate bilateral ventrotemporal-fusiform network.