The resilience of the developing reading system: multi-modal evidence of incident and recovery after a pediatric stroke.

Decades of neuroscientific findings have elucidated the highly specialized brain areas involved in reading, especially along the ventral occipitotemporal stream where the critical step of recognizing words occurs. We report on a 14-year-old female with temporary dyslexia after a left ventral occipitotemporal ischemic stroke. Our longitudinal multimodal findings show that the resolution of the reading impairment was associated with heightened activity in the left posterior superior and inferior temporal gyri. Our findings highlight the role of the left inferior temporal gyrus in reading and the importance of perilesional and ipsilateral cortical areas for functional recovery after childhood stroke.

Profiles of mathematical deficits in children with dyslexia.

Despite a high rate of concurrent mathematical difficulties among children with dyslexia, we still have limited information regarding the prevalence and severity of mathematical deficits in this population. To address this gap, we developed a comprehensive battery of cognitive tests, known as the UCSF Mathematical Cognition Battery (MCB), with the aim of identifying deficits in four distinct mathematical domains: number processing, arithmetical procedures, arithmetic facts retrieval, and geometrical abilities. The mathematical abilities of a cohort of 75 children referred to the UCSF Dyslexia Center with a diagnosis of dyslexia, along with 18 typically developing controls aged 7 to 16, were initially evaluated using a behavioral neurology approach. A team of professional clinicians classified the 75 children with dyslexia into five groups, based on parents' and teachers' reported symptoms and clinical history. These groups included children with no mathematical deficits and children with mathematical deficits in number processing, arithmetical procedures, arithmetic facts retrieval, or geometrical abilities. Subsequently, the children underwent evaluation using the MCB to determine concordance with the clinicians' impressions. Additionally, neuropsychological and cognitive standardized tests were administered. Our study reveals that within a cohort of children with dyslexia, 66% exhibit mathematical deficits, and among those with mathematical deficits, there is heterogeneity in the nature of these deficits. If these findings are confirmed in larger samples, they can potentially pave the way for new diagnostic approaches, consistent subtype classification, and, ultimately personalized interventions.

Neural dynamics of semantic categorization in semantic variant of primary progressive aphasia.

Semantic representations are processed along a posterior-to-anterior gradient reflecting a shift from perceptual (e.g., it has eight legs) to conceptual (e.g., venomous spiders are rare) information. One critical region is the anterior temporal lobe (ATL): patients with semantic variant primary progressive aphasia (svPPA), a clinical syndrome associated with ATL neurodegeneration, manifest a deep loss of semantic knowledge. We test the hypothesis that svPPA patients perform semantic tasks by over-recruiting areas implicated in perceptual processing. We compared MEG recordings of svPPA patients and healthy controls during a categorization task. While behavioral performance did not differ, svPPA patients showed indications of greater activation over bilateral occipital cortices and superior temporal gyrus, and inconsistent engagement of frontal regions. These findings suggest a pervasive reorganization of brain networks in response to ATL neurodegeneration: the loss of this critical hub leads to a dysregulated (semantic) control system, and defective semantic representations are seemingly compensated via enhanced perceptual processing.

Regional and hemispheric susceptibility of the temporal lobe to FTLD-TDP type C pathology.

Post-mortem studies show that focal anterior temporal lobe (ATL) neurodegeneration is most often caused by frontotemporal lobar degeneration TDP-43 type C pathology. Clinically, these patients are described with different terms, such as semantic variant primary progressive aphasia (svPPA), semantic dementia (SD), or right temporal variant frontotemporal dementia (FTD) depending on whether the predominant symptoms affect language, semantic knowledge for object or people, or socio-emotional behaviors. ATL atrophy presents with various degrees of lateralization, with right-sided cases considered rarer even though estimation of their prevalence is hampered by the paucity of studies on well-characterized, pathology-proven cohorts. Moreover, it is not clear whether left and right variants show a similar distribution of atrophy within the ATL cross-sectionally and longitudinally. Here we study the largest cohort to-date of pathology-proven TDP-43-C cases diagnosed during life as svPPA, SD or right temporal variant FTD. We analyzed clinical, cognitive, and neuroimaging data from 30 cases, a subset of which was followed longitudinally. Guided by recent structural and functional parcellation studies, we constructed four bilateral ATL regions of interest (ROIs). The computation of an atrophy lateralization index allowed the comparison of atrophy patterns between the two hemispheres. This led to an automatic, imaging-based classification of the cases as left-predominant or right-predominant. We then compared the two groups in terms of regional atrophy patterns within the ATL ROIs (cross-sectionally) and atrophy progression (longitudinally). Results showed that 40% of pathology proven cases of TDP-43-C diagnosed with a temporal variant presented with right-lateralized atrophy. Moreover, the findings of our ATL ROI analysis indicated that, irrespective of atrophy lateralization, atrophy distribution within both ATLs follows a medial-to-lateral gradient. Finally, in both left and right cases, atrophy appeared to progress to the contralateral ATL, and from the anterior temporal pole to posterior temporal and orbitofrontal regions. Taken together, our findings indicate that incipient right predominant ATL atrophy is common in TDP-43-C pathology, and that distribution of damage within the ATLs appears to be the same in left- and right- sided variants. Thus, regardless of differences in clinical phenotype and atrophy lateralization, both temporal variants of FTD should be viewed as a spectrum presentation of the same disease.

Of brain and bone: the unusual case of Dr. A.

Frontotemporal dementia (FTD) is a clinical syndrome characterized by progressive decline in social conduct and a focal pattern of frontal and temporal lobe damage. Its biological basis is still poorly understood but the focality of the brain degeneration provides a powerful model to study the cognitive and anatomical basis of social cognition. Here, we present Dr. A, a patient with a rare hereditary bone disease (hereditary multiple exostoses) and FTD (pathologically characterized as Pick's disease), who presented with a profound behavioral disturbance characterized by acquired sociopathy. We conducted a detailed genetic, pathological, neuroimaging and cognitive study, including a battery of tests designed to investigate Dr. A's abilities to understand emotional cues and to infer mental states and intentions to others (theory of mind). Dr. A's genetic profile suggests the possibility that a mutation causing hereditary multiple exostoses, Ext2, may play a role in the pattern of neurodegeneration in frontotemporal dementia since knockout mice deficient in the Ext gene family member, Ext1, show severe CNS defects including loss of olfactory bulbs and abnormally small cerebral cortex. Dr. A showed significant impairment in emotion comprehension, second order theory of mind, attribution of intentions, and empathy despite preserved general cognitive abilities. Voxel-based morphometry on structural MRI images showed significant atrophy in the medial and right orbital frontal and anterior temporal regions with sparing of dorsolateral frontal cortex. This case demonstrates that social and emotional dysfunction in FTD can be dissociated from preserved performance on classic executive functioning tasks. The specific pattern of anatomical damage shown by VBM emphasizes the importance of the network including the superior medial frontal gyrus as well as temporal polar areas, in regulation of social cognition and theory of mind. This case provides new evidence regarding the neural basis of social cognition and suggests a possible genetic link between bone disease and FTD.

Dopamine receptor D4 (DRD4) polymorphisms with reduced functional potency intensify atrophy in syndrome-specific sites of frontotemporal dementia.

OBJECTIVE: We aimed to understand the impact of dopamine receptor D4 (DRD4) polymorphisms on neurodegeneration in patients with dementia. We hypothesized that DRD4dampened-variants with reduced functional potency would be associated with greater atrophy in regions with higher receptor density. Given that DRD4 is concentrated in anterior regions of the limbic and cortical forebrain we anticipated genotype effects in patients with a more rostral pattern of neurodegeneration. METHODS: 337 subjects, including healthy controls, patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) underwent genotyping, structural MRI, and cognitive/behavioral testing. We conducted whole-brain voxel-based morphometry to examine the relationship between DRD4 genotypes and brain atrophy patterns within and across groups. General linear modeling was used to evaluate relationships between genotype and cognitive/behavioral measures. RESULTS: DRD4 dampened-variants predicted gray matter atrophy in disease-specific regions of FTD in anterior cingulate, ventromedial prefrontal, orbitofrontal and insular cortices on the right greater than the left. Genotype predicted greater apathy and repetitive motor disturbance in patients with FTD. These results covaried with frontoinsular cortical atrophy. Peak atrophy patterned along regions of neuroanatomic vulnerability in FTD-spectrum disorders. In AD subjects and controls, genotype did not impact gray matter intensity. CONCLUSIONS: We conclude that DRD4 polymorphisms with reduced functional potency exacerbate neuronal injury in sites of higher receptor density, which intersect with syndrome-specific regions undergoing neurodegeneration in FTD.

Regional grey matter atrophy in clinically isolated syndromes at presentation.

BACKGROUND: The presence and degree of neuronal degeneration already existing in patients at their initial presentation with a clinically isolated syndrome suggestive of multiple sclerosis (CIS) is unclear, and whole brain or whole normalised grey matter analyses have not demonstrated significant atrophy in CIS cohorts at clinical presentation. Voxel-based analyses allow detection of regional atrophy throughout the brain and, therefore, may be sensitive to regional atrophy in CIS patients, and these changes may correspond with clinical disability. METHODS: This study used a modified voxel-based morphometry (VBM) method to correct for lesion effects to analyse regional atrophy and perform voxel-wise correlations between volume and clinical metrics in 41 untreated CIS patients at presentation compared with 49 healthy controls. RESULTS: The results confirmed that there was no significant difference in whole normalised grey matter volume between CIS and controls, whereas VBM showed significant areas of bilateral thalamic, hypothalamic, putamen and caudate atrophy. Voxel-wise correlations with clinical measures showed that cerebellar volumes correlated with clinical cerebellar function, nine-hole peg test scores and the Multiple Sclerosis Functional Composite (MSFC) score, and that the MSFC score was also correlated with putamen volume. Lastly, T1 lesion volumes were found to correlate with thalamic and hippocampal atrophy, suggesting a link between white matter lesions and grey matter degeneration at the earliest stages of multiple sclerosis. CONCLUSIONS: Atrophy is present in CIS patients at presentations, particularly in the thalamus, and other deep grey matter structures. Furthermore, the correlations with clinical metrics suggest the importance of this atrophy to clinical status and the correlation with T1 lesion load suggests a possible role of Wallerian degeneration.

Patterns of MRI atrophy in tau positive and ubiquitin positive frontotemporal lobar degeneration.

We applied optimised voxel based morphometry (VBM) to brain MRIs from autopsy proven cases of tau positive frontotemporal lobar degeneration (FTLD-T, n = 6), ubiquitin and TDP-43 positive/tau negative FTLD (FTLD-U, n = 8) and cognitively normal controls (n = 61). The analysis revealed that FTLD-T and FTLD-U both show atrophy in the frontal cortex and striatum, but striatal atrophy is more severe in FTLD-T. Manual region of interest tracing of caudate and putamen volumes confirmed the VBM findings. These anatomical differences may help distinguish between FTLD spectrum pathological subtypes in vivo.

Distinct MRI atrophy patterns in autopsy-proven Alzheimer's disease and frontotemporal lobar degeneration.

To better define the anatomic distinctions between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), we retrospectively applied voxel-based morphometry to the earliest magnetic resonance imaging scans of autopsy-proven AD (N = 11), FTLD (N = 18), and controls (N = 40). Compared with controls, AD patients showed gray matter reductions in posterior temporoparietal and occipital cortex; FTLD patients showed atrophy in medial prefrontal and medial temporal cortex, insula, hippocampus, and amygdala; and patients with both disorders showed atrophy in dorsolateral and orbital prefrontal cortex and lateral temporal cortex (P(FWE-corr) < .05). Compared with FTLD, AD patients had decreased gray matter in posterior parietal and occipital cortex, whereas FTLD patients had selective atrophy in anterior cingulate, frontal insula, subcallosal gyrus, and striatum (P < .001, uncorrected). These findings suggest that AD and FTLD are anatomically distinct, with degeneration of a posterior parietal network in AD and degeneration of a paralimbic fronto-insular-striatal network in FTLD.

Patterns of brain atrophy in frontotemporal dementia and semantic dementia.

OBJECTIVE: To identify and compare the patterns of cerebral atrophy associated with two clinical variants of frontotemporal lobar degeneration (FTLD): frontotemporal dementia (FTD) and semantic dementia (SemD). METHODS: Twenty patients with FTLD were classified as having FTD (N = 8) or SemD (N = 12) based on current clinical criteria. Both groups showed a similar spectrum of behavioral abnormalities, as indicated by the neuropsychiatric inventory. T1-weighted MRI was obtained for each patient and 20 control subjects. The regions of focal gray matter tissue loss associated with both FTD and SemD, as well as those differing between the two groups were examined using voxel-based morphometry. RESULTS: Regions of significant atrophy seen in both groups were located in the ventromedial frontal cortex, the posterior orbital frontal regions bilaterally, the insula bilaterally, and the left anterior cingulate cortex. The FTD, but not the SemD, group showed atrophy in the right dorsolateral frontal cortex and the left premotor cortex. The SemD, but not the FTD, group showed tissue loss in the anterior temporal cortex and the amygdala/anterior hippocampal region bilaterally. CONCLUSIONS: Although FTD and SemD are associated with different overall patterns of brain atrophy, regions of gray matter tissue loss in the orbital frontal, insular, and anterior cingulate regions are present in both groups. The authors suggest that pathology in the areas of atrophy associated with both FTD and SemD may underlie some the behavioral symptoms seen in the two disorders.

Category differences in brain activation studies: where do they come from?

Differences in the neural processing of six categories of pictorial stimuli (maps, body parts, objects, animals, famous faces and colours) were investigated using positron emission tomography. Stimuli were presented either with or without the written name of the picture, thereby creating a naming condition and a reading condition. As predicted, naming increased the demands on lexical processes. This was demonstrated by activation of the left temporal lobe in a posterior region associated with name retrieval in several previous studies. This lexical effect was common to all meaningful stimuli and no category-specific effects were observed for naming relative to reading. Nevertheless, category differences were found when naming and reading were considered together. Stimuli with greater visual complexity (animals, faces and maps) enhanced activation in the left extrastriate cortex. Furthermore, map recognition, which requires greater spatio-topographical processing, also activated the right occipito-parietal and parahippocampal cortices. These effects in the visuo-spatial regions emphasize inevitable differences in the perceptual properties of pictorial stimuli. In the semantic temporal regions, famous faces and objects enhanced activation in the left antero-lateral and postero-lateral cortices, respectively. In addition, we showed that the same posterior left temporal region is also activated by body parts. We conclude that category-specific brain activations depend more on differential processing at the perceptual and semantic levels rather than at the lexical retrieval level.

Treatment for apraxia of speech in nonfluent variant primary progressive aphasia.

There is a growing body of literature examining the utility of behavioral treatment in primary progressive aphasia (PPA). There are, however, no studies exploring treatment approaches to improve speech production in individuals with apraxia of speech (AOS) associated with the nonfluent variant of PPA. The purpose of this study was to examine a novel approach to treatment of AOS in nonfluent PPA. We implemented a treatment method using structured oral reading as a tool for improving production of multisyllabic words in an individual with mild AOS and nonfluent variant PPA. Our participant showed a reduction in speech errors during reading of novel text that was maintained at one year post-treatment. Generalization of improved speech production was observed on repetition of words and sentences and the participant showed stability of speech production over time in connected speech. Results suggest that oral reading treatment is an efficient and effective means of addressing multisyllabic word production in AOS associated with nonfluent PPA, with lasting and generalized treatment effects.

Examining the value of lexical retrieval treatment in primary progressive aphasia: two positive cases.

Individuals with primary progressive aphasia (PPA) suffer a gradual decline in communication ability as a result of neurodegenerative disease. Language treatment shows promise as a means of addressing these difficulties but much remains to be learned with regard to the potential value of treatment across variants and stages of the disorder. We present two cases, one with semantic variant of PPA and the other with logopenic PPA, each of whom underwent treatment that was unique in its focus on training self-cueing strategies to engage residual language skills. Despite differing language profiles and levels of aphasia severity, each individual benefited from treatment and showed maintenance of gains as well as generalization to untrained lexical items. These cases highlight the potential for treatment to capitalize on spared cognitive and neural systems in individuals with PPA, improving current language function as well as potentially preserving targeted skills in the face of disease progression.

COMT Val158Met genotype influences neurodegeneration within dopamine-innervated brain structures.

OBJECTIVE: We sought to determine whether the Val(158)Met polymorphism in the catechol-O-methyltransferase (COMT) gene influences neurodegeneration within dopamine-innervated brain regions. METHODS: A total of 252 subjects, including healthy controls and patients with Alzheimer disease, behavioral variant frontotemporal dementia, and semantic dementia, underwent COMT genotyping and structural MRI. RESULTS: Whole-brain voxel-wise regression analyses revealed that COMT Val(158)Met Val allele dosage, known to produce a dose-dependent decrease in synaptic dopamine (DA) availability, correlated with decreased gray matter in the region of the ventral tegmental area (VTA), ventromedial prefrontal cortex, bilateral dorsal midinsula, left dorsolateral prefrontal cortex, and right ventral striatum. Unexpectedly, patients carrying a Met allele showed greater VTA volumes than age-matched controls. Gray matter intensities within COMT-related brain regions correlated with cognitive and behavioral deficits. CONCLUSIONS: The results are consistent with the hypothesis that increased synaptic DA catabolism promotes neurodegeneration within DA-innervated brain regions.

Semantic dementia and persisting Wernicke's aphasia: linguistic and anatomical profiles.

Few studies have directly compared the clinical and anatomical characteristics of patients with progressive aphasia to those of patients with aphasia caused by stroke. In the current study we examined fluent forms of aphasia in these two groups, specifically semantic dementia (SD) and persisting Wernicke's aphasia (WA) due to stroke. We compared 10 patients with SD to 10 age- and education-matched patients with WA in three language domains: language comprehension (single words and sentences), spontaneous speech and visual semantics. Neuroanatomical involvement was analyzed using disease-specific image analysis techniques: voxel-based morphometry (VBM) for patients with SD and overlays of lesion digitized lesion reconstructions in patients with WA. Patients with SD and WA were both impaired on tasks that involved visual semantics, but patients with SD were less impaired in spontaneous speech and sentence comprehension. The anatomical findings showed that different regions were most affected in the two disorders: the left anterior temporal lobe in SD and the left posterior middle temporal gyrus in chronic WA. This study highlights that the two syndromes classically associated with language comprehension deficits in aphasia due to stroke and neurodegenerative disease are clinically distinct, most likely due to distinct distributions of damage in the temporal lobe.

Classification of primary progressive aphasia and its variants.

This article provides a classification of primary progressive aphasia (PPA) and its 3 main variants to improve the uniformity of case reporting and the reliability of research results. Criteria for the 3 variants of PPA--nonfluent/agrammatic, semantic, and logopenic--were developed by an international group of PPA investigators who convened on 3 occasions to operationalize earlier published clinical descriptions for PPA subtypes. Patients are first diagnosed with PPA and are then divided into clinical variants based on specific speech and language features characteristic of each subtype. Classification can then be further specified as "imaging-supported" if the expected pattern of atrophy is found and "with definite pathology" if pathologic or genetic data are available. The working recommendations are presented in lists of features, and suggested assessment tasks are also provided. These recommendations have been widely agreed upon by a large group of experts and should be used to ensure consistency of PPA classification in future studies. Future collaborations will collect prospective data to identify relationships between each of these syndromes and specific biomarkers for a more detailed understanding of clinicopathologic correlations.

Distinct clinical and metabolic deficits in PCA and AD are not related to amyloid distribution.

BACKGROUND/OBJECTIVE: Patients with posterior cortical atrophy (PCA) often have Alzheimer disease (AD) at autopsy, yet are cognitively and anatomically distinct from patients with clinical AD. We sought to compare the distribution of ß-amyloid and glucose metabolism in PCA and AD in vivo using Pittsburgh compound B (PiB) and FDG-PET. METHODS: Patients with PCA (n = 12, age 57.5 ± 7.4, Mini-Mental State Examination [MMSE] 22.2 ± 5.1), AD (n = 14, age 58.8 ± 9.6, MMSE 23.8 ± 6.7), and cognitively normal controls (NC, n = 30, age 73.6 ± 6.4) underwent PiB and FDG-PET. Group differences in PiB distribution volume ratios (DVR, cerebellar reference) and FDG uptake (pons-averaged) were assessed on a voxel-wise basis and by comparing binding in regions of interest (ROIs). RESULTS: Compared to NC, both patients with AD and patients with PCA showed diffuse PiB uptake throughout frontal, temporoparietal, and occipital cortex (p < 0.0001). There were no regional differences in PiB binding between PCA and AD even after correcting for atrophy. FDG patterns in PCA and AD were distinct: while both groups showed hypometabolism compared to NC in temporoparietal cortex and precuneus/posterior cingulate, patients with PCA further showed hypometabolism in inferior occipitotemporal cortex compared to both NC and patients with AD (p < 0.05). Patients with AD did not show areas of relative hypometabolism compared to PCA. CONCLUSIONS: Fibrillar amyloid deposition in PCA is diffuse and similar to AD, while glucose hypometabolism extends more posteriorly into occipital cortex. Further studies are needed to determine the mechanisms of selective network degeneration in focal variants of AD.

Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD.

OBJECTIVE: To compare the diagnostic performance of PET with the amyloid ligand Pittsburgh compound B (PiB-PET) to fluorodeoxyglucose (FDG-PET) in discriminating between Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD). METHODS: Patients meeting clinical criteria for AD (n = 62) and FTLD (n = 45) underwent PiB and FDG-PET. PiB scans were classified as positive or negative by 2 visual raters blinded to clinical diagnosis, and using a quantitative threshold derived from controls (n = 25). FDG scans were visually rated as consistent with AD or FTLD, and quantitatively classified based on the region of lowest metabolism relative to controls. RESULTS: PiB visual reads had a higher sensitivity for AD (89.5% average between raters) than FDG visual reads (77.5%) with similar specificity (PiB 83%, FDG 84%). When scans were classified quantitatively, PiB had higher sensitivity (89% vs 73%) while FDG had higher specificity (83% vs 98%). On receiver operating characteristic analysis, areas under the curve for PiB (0.888) and FDG (0.910) were similar. Interrater agreement was higher for PiB (κ = 0.96) than FDG (κ = 0.72), as was agreement between visual and quantitative classification (PiB κ = 0.88-0.92; FDG κ = 0.64-0.68). In patients with known histopathology, overall classification accuracy (2 visual and 1 quantitative classification per patient) was 97% for PiB (n = 12 patients) and 87% for FDG (n = 10). CONCLUSIONS: PiB and FDG showed similar accuracy in discriminating AD and FTLD. PiB was more sensitive when interpreted qualitatively or quantitatively. FDG was more specific, but only when scans were classified quantitatively. PiB slightly outperformed FDG in patients with known histopathology.

Reading disorders in primary progressive aphasia: a behavioral and neuroimaging study.

Previous neuropsychological studies on acquired dyslexia revealed a double dissociation in reading impairments. Patients with phonological dyslexia have selective difficulty in reading pseudo-words, while those with surface dyslexia misread exception words. This double dissociation in reading abilities has often been reported in brain-damaged patients, but it has not been consistently shown in patients with neurodegenerative diseases. In this study, we investigated reading impairments and their anatomical correlates in various neurodegenerative diseases. First, we performed a behavioral analysis to characterize the reading of different word types in primary progressive aphasia (PPA). Then, we conducted a voxel-based morphometry neuroimaging study to map the brain areas in which gray matter volume correlated with the accurate reading of exception and pseudo-words. The results showed a differential pattern of exception and pseudo-word reading abilities in different clinical variants of PPA. Patients with semantic dementia, a disorder characterized by selective loss of semantic memory, revealed a pattern of surface dyslexia, while patients with logopenic/phonological progressive aphasia, defined by phonological loop deficits, showed phonological dyslexia. Neuroimaging results showed that exception word reading accuracy correlated with gray matter volume in the left anterior temporal structures, including the temporal pole, the anterior superior and middle temporal and fusiform gyri, while pseudo-word reading accuracy correlated with left temporoparietal regions, including the posterior superior and middle temporal and fusiform gyri, and the inferior parietal lobule. These results suggest that exception and pseudo-word reading not only rely upon different language mechanisms selectively damaged in PPA, but also that these processes are sustained by separate brain structures.

Clinical syndromes associated with posterior atrophy: early age at onset AD spectrum.

OBJECTIVE: Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are clinical syndromes associated with posterior brain atrophy. We compared PCA and LPA to each other and to an age-matched group of patients with early age at onset of Alzheimer disease (EO-AD). We hypothesized that these 3 syndromes are part of a single clinical and biologic continuum. METHODS: Voxel-based morphometry (VBM) was used to assess atrophy in 14 PCA, 10 LPA, and 16 EO-AD patients compared to 65 healthy controls. Genetic analysis for APOE was conducted in 30 patients and 44 controls. Four patients came to autopsy. An additional 14 were studied with the beta-amyloid specific PET with tracer (11)C-labeled Pittsburgh Compound-B (PIB). RESULTS: VBM results demonstrated that, compared to controls, each patient group showed a large area of overlapping atrophy in bilateral parietal, occipital, precuneus, posterior cingulate, posterior temporal, and hippocampal regions. Surrounding this common area, group-specific atrophy was found in small, symptom-specific regions for each group: the right ventral-occipital and superior parietal regions in PCA, the left middle and superior temporal gyri in LPA, and the prefrontal cortex in EO-AD. APOE epsilon4 frequency was higher in all patient groups compared to controls. Four PCA, 5 LPA, and 8 EO-AD patients showed evidence of cortical amyloid at pathology (n = 3) or on PIB-PET (n = 14). CONCLUSIONS: Logopenic progressive aphasia and posterior cortical atrophy showed largely overlapping anatomic and biologic features with early age at onset of Alzheimer disease, suggesting that these clinical syndromes represent the spectrum of clinical manifestation of the nontypical form of Alzheimer disease that presents at an early age.