Neurodegenerative Syndrome Research Articles

A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome.

Trafficking protein particle (TRAPP) complexes, which include the TRAPPC4 protein, regulate membrane trafficking between lipid organelles in a process termed vesicular tethering. TRAPPC4 was recently implicated in a recessive neurodevelopmental condition in four unrelated families due to a shared c.454+3A>G splice variant. Here, we report 23 patients from 17 independent families with an early-infantile-onset neurodegenerative presentation, where we also identified the homozygous variant hg38:11:119020256 A>G (NM_016146.5:c.454+3A>G) in TRAPPC4 through exome or genome sequencing. No other clinically relevant TRAPPC4 variants were identified among any of over 10,000 patients with neurodevelopmental conditions. We found the carrier frequency of TRAPPC4 c.454+3A>G was 2.4-5.4 per 10,000 healthy individuals. Affected individuals with the homozygous TRAPPC4 c.454+3A>G variant showed profound psychomotor delay, developmental regression, early-onset epilepsy, microcephaly and progressive spastic tetraplegia. Based upon RNA sequencing, the variant resulted in partial exon 3 skipping and generation of an aberrant transcript owing to use of a downstream cryptic splice donor site, predicting a premature stop codon and nonsense mediated decay. These data confirm the pathogenicity of the TRAPPC4 c.454+3A>G variant, and refine the clinical presentation of TRAPPC4-related encephalopathy.

Convergence Along the Visual Hierarchy Is Altered in Posterior Cortical Atrophy.

PurposePosterior cortical atrophy (PCA) is a rare neurodegenerative syndrome manifesting with visuospatial processing impairment. We recently suggested that abnormal population receptive field properties are associated with the symptoms of PCA patients. Specifically, simultanagnosia, the inability to perceive multiple items simultaneously, can be explained by smaller peripheral population receptive fields, and foveal crowding, in which nearby distractors interfere with object perception, may result from larger foveal population receptive fields. These effects occurred predominantly in V1, even though atrophy mainly involves high-order areas. In this study, we used connective field modeling to better understand these inter-area interactions.MethodsWe used functional magnetic resonance imaging to scan six PCA patients and eight controls while they viewed drifting bar stimuli. Resting-state data were also collected. Connective field modeling was applied for both conditions: once when the source was V1 and the targets were extrastriate areas and once for the opposite direction. The difference between the two was defined as convergence magnitude.ResultsWith stimulus, the convergence magnitude of the controls increased along the visual pathway, suggesting that spatial integration from V1 becomes larger up the visual hierarchy. No such slope was found in the PCA patients. The difference between the groups originated mainly from the dorsal pathway. Without stimulus, the convergence magnitude was negative, slightly more so for the PCA patients, with no slope, suggesting constant divergence along the visual hierarchy.ConclusionsAtrophy in one part of the visual system can affect other areas within the network through complex intervisual area interactions, resulting in modulation of population receptive field properties and an ensemble of visuocognitive function impairments.

Recommendation for the differentiated use of nuclear medical diagnostic for parkinsonian syndromes

The present work provides an overview of the various nuclear medicine methods in the diagnosis of neurodegenerative parkinsonian syndromes and their respective evidence and is intended to enable practical decision-making aids in the application and interpretation of the methods and findings. The value of the procedures differs considerably in relation to the two relevant diagnostic questions. On the one hand, it is the question of whether there is a neurodegenerative parkinsonian syndrome at all, and on the other hand the question of which one. While the DAT-SPECT is undisputedly the method of choice for answering the first question (taking certain parameters into account), this method is not suitable for answering the second question. To categorise parkinsonian syndromes into idiopathic (i. e. Parkinson´s disease) or atypical, various procedures are used in everyday clinical practice including MIBG scintigraphy, and FDG-PET. We explain why FDG-PET currently is not only the most suitable of these methods to differentiate an idiopathic parkinsonian syndrome, from an atypical Parkinson's syndrome, but also enables sufficiently valid to distinguish the various atypical neurodegenerative Parkinson's syndromes (i. e. MSA, PSP and CBD) from each other and therefore should be reimbursed by health insurances.

Dehydroabietylamine-based thiazolidin-4-ones and 2-thioxoimidazolidin-4-ones as novel tyrosyl-DNA phosphodiesterase 1 inhibitors.

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a DNA repair enzyme that plays a key role in repairing damage caused by various antitumor drugs. It is a promising target in medicinal chemistry for the creation of cancer adjuvant therapy. Inhibition of this enzyme together with the use of anticancer chemotherapy enhances the effect of the latter. The natural mutant of TDP1, TDP1(H493R), causes severe neurodegenerative disease spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1). Inhibition of TDP1(H493R) appears to be useful in containment the progression of the disease. A library of compounds was synthesized starting from dehydroabietylamine including heterocyclic pharmacophore groups in the core. To obtain the desired products, the starting dehydroabietylamine was introduced sequentially in reaction with isothiocyanate and ethyl bromoacetate. Different classes of heterocyclic derivatives-2-iminothiazolidin-4-ons and 2-thioxoimidazolidin-4-ones-were obtained depending on the addition order of reagents. 2-Iminothiazolidin-4-thiones were obtained from 2-iminothiazolidin-4-ones under the action of the Lawesson's reagent. Effective TDP1 inhibitors were found among the obtained compounds that work in submicromolar concentrations. The inhibitor of TDP1(H493R) was also detected.

COVID-19 Catatonia—Would We Even Know?

COVID-19 Catatonia—Would We Even Know?

Rapid Eye Movement Sleep Behavior Disorder and Other Rapid Eye Movement Parasomnias

The discovery of rapid eye movement (REM) sleep and, in particular, REM sleep behavior disorder (RBD) have brought elusive nightmarish experiences to scientific scrutiny. This article summarizes a century of sleep research to examine the maladies of dreaming, their pathophysiologic significance, and management. Under healthy physiologic conditions, REM sleep is characterized by vivid mentation combined with skeletal muscle paralysis. The loss of REM sleep atonia in RBD results in vivid, potentially injurious dream enactment to patients and bed partners. RBD is common, affecting at least 1% of the population and is primarily caused by α-synuclein pathology of REM sleep-related brainstem neurons. The majority of patients with RBD ultimately develop a neurodegenerative syndrome such as Parkinson disease, dementia with Lewy bodies, or multiple system atrophy. Among patients with Parkinson disease, RBD predicts an aggressive disease course with rapid cognitive, motor, and autonomic decline. RBD is diagnosed by the presence of dream enactment episodes (either recorded or clinically recalled) and physiologic evidence of REM sleep without atonia demonstrated on polysomnography. Bedroom safety is of paramount importance in the management of RBD while pharmacokinetic options include melatonin or clonazepam. The injurious dream enactment of RBD is common and treatable. It is a syndrome of α-synuclein pathology with most patients ultimately developing Parkinson disease, dementia with Lewy bodies, or a related disorder.

Ataxia telangiectasia: A diagnostic challenge. Case report

Introduction: Ataxia-telangiectasia (AT) is a neurodegenerative syndrome with low incidence and prevalence worldwide, which is caused by a mutation of the ATM gene. It is an autosomal recessive disorder that is associated with defective cell regeneration and DNA repair mechanisms. It is characterized by progressive cerebellar ataxia, abnormal eye movements, oculocutaneous telangiectasias and immunodeficiency. Early diagnosis is critical to initiate a timely interdisciplinary treatment, improve acute symptoms, and control the multiple comorbidities of the disease. The following is the case of a patient who presented with the aforementioned characteristics and had an adequate response to the established medical treatment.Case presentation: A 7-year-old female patient from Bogotá, who presented clinical signs of global neurodevelopmental delay, cerebelar ataxia, frequent respiratory infections and ocular telangiectasias. Symptoms were associated with elevation of alpha fetoprotein and immunodeficiency, which allowed for a diagnosis of AT and the initiation of a timely interdisciplinary treatment.Conclusion: AT is a chromosomal instability syndrome with characteristic signs and symptoms. It is essential to know the etiopathogenesis, clinical manifestations, diagnostic criteria, and therapeutic options, emphasizing that early detection and clinical suspicion could favor the proper management of the comorbidities and improve the progressive course of the disease.

Cerebellar contributions to cognition in corticobasal syndrome and progressive supranuclear palsy.

Mounting evidence suggests an association between cerebellar atrophy and cognitive impairment in the main frontotemporal dementia syndromes. In contrast, whether cerebellar atrophy is present in the motor syndromes associated with frontotemporal lobar degeneration (corticobasal syndrome and progressive supranuclear palsy) and the extent of its contribution to their cognitive profile remain poorly understood. The current study aimed to comprehensively chart profiles of cognitive impairment in relation to cerebellar atrophy in 49 dementia patients (corticobasal syndrome = 33; progressive supranuclear palsy = 16) compared to 33 age-, sex- and education-matched healthy controls. Relative to controls, corticobasal syndrome and progressive supranuclear palsy patients demonstrated characteristic cognitive impairment, spanning the majority of cognitive domains including attention and processing speed, language, working memory, and executive function with relative preservation of verbal and nonverbal memory. Voxel-based morphometry analysis revealed largely overlapping patterns of cerebellar atrophy in corticobasal syndrome and progressive supranuclear palsy relative to controls, primarily involving bilateral Crus II extending into adjacent lobules VIIb and VIIIa. After controlling for overall cerebral atrophy and disease duration, exploratory voxel-wise general linear model analysis revealed distinct cerebellar subregions differentially implicated across cognitive domains in each patient group. In corticobasal syndrome, reduction in grey matter intensity in the left Crus I was significantly correlated with executive dysfunction. In progressive supranuclear palsy, integrity of the vermis and adjacent right lobules I–IV was significantly associated with language performance. These results are consistent with the well-established role of Crus I in executive functions and provide further supporting evidence for vermal involvement in cognitive processing. The current study presents the first detailed exploration of the role of cerebellar atrophy in cognitive deficits in corticobasal syndrome and progressive supranuclear palsy, offering insights into the cerebellum’s contribution to cognitive processing even in neurodegenerative syndromes characterized by motor impairment.

Rhythm and speech rate as a diagnostic aid in neurodegenerative syndromes of the front-temporal lobes

Temporal variables have proven to be an effective tool to characterize speech in neurodegenerative diseases and primary progressive aphasia variants, but the evidence available so far is essentially limited to English. This article analyses, by means of a small sample of seven patient groups and a control group (total n = 34; control group = 6; progressive primary aphasia, en three variants = 15; fronto-temporal dementia in two variants = 9; supranuclear progressive palsy = 3; cortico-basal syndrome = 2), the temporal parameters of speech rate, vowel duration, consonant duration, and nine rhythmic metrics (%V, %C, ΔV, ΔC, VarcoV, VarcoC, rPVI-V, rPVI-C, nPVI-V). The results indicate that speech rate is slower in patients with primary progressive non-fluent aphasia (APPnf), amyotrophic lateral sclerosis (ALS), or corticobasal syndrome (CBS) than in controls. These three clinical groups, as well as those suffering from progressive supranuclear palsy (PSP), have longer segmental durations, especially in consonants. Among the rhythm metrics, %C, ΔV and rPVI-C also allow to differentiate between groups, specifically, between control and APPlog, ELA-DFT y SCB.

In silico drug repositioning of FDA-approved drugs to predict new inhibitors for alpha-synuclein aggregation

One of the hallmarks of Parkinson’s disease (PD), a long-term neurodegenerative syndrome, is the accumulation of alpha-synuclein (α-syn) fibrils. Despite numerous studies and efforts, inhibition of α-syn protein aggregation is still a challenge. To overcome this issue, we propose an in silico pharmacophore-based repositioning strategy, to find a pharmaceutical drug that, in addition to their defined role, can be used to prevent aggregation of the α-syn protein. Ligand-based pharmacophore modeling was developed and the best model was selected with validation parameters including 72 % sensitivity, 98 % specificity and goodness score about 0.7. The optimal model has three groups of hydrogen bond donor (HBD), three groups of hydrogen bond acceptor (HBA), and two aromatic rings (AR). The FDA-Approved reports in the ZINC15 database were screened with the pharmacophore model taken from inhibitor compounds. The model identified 22 hits, as promising candidate drugs for Parkinson's therapy. It is noteworthy that among these, 10 drugs have been reported to inhibition of α-syn aggregation or treat/reduce Parkinson's pathogenesis. This model was used to virtual screen ZINC, NCI databases, and natural products from the pomegranate. The results of this screen were filtered for their inability to cross the blood-brain barrier, poor oral bioavailability, etc. Finally, the selected compounds of two ZINC and NCI databases were combined and structurally clustered. Remained compounds were clustered in 28 different clusters, and the 17 compounds were introduced as final candidates.

Fifteen Years of Wireless Sensors for Balance Assessment in Neurological Disorders.

Balance impairment is a major mechanism behind falling along with environmental hazards. Under physiological conditions, ageing leads to a progressive decline in balance control per se. Moreover, various neurological disorders further increase the risk of falls by deteriorating specific nervous system functions contributing to balance. Over the last 15 years, significant advancements in technology have provided wearable solutions for balance evaluation and the management of postural instability in patients with neurological disorders. This narrative review aims to address the topic of balance and wireless sensors in several neurological disorders, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, stroke, and other neurodegenerative and acute clinical syndromes. The review discusses the physiological and pathophysiological bases of balance in neurological disorders as well as the traditional and innovative instruments currently available for balance assessment. The technical and clinical perspectives of wearable technologies, as well as current challenges in the field of teleneurology, are also examined.

Salience Network Atrophy Links Neuron Type-Specific Pathobiology to Loss of Empathy in Frontotemporal Dementia.

Each neurodegenerative syndrome reflects a stereotyped pattern of cellular, regional, and large-scale brain network degeneration. In behavioral variant of frontotemporal dementia (bvFTD), a disorder of social-emotional function, von Economo neurons (VENs), and fork cells are among the initial neuronal targets. These large layer 5 projection neurons are concentrated in the anterior cingulate and frontoinsular (FI) cortices, regions that anchor the salience network, a large-scale system linked to social-emotional function. Here, we studied patients with bvFTD, amyotrophic lateral sclerosis (ALS), or both, given that these syndromes share common pathobiological and genetic factors. Our goal was to determine how neuron type-specific TAR DNA-binding protein of 43kDa (TDP-43) pathobiology relates to atrophy in specific brain structures and to loss of emotional empathy, a cardinal feature of bvFTD. We combined questionnaire-based empathy assessments, in vivo structural MR imaging, and quantitative histopathological data from 16 patients across the bvFTD/ALS spectrum. We show that TDP-43 pathobiology within right FI VENs and fork cells is associated with salience network atrophy spanning insular, medial frontal, and thalamic regions. Gray matter degeneration within these structures mediated loss of emotional empathy, suggesting a chain of influence linking the cellular, regional/network, and behavioral levels in producing signature bvFTD clinical features.

Posterior Cortical Atrophy: Characteristics From a Clinical Data Registry.

Background: Posterior cortical atrophy (PCA) is a neurodegenerative syndrome that presents with higher-order visual dysfunction with relative sparing of memory and other cognitive domains, and it is most commonly associated with Alzheimer's disease pathology. There is a lack of data regarding the presentation of PCA to non-cognitive specialists. Therefore, we collected clinical data from neuro-ophthalmologists regarding the presentation of PCA to their practices and compared data to published cohorts and a published survey of cognitive specialists.Methods: Members of the North American Neuro-Ophthalmology Society Listserv (NANOSnet) were invited to complete an online, retrospective, chart-review data-entry survey regarding their patients with PCA, and REDCap was used for data collection.Results: Data for 38 patients were entered by 12 neuro-ophthalmologists. Patient mean age at presentation was 67.8 years, and 74% of patients were women. Difficulty reading was reported at presentation by 91% of patients, and poor performance on color vision, stereopsis, and visual field testing (performed reliably by 36/38 patients) were common findings. Most patients who were treated were treated with donepezil and/or memantine.Conclusions: Compared to published data from cognitive specialists, patients presenting to neuro-ophthalmology with PCA were more likely to be older and female and have a reading complaint. Reliable visual field testing was the norm with homonymous defects in the majority of patients. The neuro-ophthalmologist plays an important role in diagnosing PCA in older adults with unexplained visual signs and symptoms, and future studies of PCA should involve multiple specialists in order to advance our understanding of PCA and develop effective treatments.

Ethical and Practical Challenges of the Communication and Behavioral Manifestations of Primary Progressive Aphasia.

The communication and behavioral manifestations of primary progressive aphasia (PPA) present ethical and practical challenges for individuals with this clinical syndrome as well as for individuals who are involved closely in their care. In this article, cases representing all three PPA variants (logopenic variant, nonfluent agrammatic, semantic variant) are presented to illustrate commonly encountered situations in which self-determination is at risk in decisions about housing, driving, social interactions, finances, and treatment interventions. Potential approaches, including patient/family education, implementation of safeguards, redirection to meaningful activities, and protections against vulnerability in treatment decisions, are described to preserve autonomy in patients with this neurodegenerative clinical syndrome.

Depressive Symptom Profiles Predict Specific Neurodegenerative Disease Syndromes in Early Stages.

Background: During early stages, patients with neurodegenerative diseases (NDG) often present with depressive symptoms. However, because depression is a heterogeneous disorder, more precise delineation of the specific depressive symptom profiles that arise early in distinct NDG syndromes is necessary to enhance patient diagnosis and care.Methods and Findings: Five-hundred and sixty four participants self-reported their depressive symptoms using the Geriatric Depression Scale (GDS), including 111 healthy older control subjects (NC) and 453 patients diagnosed with one of six NDGs who were at the mild stage of disease (CDR® Dementia Staging Instrument ≤ 1) [186 Alzheimer's disease (AD), 76 behavioral variant frontotemporal dementia (bvFTD), 52 semantic variant primary progressive aphasia (svPPA), 46 non-fluent variant PPA (nfvPPA), 49 progressive supranuclear palsy syndrome (PSPS), 44 corticobasal syndrome (CBS)]. The GDS was divided into subscales based on a previously published factor analysis, representing five symptoms (dysphoria, hopelessness, withdrawal, worry, and cognitive concerns). Mixed models were created to examine differences in depression subscale by group, and logistic regression analyses were performed to determine if patterns of depressive symptoms could predict a patient's NDG syndrome. PSPS patients presented with a hopeless, dysphoric, and withdrawn pattern, while patients with CBS presented with a similar but less severe pattern. Worry was a key symptom in the profile of patients with svPPA, while ADs only had abnormally elevated cognitive concerns. Depressive profile accurately predicted NDG diagnosis at a rate of between 70 and 84% accuracy.Conclusions: These results suggest that attention to specific depressive symptom profile can improve diagnostic sensitivity and can be used to provide more individualized patient care.

TRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca2+

The cation channel transient receptor potential vanilloid 4 (TRPV4) is one of the few identified ion channels that can directly cause inherited neurodegeneration syndromes, but the molecular mechanisms are unknown. Here, we show that in vivo expression of a neuropathy-causing TRPV4 mutant (TRPV4R269C) causes dose-dependent neuronal dysfunction and axonal degeneration, which are rescued by genetic or pharmacological blockade of TRPV4 channel activity. TRPV4R269C triggers increased intracellular Ca2+ through a Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated mechanism, and CaMKII inhibition prevents both increased intracellular Ca2+ and neurotoxicity in Drosophila and cultured primary mouse neurons. Importantly, TRPV4 activity impairs axonal mitochondrial transport, and TRPV4-mediated neurotoxicity is modulated by the Ca2+-binding mitochondrial GTPase Miro. Our data highlight an integral role for CaMKII in neuronal TRPV4-associated Ca2+ responses, the importance of tightly regulated Ca2+ dynamics for mitochondrial axonal transport, and the therapeutic promise of TRPV4 antagonists for patients with TRPV4-related neurodegenerative diseases.

Ioflupane 123I (DAT scan) SPECT identifies dopamine receptor dysfunction early in the disease course in progressive apraxia of speech

To describe 123I-FP-CIT (DAT scan) SPECT findings in progressive apraxia of speech (PAOS) patients and to compare those findings with progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). PAOS is a neurodegenerative syndrome in which patients present with apraxia of speech, a motor speech disorder affecting programming and planning of speech. Patients with PAOS predictably develop Parkinsonism. DAT scan is a neuroimaging tool that assesses the integrity of presynaptic dopamine transporters in striatum and is usually abnormal in PSP and CBS. As part of an NIH-funded grant, we performed a DAT scan on 17 PAOS patients early in the disease course. DaTQUANT software was used to quantify uptake in the left and right caudate and anterior/posterior putamen, with striatum to background ratios (SBRs). The PAOS cohort was compared to 15 PSP and 8 CBS patients. Five PAOS patients (29%) showed abnormalities in at least one striatal region on DAT scan. When the five PAOS patients with abnormal DAT were compared to the PSP and CBS patients, the only difference observed was lower uptake in the posterior putamen in PSP (p = 0.03). There were no differences is putamen/caudate ratio or in symmetry of uptake, across all groups. There was also no difference in MDS-UPDRS-III scores between PAOS patients with and without abnormal DAT scans (p = 0.56). Abnormal DAT scan is observed early in the disease course in approximately 30% of PAOS patients, with striatal abnormalities similar to those in PSP and CBS.

Connections Between the Ability to Cope with Stress and Tau Burden

The relationship between psychological stress and neurodegenerative syndromes has been established clinically. In animal models, paradigms of chronic

Wolfram syndrome: clinical and genetic profiling of a cohort from a tertiary care centre with characterization of the primary gonadal failure.

Wolfram syndrome (WFS) is a rare, monogenic neurodegenerative syndrome characterised by insulin requiring non-autoimmune diabetes mellitus (DM) and optic atrophy which are usually the earliest and commonest manifestations. However, there are other features which are under-recognized, adding to morbidity and premature mortality in these patients. Five patients (three males, two females) with genetically confirmed WFS at a single tertiary care centre were prospectively followed up. Their symptomatology, clinical profile, genetic analysis and radiology were analyzed. Multidisciplinary approach was used for comprehensive clinical care of this cohort. Patients with primary gonadal failure were subjected to biopsy and immunohistochemistry (IHC) for wolframin was performed. DM was the earliest presenting manifestation at 6.2 ± 1.3 years followed by optic atrophy at 10.4 ± 2.3 years, diabetes insipidus at 12 ± 2.1 years and deafness at 12.8 ± 2.1 years. All patients were autoantibody negative with low C-peptide(<0.6 ng/ml). Hypoglycemic episodes were frequent (upto 60%) but there was no instance of diabetic ketoacidosis. Optic atrophy was present alongwith proliferative diabetic retinopathy and cataract in 40%. Uncommon manifestations included neuropsychiatric features, parasuicide, cystopathy, brainstem atrophy and hypergonadotropic hypogonadism only in adult males (n = 2). Testicular biopsy revealed partly hyalinised seminiferous tubules and prominence of Leydig cells. IHC confirmed the presence of mutated wolframin, which was not significantly different from normal testis specimen on protein quantification. WFS requires a multidisciplinary approach with special emphasis on early diagnosis and management of other endocrine and non-endocrine features so as to improve long-term outcomes. Gonadal functions need periodic assessment, especially in adult males.

Using narratives in differential diagnosis of neurodegenerative syndromes

PurposeLanguage decline has been associated with healthy aging and with various neurodegenerative conditions, making it challenging to differentiate among these conditions. This study examined the utility of linguistic measures derived from a short narrative language sample for 1) identifying language characteristics and cut-off scores to differentiate between healthy aging, Primary Progressive Aphasia (PPA), Mild Cognitive Impairment (MCI), and Alzheimer’s dementia (AD); and 2) differentiating among PPA variants in which language is the primary impairment. MethodParticipants were 25 neurologically healthy English speakers, 20 individuals with MCI, 20 with AD, and 26 with PPA (non-fluent/agrammatic N = 10, logopenic N = 9, semantic N = 7). Narrative language samples of the Cookie Theft Picture of persons with healthy aging, MCI and AD were retrospectively obtained from the DementiaBank database (https://talkbank.org/DementiaBank/) and PPA samples were obtained from an ongoing research study. The language samples were analyzed for fluency, word retrieval success, grammatical accuracy, and errors using automated and manual analysis methods. The sensitivity and specificity of various language measures was computed. ResultsParticipants with PPA scored lower than neurologically healthy and MCI groups on fluency (words per minute and disfluencies), word retrieval (Correct Information Units and number of errors), and sentence grammaticality. PPA and AD groups did not differ on language measures. Agrammatic PPA participants scored lower than logopenic and semantic PPA groups on several measures, while logopenic and semantic PPA did not differ on any measures. ConclusionMeasures derived from brief language samples and analyzed using mostly automated methods are clinically useful in differentiating PPA from healthy aging and MCI, and agrammatic PPA from other variants. The sensitivity and specificity of these measures is modest and can be improved when coupled with clinical presentation.