Logopenic Primary Progressive Aphasia Research Articles

Atypical Presentations of Alzheimer Disease.

This article provides a comprehensive review of the distinct features of four atypical Alzheimer disease (AD) variants: dysexecutive AD, behavioral variant AD, posterior cortical atrophy, and the logopenic variant of primary progressive aphasia. It also elucidates their clinical presentations, underlying pathophysiologic pathways, diagnostic indicators, and management requirements. Recent research has revealed that these atypical AD forms vary not only in clinical manifestations but in their functional neuroanatomy spanning a common pathophysiologic spectrum. Imaging techniques, such as MRI, fludeoxyglucose positron emission tomography (FDG-PET), and tau PET, have identified distinct abnormalities in specific brain regions associated with each variant. This same variability is less tightly coupled to amyloid imaging. Emerging diagnostic and therapeutic strategies should be tailored to each variant's unique features. Atypical forms of AD often present with symptoms that are predominantly nonmemory related, distinguishing them from the more common memory-centric presentation of the disease. Two distinct clinical and pathologic entities, dysexecutive AD and behavioral variant AD, have replaced the outdated term frontal AD. Posterior cortical atrophy is another variant that mainly affects higher-order visual functions, which can lead to misdiagnoses because of its atypical symptom profile. Logopenic primary progressive aphasia is marked by difficulties in word retrieval, a challenge that may not be readily apparent if the person compensates by using circumlocution. Modern diagnostic techniques, such as MRI, PET, and biomarker analysis, have proven crucial for the accurate diagnosis and differentiation of these atypical AD variants. In treating these forms, it is critical to use tailored therapeutic interventions that combine pharmacotherapy with nonpharmacologic strategies to effectively manage the disease.

Resolving the problem of surface dyslexia in Italian through inflection of irregular verbs.

Surface dyslexia and dysgraphia are considered diagnostic features of semantic variant primary progressive aphasia (svPPA) and are useful signs in English, a language whose attributes afford numerous opportunities to observe these phenomena. This, however, is not the case in many languages, including Italian, that have high transparency between orthography and phonology, making surface reading and spelling errors scarce. This creates a problem in applying the diagnostic recommendations for svPPA in such languages. Surface dyslexia and dysgraphia are examples of 'regularization' errors in which semantic knowledge loss leads to a failure to recognize exceptions that do not follow standard rules of pronunciation. Another form of regularization involves the incorrect inflection of irregular verbs using the rules that govern regular verbs. Unlike irregularly pronounced words, Italian, as with many languages, has numerous irregular verbs. The Italian Verb Inflection Test (IVIT) was developed to test the hypothesis that svPPA would regularize irregular verbs when inflecting them into two Italian past tenses. Results confirmed that people with svPPA made a significantly greater proportion of regularization errors compared to people with typical Alzheimer's disease or logopenic variant PPA. Without recourse to the other diagnostic features of PPA subgroups, the IVIT on its own could separate svPPA from these other two groups with 70% sensitivity and ~ 80% specificity. Regularization of irregular verb inflection offers a solution to the problem of applying the surface dyslexia/dysgraphia criterion for svPPA diagnosis in Italian.

Assessing the metabolism of the olfactory circuit by use of 18F-FDG PET-CT imaging in patients suspected of suffering from Alzheimer’s disease or frontotemporal dementia

PurposeThe loss of olfactory function is known to occur in patients suffering from (behavioral variant) frontotemporal dementia ((bv)FTD) and Alzheimer’s disease (AD), although different pathophysiological mechanisms underpin this clinical symptom in both disorders. This study assessed whether brain metabolism of the olfactory circuit as assessed by positron emission tomography (PET) imaging with 2-[fluorine-18]fluoro-2-deoxy-d-glucose ([18F]-FDG) can distinguish these entities in different subsets of patients.MethodsPatients presenting with cognitive decline were included from a prospectively kept database: (1) bvFTD patients, (2) AD patients and (3) patients with logopenic primary progressive aphasia (PPA). Metabolic rates were calculated for different regions of the olfactory circuit for each subgroup and compared with a cohort of subjects with normal brain metabolism. Additionally, in patients with a logopenic PPA pattern on PET-imaging, statistical parametric mapping (SPM) analysis was performed.ResultsThe metabolism of subdivisions of the olfactory circuit as assessed by [18F]-FDG PET brain imaging to bvFTD and AD from control subjects resulted in sensitivity/specificity rates of 95/87.5% and 80/83.3%, respectively. A sensitivity/specificity rate of 100/87.5% was achieved when used to differentiate AD from bvFTD. In patients with the PPA pattern on imaging, the underlying cause (either FTD or AD) could be determined with a sensitivity/specificity rate of 88/82%. SPM analysis concurred that different regions of the olfactory circuit were affected in patients suffering from AD PPA or bvFTD PPA.ConclusionMetabolic dysfunction in the olfactory circuit is different in various neurodegenerative disorders. Further investigation of the correlations between the cerebral metabolism and the mechanisms which drive olfactory dysfunction is needed.

Psycholinguistic predictors of naming accuracy and decline in bilingual logopenic primary progressive aphasia: a cross-linguistic case study

ABSTRACT Naming impairment is a hallmark of logopenic primary progressive aphasia (lvPPA), yet its effects in bilingualism remain understudied. This study examined naming accuracy in a 78-year-old Chinese-English bilingual woman with lvPPA over two years using a modified Boston Naming Test. Naming accuracy was higher in her second, but more frequently used language (English) than her first, but less frequently used language (Chinese). Regression analyses revealed that familiarity predicted naming in Chinese, while word length and age of acquisition influenced English. Decline was linked to age of acquisition in Chinese and emotional properties in English, highlighting language-specific patterns in bilingual lvPPA.

Neurofilaments and progranulin are related to atrophy in frontotemporal lobar degeneration - A transdiagnostic study cross-validating atrophy and fluid biomarkers.

Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal syndrome/degeneration, and primary progressive aphasias (PPAs). We cross-validated fluid biomarkers and neuroimaging. Seven fluid biomarkers from cerebrospinal fluid and serum were related to atrophy in 428 participants including these FTLD subtypes, logopenic variant PPA (lvPPA), Alzheimer's disease (AD), and healthy subjects. Atrophy was assessed by structural magnetic resonance imaging and atlas-based volumetry. FTLD subtypes, lvPPA, and AD showed specific profiles for neurofilament light chain, phosphorylated heavy chain, tau, phospho-tau, amyloid beta1-42 from serum/cerebrospinal fluid, and brain atrophy. Neurofilaments related to regional atrophy in bvFTD, whereas progranulin was associated with atrophy in semantic variant PPA. Ubiquitin showed no effects. Results specify biomarker and atrophy patterns in FTLD and AD supporting differential diagnosis. They identify neurofilaments and progranulin in interaction with structural imaging as promising candidates for monitoring disease progression and therapy. Study cross-validated neuroimaging and fluid biomarkers in dementia. Five kinds of frontotemporal lobar degeneration and two variants of Alzheimer's disease. Study identifies disease-specific fluid biomarker and atrophy profiles. Fluid biomarkers and atrophy interact in a disease-specific way. Neurofilaments and progranulin are proposed as biomarkers for diagnosis and therapy.

Utility of visual rating scales in primary progressive aphasia

IntroductionDifferential diagnosis among subjects with Primary Progressive Aphasia (PPA) can be challenging. Structural MRI can support the clinical profile. Visual rating scales are a simple and reliable tool to assess brain atrophy in the clinical setting.The aims of the study were to establish to what extent the visual rating scales could be useful in the differential diagnosis of PPA, to compare the clinical diagnostic impressions derived from routine MRI interpretations with those obtained using the visual rating scale and to correlate results of the scales in a voxel-based morphometry (VBM) analysis.MethodPatients diagnosed with primary progressive aphasia (PPA) according to current criteria from two centers—Ospedale Maggiore Policlinico of Milan and Hospital Clínic de Barcelona—were included in the study. Two blinded clinicians evaluated the subjects MRIs for cortical atrophy and white matter hyperintensities using two protocols: routine readings and the visual rating scale. The diagnostic accuracy between patients and controls and within PPA subgroups were compared between the two protocols.ResultsOne hundred fifty Subjects were studied. All the scales showed a good to excellent intra and inter-rater agreement. The left anterior temporal scale could differentiate between semantic PPA and all other variants.The rater impression after the protocol can increase the accuracy just for the logopenic PPA. In the VBM analysis, the scores of visual rating scales correlate with the corresponding area of brain atrophy.ConclusionThe Left anterior temporal rating scale can distinguish semantic PPA from other variants. The rater impression after structured view improved the diagnostic accuracy of logopenic PPA compared to normal readings. The unstructured view of the MRI was reliable for identifying semantic PPA and controls. Neither the structured nor the unstructured view could identify the nonfluent and undetermined variants.

Structural gray matter changes in primary progressive aphasia variants

BACKGROUND: Primary progressive aphasia is a rare neurodegenerative disease with high clinical, genetic, and pathomorphological heterogeneity that greatly complicates its diagnosis. Voxel-based morphometry can be used to objectively assess structural gray matter changes and determine atrophy patterns in variants of primary progressive aphasia, which can improve the diagnosis and our understanding of its pathogenesis. AIMS: This study aimed to evaluate the patterns of atrophy in each of the primary progressive aphasia variants in comparison with the control group. MATERIALS AND METHODS: Patients diagnosed with one of the primary progressive aphasia variants, established in accordance with the current diagnostic criteria, were included in the main group. The control group consisted of healthy volunteers without any neurological symptoms or structural brain changes. All participants underwent brain magnetic resonance imaging. The obtained images were processed and used for voxel-based morphometry, which was performed by comparing the gray matter volume between each of the primary progressive aphasia variants and the control group. The study was adjusted for the sex, age, and intracranial volume of the participants. RESULTS: The study enrolled 25 patients with nonfluent, 11 with semantic, and 9 with logopenic variants of primary progressive aphasia, as well as 20 healthy volunteers. Voxel-based morphometry showed a specific atrophy pattern in each of the variants of primary progressive aphasia, with predominant involvement of the frontal and insular lobes in nonfluent, temporal lobe and hippocampus in semantic, and a more diffuse frontotemporal pattern in logopenic variants. CONCLUSIONS: The study revealed gray matter atrophy patterns specific to each variant of primary progressive aphasia. The obtained results mainly correspond to the clinical presentations of the disease. Moreover, some findings (e.g., absence of the posterior perisylvian atrophy and reduced motor cortex volume in the logopenic variant, atrophy of the orbitofrontal cortex and cerebellum in the nonfluent variant, and premotor cortex, precentral, and inferior frontal gyrus degeneration in the semantic variant) do not correlate with the usual understanding of primary progressive aphasia pathogenesis and require further study.

Anomia: Deciphering Functional Neuroanatomy in Primary Progressive Aphasia Variants.

Naming decline is one of the most common symptoms of primary progressive aphasia (PPA). Most studies on anomia in PPA are performed without taking into account PPA variants, especially for action naming. Only limited data are available for the neuroanatomical basis of anomia considering differences in the pathogenesis of PPAs. The aim of our study is to investigate the associations between anomia severity for both noun and verb naming and gray matter (GM) atrophy, as well as accompanying functional connectivity (FC) changes in three PPA variants. A total of 17 patients with non-fluent (nfvPPA), 11 with semantic (svPPA), and 9 with logopenic (lvPPA) PPA variants were included in the study and underwent cognitive/naming assessments and brain MRIs. Voxel-based morphometry was performed to evaluate GM volume. A resting-state functional MRI was applied to investigate FC changes in the identified GM areas. The study shows that different brain regions are involved in naming decline in each PPA variant with a predominantly temporal lobe involvement in svPPA, parietal lobe involvement in lvPPA, and frontal lobe involvement in nfvPPA. Separate data for object and action naming in PPA variants are provided. The obtained results mainly correspond to the current understanding of language processing and indicate that the evaluation of language impairments is preferable for each PPA variant separately. A further analysis of larger cohorts of patients is necessary to confirm these preliminary results.

Transcranial Magnetic Stimulation improves language and language network functional connectivity in a patient with logopenic Primary Progressive Aphasia

AbstractBackgroundPrimary progressive aphasia (PPA) refers to a group of neurodegenerative disorders characterized by early language impairments. Neuroimaging evidence suggests that language networks anchored in prefrontal, temporal and parietal cortices are selectively affected in these syndromes. Focal neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), are able to change resting‐state functional connectivity in a network‐specific manner.MethodHere, we characterized the language network of a patient with logopenic PPA and targeted this network in an individualized manner with high frequency (20Hz) rTMS and with sham rTMS. We used detailed language testing and resting‐state functional connectivity MRI as outcome measures.ResultThe patient’s language performance improved following active but not sham rTMS. This was accompanied by increased functional connectivity in the patient’s individually characterized language network after active but not sham rTMS.ConclusionThis case report supports further controlled clinical trials of individually‐targeted rTMS in PPA.

Clinical Manifestations.

Repetitive head impacts (RHI) occur routinely in sports like American football (AmFootball) and are the most well-established risk factor for chronic traumatic encephalopathy, a neurodegenerative tauopathy. However, RHI is not routinely evaluated in older adults with other suspected neurodegenerative diseases. The prevalence of RHI among older adults with neurodegenerative diseases and the influence on clinical symptoms is unknown. RHI was defined by AmFootball participation and analyzed based on frequency of any and "substantial" exposure (> 4 years). The Boston University Head Impact Exposure Assessment was administered to 195 older adult males at the UCSF Memory and Aging Center. Of these 106 (54%) were clinically normal (CN) participants in the Brain Aging Network for Cognitive Health (BRANCH) study and 89 (46%) were cognitively impaired participants from the Alzheimer's Disease Research Center. Diagnostic groups included AD-related phenotypes ("clinAD"; amnestic-predominant MCI/dementia, logopenic PPA; N = 26) and frontotemporal dementia spectrum conditions ("FTD"; behavioral variant FTD, semantic PPA, nonfluent PPA; N = 46). Our aims were: 1) investigate frequency of prior RHI between diagnostic groups (chi square), 2) compare age of symptom onset between participants with and without prior RHI (ANOVA), and 3) evaluate associations between RHI and cognition within the largest single diagnostic group (bvFTD N = 20; ANCOVA adjusted for age and education). Cohen's d effect sizes are reported. Males with clinAD (27%; χ2 = 8.3, p = .009; d = 0.53) and FTD (21%; χ2 = 5.6, p = .02, d = 0.40) were more likely than CN (7%) to have had substantial prior RHI. Prior RHI was associated with younger age of symptom onset (62.1±7.6 vs. 56.7±7.7 years old; p = .001, d = 0.69). This effect was stronger within clinAD (63.1±7.2 vs. 53.3±7.5; d = 1.3) than FTD (60.1±7.0 vs. 55.9±6.0; d = 0.54). In participants with bvFTD, those with prior RHI scored significantly worse on memory testing (w-scores -2.6±1.1 vs. -1.1±1.2, p = .02, d = 1.4). RHI through AmFootball is more common in AD and FTD than healthy controls. Prior RHI may contribute to variability in age of symptom onset in both AD and FTD. Exposure to RHI may also partly explain why some participants with bvFTD, a classically nonamnestic syndrome, develop memory decline. Prior RHI should be routinely evaluated in neurodegenerative disease workups.

53 Case Study Comparison of Logopenic and Semantic PPA Variants within the Medically Complex Veteran Population

Objective:To explore the utility of neuropsychological testing for patients with Primary Progressive Aphasia and compare testing data for a Logopenic and Semantic PPA variants within the medically complex Veteran population.Participants and Methods:Both participants were referred by their psychiatrist due to memory concerns. The case studies testing data will be compared to look at the differences on testing between different PPA presentations within the Veteran population. Patient A is a 77 year old, right handed, African American, divorced man with approximately 14 years of formal education. Patient B is a 76 year old, right handed, Caucasian, widowed man with approximately 16 years of formal education.Results:Patient A displayed problems with single-word retrieval, repetition of nonsense words and sentences, comprehension, reading, spelling, and naming. He also displayed impairments in aspects of working memory, along with learning and memory. His cognitive profile raises concern for a logopenic variant of primary progressive aphasia, which often has Alzheimer's disease pathology. Patient B displayed empty speech, impairments in fluency and reduced semantic knowledge that raises concern for a semantic variant of primary progressive aphasia. However, aspects of his presentation are not consistent with this diagnosis, specifically intact confrontation visual naming. Patient has a history of significant alcohol abuse, although he has mostly remained sober since moving to Texas. This evaluation cannot rule out the contribution of sustained alcohol use on his cognitive functioning; however, this is likely not the primary etiology given his significant language issues.Conclusions:Patients with medically complex histories and unclear timelines of symptom progressive make it difficult for diagnostic clarity. Diagnoses can be additionally difficult to determine at times when the clinical presentation is not as clearly defined in textbooks. This case study comparison displays the importance of integrating all data to determine the proper diagnosis to optimize patient care and provide recommendations tailored to that individual.

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

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

Subcortical atrophy imaging biomarker performance across the sporadic and genetic frontotemporal dementias

AbstractBackgroundFrontotemporal dementia (FTD) is a common cause of young‐onset dementia, with promising disease‐modifying candidates. Cortical signatures are well established; however, comprehensive longitudinal investigations of subcortical atrophy are limited and sample size estimates to inform imaging biomarker choice are lacking. Therefore, the current study investigated the relative utility of automated subcortical atrophy measures to detect putative disease‐modifying treatment effects in clinical, genetic and pathologically‐confirmed FTD.MethodLongitudinal registration and segmentation algorithms were applied to a cohort of 262 people, 184 of whom were diagnosed with FTD, to measure atrophy in the amygdala, hippocampus, caudate and thalamus. Clinical diagnoses were behavioural variant FTD (n = 66) and primary progressive aphasia (PPA, n = 118), comprising semantic variant PPA (n = 45), non‐fluent variant PPA (n = 45), logopenic variant PPA (n = 21), and PPA‐not otherwise specified (n = 7). Fifty‐three patients had either a known pathogenic mutation (in the MAPT, C9orf72 or GRN genes) and/or underlying tau or TDP‐43 pathology confirmed at post‐mortem. Seventy‐eight cognitively normal controls were included for comparison. Sample size estimates were computed to explore the relative feasibility of subcortical atrophy measures to track disease progression and detect treatment‐related effects across the different subgroups.ResultRelatively distinct patterns of significantly increased atrophy across the amygdala, hippocampus, caudate and/or thalamus were detected (p < 0.001) for all sporadic, genetic, and pathology‐confirmed FTD subgroups, with a strong left‐dominant pattern evident for PPA‐NOS and GRN patients. The best performing marker (as determined by lowest sample size required to detect a treatment effect) varied by subgroup supporting the importance of informed regional biomarker choice based on the population enrolled. Measures of the caudate and thalamus performed particularly well across all the subgroups, producing estimates well below 100 patients per treatment arm. The left hippocampal BSI (boundary shift integral) measure produced the lowest estimate overall in PPA‐NOS, with 12 individuals required to detect a 30% reduction in atrophy.ConclusionThis work confirms the relative utility of subcortical atrophy measures across the FTD spectrum and provides valuable sample size information to inform non‐invasive biomarker choice for sporadic and genetic FTD trials.

Do age and language impairment affect speed of recognition for words with high and low closeness centrality within the phonological network?

Purpose Speed and accuracy of lexical access change with healthy ageing and neurodegeneration. While a word's immediate phonological neighbourhood density (i.e. words differing by a single phoneme) influences access, connectivity to all words in the phonological network (i.e. closeness centrality) may influence processing. This study aimed to investigate the effect of closeness centrality on speed and accuracy of lexical processing pre- and post- a single word-training session in healthy younger and older adults, and adults with logopenic primary progressive aphasia (lvPPA), which affects phonological processing. Method Participants included 29 young and 17 older healthy controls, and 10 adults with lvPPA. Participants received one session of word-training on words with high or low closeness centrality, using a picture-word verification task. Changes in lexical decision reaction times (RT) and accuracy were measured. Result Baseline RT was unaffected by age and accuracy was at ceiling for controls. Post-training, only young adults' RT were significantly faster. Adults with lvPPA were slower and less accurate than controls at baseline, with no training effect. Closeness centrality did not influence performance. Conclusion Absence of training effect for older adults suggests higher threshold to induce priming, possibly associated with insufficient dosage or fatigue. Implications for word-finding interventions with older adults are discussed.

Evaluating the Association Between Genetically Proxied Neurodevelopmental Language Phenotypes and the Risk of Primary Progressive Aphasia.

Primary progressive aphasia (PPA) is a neurodegenerative syndrome of progressive language decline. PPA has 3 main subtypes: logopenic, semantic, and agrammatic. Observational studies suggested an association between language-related neurodevelopmental phenotypes and an increased risk of PPA. We sought to assess such relationships through Mendelian randomization (MR) approach, which can suggest potentially causal associations. Genome-wide significant single-nucleotide polymorphisms (SNPs) associated with dyslexia (42 SNPs), developmental speech disorders (29 SNPs), and left-handedness (41 SNPs) were used as genetic proxies for the exposures. Eighteen of 41 SNPs of left-handedness were associated with structural asymmetry of the cerebral cortex. Genome-wide association study summary statistics were obtained from publicly available databases for semantic (308 cases/616 controls) and agrammatic PPA (269 cases/538 controls). The logopenic PPA (324 cases/3,444 controls) was approximated by proxy through the rubric of clinically diagnosed Alzheimer disease with salient language impairment. Inverse-weighted variance MR was performed as the main analysis for testing the relationship between the exposures and outcomes. Sensitivity analyses were completed to test the robustness of the results. Dyslexia, developmental speech disorders, and left-handedness were not associated with any PPA subtype (p > 0.05). The genetic proxy of cortical asymmetry in left-handedness was significantly associated with agrammatic PPA (β = 4.3, p = 0.007), but not with other PPA subtypes. This association was driven by microtubule-related genes, primarily by a variant that is in complete linkage disequilibrium with MAPT gene. Sensitivity analyses were overall consistent with the primary analyses. Our results do not support a causal association between dyslexia, developmental speech disorders, and handedness with any of the PPA subtypes. Our data suggest a complex association between cortical asymmetry genes and agrammatic PPA. Whether the additional association with left-handedness is necessary remains to be determined but is unlikely, given the absence of association between left-handedness and PPA. Genetic proxy of brain asymmetry (regardless of handedness) was not tested as an exposure due to lack of suitable genetic proxy. Furthermore, the genes related to cortical asymmetry associated with agrammatic PPA are implicated in microtubule-related proteins (TUBA1B, TUBB, and MAPT), which is keeping with the association of tau-related neurodegeneration in this PPA variant.

Addition of the FTD Module to the Neuropsychiatric Inventory improves classification of frontotemporal dementia spectrum disorders

Most neuropsychiatric symptoms (NPS) common in frontotemporal dementia (FTD) are currently not part of the Neuropsychiatric Inventory (NPI). We piloted an FTD Module that included eight extra items to be used in conjunction with the NPI. Caregivers of patients with behavioural variant FTD (n = 49), primary progressive aphasia (PPA; n = 52), Alzheimer’s dementia (AD; n = 41), psychiatric disorders (n = 18), presymptomatic mutation carriers (n = 58) and controls (n = 58) completed the NPI and FTD Module. We investigated (concurrent and construct) validity, factor structure and internal consistency of the NPI and FTD Module. We performed group comparisons on item prevalence, mean item and total NPI and NPI with FTD Module scores, and multinomial logistic regression to determine its classification abilities. We extracted four components, together explaining 64.1% of the total variance, of which the largest indicated the underlying dimension ‘frontal-behavioural symptoms’. Whilst apathy (original NPI) occurred most frequently in AD, logopenic and non-fluent variant PPA, the most common NPS in behavioural variant FTD and semantic variant PPA were loss of sympathy/empathy and poor response to social/emotional cues (part of FTD Module). Patients with primary psychiatric disorders and behavioural variant FTD showed the most severe behavioural problems on both the NPI as well as the NPI with FTD Module. The NPI with FTD Module correctly classified more FTD patients than the NPI alone. By quantifying common NPS in FTD the NPI with FTD Module has large diagnostic potential. Future studies should investigate whether it can also prove a useful addition to the NPI in therapeutic trials.

Bridging the Gap between Psychiatry and Neurology: Alzheimer's disease- symptoms beyond memory impairment

It is increasingly recognized that there is significant heterogeneity in phenotype and clinical trajectories in Alzheimer's disease.Up to 25% of Alzheimer's disease (AD) cases do not show the typical neuropathology. Recently subtypes and atypical non-amnestic AD presentations have been formalized in the International Working Group (IWG) clinical diagnosis criteria. Clinical diagnosis of atypical AD has significantly been improved by the availability of biomarkers, including cerebrospinal fluid levels of Aβ42, total tau (t-tau) and phosphorylated tau181 (p-tau), MRI volumetric estimation of hippocampal and medial temporal atrophy, and amyloid brain PET imaging. Special attention will be given to language variant of Alzheimer's disease. A predominant deficit in the language domain is a key feature of primary progressive aphasia but language impairment is commonly present in Alzheimer's disease. International diagnostic criteria for PPA and its three variants (agrammatic, logopenic, semantic) were published in 2011. Since then, studies have investigated the validity of these criteria in classifying patients which includes clinical symptoms, neurocognitive presentations, distinct MRI signatures, and neuropathological differences. In this session special attention will be given of logopenic PPA a syndrome frequently seen in atypical Alzheimer's disease. Even though Alzheimer's disease is most notable for memory impairment, language impairments are also found early in the disease course. Indeed, neuropsychological testing shows changes in confrontation naming and semantic fluency. However, there is an additional body of research that shows that changes in spontaneous language, including idea density, speech quantity, fluency, and tempo can differentiate between normal aging and Alzheimer's disease.A physiologic sleep pattern is essential in the process of memory formation. Inadequate sleep results in cognitive impairment. MCI has an increased rate of sleeping problems compared to healthy people of the same age. In MCI, primary sleep disorders like sleep-disordered breathing, PLMS, RLS, RBD are more common, and also associated with a high rate of progression from MCI to AD. MCI also showed shorter total sleep time (longer in non-amnestic MCI), sleep efficiency, and cyclic alternating pattern. There is increased nighttime behavior. EEG power in amnestic MCI showed a reduction in the power of delta and theta frequency. There is a reduction in fast spindle counts on frontal location. Blunted and delayed onset with a duration of REM sleep reduced. A growing body of evidence supports the hypothesis that people with sleep disorders have a higher risk of developing Alzheimer's disease AD. Insomnia, self-reported sleep disturbances, decline in sleep duration, impaired sleep consolidation, delayed or decreased circadian rhythms and sleep-disordered breathing have been shown to increase AD risk, supporting the hypothesis that a chronically disrupted sleep-wake cycle can drive AD pathogenesis. Associations of sleep disorders and neurodegeneration in Alzheimer's are complex. Its understanding however is crucial for proper AD prevention, diagnosis, as well as management.Psychosis is a core syndrome in other than Alzheimer's disease and neurodegenerative disorders. It is however present in a large percentage of patients with AD. Psychosis most commonly presents as a delusional process and is linked to disruptive behavior, rapid progression, and overall morbidity. Psychotic syndromes in AD are complex but necessary to be diagnosed and managed properly.

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.

Differences and Similarities in Empathy Deficit and Its Neural Basis between Logopenic and Amnesic Alzheimer's Disease.

The aims of the study were to assess empathy deficit and neuronal correlates in logopenic primary progressive aphasia (lv-PPA) and compare these data with those deriving from amnesic Alzheimer's disease (AD). Eighteen lv-PPA and thirty-eight amnesic AD patients were included. Empathy in both cognitive and affective domains was assessed by Informer-rated Interpersonal Reactivity Index (perspective taking, PT, and fantasy, FT, for cognitive empathy; empathic concern, EC, and personal distress, PD, for affective empathy) before (T0) and after (T1) cognitive symptoms' onset. Emotion recognition was explored through the Ekman 60 Faces Test. Cerebral FDG-PET was used to explore neural correlates underlying empathy deficits. From T0 to T1, PT scores decreased, and PD scores increased in both lv-PPA (PT z = -3.43, p = 0.001; PD z = -3.62, p < 0.001) and in amnesic AD (PT z = -4.57, p < 0.001; PD z = -5.20, p < 0.001). Delta PT (T0-T1) negatively correlated with metabolic disfunction of the right superior temporal gyrus, fusiform gyrus, and middle frontal gyrus (MFG) in amnesic AD and of the left inferior parietal lobule (IPL), insula, MFG, and bilateral superior frontal gyrus (SFG) in lv-PPA (p < 0.005). Delta PD (T0-T1) positively correlated with metabolic disfunction of the right inferior frontal gyrus in amnesic AD (p < 0.001) and of the left IPL, insula, and bilateral SFG in lv-PPA (p < 0.005). Lv-PPA and amnesic AD share the same empathic changes, with a damage of cognitive empathy and a heightening of personal distress over time. The differences in metabolic disfunctions correlated with empathy deficits might be due to a different vulnerability of specific brain regions in the two AD clinical presentations.

Tau accumulation and degeneration differ across functional networks in atypical Alzheimer's disease phenotypes

AbstractBackgroundRecent models of Alzheimer's disease (AD) posit that pathogenic tau propagates through interconnected structural networks, suggesting amnestic and non‐amnestic AD (aAD &amp; naAD) phenotypes could reflect differential involvement of functional networks. We tested this hypothesis by contrasting longitudinal grey matter (GM) atrophy and tau accumulation across AD clinical phenotypes in 7 canonical functional networks.MethodsWe analyzed longitudinal 3‐Tesla T1‐weighted MRI from 122 patients [aAD=49; logopenic primary progressive aphasia (lvPPA)=31; posterior cortical atrophy (PCA)=23; behavioral/dysexecutive AD (bvAD)=6; corticobasal syndrome (CBS)=6; mixed naAD=4] with autopsy or CSF evidence of AD pathology and 91 cognitively normal controls (Table 1). Thirty‐one patients (aAD=9; lvPPA=7; PCA=9; bvAD=2; CBS=3; naAD=1) had longitudinal flortaucipir PET (FTP‐PET) data. We computed baseline values and annualized change for GM volume and FTP‐PET standardized uptake value ratios (SUVRs) in the 100‐label, 7‐network parcellation of Schaefer et al. (2018). Linear mixed effects models (α=0.05, corrected) adjusting for MMSE assessed group differences in atrophy and tau accumulation.ResultsAll groups exhibited significant baseline and longitudinal atrophy vs. controls in multiple networks (Figs. 1‐2). Differences in longitudinal atrophy rate (Fig. 2) were observed in the dorsal attention network [PCA&gt;lvPPA, t(371)=3.1, p&lt;0.04], salience network [PCA&gt;aAD, t(371)=3.1, p&lt;0.04], and limbic network [CBS&gt;aAD, t(371)=3.3, p&lt;0.02; CBS&gt;bvAD, t(371)=3.7, p&lt;0.006]. PCA patients exhibited FTP‐PET SUVR increases in all networks (all p&lt;0.02), while aAD patients displayed increases in all networks except visual and limbic (all others p&lt;0.0001). LvPPA patients exhibited net SUVR increases only in the somatomotor network [t(97)=3.5, p&lt;0.001]. At baseline, lvPPA patients had left &gt; right atrophy in all networks [all t&gt;3.7, p&lt;0.0002]; right &gt; left atrophy was observed in the visual network for PCA and CBS; the salience network for PCA and bvAD; and in the dorsal attention, frontoparietal control, and default mode networks for bvAD [all t&gt;3.0, p&lt;0.03]. In longitudinal analyses, no hemispheric differences were found in rates of GM volume loss or FTP‐PET change.ConclusionAD clinical variants exhibited GM atrophy and tau accumulation in partially overlapping networks. Investigating early‐stage disease will be crucial for assessing whether disease spread through canonical functional networks can explain anatomic differences in aAD and naAD phenotypes.