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Background: Since design and publication of the Western Aphasia Battery (WAB), increasing use to assess patients with aphasia in a clinical and research setting in stroke and in degenerative diseas...

The introduction of mild cognitive impairment (MCI) as a diagnostic category adds to the challenges of diagnosing Alzheimer’s Disease (AD). No single marker has been proven to accurately categorize patients into their respective diagnostic groups. Thus, previous studies have attempted to develop fused predictors of AD and MCI. These studies have two main limitations. Most do not simultaneously consider all diagnostic categories and provide suboptimal fused representations using the same set of modalities for prediction of all classes. In this work, we present a combined framework, cascaded multiview canonical correlation (CaMCCo), for fusion and cascaded classification that incorporates all diagnostic categories and optimizes classification by selectively combining a subset of modalities at each level of the cascade. CaMCCo is evaluated on a data cohort comprising 149 patients for whom neurophysiological, neuroimaging, proteomic and genomic data were available. Results suggest that fusion of select modalities for each classification task outperforms (mean AUC = 0.92) fusion of all modalities (mean AUC = 0.54) and individual modalities (mean AUC = 0.90, 0.53, 0.71, 0.73, 0.62, 0.68). In addition, CaMCCo outperforms all other multi-class classification methods for MCI prediction (PPV: 0.80 vs. 0.67, 0.63).

ObjectiveTo study longitudinal relationships between type 2 diabetes mellitus (T2DM), cortical thickness, and cognitive function in older people with normal cognition, mild cognitive impairment, and Alzheimer disease (AD).MethodsThe sample was derived from the Alzheimer's Disease Neuroimaging Initiative cohort who underwent brain MRI and cognitive tests annually for 5 years. Presence of T2DM was based on fasting blood glucose ≥7.0mml/L or the use of glucose-lowering agents. We used latent growth curve modeling to explore longitudinal relationships between T2DM, cortical thickness, and cognitive function, adjusting for relevant covariates and testing for interactions.ResultsThere were 124 people with T2DM (mean age 75.5 years, SD 6.2) and 693 without T2DM (mean age 75.1 years, SD 6.9) with at least 1 MRI available. AD and lower cortical thickness at study entry was associated with a lower chance of having a MRI available at each follow-up phase (all p < 0.001). T2DM was associated with lower baseline cortical thickness (p = 0.01). We found no direct effect of T2DM on decline in cortical thickness or cognitive function, but there was an indirect pathway linking T2DM and cognitive decline via baseline cortical thickness (β = −0.17, p = 0.022). There was an interaction between T2DM and education whereby the negative effect of T2DM on baseline cortical thickness was reduced in those with greater education (β = 0.34, p = 0.037). These associations changed minimally when adjusted for baseline cognitive diagnosis.ConclusionsIn an older cohort with low cerebrovascular disease burden, T2DM contributes to cognitive decline via neurodegeneration. Prior brain and cognitive reserve may protect against this effect.

Accurate diagnosis of mild cognitive impairment (MCI) before conversion to Alzheimer’s disease (AD) is invaluable for patient treatment. Many works showed that MCI and AD affect functional and structural connections between brain regions as well as the shape of cortical regions. However, ‘shape connections’ between brain regions are rarely investigated -e.g., how morphological attributes such as cortical thickness and sulcal depth of a specific brain region change in relation to morphological attributes in other regions. To fill this gap, we unprecedentedly design morphological brain multiplexes for late MCI/AD classification. Specifically, we use structural T1-w MRI to define morphological brain networks, each quantifying similarity in morphology between different cortical regions for a specific cortical attribute. Then, we define a brain multiplex where each intra-layer represents the morphological connectivity network of a specific cortical attribute, and each inter-layer encodes the similarity between two consecutive intra-layers. A significant performance gain is achieved when using the multiplex architecture in comparison to other conventional network analysis architectures. We also leverage this architecture to discover morphological connectional biomarkers fingerprinting the difference between late MCI and AD stages, which included the right entorhinal cortex and right caudal middle frontal gyrus.

This chapter charts the history of aphasiology from antiquity to the recent past. An arbitrary line is drawn to include paragraphs of only those who passed, to avoid the review of large amounts of currently active research. References are provided for original work as well as other historical reviews, the review groups, scientific and conceptual developments in historical time periods, regions of work, disciplines, and schools of thought. Contemporary aphasiology is part of the neurosciences, both basic and applied, advancing at a pace so precipitous as to be almost disorienting. We are benefiting from today’s incredible advances in MRI, PET, functional MRI, voxel-based morphometry, transcortical stimulation and white matter diffusion imaging, genetic and molecular biology laboratory work, and continuing clinical experience. History is being made at almost every minute and is better recorded than ever before. An update is already overdue.

Brain imaging genetics intends to uncover associations between genetic markers and neuroimaging quantitative traits. Sparse canonical correlation analysis (SCCA) can discover bi-multivariate associations and select relevant features, and is becoming popular in imaging genetic studies. The L1-norm function is not only convex, but also singular at the origin, which is a necessary condition for sparsity. Thus most SCCA methods impose $${\ell }_{{\bf{1}}}$$ ℓ 1 -norm onto the individual feature or the structure level of features to pursuit corresponding sparsity. However, the $${\ell }_{{\bf{1}}}$$ ℓ 1 -norm penalty over-penalizes large coefficients and may incurs estimation bias. A number of non-convex penalties are proposed to reduce the estimation bias in regression tasks. But using them in SCCA remains largely unexplored. In this paper, we design a unified non-convex SCCA model, based on seven non-convex functions, for unbiased estimation and stable feature selection simultaneously. We also propose an efficient optimization algorithm. The proposed method obtains both higher correlation coefficients and better canonical loading patterns. Specifically, these SCCA methods with non-convex penalties discover a strong association between the APOE e4 rs429358 SNP and the hippocampus region of the brain. They both are Alzheimer’s disease related biomarkers, indicating the potential and power of the non-convex methods in brain imaging genetics.

Accurate prediction of Alzheimer’s disease (AD) is important for the early diagnosis and treatment of this condition. Mild cognitive impairment (MCI) is an early stage of AD. Therefore, patients with MCI who are at high risk of fully developing AD should be identified to accurately predict AD. However, the relationship between brain images and AD is difficult to construct because of the complex characteristics of neuroimaging data. To address this problem, we present a longitudinal measurement of MCI brain images and a hierarchical classification method for AD prediction. Longitudinal images obtained from individuals with MCI were investigated to acquire important information on the longitudinal changes, which can be used to classify MCI subjects as either MCI conversion (MCIc) or MCI non-conversion (MCInc) individuals. Moreover, a hierarchical framework was introduced to the classifier to manage high feature dimensionality issues and incorporate spatial information for improving the prediction accuracy. The proposed method was evaluated using 131 patients with MCI (70 MCIc and 61 MCInc) based on MRI scans taken at different time points. Results showed that the proposed method achieved 79.4% accuracy for the classification of MCIc versus MCInc, thereby demonstrating very promising performance for AD prediction.

Background: Primary progressive aphasia (PPA) is a progressive language disorder with preserved cognitive function for at least 2 years from onset. The main variants currently distinguished are: non-fluent/agrammatic (nfvPPA), semantic (svPPA), and logopenic (lvPPA). Patients with initial language presentation may subsequently develop other symptoms, such as behavioural dysfunction or apraxia. The clinical pattern of PPA depends on the location of atrophy, the underlying pathology, and the stage of the disease.Aims: This review aims at characterising longitudinal changes in clinical presentations of different PPA variants and at presenting implications of these changes for the assessment, diagnosis, and management.Main contribution: The three PPA variants differ not only in terms of language impairment, but also with regard to cognitive and behavioural profile. Apraxia and rigidity frequently occur in the course of nfvPPA. Patients with lvPPA seem to follow the pattern of aphasic Alzheimer’s disease, wher...

Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions [with or without motor neuron disease (MND); cohort 2], and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls [11.9 vs. 19.1 %, odds ratio (OR) 0.57, p = 0.014; same direction as carriers of GRN mutations]. The strongest evidence was provided by FTD patients (OR 0.33, p = 0.009) followed by FTD/MND patients (OR 0.38, p = 0.017), whereas no significant difference was observed in MND patients (OR 0.85, p = 0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR 0.77, p = 0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR 0.26, p < 0.001). Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations and might be relevant for prognostic testing, and as a promising therapeutic target for the entire spectrum of FTLD-TDP.

Objective:To specify the presenting symptoms and clinical course of patients with frontotemporal dementia (FTD) and chromosome 9 open reading frame 72 (C9ORF72) repeat expansion.Background:The 2011 discovery of the C9ORF72 repeat expansion causing familial FTD and amyotrophic lateral sclerosis has permitted retrospective evaluation of potential defining clinical characteristics that may distinguish carriers of the C9ORF72 mutation from other patients with FTD. Prior reports identified a subset of patients with FTD who had an unusually high prevalence of psychosis, although their specific symptoms had not yet been fully described.Methods:From a cohort of 62 patients with FTD, we conducted a retrospective chart review of 7 patients who had C9ORF72 mutations on genetic testing, and 1 untested sibling of a C9ORF72 carrier.Results:Detailed histories revealed a higher prevalence of psychosis, including visual and auditory hallucinations and delusions, in the 8 C9ORF72 carriers than in our patients with sporadic FTD.Conclusions:This cohort confirms and adds clinical details to the reports of a high prevalence of psychotic phenomena in patients who have C9ORF72 mutations as well as FTD or amyotrophic lateral sclerosis.

There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin., Whether Alzheimer's disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.

Background:The neuropeptide oxytocin, produced in the supraoptic (SON) and paraventricular nuclei (PVN) of the hypothalamus, is now understood to function as a neurotransmitter critical for various aspects of social cognition and pro-social behaviour. While patients with Frontotemporal dementia (FTD) display prominent and progressive deficits in such social behaviours, the integrity of these nuclei in FTD is not known.Methods:We conducted a quantitative neuropathologic examination of the SON and PVN from patients with FTLD with TDP-43 proteinopathy, Alzheimer's disease, Lewy body disease and controls to determine whether significant pathologic changes or neuronal loss may contribute to the striking behavioural symptoms of FTD.Results:Contrary to predictions, we found both nuclei to be free of significant pathologic change (TDP-43) in FTLD. In contrast, tau related pathology was found in the PVN in Alzheimer's disease, and alpha-synuclein pathology in the SON in patients with Lewy body dementia.Conclusions:These results indicate that the SON and PVN are resistant to FTLD TDP-43 pathology. They also support prior suggestions that the SON is resistant to Alzheimer's disease (AD) related pathology, and extend this to demonstrate SON susceptibility to alpha-synuclein pathology in patients with Lewy body dementia.

Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR = 5.57; P = 0.001; repeat length > 30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR 5 5.83; P = 0.004; repeat length > 30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31-33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.

Aphasiology has undergone considerable change since Broca and Wernicke, and present day efforts, driven by technology, represent another stage of reinterpretation of theory and revamping classifica...

The importance of executive dysfunction is increasingly recognized in the dementia syndrome. Although executive dysfunction has been associated with subcortical ischemic lesions, it may not be unique to VCI or to its clinical subtypes.Secondary analysis of the CIVIC study, a multi-centre memory clinic cohort study. An executive dysfunction index variable was created using 30 items from the clinical evaluation.Of 1347 patients, 151 had a baseline diagnosis of no cognitive impairment (NCI), 463 had AD, 324 had VCI, 97 had vascular cognitive impairment not dementia (VCI-ND) and 253 had non-vascular CIND. Those with VCI and AD had higher mean executive dysfunction index values than those with NCI (F=160.2, p0.01). Within the VCI subtypes, people with VaD and mixed dementia had the highest mean executive dysfunction index values (F=92.5, p0.01). Higher executive dysfunction index values were significantly correlated with lower MMSE scores (R=0.70, p0.01), higher Functional Rating Scale scores (R=0.77, p0.01) and higher Geriatric Depression Score values (R=0.11, p0.01). Compared to those who had a lower burden of executive dysfunction, patients with more executive dysfunction (index values=0.2) were more likely to be institutionalized (HR=5.2, p0.01) or to die (HR=2.4, p0.01) during the next 30 months.Executive dysfunction is common in both AD and VCI. It is associated with poor performance on other measures of cognition and function. The presence of executive dysfunction is associated with worse near-term outcomes.

Background: Although semantic dementia (SD) is characterised by a multimodal loss of semantic knowledge, it has been demonstrated that lexical‐semantic representations are not equally disrupted in SD and that some categories may be recognised better than others. Little is known, however, about the pattern of the category‐specific comprehension deficits in SD and whether it differs from that of other forms of progressive aphasias. Aims: This exploratory study aimed to investigate the evolution of category‐specific deficits of single‐word comprehension in progressive aphasias. Methods & Procedures: A total of 19 patients with a clinical diagnosis of SD, 25 patients with primary progressive aphasia with agrammatic and relatively nonfluent speech (PPA), and 25 patients with Alzheimer's disease (AD) with aphasia were studied longitudinally with the Western Aphasia Battery (WAB). The Auditory Word Recognition subtest of the WAB was utilised to assess comprehension of words derived from different semantic catego...

APOE epsilon4 is the best-established genetic risk factor for sporadic Alzheimer's disease (AD). However, while homozygotes show greater disease susceptibility and earlier age of onset than heterozygotes, they may not show faster rates of clinical progression. We hypothesize that there are differential APOE epsilon4 allele-load dependent influences on neuropathology across the brain. Our aim was to define the relationship between APOE epsilon4 allele load and regionally-specific brain cortical atrophy in Alzheimer's Disease (AD). For this reason voxel-based morphometry (VBM) was performed using T1-weighted MR images from 83 AD patients, contrasting regional cortical grey matter by APOE epsilon4 load according to either dominant or genotypic models. Patients fulfilled NINCDS-ADRDA criteria and were genotyped for APOE epsilon4 (15 epsilon4/epsilon4, 39 epsilon4/- and 29-/-). We observed that grey matter volume (GMV) decreased additively with increasing allele load in the medial (MTL) and anterior temporal lobes bilaterally. By contrast, a 2 degree-of-freedom genotypic model suggested a dominant effect of the APOE epsilon4 allele in the left temporal lobe. Brain regions showing a significant APOE epsilon4 allele load effect on GMV in AD included only some of those typically described as having greatest amyloid plaque deposition and atrophy. Temporal regions appeared to show a dominant effect of APOE epsilon4 allele load instead of the additive effect previously strongly associated with age of onset. Regional variations with allele load may be related to different mechanisms for effects of APOE epsilon4 load on susceptibility and disease progression.

Background: Frontotemporal dementia (FTD) is associated with marked behavior changes, but hallucinations and delusions are rare. Objective: To report a case of FTD with early and persistent delusions, including de Clerambault syndrome. Design: We describe the clinical, neuroradiologic, and neuropathologic findings of a 76-year-old woman with an 11-year course of FTD with bizarre delusions and hallucinations. Results: The patient's autopsy examination of the brain revealed pathology consistent with frontotemporal lobar degeneration with ubiquitin-positive and transactive response (TAR)-DNA-binding protein-43-positive inclusions and hippocampal sclerosis. Conclusions: Delusions and hallucinations can occur in proven frontotemporal pathology.

Although misidentification syndromes (MISs) have been often described in Alzheimer disease (AD), the prevalence of these phenomena in different neurodegenerative diseases has not been systematically studied. Three hundred ninety-two individuals with probable AD, 119 patients with the behavioral variety of frontotemporal dementia (FTD-bv), 101 patients with primary progressive aphasia, 24 subjects with semantic dementia, 18 subjects with corticobasal degeneration, 8 patients with progressive supranuclear palsy, 36 individuals with probable Lewy body dementia (DLB), and 26 subjects with Parkinson disease (PD) were the participants of this study. On the basis of a semistructured interview with both patients and their reliable caregivers, MIS was identified in 15.8% of cases with AD, 16.6% of patients with DLB, and in 8.3% of individuals with semantic dementia. The most frequent form of MIS was Capgras delusions, often accompanied by reduplication of place, phantom border phenomenon, or both. Although MIS typically appears in later stages of the disease, it can also occur surprisingly early in patients with AD. None of the patients with FTD-bv, primary progressive aphasia, corticobasal degeneration/supranuclear palsy, or PD developed MIS. Thus, our findings suggest that MISs are characteristic of AD and DLB, and tend to exclude FTD/Pick complex and PD.

Objective Previous research has shown that cognitively-impaired-not-demented (CIND) individuals with at least one neuropsychiatric symptom (NPS) have more functional disability than individuals without any NPSs. The objectives of the present study were to determine whether there are consistent clusters of NPS in CIND individuals and whether certain NPS clusters are more strongly associated with measures of functional disability than other NPS clusters in this population. Methods This was a cross-sectional baseline study of NPS using the Neuropsychiatric Inventory (NPI) in a national clinic-based observational cohort study (the Canadian Cohort Study of Cognitive Impairment and Related Dementias study). The present investigation focuses on a subset of CIND subjects (73%) whose informant endorsed the presence of at least one NPI item. Results A hierarchical cluster analysis identified two NPS clusters. One consisted of mood factors (i.e., depression, anxiety, apathy, irritability, and problems with sleep) and the other cluster captured frontal symptoms (i.e., aberrant motor behavior, disinhibition, agitation, and problems with appetite). NPSs grouped within the mood cluster were more common than the frontal cluster (95% of subjects had at least one NPS within the mood cluster versus 53% in the frontal cluster). However, the frontal cluster was more strongly associated with functional disability measures even after controlling for cognitive status (i.e., the Mini-Mental State Exam) and the mood cluster score. Conclusion The frontal cluster of NPSs was more strongly associated with functional disability than the mood cluster.

Background/Aims: The treatment of frontotemporal dementia (FTD) has been mainly symptomatic. Small randomized or open-label case control studies of neurotransmitters have been inconclusive. We tried galantamine in the 2 most common varieties of FTD. Method: Thirty-six behavioral variety FTD and primary progressive aphasia (PPA) patients were treated in an open-label period of 18 weeks and a randomized, placebo-controlled phase for 8 weeks with galantamine. The primary efficacy measures were the Frontal Behavioral Inventory, the Aphasia Quotient of the Western Aphasia Battery, the Clinical Global Impression of Severity and the Clinical Global Impression of Improvement. Results: No significant differences in behavior or language were found for the total group. A treatment effect (p = 0.009), in a subgroup of subjects with PPA in the global severity score, in favor of galantamine was detected in the placebo-controlled withdrawal phase but was not considered significant after correction for multiple comparisons. The language scores for the treated PPA group also remained stable compared to the placebo group, which showed deterioration. Conclusion: Galantamine is not effective in the behavioral variety of FTD, but a trend of efficacy is shown in the aphasic subgroup, which may be clinically significant. Galantamine appeared safe in FTD/PPA.

Background: Patients with cognitive impairment no dementia (CIND) are at an increased risk of progression to Alzheimer’s disease (AD). Whether subtle impairments in functional or social abilities at the CIND stage can predict progression to AD is not yet fully determined. We evaluated whether impairments on the Disability Assessment for Dementia (DAD) and Functional Rating Scale (FRS) can predict progression to AD. Methods: We examined 70 patients with CIND from the ACCORD cohort having complete DAD and FRS baseline and 2-year follow-up data. MANCOVA adjusted for age, sex, education and baseline MMSE score compared the baseline and 2-year change in DAD and FRS scores in CIND patients who progressed to AD versus non-progressors. Results: There were no significant differences between CIND progressors and non-progressors in baseline total DAD or FRS scores. FRS domain analysis revealed that greater impairment in social/occupational functioning significantly predicted progression, while there were no predictive DAD domains. In progressors, both DAD and FRS scores significantly declined over time with the largest changes in instrumental activities of daily living (IADL). Conclusion: While changes in IADL characterize the progression from CIND to AD, impairment in complex social-cognitive competency significantly predicts risk of progression and may mark early AD.

This evidence-based review examines the utility of brief cognitive tests and neuropsychological testing (NPT) in the detection and diagnosis of mild cognitive impairment (MCI) and dementia. All patients presenting with cognitive complaints are recommended to have a brief screening test administered to document the presence and severity of memory/cognitive deficits. There is fair evidence to support the use of a range of new screening tests that can detect MCI and mild dementia with higher sensitivity (or=80%) than the Mini-Mental State Exam (MMSE). NPT should be part of a clinically integrative approach to the diagnosis and differential diagnosis of dementia. It should be applied selectively to address specific clinical and diagnostic issues including: 1) The distinction between normal cognitive functioning in the aged, MCI and early dementia: there is fair evidence that NPT can document the presence of specific diagnostic criteria and provide additional useful information on the pattern of memory/cognitive impairment. 2) The evaluation of risk for Alzheimer disease (AD) or other types of dementia in persons with MCI: there is fair evidence that NPT measures or profiles can predict progression to dementia (predictive accuracy ranges from approximately 80 to 100%, sensitivities from 53 to 80%, and specificities from 67 to 99%). 3) DIFFERENTIAL DIAGNOSIS: There is fair evidence that NPT can complement clinical history and neuroimaging in determining the dementia etiology. Different dementia types have distinguishable NPT profiles though these may be stage-dependent, and increased sensitivity may be at the expense of specificity. 4) When NPT is part of a comprehensive assessment, which also entails clinical interviews and consideration of other clinical data, there is good evidence that it can contribute to management decisions in MCI and dementia, including the determination of retained and impaired cognitive abilities, their functional and vocational impact, and opportunities for cognitive rehabilitation.

The most widely established diagnostic criteria for the behavioral variant of frontotemporal dementia have now been in use for almost a decade. Although consensus criteria have provided a much needed standard for frontotemporal dementia research, a growing body of evidence suggests that revisions are needed to improve their applicability. In this article, we discuss the limitations of current diagnostic criteria and propose the establishment of an international consortium to revise diagnostic and research criteria for the behavioral variant of frontotemporal dementia.

Background: Distinguishing between patients with frontotemporal lobar dementia (FTLD) and other dementing illnesses remains a difficult task for many clinicians. In this study, we aimed to provide further evidence for the construct validity of the frontal behavioural inventory (FBI) and assess its utility in differentiating FTLD patients from other groups using data from the Canadian Collaborative Cohort of Related Dementias (ACCORD) study. Method: Baseline scores on the FBI and neuropsychiatric inventory (NPI) were compared among several clinical groups (n = 177). Results: The FBI discriminated a higher percentage of FTLD patients (>75% correct classification) from Alzheimer’s disease and other groups compared to the NPI (54.2%). Conclusion: This study provides good evidence for convergent validity between the FBI and NPI (r = 0.72), indicating that both measures capture similar psychopathology in this nationwide cohort.

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions., Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.

Objective: To describe language impairment in the corticobasal degeneration syndrome (CBDS) presenting as either a cognitive or motor disorder, to compare the evolution of aphasia in CBDS with primary progressive aphasia (PPA), and to examine whether the side of maximal cerebral atrophy or akinesia reflects the severity of aphasia. Methods: We divided 40 patients with CBDS according to motor or cognitive onsets and conducted detailed language assessments with the Western Aphasia Battery (WAB). We analyzed scores according to the side of atrophy and motor rigidity. Longitudinal performance over three annual assessments was compared against matched patients with PPA and Alzheimer disease. Results: Language at baseline was more impaired in cognitive than motor-onset CBDS but there was no correlation between the side of atrophy or motor impairment and the WAB. Serial assessment (n = 19) showed a similar evolution of aphasia in cognitive-onset CBDS and PPA and delayed aphasia in motor-onset CBDS. Conclusion: Aphasia is common in the corticobasal degeneration syndrome but there is little correlation with the laterality of clinical deficits. Cognitive-onset corticobasal degeneration syndrome and primary progressive aphasia are similar such that their aphasia appears identical.

This study examined the impact of various degenerative dementias on access to semantic knowledge and the status of semantic representations. Patients with semantic dementia, primary progressive aphasia, and Alzheimer's disease were compared with elderly controls on tasks of category and letter fluency, with number of words generated, mean lexical frequency and errors recorded. The findings are consistent with the view that category and letter fluency rely on both common and unique cognitive processes. Fluency tasks, with the richness of data obtained, are valuable in distinguishing different dementia syndromes from one another.

Background: People who are cognitively impaired not demented (CIND) can be at an increased risk for developing dementia, but little is known about the natural history of CIND in clinical settings. Method: We examined the 2-year outcome of CIND subjects in the Canadian Cohort Study of Cognitive Impairment and Related Dementias.CIND was diagnosed when at least one positive item was endorsed on the DSM-III-R dementia criteria, but not all criteria were met. CIND was further subclassified as: pre-Alzheimer’s disease (pre-AD), vascular cognitive impairment (VCI-ND), non-AD degenerative, psychiatric, other neurologic, other medical conditions, mixed disorders and no etiology identified (not otherwise specified [NOS]). Result: Of 146 CIND patients with 2-year follow-up data available, 49 (34%) progressed to dementia, while 20 (14%) recovered to not cognitively impaired (NCI). Progressors were significantly older than stable CIND and reverters (p < 0.0001; mean age = 71.1, 64.3, and 59.1, respectively), and there were significantly (p = 0.001) more ApoE Ε4 carriers among progressors (67%) than stable CIND (29%) and reverters (12%). Pre-AD CIND and VCI-ND had the highest rate of conversion to dementia (41.0 and 40.0%, respectively), while psychiatric CIND and CIND NOS had highest rate of recovery to NCI (20.0 and 30.0%, respectively). All conversions in pre-AD CIND were to ‘probable AD’. Conclusion: CIND consists of a heterogeneous group of disorders that can be classified syndromically. Many subclassess – not just those with pre-AD CIND – are at high risk of progression to dementia, usually to Alzheimer’s disease.

Background and purpose There is a need for empirical studies to define criteria for vascular cognitive impairment (VCI) subtypes. In this paper, we report the predictive validity of a subtype classification scheme based on clinical and radiographic features. Methods Nine Canadian memory clinics participated in the Consortium to Investigate Vascular Impairment of Cognition. This cohort consisted of 1347 patients, of whom 324 had VCI, and was followed for up to 30 months. Results Clinical and neuroimaging features defined three subtypes: vascular cognitive impairment, no dementia, ( n = 97), vascular dementia ( n = 101) and mixed neurodegenerative/vascular dementia ( n = 126). Any ischemic lesion on neuroimaging increased the odds (odds ratio = 9.31; 95% confidence interval 6.46, 13.39) of a VCI diagnosis. No VCI subtype, however, was associated with a specific neuroimaging abnormality. Compared to those with no cognitive impairment, patients with each VCI subtype had higher rates of death and institutionalization (hazard ratio for combined adverse events = 6.08, p Conclusions Both clinical features and radiographic features help establish a diagnosis of VCI. The outcomes of VCI subtypes, however, are more strongly associated with clinical features than with radiographic ones.

Objective: To determine the safety and tolerability of 3 doses of intranasal oxytocin (Syntocinon; Novartis, Bern, Switzerland) administered to patients with frontotemporal dementia (FTD). Methods: We conducted a randomized, parallel-group, double-blind, placebo-controlled study using a dose-escalation design to test 3 clinically feasible doses of intranasal oxytocin (24, 48, or 72 IU) administered twice daily for 1 week to 23 patients with behavioral variant FTD or semantic dementia (clinicaltrials.gov registration number NCT01386333). Primary outcome measures were safety and tolerability at each dose. Secondary measures explored efficacy across the combined oxytocin vs placebo groups and examined potential dose-related effects. Results: All 3 doses of intranasal oxytocin were safe and well tolerated. Conclusions: A multicenter trial is warranted to determine the therapeutic efficacy of long-term intranasal oxytocin for behavioral symptoms in FTD. Classification of evidence: This study provides Class I evidence that for patients with FTD, intranasal oxytocin is not significantly associated with adverse events or significant changes in the overall neuropsychiatric inventory.

Accumulating evidence suggest that frontotemporal dementia is best viewed as a clinical syndrome even though there are distinct presentations of the behavioral variety, progressive aphasia, semantic dementia, corticobasal degeneration and progressive supranuclear palsy. Similarly the pathology should be regarded as a spectrum even though histological varieties are distinguished. More than half of FTD pathology is associated with ubiquitin positive and tau negative inclusions that are common in ALS. However the majority of FTD cases do not have ALS clinically and relatively few ALS cases develop FTD. The pathological and biochemical varieties can be dichotomized as tau positive and tau negative pathology and biochemistry. The genetics of the tau positive variety is associated with tau mutations and so far the tau negative variety is not, although some are linked to chromosome-17 also. There is a corresponding clinical dichotomy combining the behavioral variety of FTD presentation with semantic dementia and usually ubiquitin positive tau negative pathology on one hand and the association of primary progressive aphasia and cortical basal degeneration/PSP syndrome with tau positive pathology on the other. The overlap between them is too great to establish two separate diseases.

This is a clinicopathologic study of a prospective, clinic-based cohort of patients with frontotemporal dementia (FTD)/Pick complex, who were followed to autopsy. A total of 60 patients with the clinical syndromes of the behavioural variant of FTD (FTD-bv) (n = 32), primary progressive aphasia (PPA) (n = 22), corticobasal degeneration syndrome (CBDS) (n = 4) and progressive supranuclear palsy (PSP) (n = 2) at onset, referred to a cognitive neurology clinic who had subsequent post-mortem examination were included. The most common histological variety was motor neurone disease type inclusion (MNDI) (n = 18), followed by corticobasal degeneration (CBD) (n = 12), then Pick's disease (n = 6), dementia lacking distinctive histology (DLDH) (n = 6) and PSP (n = 3). Others fulfilled the histological criteria for Alzheimer's disease combined with glial pathology (n = 6), Alzheimer's disease only (n = 4), Lewy body variant (n = 2), prion disease (n = 1), vascular dementia (n = 1) and undetermined (n = 1). The most common first syndrome among the MNDI and DLDH (tau negative) pathologies was FTD-bv, but subsequently progressive aphasia (PA), occasionally CBDS and semantic dementia also developed. Tau positive histologies of CBD, PSP and Pick bodies were most frequently associated with PPA onset or CBDS/PSP, but behavioural symptoms were also common. Age of onset was earlier in tau negative cases, but the duration of illness and gender distribution were about the same in all histological variants. Although the tau negative and positive histologies are predicted to some extent by the clinical onset, the extent of the overlap and the convergence of the syndromes in the course of the disease argue in favour of maintaining the clinical and pathological varieties under a single umbrella.

SUMMARY150 aphasiacs and 59 controls were examined with a scorable, comprehensive battery, designed to be used by the clinician and the research worker. The subtests of Fluency, Information, Comprehension, Repetition and Naming were added and compared to a hypothetical normal of 100 obtaining the “aphasia Quotient.” This is a measurement of the severity of language impairment. On the basis of their performance on the subtests, the patients were classified according to taxonomic principles into Global, Motor (Broca’s), Isolation, Sensory (Wernicke’s), Transcortical Motor, Transcortical Sensory, Conduction and Anomic groups (in order of severity). This classification is considered a clinically valid baseline for research, diagnosis and prognosis.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) were described as separate entities, but prior to that an extrapyramidal variety of Pick’s disease was recognized. Subsequently a pathological overlap between these conditions and clinical overlap between frontotemporal dementia, primary progressive aphasia, corticobasal degeneration syndrome and more recently PSP was recognized. Initially only the movement disorder had been emphasized, but now the behavioral and language symptoms are considered common. The syndromes of frontotemporal dementia/Pick’s disease can be produced by underlying CBD, PSP or Pick pathology as well as with neural inclusions of the motor neuron disease type. The concept of this overlap has been confirmed genetically finding a similar spectrum of pathology with different tau mutations and even with tau negative pathology, which could be a deficiency of normal tau. The overlap of CBD with PSP and both with PPA and FTD allows to consider these relatively rare conditions as part of a more commonly occurring degenerative disease than previously recognized.

Background:The Consortium to Investigate Vascular Impairment of Cognition (CIVIC) is a Canadian, multi-centre, clinic-based prospective cohort study of patients with Vascular Cognitive Impairment (VCI). We report its organization and the impact of diagnostic criteria on the study of VCI.Methods:Nine memory disability clinics enrolled patients and recorded their usual investigations and care. A case report form included all vascular dementia (VaD) individual criteria for each of four sets (National Institute of Neurological Disorders and Stroke (NINDS-AIREN), Alzheimer’s Disease Diagnostic Treatment Centers (ADDTC), the ICD-10 Classification of Mental and Behavioural Disorders (ICD-10), and the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)) of consensus-based diagnostic criteria and for the Hachinski Ischemia Score (HIS). Investigators, having completed the case report form, were asked to make a clinical judgement about the cognitive diagnosis based on the best available information, including neuroimaging.Results:Of 1,347 patients (mean age 72 years; 56% women), 846 (63%) were diagnosed with dementia and 324 (24%) were diagnosed with VCI. The proportion of patients diagnosed with VaD by the diagnostic criteria was: 23.9% (n=322) by DSM-IV, 10.2% (n=137) by HIS, 4.3% (n=58) by ICD-10, 3.8% (n=51) by ADTCC, and 3.6% (n=48) by NINDS-AIREN. Judged against a clinical diagnosis of VaD, the sensitivity/specificity of each was: DSM-IV (0.77/0.80); HIS (0.41/0.92); ICD-10 (0.29/0.98); ADTCC (0.24/0.98); NINDS-AIREN (0.42/0.995). Compared with a clinical diagnosis of VCI, sensitivities were lower for the diagnostic criteria, reflecting the exclusion of patients who did not have dementia.Conclusions:Consensus-based criteria for VaD omit patients who do not meet dementia criteria that are modeled on Alzheimer’s disease. Even for patients who do, the proportion identified with VaD varies widely. Criteria based on empirical analyses need to be developed and validated.

A referred cohort of 67 clinically defined PPA patients were compared to 99 AD patients with formal language and nonverbal cognitive tests in a case control design. Language fluency was determined at the first and last follow up visits. Quantitation of sulcal and ventricular atrophy on MRI was carried out in 46 PPA and 53 AD patients. Most PPA patients (57%) are relatively fluent when first examined. Visuospatial and memory functions are initially preserved. Aphemic, stuttering, “pure motor” presentation, or agrammatic aphasia are seen less frequently. Later most PPAs become logopenic and nonfluent, even those with semantic aphasia (dementia). In contrast, AD patients were more fluent and had relatively lower comprehension, but better overall language performance. MRI showed significant left sided atrophy in most PPA patients. Subsequent to PPA, 25 patients developed behavioral manifestations of frontotemporal dementia and 15 the corticobasal degeneration syndrome, indicating the substantial clinical overlap of these conditions. Language testing, particularly fluency scores supported by neuroimaging are helpful differentiating PPA from AD. The fluent–nonfluent dichotomy in PPA is mostly stage related. The aphemic-logopenic-agrammatic and semantic distinction is useful, but the outcomes converge. (JINS, 2003, 9, 710–719.)