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Ten autopsied patients from a prospectively followed, clinically defined, neuropsychologically and radiologically documented cohort with primary progressive aphasia were histologically characterized. All were variants of frontotemporal degeneration (Pick complex): Pick body dementia, n =3, corticobasals degeneration (CBD), n =4, and tau and synuclein negative ubiquitinated inclusions of the motor neuron disease type, n =3. All shared superficial cortical spongiosis, neuronal loss, and gliosis. Although most patients had fluent anomic aphasia at onset, all progressed to a nonfluent or mute state. Comprehension, episodic memory, and activities of daily living were initially preserved. Three cases with Pick body dementia had verbal apraxia and stuttering at onset. Two of the patients with CBD pathology were older than the average primary progressive aphasia (PPA). All patients developed secondary syndromes either of frontotemporal dementia (FTD) and/or extrapyramidal-apraxic manifestations (CBD). By the time autopsy was obtained, the pathology appeared outside the language areas. Progressive aphasias secondary to Alzheimer's disease (AD) were excluded on the basis of early loss of memory and comprehension. Rather than the previously emphasized histological heterogeneity, clinically probable PPA has a predictive value of a group of related pathologies, collectively named frontotemporal degeneration, or Pick complex. This series of autopsied cases provides evidence for the clinical and pathological overlap of PPA with FTD and CBD, and contributes to the diagnostic and neuropsychological definition of PPA.

Primary progressive aphasia (PPA) is a language-based dementia. It is diagnosed by distinctive clinical features that set it apart from typical forms of Alzheimer’s disease (AD). In contrast to the patient with AD, who usually comes with a history of forgetfulness, the patient with PPA comes with reports of word-finding difficulties, abnormal speech patterns, or a deterioration of spelling. The clinical diagnosis of PPA is made when other mental faculties such as memory for daily events, visuospatial skills, and comportment display no major deficits; when language is the only area of salient and progressive dysfunction for at least the first 2 years of the disease; and when brain imaging does not show a specific lesion, other than atrophy, that can account for the language deficit. Standardized neuropsychological tests of language function are helpful for detecting early stages of the disease. However, a strict reliance on neuropsychological tests, most of which depend on verbal instructions, verbal responses, or covert verbal reasoning, may occasionally lead to the erroneous conclusion that areas other than language are also impaired. Scores on the Mini-Mental Status Examination, for example, can greatly exaggerate the degree of disability. Although the language disorder in PPA may interfere with the ability to memorize word lists or solve reasoning tasks, the patient typically has no difficulty recalling daily events or behaving with sound judgment, indicating that explicit memory, reasoning, and social skills remain relatively intact. PPA is a form of dementia because it causes a gradual cognitive decline to the point at which daily living functions become compromised. It is also an unusual dementia because core memory functions, which are severely impaired in AD, remain largely preserved.

Frontotemporal dementia is a new name for clinical Pick's disease; the eponymic term PiD has been increasingly restricted to the pathologic variant with Pick bodies. This article describes the clinical picture, pathology, and genetic mechanisms of frontal lobe dementia. Frontotemporal dementia is still under-diagnosed and underestimated, partly because the individual components of the complex are considered separately or are considered "heterogeneous," a somewhat misleading adjective used in many descriptions. This article emphasizes the considerable overlap among the different varieties of frontotemporal dementia, as well as the distinctive features of each.

Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are an important cause of both motor neuron disease (MND) and frontotemporal dementia (FTD). Currently, little is known about factors that could account for the phenotypic heterogeneity detected in C9ORF72 expansion carriers. In this study, we investigated 4 genes that could represent genetic modifiers: ataxin-2 (ATXN2), non-imprinted in Prader-Willi/Angelman syndrome 1 (NIPA1), survival motor neuron 1 (SMN1), and survival motor neuron 2 (SMN2). Assessment of these genes, in a unique cohort of 331 C9ORF72 expansion carriers and 376 control subjects, revealed that intermediate repeat lengths in ATXN2 possibly act as disease modifier in C9ORF72 expansion carriers; no evidence was provided for a potential role of NIPA1, SMN1, or SMN2. The effects of intermediate ATXN2 repeats were most profound in probands with MND or FTD/MND (2.1% vs. 0% in control subjects, p = 0.013), whereas the frequency in probands with FTD was identical to control subjects. Though intermediate ATXN2 repeats were already known to be associated with MND risk, previous reports did not focus on individuals with clear pathogenic mutations, such as repeat expansions in C9ORF72. Based on our present findings, we postulate that intermediate ATXN2 repeat lengths may render C9ORF72 expansion carriers more susceptible to the development of MND; further studies are needed, however, to validate our findings. (C) 2014 Elsevier Inc. All rights reserved.

Recovery from aphasia is presented as a model of compensation after vascular or traumatic brain damage. Initial severity, time from onset, and etiology are the major prognostic factors. Initial severity is closely related to the size and location of the lesion. Asphasic syndromes reflect the deficit in various language networks. Lesion studies suggest that ipsilateral connected cortex plays a major role in compensation; contralateral contribution may occur in large lesions. Articulated language output network includes Broca's area, rolandic operculum, anterior insula, and the striatum. The comprehension network includes the superior posterior temporal gyrus and temporal operculum, the supramarginal gyrus and the angular gyrus.

A member of a family with an autosomal dominant pattern of frontotemporal dementia (FTD) with a TDP-43 pathological substrate in other members and no mutations in FTD-associated genes developed behavioral variant FTD followed by Progressive Supranuclear Palsy. Autopsy revealed a pure tauopathy of PSP pattern. Conclusions: The findings raise the possibility of shared pathogenic pathways and a proximal genetic abnormality between PSP and FTLD-43.

Errors of repetition in aphasia are most often nonword substitutions. Phonologically related lexical errors, or formal errors, are real-word substitutions that overlap with target words in sound. In the present research we present the case of an aphasic patient, MMB, who produced an unusually high rate of formal paraphasias in repetition. Six experiments were conducted to investigate the combination of impairments contributing to MMB's pattern of repetition and to test the predictions made by two theories of formal errors. MMB's formal errors in repetition were influenced by target frequency, but not by target length or imageability. Formal errors tended to be more frequent than their targets and showed greatest phonological overlap with targets at initial consonant. These findings provided partial support for Martin and Saffran's fully interactive spreading activation account of formal errors and did not support Blanken's phonological interactive encoding account. In Experiment 6, the effect on repetition of increasing auditory verbal short-term memory (AVSTM) demands was examined using a paired word repetition experiment. Under these conditions, MMB produced semantic paraphasias for the first time, providing strong support for the Martin-Saffran hypothesis that phonologically related, and semantic, lexical repetition disorders lie on a continuum of severity moderated by the degree of AVSTM impairment.

The characteristics of Hungarian aphasics reflect the difference in the features of Hungarian as a Finnish-Ugric language. These features are the highly complex use of inflectional morphemes, which are concatenated, providing markers for several functions in one word. Hungarian aphasics were systematically studied for features of agrammatism in language output, as well as in comprehension. The results of these studies suggest that in Hungarian there is a direct mapping of inflectional markings to semantics. The competition between definite and conditional conjugation is a major source of error just like in French, as well as competition between first and third persons. Omission errors occurred frequently, especially among Broca's aphasics omitting the indirect objects and Wernicke's aphasics the direct objects. Broca's aphasics also showed a lower level of pronoun use and article omission. Omissions and substitutions amounted to telegraphic speech in some patients, although this is not as marked as in English because of the high rate of omission in normal Hungarian. Wernicke's aphasics tended to produce paraphasic nouns and pronouns with some errors in inflection. Vowel harmony in the inflections was particularly resistant to deficit. Studies of sentence comprehension revealed that subject-verb agreement cues were most affected in Wernicke's aphasics and animacy cues were the weakest in Broca's aphasics. Although word order is rather free in Hungarian, canonical word orders were used for interpretation by all aphasics. Systematic studies of comprehension in Hungarian aphasics show that phonemic contrasts in words are more sensitive than sound discrimination tasks. Higher levels of sentence processing are influenced by the availability of case marking suffixes, which are numerous in Hungarian.

Objective: To provide evidence for the hypothesis that the corticobasal degeneration syndrome (CBDs) overlaps significantly with primary progressive aphasia and frontotemporal dementia, and that CBDs is part of the Pick complex. Background: Corticobasal degeneration has been mainly described as a movement disorder, but cognitive impairment is also increasingly noted. Methods: Thirty-five cases of clinically diagnosed CBDs were followed-up with clinical, neuropsychological, and neuroimaging investigations. Twenty-nine patients were seen prospectively in movement disorder and cognitive neurology clinics; five of these came to autopsy. Six other autopsied cases that fulfilled the clinical criteria of CBDs were added with retrospective review of records. Results: All 15 patients presenting with movement disorders developed behavioral, cognitive, or language deficits shortly after onset or after several years. Patients presenting with cognitive problems (n = 20), progressive aphasia (n = 13), or frontotemporal dementia (n = 7) developed the movement disorder subsequently. Eleven cases with autopsy had CBD or other forms of the Pick complex. Conclusions: There is a clinical overlap between CBD, frontotemporal dementia, and primary progressive aphasia. There is also a pathologic overlap between these clinical syndromes. The recognition of this overlap will facilitate the diagnosis and avoid consideration of CBD as “heterogenous.”

Frontotemporal dementia, or Pick's disease, begins with personality and behavioral changes, in contrast to Alzheimer's disease (AD), which begins with memory deficits. Frontotemporal dementia is a term widely used for both the behavioral-personality component of frontal lobe dementia and for the disease itself (Brun et al., 1994). According to consensus criteria developed by the Manchester/Lund group (Brun et al., 1994), the core features of frontal lobe dementia or frontotemporal degeneration are disinhibition, loss of insight, apathy, disorganization, aspontaneity, indifference, lack of personal hygiene, mental rigidity, perseveration, hyperorality, and utilization behaviors. The clinical features of frontal lobe dementia often overlap with those of primary progressive aphasia, a condition characterized by language deficit in the first 2 years of the disease (Mesulam, 1987). Pick's original patient with lobar atrophy was also aphasic (Pick, 1892), and primary progressive aphasia has a course, eventual outcome, and pathology similar to that of frontal lobe dementia (Kertesz et al., 1994). In some patients with primary progressive aphasia, extrapyramidal symptoms similar to those that occur with corticobasal degeneration and motor neuron disease are superimposed.

A personality and behavioral disorder is an important and defining feature of frontal lobe dementia (FLD) or frontotemporal degeneration (FTD). The diagnosis usually depends on the progressive development of various behavioral symptoms rather than a set of neuropsychological measures. Quantification of the personality–behavior disorder is important for standardizing the diagnosis. An inventory was constructed to capture the major positive and negative behaviors and personality change, and it was administered prospectively to caregivers of 108 patients in a cognitive neurology clinic, at the time of first diagnostic assessment. The prevalence and extent of behavioral abnormality was quantitated in the clinic population of FLD, vascular dementia (VaD), Alzheimer's disease (AD), primary progressive aphasia (PPA), and depressive disorder (DD) patients. The mean scores of FLD patients were significantly above all other groups. Scores in VaD were also higher than in AD, PPA, and DD. Interrater reliability (Cohen's kappa of .90) and item consistency (a Cronbach alpha of .89) were both high. Perseveration, indifference, inattention, inappropriateness, and loss of insight rated highest in FLD, significantly different from all other groups. Apathy, aspontaneity, inflexibility, disorganization, impulsivity, personal neglect, and poor judgment were also significantly higher in FLD. Discriminant function correctly classified 92.7% versus all other patients (NON-FLD) in the study. A total of 18.8% of VaD patients were misclassified as FLD. Indifference, alien hand, and inappropriateness were the highest discriminant functions. Perseveration and verbal apraxia were important discriminatory items for FLD and PPA, respectively. The FBI is a standardized behavioral inventory useful to diagnose FLD, to differentiate it from other dementias, and to quantify the behavior disorder. (JINS, 2000, 6, 460–468.)

If vascular risk factors are risks for Alzheimer's disease (AD), and if “pure” vascular dementia (VaD) is less common than has been thought, what do we make of the diagnosis of mixed dementia? We report characteristics of those with mixed dementia in a prospective, seven center, clinic-based Canadian study. Of 1,008 patients, 372 were diagnosed with AD, 149 with vascular cognitive impairment (VCI) including 76 with mixed AD/VaD, and 82 with other types of dementia. The mean age of patients with mixed AD/VaD was 78.0 ± 7.6 years; 49% were female. These proportions differed significantly between dementia diagnosis subgroup (p

A substantive overlap between the clinical syndromes of frontal lobe dementia (FLD), frontotemporal dementia (FTD), or primary progressive aphasia (PPA), and corticobasal degeneration syndrome (CBDS) has been demonstrated in a population of 55 patients followed for more than 3 years in a cognitive neurology clinic. Patients presenting with the personality behavior disorder (FLD) often develop progressive aphasia (PA) and vice versa. CBDS is often associated with FLD and PA, and the extrapyramidal-apractic syndrome of CBDS often appears in FLD and PPA. The histopathological variations do not predict the clinical phenotype. The term Pick complex is suggested to indicate that these clinical and pathological variations are related and they were first described by Pick as clinical manifestations of fronotemporal atrophy. This term will avoid the confusion of using FLD or FTD or for the whole complex and also for the personality behavioral presentation. The relationship of the various clinical presentations has been strengthened by the discovery of chromosome 17 linkage in families manifesting them.

Pick complex［PiC : frontotemporal dementia (FTD) ，primary progressive aphasia (PPA) ，semantic dementia (SD) ］とアルツハイマー病 (AD) における認知機能検査の意義について検討した。FTD11例，PPA17例，SD３例，probable AD24例を対象にして，改訂版Wechsler Adult Intelligence Scale (WAIS-R) ，Mattis Dementia Rating Scale (DRS) ，Western Aphasia Battery (WAB) ，Frontal Behavioral Inventory (FBI) の成績を比較し，それらが臨床診断を予測しえるか否かを判別分析により検討した。さらに，脳MRIから求めた局所脳体積と認知機能検査との相関を検討した。その結果，FBI，DRSと一部の WAIS-R 下位検査成績が PiC と AD の間において，また，WAB の成績が PiC 内の臨床型の間で有意に異なっていた。判別分析では FBI が有意な判別変数であり，69.6% に相当する症例が臨床診断と同様に分類された。FTD と PPA では WAB などの言語性検査の成績が左前頭側頭葉～頭頂葉の体積と相関した。脳体積と認知機能の相関関係が PiC においてのみ認められたことから，その痴呆は脳部位特異的な認知機能障害の集積であるのに対して，AD の痴呆はよりびまん性に分布する認知機能の障害に基づくものと推測された。

A combination of social science with neuroscience, frequently using new technology, such as neuroimaging with functional activation and other methods of neurophysiology, can be called social neuros...

The purpose of this study was to document the pragmatic performance of subjects with frontal lobe dementia (FLD), non-fluent primary progressive aphasia (PPA), and fluent PPA using topic-directed conversationbased interviews. Unique profiles of pragmatic performance emerged for the three subject groups using objective measures of discourse, pragmatics, and scores from the Profile of Communicative Appropriateness (PCA) (Penn, 1985). The differences in performance provide a clearer understanding of the selective influences of frontal and frontotemporal pathology on the pragmatics of patients with FLD and PPA.

Objective:To utilize the diagnostic criteria of frontal lobe dementia (FLD).Methods:We studied 12 patients with FLD diagnosed clinically, with radiological confirmation in 10 and autopsy confirmation in 2; sixteen patients with Alzheimer's disease matched for stage and severity to FLD and 11 patients with depressive dementia were used as control groups. A 24-item Frontal Behavioral Inventory (FBI) using the most relevant behavioral manifestations of FLD was administered in these populations.Results:FLD patient scores on the FBI were much higher compared with control groups (AD and DD). Item analysis showed loss of insight, indifference, distractibility, personal neglect and apathy as the most frequent negative symptoms. Perseveration, disinhibition, inappropriateness, impulsivity, and irresponsibility were the most significant positive symptoms. An operational definition of FLD included a minimum FBI score of 27. Only one false positive was shown in the depressive group and none among the AD group, indicating little overlap between patient groups, and a high discriminating value of the FBI.Conclusions:The FBI appears to be a useful diagnostic instrument and a method to operate the behavioral criteria of FLD. Further prospective studies are warranted to establish validity.

Objective: To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 ( C9ORF72 ), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases. Methods: A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72 . For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology. Results: We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin ( GRN : p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau ( MAPT : p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations. Conclusions: Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.

Background A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer’s disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders. Results The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson’s disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson’s disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed. Conclusions Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson’s disease in addition to Alzheimer’s disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response.

BACKGROUND Frontotemporal dementia (FTD) is a neurodegenerative disorder resulting in social-cognitive deficits partially attributed to abnormalities processing social cues, such as facial expressions. However, to our knowledge, the functional neuroanatomy of deficient social cue processing in individuals with FTD has not been examined. The objective of this study was to delineate the functional abnormalities under lying altered facial expression processing in individuals with FTD using functional magnetic resonance imaging (fMRI). METHODS Patients meeting Neary criteria for behavioural variant FTD (bvFTD) with supportive neuroimaging and 18 age-matched healthy controls completed an implicit facial expression task during fMRI. We conducted volumetric brain morphometry to correct functional imaging data for volume differences. RESULTS We included 20 patients with bvFTD and 18 controls in our study. The results demonstrate emotion-specific functional abnormalities in frontal and limbic regions in patients with bvFTD. Patients also showed decreased activity in posterior ventral visual regions, specifically the fusiform cortex, possibly reflecting reduced afferent input from limbic regions. Finally, bvFTD was associated with increased activity in posterior regions, including the inferior parietal cortex. LIMITATIONS Autopsy validation of frontotemporal dementia is not yet available for this cohort. CONCLUSION Together, these findings suggest that fMRI combined with tasks targeting social-cognitive deficits is a powerful technique to objectively measure neural systems involved in emotion processing in individuals with bvFTD. As viewing emotional expressions is known to engage many of the same neural systems that are active when experiencing the emotion itself, fMRI during expression processing provides a novel window into the emotions of patients with FTD.

Current criteria for the clinical diagnosis of pathologically confirmed corticobasal degeneration (CBD) no longer reflect the expanding understanding of this disease and its clinicopathologic correlations. An international consortium of behavioral neurology, neuropsychology, and movement disorders specialists developed new criteria based on consensus and a systematic literature review. Clinical diagnoses (early or late) were identified for 267 nonoverlapping pathologically confirmed CBD cases from published reports and brain banks. Combined with consensus, 4 CBD phenotypes emerged: corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Clinical features of CBD cases were extracted from descriptions of 209 brain bank and published patients, providing a comprehensive description of CBD and correcting common misconceptions. Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies. Probable CBD criteria require insidious onset and gradual progression for at least 1 year, age at onset ≥ 50 years, no similar family history or known tau mutations, and a clinical phenotype of probable CBS or either FBS or naPPA with at least 1 CBS feature. The possible CBD category uses similar criteria but has no restrictions on age or family history, allows tau mutations, permits less rigorous phenotype fulfillment, and includes a PSPS phenotype. Future validation and refinement of the proposed criteria are needed.

Circumscribed focal atrophy with frontal lobe dementia and progressive aphasia, as described originally by Arnold Pick, has been recognized recently as being much more common than previously believed. Although Pick disease became linked with argyrophilic inclusions (Pick bodies) and swollen neurons (Pick cells), the majority of focal atrophies have findings that are a variation of the classic histologic features. We discuss Pick's background and the circumstances that led to his major contributions to the study of behavioral neurology. We also review his original articles, the articles that subsequently established the entity of Pick disease, and historical documents pertaining to the continuation of German-language education in Prague after Prague's independence from the Austro-Hungarian monarchy. Arnold Pick's life and career exemplify the integration of neurology, psychiatry, and neuropathology, which represents one of the major contributions of German neuropsychiatry to the study of the nervous system. Pick is a major intellectual ancestor of present-day behavioral neurology.

Objective: To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD). Methods: The Alzheimer9s Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005–2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI. Results: CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ 42 . Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD. Conclusion: The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.

Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.

Expansions of the non-coding GGGGCC hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene were recently identified as the long sought-after cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) on chromosome 9p. In this study we aimed to determine whether the length of the normal - unexpanded - allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS and 160 FTD-ALS patients and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions and an accurate quantification of the length of the normal alleles in all patients and controls. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or non-mutation carriers.

Interest in vascular causes for cognitive impairment is increasing, in recognition that such causes are common, and possibly preventable. This has led to attempts to better define vascular dementia and its natural history. Several sets of criteria for the diagnosis of vascular dementia have been proposed. We provide a brief overview of the background to the initiation of a Canadian consensus conference, established by the Consortium of Canadian Centres for Clinical Cognitive Research (C5R) and report the conclusions reached at that conference. To date, no one set of criteria is demonstrably superior to another; we have therefore not endorsed any of the competing sets, nor have we recommended our own. Instead we suggest that empiric studies are required to establish valid criteria. A diagnostic checklist, which combines existing criteria and additional data, is attached for clinicians wishing to participate in such studies.

Neuropsychological evaluation of language may be based on the psychometric approach or on extensive exploration of modular functions according to cognitive or linguistic theory. Various approaches have several features in common, although some emphasize individual functions, and others explore syndromes in brain-damaged populations. Systematic assessment of language has been developed according to the goals of various clinicians and researchers. Beyond the diagnostic need, prognosis, and planning for therapy, there are important theoretical reasons to have standardized aphasia tests and complementary experimental explorations of language deficit. Objective quantitation of deficit allows the study of the anatomical and physiological organization of language-related structures. It also contributes to the relationship of language and other modalities of cognition, hemispheric lateralization, language development in children, and language dissolution in degenerative disease. The requirements, content, standardization, and application of aphasia tests are discussed.

Controversy surrounds differences between cortical and subcortical aphasias and their underlying pathophysiological mechanisms, but the necessary direct comparisons between clinical characteristics of patients with the two lesion types are lacking. We compared 36 stroke patients with subcortical lesions to 42 with cortical lesions of similar volume to determine the frequency, severity, and types of aphasia found in each group, and to examine subcortical clinicoanatomical correlations. Tested on the Western Aphasia Battery (WAB), the two groups did not significantly differ either in overall aphasia severity or on any WAB subtest scores. Although some individuals had relative preservation of repetition, we did not confirm an overall difference between patients with cortical and subcortical lesions in their ability to repeat. All subcortical patients were classifiable using the WAB and a broad spectrum of aphasia types was seen. Lesion volume did not significantly correlate with aphasia severity but...

Patients with behavioural variant frontotemporal dementia demonstrate abnormalities in behaviour and social cognition, including deficits in emotion recognition. Recent studies suggest that the neuropeptide oxytocin is an important mediator of social behaviour, enhancing prosocial behaviours and some aspects of emotion recognition across species. The objective of this study was to assess the effects of a single dose of intranasal oxytocin on neuropsychiatric behaviours and emotion processing in patients with behavioural variant frontotemporal dementia. In a double-blind, placebo-controlled, randomized cross-over design, 20 patients with behavioural variant frontotemporal dementia received one dose of 24 IU of intranasal oxytocin or placebo and then completed emotion recognition tasks known to be affected by frontotemporal dementia and by oxytocin. Caregivers completed validated behavioural ratings at 8 h and 1 week following drug administrations. A significant improvement in scores on the Neuropsychiatric Inventory was observed on the evening of oxytocin administration compared with placebo and compared with baseline ratings. Oxytocin was also associated with reduced recognition of angry facial expressions by patients with behavioural variant frontotemporal dementia. Together these findings suggest that oxytocin is a potentially promising, novel symptomatic treatment candidate for patients with behavioural variant frontotemporal dementia and that further study of this neuropeptide in frontotemporal dementia is warranted. * Abbreviations : FTD : frontotemporal dementia

Descriptions of extrapyramidal (EP) involvement in Pick’s disease (renamed recently as FTD) appeared 80 years ago. CBD pathology was confirmed as a common substrate for primary progressive aphasia (PPA). We suggested that CBD and PPA should be included with frontal lobe dementia as Pick complex. PSP was prototype for “subcortical dementia”, and aphasia and apraxia, considered unusual for PSP, are now seen as a rule. The overlap of PSP and CBD is considerable. We recently reviewed our cohort with EPS in FTD and identified 22 patients with the movement disorder as a first syndrome and another larger group of 48 patients who developed EPS after an initial onset with a cognitive disorder: aphasic, behavioral or both. All cognitive onset CBD/PSP patients and all but two with motor onset developed aphasia during the course of their illness. General cognitive and behavioral measures are similar for each presentation, but language scores are worse in cognitive onset cases, reflecting the frequency of aphasic presentations. Anomic patients become non-fluent, logopenic, agrammatic and mute. Using the Frontal Behavioral Inventory (FBI), a questionnaire specifically designed for the spectrum of apathy and disinhibition displayed by patients with FTD, we have documented the behavior change in CBD/PSP with motor and cognitive onsets. The significant personality changes consisted of apathy, disinhibition, perseveration and inattention, some of the core symptoms of FTD. In 18 autopsied cases, 15 had tau pathology. The overlap of CBD/PSP with PPA and bvFTD suggests a spectrum of related entities and predicts tau-positive pathology. Cross-sectional studies without significant follow-up may not observe the subsequent development language or behavior deficit, or the evolution from PPA and/or FTD-bv to CBD/PSP.

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

Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, 'possible' behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). 'Probable' behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia 'with definite frontotemporal lobar degeneration' requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer's disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met 'possible' criteria, and 104 (76%) met criteria for 'probable' behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with 'possible' and 'probable' criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.

Constructional impairment is often considered a sign of cortical damage. However, aphasia, agraphia, and apraxia, disorders traditionally deemed cortical, have been well described following subcortical lesions, suggesting an important role for subcortical structures in cognition. Drawing impairment following subcortical lesions has not been systematically explored or compared with that following cortical damage. We examined relative incidence and severity of drawing impairment after cortical and subcortical strokes and whether there were qualitative differences between these two groups' drawings. Drawings by 125 patients with single hemispheric strokes of similar volume (42 left cortical, 36 left subcortical, 20 right cortical, 27 right subcortical) were compared using a standardized scoring system. Although previously noted right/left differences were confirmed, "subcortical drawings" did not differ from "cortical drawings" on any measures, including overall impairment. Compared with cortical patients, drawing impairment in those with subcortical lesions (especially left) was more strongly associated with impairment of other cognitive abilities. Thus, although a subcortical lesion does not cause more severe drawing impairment, subcortical lesions affecting drawing lead to more widespread cognitive dysfunction than do similarly sized cortical lesions. Drawing impairment often follows subcortical strokes and is by no means an indicator of cortical lesion localization.

Frontotemporal dementia (FTD) is one of the most common forms of dementia in persons younger than 65 years. Variants include behavioral variant FTD, semantic dementia, and progressive nonfluent aphasia. Behavioral and language manifestations are core features of FTD, and patients have relatively preserved memory, which differs from Alzheimer disease. Common behavioral features include loss of insight, social inappropriateness, and emotional blunting. Common language features are loss of comprehension and object knowledge (semantic dementia), and nonfluent and hesitant speech (progressive nonfluent aphasia). Neuroimaging (magnetic resonance imaging) usually demonstrates focal atrophy in addition to excluding other etiologies. A careful history and physical examination, and judicious use of magnetic resonance imaging, can help distinguish FTD from other common forms of dementia, including Alzheimer disease, dementia with Lewy bodies, and vascular dementia. Although no cure for FTD exists, symptom management with selective serotonin reuptake inhibitors, antipsychotics, and galantamine has been shown to be beneficial. Primary care physicians have a critical role in identifying patients with FTD and assembling an interdisciplinary team to care for patients with FTD, their families, and caregivers.

A brief history of the establishment and the activities of the WFN Research Group on Aphasia and Cognitive disorders is presented, based on the archives of the group. The purpose is to achieve continuity between the past and present and to document the collective memories of the activities of the group, hereby strengthening its future.

A significant expansion of knowledge in the last few years, especially in the molecular biology of frontotemporal dementia (FTD) is summarized. This condition, formerly known as Pick's disease and considered rare, is estimated to be 12-15% of all dementias and 30-50% early onset ones. The clinical picture is protean, mainly a behavioural and language impairment, but the extrapyramidal syndromes of CBD and PSP also belong. These seemingly different presentations converge, as one or other areas in the brain are affected. Less than half of the cases are tauopathies, the majority has been discovered to have a TDP-43 and most recently a FUS proteinopathy, shared with ALS, opening potential opportunities for pharmacological approaches to treatment. Tau and progranulin mutations on Ch-17 and some others, point to molecular mechanisms. A glossary is provided to navigate the complex terminology.

Objectives To describe a large, clinically defined cohort of patients with semantic dementia (SD) that highlights important, sometimes overlooked features and to compare it with similar entities. Design Cohort study. Setting A cognitive neurology clinic. Patients A population of 48 patients clinically diagnosed with SD was contrasted with 52 patients with progressive nonfluent aphasia, 42 patients with a behavioral variety of frontotemporal dementia, and 105 patients with Alzheimer disease on speech output characteristics, comprehension, naming, and repetition subtests of the Western Aphasia Battery, the Frontal Behavioral Inventory, and other cognitive tests. Neuroimaging was visually analyzed, and 6 patients with SD had autopsy. Results Of 37 patients with probable SD, 48.6% had semantic jargon; 21.6%, excessive garrulous output; and 75.7%, some pragmatic disturbance. Semantic substitutions were frequent in SD (54.1%) but phonological errors were absent, in contrast to progressive nonfluent aphasia with the opposite pattern. All but 3 patients with probable SD questioned the meaning of words. Patients with SD had significantly lower naming and comprehension scores, and their fluency was between progressive nonfluent aphasia and Alzheimer disease or behavioral frontotemporal dementia. Behavior was abnormal in 94.6% of patients with probable SD. Conclusions Semantic dementia is distinguishable from other presentations of frontotemporal dementia and Alzheimer disease, not only by fluent speech and impaired comprehension without loss of episodic memory, syntax, and phonology but also by empty, garrulous speech with thematic perseverations, semantic paraphasias, and poor category fluency. Questioning the meaning of words (eg, “What is steak?”) is an important diagnostic clue not seen in other groups, and behavior change is prevalent.

Replications of the association between APOE-e4 allele load and regional brain atrophy in Alzheimer's disease (AD) patients hold promise for future studies testing relationships between other disease risk gene variants and brain structure. A polymorphism, rs10868366, in the Golgi phosphoprotein 2 gene, GOLM1, was recently identified as an AD risk factor in a genome-wide association study. In a subset of the same AD cohort, we used voxel-based morphometry to test for association between the disease risk genotype and reduced regional gray matter (GM) volume in AD patients (n = 72). A mean 14% reduction in GM volume was observed in the left frontal gyrus with the higher risk GG genotype. A similar association was observed in an independent, dataset of nondemented subjects (n = 278), although with a smaller effect (1%). This replicated association with GM structural variation suggests that GOLM1 polymorphisms may be related to cognitive phenotypes. The greater effect size in AD patients also suggests that the GG genotype could be a risk factor for the expression of cognitive deficits in AD.

Heterogeneity is observed in the patterns of cognition in Alzheimer’s disease (AD). Such heterogeneity might suggest the involvement of different etiological pathways or different host responses to pathology. A total of 627 subjects with mild/moderate AD underwent cognitive assessment with the Mini-Mental State Examination (MMSE) and the Dementia Rating Scale-2 (DRS-2). Latent class analysis (LCA) was performed on cognition subscale data to identify and characterize cognitive subgroups. Clinical, demographic, and genetic factors were explored for association with class membership. LCA suggested the existence of four subgroups; one group with mild and another with severe global impairment across the cognitive domains, one group with primary impairments in attention and construction, and another group with primary deficits in memory and orientation. Education, disease duration, age, Apolipoprotein E-ε4 (APOE ε4) status, gender, presence of grasp reflex, white matter changes, and early or prominent visuospatial impairment were all associated with class membership. Our results support the existence of heterogeneity in patterns of cognitive impairment in AD. Our observation of classes characterized by predominant deficits in attention/construction and memory respectively deserves further exploration as does the association between membership in the attention/construction class and APOE ε4 negative status. (JINS, 2010, 16, 233–243.)

A patient was well until 3 years prior to review when she developed a right upper extremity resting tremor. The tremor became progressively more severe over the next year and she had difficulty with writing, knitting, and gardening. A year and a half later, she experienced difficulty using her right leg, and she developed an asymmetric impaired gait. She described a feeling of “restlessness” throughout the right side of her body that was not present on the left. One year prior to review, she began using a cane for ambulation and then 8 months later transitioned to a walker. She would drag her leg and seemed unable to bear weight on it. She had some falls a year prior, but no recent falls, as her mobility was very limited. She denied symptoms of REM sleep behavior disorder or constipation. She had occasional bladder urgency without incontinence but no orthostatic hypotension. She denied involuntary movements, alien limb phenomena, or sensory changes involving the right side. She did not feel truly weak; rather, the right side of her body “doesn’t do what she wants it to do.” When initially evaluated, the patient was diagnosed with Parkinson disease (PD). Initially no treatment was implemented, but subsequently, pramipexole was initiated. She discontinued this following a brief trial when she read about possible side effects. One year later, she received a second neurologic evaluation and was again diagnosed with PD and therapy with levodopa/carbidopa was initiated. Again, she discontinued this medication because of concerns regarding possible side effects. The trial was brief, and of uncertain benefit. Following a third neurologic evaluation, she was started on amantadine, which was discontinued because of drowsiness. She had no cognitive impairment but had become depressed and was crying frequently. Her past medical history was significant for hypertension, fibromyalgia, hypothyroidism, …

Objective Individuals with a clinical diagnosis of Alzheimer's disease (AD) may have prominent features of executive dysfunction and language impairment as well as behavioral abnormalities early in the disease (‘high frontality’). When this occurs differentiation from frontotemporal dementia (FTD) is difficult. It is hypothesized that AD patients with high frontality may have clinical and pathological features that distinguish them from less frontal AD patients. Methods In a well-characterized cohort of people with cognitive impairment, we used the Frontal Behavioral Inventory (FBI) in an attempt to identify AD patients with prominent frontal features (high-FBI AD) and distinguish them from the remainder of AD patients (low-FBI AD). Results The 18 high-FBI AD patients were compared with the 26 FTD patients who had an FBI performed and the 53 other low FBI AD patients. The individual FBI items did not differ significantly between the FTD and the high-FBI AD patients, and the high FBI AD patients were more like the FTD patients than the other AD patients with respect to presence of a family history of AD, proportion with homozygous apolipoprotein E4 status, disability as measured by the Disability Assessment for Dementia (DAD) Scale and the Functional Rating Scale (FRS) and neuropsychiatric impairment as measured by the Neuropsychiatric Inventory (NPI). Memory symptom duration was similar in the high FBI AD group compared to the low FBI AD group. Conclusions There is a subgroup of AD patients with high frontality that can be clinically distinguished from the remainder of AD patients but which requires pathological verification. Copyright © 2009 John Wiley & Sons, Ltd.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), previously described as Parkinsonian syndromes are also cognitive disorders, and biologically related to the frontotemporal dementia or Pick's disease. PSP and CBD overlap clinically, pathologically and genetically, sharing tau haplotypes and mutations. In our series of CBD/PSP patients with cognitive presentation (n=36), primary progressive aphasia (PPA) was particularly common, but behavioral onset occurred also. CBD or PSP as motor presentations developed significant language disorder in 17/19. The underlying pathology is predictably tau positive in these clinical combinations, regardless of the presentation. Other cognitive features of CBDS include apraxia, alien hand and apathy, but often frontal lobe dementia with disinhibition develops also. CBDS also has visuospatial deficit, because of the parietal involvement. PSP was considered the prototype of subcortical dementia, with bradyphrenia, poor recall and executive deficit, but cortical features were recognized to be important also. Language testing and a behavioral inventory should be part of neuropsychological tests to facilitate diagnosis and to quantify the deficit. The clinical, genetic and pathological relationship is strong between CBD /PSP and the aphasic and behavioral components of the Pick complex.