Andrew Kertesz

Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria.

Objective: To improve clinical recognition and provide research diagnostic criteria for three clinical syndromes associated with frontotemporal lobar degeneration. Methods: Consensus criteria for the three prototypic syndromes-frontotemporal dementia, progressive nonfluent aphasia, and semantic dementia-were developed by members of an international workshop on frontotemporal lobar degeneration. These criteria build on earlier published clinical diagnostic guidelines for frontotemporal dementia produced by some of the workshop members. Results: The consensus criteria specify core and supportive features for each of the three prototypic clinical syndromes and provide broad inclusion and exclusion criteria for the generic entity of frontotemporal lobar degeneration. The criteria are presented in lists, and operational definitions for features are provided in the text. Conclusions: The criteria ought to provide the foundation for research work into the neuropsychology, neuropathology, genetics, molecular biology, and epidemiology of these important clinical disorders that account for a substantial proportion of cases of primary degenerative dementia occurring before the age of 65 years.

Classification of primary progressive aphasia and its variants

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

Criteria for the diagnosis of corticobasal degeneration.

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.

A study of language functioning in Alzheimer patients

Abstract Language functioning in Alzheimers disease is reviewed and the performance of 25 Alzheimer patients on a standard battery is reported. All these hospitalized patients were aphasic to some degree. As a group, they differed from normals on all language variables, and from stroke patients in terms of higher fluency and lower comprehension. Spontaneous speech showed high incidence of circumlocutions and semantic jargon, but no phonemic paraphasias or target approximations. Syllabic perseverations, shouting, inappropriate laughter, and mutism were late-appearing features. Transcortical Sensory, and Wernickes aphasias were frequent, but Brocas and Transcortical Motor aphasias notably absent. Extent of language impairment correlated with current length of hospitalization but not age. Reading, writing, and performance scores except praxis, were lower than oral language scores. Findings were discussed in relation to previous results, methodology, and language organization in the brain.

Frontal Behavioral Inventory : Diagnostic criteria for Frontal Lobe Dementia

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 Alzheimers 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.

Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype

Objective: To analyze the association of polymorphisms in the tau gene with pathologically confirmed corticobasal degeneration (CBD). Background: The authors previously described an extended tau haplotype (H1) that covers the human tau gene and is associated with the development of progressive supranuclear palsy (PSP). The authors now extend this analysis to CBD, a neurodegenerative condition with clinical and neuropathologic similarities to PSP. Like PSP, CBD is associated with accumulation of aggregates containing the 4-repeat isoforms of tau. Because of difficulty in diagnosis of CBD, the authors only analyzed cases with pathologically confirmed CBD. Methods: The authors collected 57 unrelated, neuropathologically confirmed cases of CBD. Tau sequencing in these cases failed to show the presence of pathogenic mutations. Polymorphisms that spanned the tau gene were analyzed in all CBD cases and controls. Results: Analyzing tau polymorphisms in CBD cases showed that the frequency of H1 and H1/H1 was significantly increased when analyzing all cases and when separating by country of origin. H1 frequency in all CBD cases was 0.921, compared with a control frequency of 0.766 (X2 = 9.1, p = 0.00255 [1df], OR 3.56 [8.43 > CI 95% > 1.53]). The H1/H1 frequency was also significantly higher at 0.842 compared with 0.596 in age-matched controls (X2 = 17.42, p = 0.00016, 2df), OR 3.61 [7.05 > CI 95% > 1.85]). Conclusions: The CBD tau association described here suggests that PSP and CBD share a similar cause, although the pathogenic mechanism behind the two diseases leads to a different clinical and pathologic phenotype.

Diagnosis and treatment of dementia: 2. Diagnosis

Background: Dementia can now be accurately diagnosed through clinical evaluation, cognitive screening, basic laboratory evaluation and structural imaging. A large number of ancillary techniques are also available to aid in diagnosis, but their role in the armamentarium of family physicians remains controversial. In this article, we provide physicians with practical guidance on the diagnosis of dementia based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, held in March 2006. Methods: We developed evidence-based guidelines using systematic literature searches, with specific criteria for study selection and quality assessment, and a clear and transparent decision-making process. We selected studies published from January 1996 to December 2005 that pertained to key diagnostic issues in dementia. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care. Results: Of the 1591 articles we identified on all aspects of dementia diagnosis, 1095 met our inclusion criteria; 620 were deemed to be of good or fair quality. From a synthesis of the evidence in these studies, we made 32 recommendations related to the diagnosis of dementia. There are clinical criteria for diagnosing most forms of dementia. A standard diagnostic evaluation can be performd by family physicians over multiple visits. It involves a clinical history (from patient and caregiver), a physical examination and brief cognitive testing. A list of core laboratory tests is recommended. Structural imaging with computed tomography or magnetic resonance imaging is recommended in selected cases to rule out treatable causes of dementia or to rule in cerebrovascular disease. There is insufficient evidence to recommend routine functional imaging, measurement of biomarkers or neuropsychologic testing. Interpretation: The diagnosis of dementia remains clinically integrative based on history, physical examination and brief cognitive testing. A number of core laboratory tests are also recommended. Structural neuroimaging is advised in selected cases. Other diagnostic approaches, including functional neuroimaging, neuropsychological testing and measurement of biomarkers, have shown promise but are not yet recommended for routine use by family physicians.

Lesion localization in acquired deficits of emotional expression and comprehension

This study investigated the relationship between intrahemispheric location of lesion and disturbances of emotional expression and comprehension. Twenty-eight right hemisphere strokes, 18 left hemisphere strokes, and 20 controls were examined on a standardized test of the expression, repetition, and comprehension of emotional prosody as well as the visual recognition of emotional situations and faces. The patients were classified into aprosodic syndromes according to the test scores. The lesions were independently traced, and overlapped for each aprosodic syndrome. The results, for lesions in either hemisphere, indicated involvement of the basal ganglia most frequently in aprosodic syndromes followed by anterior temporal lobe and insula lesions. Basal ganglia damage was also seen most frequently in patients with impaired comprehension of emotional facial expressions and situations. The anterior temporal lobe was also frequently involved in patients with such deficits. The basal ganglia emerged as a structure of particular importance in the mediation of emotional expression and comprehension.

The corticobasal degeneration syndrome overlaps progressive aphasia and frontotemporal dementia.

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.”

The Frontal Behavioral Inventory in the differential diagnosis of frontotemporal dementia.

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), Alzheimers 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 (Cohens 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.