Clinical marker for Alzheimer disease pathology in logopenic primary progressive aphasia.

OBJECTIVE: To determine whether logopenic features of phonologic loop dysfunction reflect Alzheimer disease (AD) neuropathology in primary progressive aphasia (PPA). METHODS: We performed a retrospective case-control study of 34 patients with PPA with available autopsy tissue. We compared baseline and longitudinal clinical features in patients with primary AD neuropathology to those with primary non-AD pathologies. We analyzed regional neuroanatomic disease burden in pathology-defined groups using postmortem neuropathologic data. RESULTS: A total of 19/34 patients had primary AD pathology and 15/34 had non-AD pathology (13 frontotemporal lobar degeneration, 2 Lewy body disease). A total of 16/19 (84%) patients with AD had a logopenic spectrum phenotype; 5 met published criteria for the logopenic variant (lvPPA), 8 had additional grammatical or semantic deficits (lvPPA+), and 3 had relatively preserved sentence repetition (lvPPA-). Sentence repetition was impaired in 68% of patients with PPA with AD pathology; forward digit span (DF) was impaired in 90%, substantially higher than in non-AD PPA (33%, p < 0.01). Lexical retrieval difficulty was common in all patients with PPA and did not discriminate between groups. Compared to non-AD, PPA with AD pathology had elevated microscopic neurodegenerative pathology in the superior/midtemporal gyrus, angular gyrus, and midfrontal cortex (p < 0.01). Low DF scores correlated with high microscopic pathologic burden in superior/midtemporal and angular gyri (p ≤ 0.03). CONCLUSIONS: Phonologic loop dysfunction is a central feature of AD-associated PPA and specifically correlates with temporoparietal neurodegeneration. Quantitative measures of phonologic loop function, combined with modified clinical lvPPA criteria, may help discriminate AD-associated PPA.

The frontal assessment battery in the differential diagnosis of dementia.

AIM: The Frontal Assessment Battery (FAB) has been used in different clinical settings as a valuable quick bedside test for executive dysfunction. The aim of the study was to evaluate clinical utility of the FAB for differential diagnosis of Alzheimer disease (AD), subcortical vascular cognitive impairment (scVCI), and frontotemporal lobar degeneration (FTLD). METHODS: Scores of the total FAB test and subtests were compared between consecutive series of 37 patients with AD, 31 patients with scVCI, 13 patients with FTLD, and 29 cognitively healthy individuals. RESULTS: There was no statistically significant difference in the total FAB scores among the groups of patients with dementia. When comparing subtest scores, patients with FTLD had significantly lower scores on the lexical fluency subtest compared to the patients with AD (P<.001) or scVCI (P<.001); patients with scVCI had significantly lower scores on the motor series subtest compared to patients with FTLD (P=.02) and AD (P=.035) and on conflicting instructions subtest compared to patients with AD (P=.033). CONCLUSION: Some FAB subtests might enhance diagnostic accuracy taking into account clinical history and other tests of executive function.

Frontotemporal lobar degeneration: epidemiology, pathology, diagnosis and management.

Frontotemporal lobar degeneration (FTLD) describes a spectrum of clinically, pathologically and genetically heterogeneous neurodegenerative disorders of unknown aetiology. FTLD spectrum disorders collectively represent a leading cause of early-onset dementia, with most cases presenting between 45 and 64 years of age. FTLD is characterized by progressive changes in behaviour, executive dysfunction and/or language impairment and can be differentiated clinically into three frontotemporal dementia (FTD) syndromes as follows: (i) behavioural variant (bvFTD); (ii) semantic dementia (SD); and (iii) progressive nonfluent aphasia (PNFA). Additionally, there is a significant clinical, pathological and genetic overlap between FTD and motor neuron disease/amyotrophic lateral sclerosis (FTD-ALS) and the atypical parkinsonian syndromes, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). bvFTD is characterized by progressive behavioural impairment and a decline in executive function with frontal lobe-predominant atrophy, SD by a loss of object knowledge with prominent anomia and asymmetrical atrophy of the anterior temporal lobes and PNFA by expressive or motor speech deficits with predominantly left peri-sylvian atrophy. Recent advances in molecular biology and immunohistochemical staining techniques have further classified the FTLD spectrum disorders based upon the predominant neuropathological protein into three main categories: (i) microtubule-associated protein tau (FTLD-TAU); (ii) TAR DNA-binding protein-43 (FTLD-TDP); and (iii) fused in sarcoma protein (FTLD-FUS). Up to 40% of FTD patients report a family history of neurodegenerative illness, and one-third to one-half of familial cases of FTD follow an autosomal dominant inheritance pattern. Mutations in MAPT, PGRN, TARDBP, VCP and CHMP2B have been described, along with a recently identified C9ORF72 hexanucleotide repeat expansion. To date, there are no US FDA-approved treatments or disease-modifying therapies for FTD. Pharmacological strategies have focused on neurotransmitter replacement and modulation for the treatment of behavioural, motor and cognitive symptoms of FTD, and include selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics, acetylcholinesterase inhibitors and glutamate NMDA receptor antagonists. At present, adequate management of FTD symptoms involves a combination of pharmacological therapy with behavioural, physical and environmental modification techniques.

The SEA (Social cognition and Emotional Assessment): a clinical neuropsychological tool for early diagnosis of frontal variant of frontotemporal lobar degeneration.

OBJECTIVE: The frontal variant of frontotemporal degeneration (fvFTD) is characterized by a predominant behavioral syndrome, which is mostly attributable to an orbital-medial prefrontal dysfunction. The orbital and ventral medial prefrontal functions in humans are difficult to assess in clinical practice. Here, we propose a new tool, the SEA (Social cognition and Emotional Assessment), for use in evaluating the functions of the orbital and ventral-medial portions of the prefrontal cortex. METHOD: The SEA is composed of five subtests, each assessing a specific orbitofrontal-related function: a test of identification of facial emotions, a reversal/extinction task, a behavioral control task, a theory of mind test, and an apathy scale. The maximum score is 55. Three groups have been tested: 22 fvFTD patients, 22 patients with Alzheimer's disease (AD) or amnesic mild cognitive impairment (aMCI), and 30 healthy control subjects, all matched for age and educational level. RESULTS: FvFTD patients showed significantly lower performances in all subtests of the SEA. A cut-off score of 39.4/55 was proposed to separate normal controls from fvFTD patients, with a maximum sensitivity and specificity of 100%. A very high specificity (88.5%) was obtained using the same cut-off with AD/aMCI patients and normal controls versus fvFTD patients. FvFTD patients' performance in the SEA did not correlate with any other neuropsychological scores, particularly the classical cognitive executive tests. CONCLUSIONS: The SEA is a new and useful tool for diagnosing fvFTD and, more generally, all of the diseases affecting the orbital and medial prefrontal functions.

An algorithm for genetic testing of frontotemporal lobar degeneration.

OBJECTIVE: To derive an algorithm for genetic testing of patients with frontotemporal lobar degeneration (FTLD). METHODS: A literature search was performed to review the clinical and pathologic phenotypes and family history associated with each FTLD gene. RESULTS: Based on the literature review, an algorithm was developed to allow clinicians to use the clinical and neuroimaging phenotypes of the patient and the family history and autopsy information to decide whether or not genetic testing is warranted, and if so, the order for appropriate tests. CONCLUSIONS: Recent findings in genetics, pathology, and imaging allow clinicians to use the clinical presentation of the patient with FTLD to inform genetic testing decisions.

Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management.

Frontotemporal lobar degeneration (FTLD) is a clinically and pathologically heterogeneous syndrome, characterized by progressive decline in behaviour or language associated with degeneration of the frontal and anterior temporal lobes. While the seminal cases were described at the turn of the 20th century, FTLD has only recently been appreciated as a leading cause of dementia, particularly in patients presenting before the age of 65 years. Three distinct clinical variants of FTLD have been described: (i) behavioural-variant frontotemporal dementia, characterized by changes in behaviour and personality in association with frontal-predominant cortical degeneration; (ii) semantic dementia, a syndrome of progressive loss of knowledge about words and objects associated with anterior temporal neuronal loss; and (iii) progressive nonfluent aphasia, characterized by effortful language output, loss of grammar and motor speech deficits in the setting of left perisylvian cortical atrophy. The majority of pathologies associated with FTLD clinical syndromes include either tau-positive (FTLD-TAU) or TAR DNA-binding protein 43 (TDP-43)-positive (FTLD-TDP) inclusion bodies. FTLD overlaps clinically and pathologically with the atypical parkinsonian disorders corticobasal degeneration and progressive supranuclear palsy, and with amyotrophic lateral sclerosis. The majority of familial FTLD cases are caused by mutations in the genes encoding microtubule-associated protein tau (leading to FTLD-TAU) or progranulin (leading to FTLD-TDP). The clinical and pathological heterogeneity of FTLD poses a significant diagnostic challenge, and in vivo prediction of underlying histopathology can be significantly improved by supplementing the clinical evaluation with genetic tests and emerging biological markers. Current pharmacotherapy for FTLD focuses on manipulating serotonergic or dopaminergic neurotransmitter systems to ameliorate behavioural or motor symptoms. However, recent advances in FTLD genetics and molecular pathology make the prospect of biologically driven, disease-specific therapies for FTLD seem closer than ever.

Assessment of functional impairment in dementia with the Spanish version of the Activities of Daily Living Questionnaire.

BACKGROUND/AIMS: Functional assessment is essential in dementia as it provides an invaluable tool for diagnosis and treatment. To date, most scales of activities of daily living (ADL) have focused either on basic or instrumental activities, providing an incomplete profile of the patients' level of dependence on their caregivers. Some scales concentrate too intensely on the way in which physical impairment affects ADL, with a decreasing sensitivity to the detection of demented patients who do not necessarily present with physical impediments. The Activities of Daily Living Questionnaire (ADLQ) assesses functioning in self-care, household care, employment and recreation, shopping and money, travel and communication. The present study sought to determine the usefulness of the Spanish version of the ADLQ (ADLQ-SV) for assessing functional impairment in different types of dementia. METHODS: The ADLQ-SV, the Clinical Dementia Rating (CDR) scale and the Functional Activities Questionnaire (FAQ) were administered to the caregivers of patients (n = 40) with different types of dementia. RESULTS: Strong internal consistency (Cronbach's alpha = 0.88) and concurrent validity (significant correlations with CDR and FAQ, both p < 0.001) were observed. CONCLUSIONS: The authors discuss response trends in the ADLQ-SV and show the utility of the scale in Spanish-speaking populations of patients with dementia.