The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

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The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease

Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268

Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.

http://science.sciencemag.org/content/sci/314/5796/130.full.pdf

Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

Dementia prevention, intervention, and care

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.

/pdf/sensitivity-of-revised-diagnostic-criteria-for-the-2f3gs00fp5.pdf

Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.

The primary progressive aphasia (PPA) syndromes are heterogeneous neurodegenerative disorders. The 3 major PPA syndromes are not identical to the usual aphasia syndromes from strokes. Progressive nonfluent aphasia (PNFA) involves effortful speech with agrammatism and frequent apraxia of speech. The semantic variant or semantic dementia (SemD) involves fluent speech with loss of word and object meaning. Logopenic progressive aphasia (LPA), the third and most recently described PPA, involves word-finding pauses, moderate anomia, and impaired repetition of sentences. Each PPA syndrome correlates with a specific patterns of focal atrophy, but has a less robust relationship with the underlying neuropathology. An important reason for clarifying the relationship between clinical syndrome and neuropathology is that it facilitates clinical trials with disease-modifying therapies.

In this issue of Neurology ®, Deramecourt et al.1 have decreased the gap between the clinical syndromes of PPA and their neuropathology. This clinicopathologic study investigated 18 patients followed in the Lille Memory Clinic over a 15-year period. These patients presented with progressive …

What progressive aphasia says about its neuropathology

Impaired knowledge for fruits and vegetables in semantic dementia.

Alien hand syndrome in adult onset orthochromatic leukodystrophy: Disconnection of a limb from supplementary motor areas

Clinical studies report abnormal socioemotional behavior in patients with right frontotemporal disease, but neuroimaging studies of socioemotional behavior usually show bilateral activations in normal subjects. This discrepancy suggests that impaired interhemispheric collaboration for socioemotional functions results from asymmetric frontotemporal disease. Behavioral variant frontotemporal dementia (bvFTD) can clarify the contribution of direction-independent frontotemporal asymmetry. In a two-part study, we evaluated bvFTD patients using socioemotional scales and magnetic and resonance imaging measures. Part A compared 18 patients on scales of social dysfunction and emotional intelligence with degree of asymmetry in frontal lobe volumes and analyzed differences between lower and higher asymmetry groups. Part B compared 24 patients on scales of social observation and emotional blunting with degree of asymmetry in frontotemporal cortical thickness using multiple linear regression. Both results showed that left or right hemispheric-specific contributions did not account for all socioemotional differences and that frontal lobe and frontotemporal differences in atrophy between the hemispheres accounted for significant variance in abnormalities in social and emotional behavior. These preliminary results indicate that the degree of frontal lobe and frontotemporal asymmetric involvement, regardless of direction or laterality, significantly contribute to socioemotional dysfunction and support the hypothesis that interhemispheric collaboration is important for complex socioemotional behavior.

Frontotemporal asymmetry in socioemotional behavior: A pilot study in frontotemporal dementia.

BACKGROUND Bilingualism is increasingly recognized as protective in persons at risk for Alzheimer's disease (AD). OBJECTIVE Compare MRI measured brain volumes in matched bilinguals versus monolinguals with AD. METHODS This IRB approved study analyzed T1 volumetric brain MRIs of patients with criteria-supported Probable AD. We identified 17 sequential bilinguals (any native language) with Probable AD, matched to 28 (62%) monolinguals on age and MMSE. Brain volumes were quantified with Neuroreader. Regional volumes as fraction of total intracranial volume (TIV) were compared between both groups, and Cohen's D effect sizes were calculated for statistically significant structures. Partial correlations between bilingualism and brain volumes adjusted for age, gender, and TIV. RESULTS Bilinguals had higher brain volumes in 37 structures. Statistical significance (p < 0.05) was observed in brainstem (t = 2.33, p = 0.02, Cohen's D = 0.71) and ventral diencephalon (t = 3.01, p = 0.004, Cohen's D = 0.91). Partial correlations showed statistical significance between bilingualism and larger volumes in brainstem (rp = 0 . 37, p = 0.01), thalamus (rp = 0.31, p = 0.04), ventral diencephalon (rp = 0.50, p = 0.001), and pallidum (rp = 0.38, p = 0.01). Bilingualism positively correlated with hippocampal volume, though not statistically significant (rp = 0.17, p = 0.26). No brain volumes were larger in monolinguals. CONCLUSION Bilinguals demonstrated larger thalamic, ventral diencephalon, and brainstem volumes compared to matched monolinguals with AD. This may represent a neural substrate for increased cognitive reserve in bilingualism. Future studies should extrapolate this finding into cognitively normal persons at risk for AD.

Mario F. Mendez

Papers

What progressive aphasia says about its neuropathology

Impaired knowledge for fruits and vegetables in semantic dementia.

Alien hand syndrome in adult onset orthochromatic leukodystrophy: Disconnection of a limb from supplementary motor areas

Frontotemporal asymmetry in socioemotional behavior: A pilot study in frontotemporal dementia.

Brain Structure in Bilingual Compared to Monolingual Individuals with Alzheimer's Disease: Proof of Concept.