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

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.

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

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.

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Classification of primary progressive aphasia and its variants

The term frontotemporal dementia (FTD) encompasses a range of clinical syndromes that are believed not to map reliably onto the spectrum of recognized pathologies. This study reexamines the relationships between clinical and pathological subtypes of FTD in a large series from two centers (n = 61). Clinical subtypes defined were behavioral variant FTD (n = 26), language variants (semantic dementia, n = 9; and progressive nonfluent aphasia, n = 8), and motor variants (corticobasal degeneration, n = 9; and motor neuron disease, n = 9), although most cases presented with a combination of behavioral and language problems. Unexpectedly, some behavioral cases (n = 5) had marked amnesia at presentation. The pathological subtypes were those with tau-immunopositive inclusions (with Pick bodies, n = 20; or without, n = 11), those with ubiquitin immunopositive inclusions (n = 16), and those lacking distinctive histology (n = 14). Behavioral symptoms and semantic dementia were associated with a range of pathologies. In contrast, other clinical phenotypes had relatively uniform underlying pathologies: motor neuron disease predicted ubiquitinated inclusions, parkinsonism and apraxia predicted corticobasal pathology, and nonfluent aphasia predicted Pick bodies. Therefore, the pathological substrate can be predicted in a significant proportion of FTD patients, which has important implications for studies targeting mechanistic treatments.

/pdf/clinicopathological-correlates-in-frontotemporal-dementia-2e2i9lm8kc.pdf

Clinicopathological correlates in frontotemporal dementia.

Objectives: To establish survival in patients with pathologically confirmed frontotemporal dementia (FTD) and to determine whether clinical or pathologic subtype affects prognosis. Methods: The authors reviewed the presenting clinical features of 61 patients with dementia and pathologically confirmed FTD studied in Sydney (n = 31) and Cambridge (n = 30) over a 10-year period. Data were available on time of symptom onset, diagnosis, institutionalization, and death. Cases were classified pathologically as tau-positive and tau-negative. Results: Of the 61 patients with FTD, 26 presented with frontal variant (fvFTD), 9 with semantic dementia, 8 with progressive nonfluent aphasia (PNFA), 9 with associated motor neuron disease (FTD-MND), and 9 with corticobasal degeneration features. There was no difference between the groups in age at symptom onset (overall mean 58.5 ± 7.8 years), but at diagnosis the PNFA (68.3 ± 2.7) group was significantly older than the fvFTD (59.9 ± 7.4) and FTD-MND (57.7 ± 7.9) groups. The median survival from symptom onset and from diagnosis was 6 ± 1.1 years (95% CI) for fvFTD and 3 ± 0.4 years for FTD-MND. Survival across subgroups was equivalent except for the FTD-MND group, which had significantly shorter survival. Cases with tau-positive pathology had an older age at onset and a significantly better prognosis: median survival 9.0 ± 0.9 years vs 5.0 ± 1.1 years. Conclusions: FTD is a malignant disorder with limited life expectancy. FTD-MND has the shortest duration both before and after diagnosis. Tau-positivity is associated with a more slowly progressive form of FTD.

Survival in frontotemporal dementia

There has been considerable debate as to whether the hippocampus and perirhinal cortex may subserve both memory and per- ception. We administered a series of oddity tasks, in which subjects selected the odd stimulus from a visual array, to amnesic patients with either selective hippocampal damage (HC group) or more extensive medial temporal damage, including the perirhinal cortex (MTL group). All patients performed normally when the stimuli could be discrimi- nated using simple visual features, even if faces or complex virtual real- ity scenes were presented. Both patient groups were, however, severely impaired at scene discrimination when a significant demand was placed on processing spatial information across viewpoint independent repre- sentations, while only the MTL group showed a significant deficit in oddity judgments of faces and objects when object viewpoint inde- pendent perception was emphasized. These observations provide com- pelling evidence that the human hippocampus and perirhinal cortex are critical to processes beyond long-term declarative memory and may subserve spatial and object perception, respectively. V C 2005 Wiley-Liss, Inc.

Specialization in the medial temporal lobe for processing of objects and scenes.

Semantic dementia is a syndrome of progressive deterioration in semantic memory (knowledge of objects, people, concepts and words). It falls within the clinical spectrum of frontotemporal dementia but its pathology is yet to be studied systematically. This study included 18 consecutive post mortem cases meeting clinical criteria for semantic dementia. Clinic records and diagnostic histopathology were available for all cases; structural neuroimaging, neuropsychology and semi-quantitative histopathology/immunohistochemistry data were analysed where possible. The pathological diagnosis in a clear majority of cases was frontotemporal degeneration with ubiquitin inclusions (n = 13). Eleven of these cases had characteristic motor neuron disease-type inclusions in the dentate gyrus and cerebral cortex. Ubiquitin inclusions were found only in the inferior olivary nucleus in the other two, one of which was the only case to show degeneration of motor tracts and also to have shown evidence of motor neuron disease during life. None of the patients had motor symptoms or signs at presentation. A family history of motor neuron disease was documented in one case. Pick body-positive Pick's disease appeared three times. Two cases had Alzheimer's disease and significant coincidental Alzheimer-type pathology was also found in one of the ubiquitin inclusion cases. One of the Alzheimer's disease patients had changes in white matter signal on scanning, whereas all other scans showed cerebral atrophy only. Semi-quantitative assessment of regional neuronal loss found that anterior and inferior temporal regions bore the brunt of disease across all histopathological subtypes, usually on the left side, implicating this region in semantic processing.

/pdf/the-pathological-basis-of-semantic-dementia-24w91wigu6.pdf

The Pathological Basis of Semantic Dementia

Investigations of memory in rats and nonhuman primates have demonstrated functional specialization within the medial temporal lobe (MTL), a set of heavily interconnected structures including the hippocampal formation and underlying entorhinal, perirhinal, and parahippocampal cortices. Most studies in humans, however, especially in patients with brain damage, suggest that the human MTL is a unitary memory system supporting all types of declarative memory, our conscious memory for facts and events. To resolve this discrepancy, amnesic patients with either selective hippocampal damage or more extensive MTL damage were tested on variations of an object discrimination task adapted from the nonhuman primate literature. Although both groups were equally impaired on standard recall-based memory tasks, they exhibited different profiles of performance on the object discrimination test, arguing against a unitary view of MTL function. Cases with selective hippocampal damage performed normally, whereas individuals with broader MTL lesions were impaired. Furthermore, deficits in this latter group were related not to the number of discriminations to be learned and remembered, but to the degree of “feature ambiguity,” a property of visual discriminations that can emerge when features are part of both rewarded and unrewarded stimuli. These findings resolve contradictions between published studies in humans and animals and introduce a new way of characterizing the impairments that arise after damage to the MTL.

https://www.jneurosci.org/content/jneuro/25/44/10239.full.pdf

R. Rhys Davies

Papers

Clinicopathological correlates in frontotemporal dementia.

Survival in frontotemporal dementia

Specialization in the medial temporal lobe for processing of objects and scenes.

The Pathological Basis of Semantic Dementia

Functional specialization in the human medial temporal lobe