Objective-To identify predictors of Alzheimer's disease (AD) versus frontotemporal lobar degeneration pathology in primary progressive aphasia (PPA), and determine whether the AD pathology is atypically distributed to fit the aphasic phenotype.Methods-Neuropsychological and neuropathological analyses of 23 consecutive PPA autopsies. All had qualitative determination of neurofibrillary tangle (NFT) density. Additional quantitation was done in four of the PPA/AD cases and four AD cases with the typical amnestic dementia of the Alzheimer type.Results-The sample contained mostly logopenic, agrammatic, and mixed forms of PPA. All six agrammatics had frontotemporal lobar degeneration (five of six with tauopathy). Seven of the 11 logopenics had AD. In logopenics, lower memory scores increased the probability of AD, but there were exceptions. The PPA/AD group showed predominance of entorhinal NFT typical of the amnestic dementia of the Alzheimer type. In the small subgroup examined quantitatively, neocortical NFTs were more numerous in the left hemisphere of PPA/AD. However, the asymmetry was low and inconsistent. Neuritic plaques did not display consistent asymmetry. Apolipoprotein E4, a major risk factor for typical AD, did not predict AD pathology in PPA.Interpretation-Subtyping PPA helps to predict AD versus frontotemporal lobar degeneration pathology at the group level. However, our results and the literature also indicate that no clinical predictor is completely reliable in individual patients. The inconsistent concordance of NFT distribution with the asymmetric atrophy and the nonamnestic phenotype also raises the possibility that the AD markers encountered at autopsy in PPA may not always reflect the nature of the initiating neurodegenerative process.The relation of disease markers to dementia phenotypes has been investigated most productively in Alzheimer's disease (AD). In most AD cases, neurofibrillary tangles (NFTs) This report includes 23 consecutive, unselected autopsies on patients with the clinical syndrome of PPA. One goal was to explore factors that could predict AD versus FTLD pathology. Another was to determine whether AD pathology in the aphasic dementia of PPA had a different distribution than in the amnestic dementia of DAT. following account of her problem: "I have to force myself to tell people about understand me. Words come out wrong the way." Patient 4 was the only one classified as semantic based on the constellation of preserved fluency and syntax but abnormal language comprehension. Patients with intact syntax and comprehension but frequent word-finding pauses and variable fluency were classified as logopenic. Patients with agrammatism and also comprehension deficits of comparable magnitude, or whose language output was too limited for specific characterization, were designated as "mixed" in Table 1. Demographic data were analyzed using independent samples t tests. Fisher's exact test was used to examine group differences in categoric data.© Patients and Methods PatientsAll specime...

Neuropsychological assessment has featured prominently over the past 30 years in the characterization of dementia associated with Alzheimer disease (AD). Clinical neuropsychological methods have identified the earliest, most definitive cognitive and behavioral symptoms of illness, contributing to the identification, staging, and tracking of disease. With increasing public awareness of dementia, disease detection has moved to earlier stages of illness, at a time when deficits are both behaviorally and pathologically selective. For reasons that are not well understood, early AD pathology frequently targets large-scale neuroanatomical networks for episodic memory before other networks that subserve language, attention, executive functions, and visuospatial abilities. This chapter reviews the pathognomonic neuropsychological features of AD dementia and how these differ from "normal," age-related cognitive decline and from other neurodegenerative diseases that cause dementia, including cortical Lewy body disease, frontotemporal lobar degeneration, and cerebrovascular disease.O ver the past 30 years, neuropsychological assessment has featured centrally in characterizing the dementia associated with Alzheimer disease (AD), identifying the most salient and earliest cognitive and behavioral symptoms and contributing to the staging and tracking of disease (Flicker et al. 1984;Morris et al. 1989;Storandt and Hill 1989;Storandt 1991;Welsh et al. 1991Welsh et al. , 1992Locascio et al. 1995;Albert 1996;Storandt et al. 1998; see also Salmon and Bondi 2009). As research has increasingly focused on earlier stages of illness, it has become clear that biological markers of AD can precede cognitive and behavioral symptoms by years. It has also become clear that the early symptoms of AD represent the selective targeting by disease of specific, "largescale" neuroanatomical networks, with clinical deficits consistent with the anatomical locus of impact (Weintraub and Mesulam 1993Seeley et al. 2009). In the usual case, AD pathology is initially selective for limbic regions that subserve episodic memory, which leads to a circumscribed memory deficit in the early stages of the disease (Braak and Braak 1991;Jack et al. 1997; de ToledoMorrell et al. 2000). It is only as pathology progresses to other neocortical regions over time (Braak and Braak 1996a,b;Braak et al. 1999;Jack et al. 2000) that additional cognitive symptoms emerge and the full dementia syndrome becomes apparent.These discoveries have prompted a revision of the established research diagnostic criteria for AD dementia that had served so well since 1984 (McKhann et al. 1984). The new criteria define not only the dementia of AD (McKhann et al. 2011) but also incorporate a fuller spectrum of cognitive aging, including an intermediate stage of mild cognitive impairment (MCI) that precedes the dementia (Albert et al. 2011). A third, even earlier, stage of "preclinical AD" has also been identified (Sperling et al. 2011). This prodromal period is characterized by the presence of bi...

Assessment of functional ability is an essential component in the clinical diagnosis of dementia. Most studies have primarily focused on disability due to Alzheimer disease (AD), and less is known about profiles of functional impairment in other dementia syndromes. Functional ability was assessed in individuals in the early stages of AD (N=100), the behavioral variant of frontotemporal dementia (FTD) (N=57), and primary progressive aphasia (PPA) (N=61), using the activities of daily living questionnaire (Johnson et al, 2004). The average duration of illness for the 3 groups ranged from 3.4 to 3.9 years. Overall level of functional impairment and the profile of abilities across subscales of Self-Care, Household Care, Employment and Recreation, Shopping and Money, Travel, and Communication were examined. Results showed that overall functional ability was moderately impaired in AD and FTD, and mildly impaired in PPA. For all groups, more complex ADLs were impaired early on, with relative preservation of self-care activities. The Communication score was the least impaired next to Self-Care for FTD and AD, and the most impaired for PPA patients. The activities of daily living questionnaire may capture aspects of preserved functioning that are not apparent from patients' scores on cognitive tests, especially for those with aphasia.

There is little information regarding the usefulness of the Mini-Mental State Examination (MMSE) for tracking progression of non-Alzheimer's disease dementias. This study examined the utility of the MMSE in capturing disease severity in the behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA), 2 nonamnestic clinical dementia syndromes. Retrospective data from 41 bvFTD and 30 PPA patients were analyzed. bvFTD patients' change in MMSE scores over time was significantly correlated with change over time on a measure of activities of daily living. In contrast, PPA patients' MMSE scores showed greater decline over time than scores on the activities of daily living scale. Results suggest that the MMSE score, heavily dependent on language skill, overestimates dementia severity in PPA patients. However, the score may be a more accurate measure of functional impairment in bvFTD due to the influence of their executive function and attentional deficits on MMSE performance.

Primary Progressive Aphasia (PPA) is a clinical dementia syndrome characterized by the gradual dissolution of language without impairment of other cognitive domains for at least the first 2 years of illness (M.-M. Mesulam, 1982, 2001). It is difficult to demonstrate the integrity of nonlanguage domains in PPA because most neuropsychological tests of memory, reasoning, and attention require language competence for their performance. In the present study, reasoning and cognitive flexibility were tested nonverbally in patients with PPA using a modified ten-item version of the Visual Verbal Test (Feldman & Drasgow, 1959). This test measures the ability to detect similarities among objects and to sort a single set of objects according to two different principles. The performance of PPA patients (n = 20) was compared with that of patients with dementia of the Alzheimer type (AD) (n = 20), patients with the comportmental/executive dysfunction variant of frontotemporal dementia (FTD) (n = 16), and cognitively intact controls (n = 20). Patients with PPA and controls performed similarly, detecting commonalities among objects and shifting from one sorting principle to another. In contrast, both AD and FTD subjects were significantly impaired on both measures. These results provide evidence of preserved reasoning in PPA, further differentiating this syndrome from other behaviorally focal dementia syndromes.