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...

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Monoamiergic neurons use dopa decarboxylase (DDC; aromatic-L-amino-acid carboxy-lyase, EC 4.1.1.28) to form dopamine from L-3,4-dihydroxyphenylalanine (L-dopa). We measured regional dopa decarboxylase activity in brains of six healthy volunteers with 6-[18F]fluoro-L-dopa and positron emission tomography. We calculated the enzyme activity, relative to its K., with a kinetic model that yielded the relative rate of conversion of 6['8Flfluoro-L-dopa to [18Fjfluorodopamine. Regional values of relative dopa decarboxylase activity ranged from nil in occipital cortex to 1.9 h-1 in caudate nucleus and putamen, in agreement with values obtained in vitro.The accumulation of metabolites of 6-[18F]fluoro-L-dopa (Fdopa) in brain reflects the activity of dopa decarboxylase (DDC; aromatic-L-amino-acid carboxy-lyase, EC 4.1.1.28), the enzyme responsible for the formation of dopamine from dopa (3,4-dihydroxyphenylalanine) (1-3). Unlike tyrosine hydroxylase, this enzyme is believed not to be regulated in response to the intensity of dopaminergic neurotransmission (4). Therefore, DDC activity may be a more precise indicator of the tissue's capacity to synthesize dopamine than tyrosine hydroxylase, the activity of which is adjusted to compensate for changes of dopaminergic activity.Recently, we used Fdopa to measure the relative activity ofDDC in vivo in rat brain (5). We defined the relative activity as the ratio between the reaction velocity and the enzyme precursor content ofthe tissue-i.e., proportional to the ratio between the enzyme's maximal velocity and the halfsaturation concentration of precursor when the precursor concentration is negligible relative to the half-saturation Michaelis constant Km (see Eqs. 7 and 8). In rat brain, the relative enzyme activity was as low as 1% of the relative activity reported in vitro. The reason for the discrepancy was unknown, but we speculated that it most probably was the loss of labeled fluorodopamine or its metabolites from one or more pools of dopamine in the tissue.In the present study, we obtained the relative activity of DDC in human brain in vivo. In vitro, the monoamine oxidase activities are lower in human brain than in rat brain (see Discussion), and metabolite diffusion distances are longer. For these reasons, we predicted the human relative DDC activity, determined in striatum in vivo with positron emission tomography (PET), to be close to the relative rate of dopamine synthesis determined in vitro. METHODSA model of the transport and metabolism of Fdopa in brain in vivo must include the compartments and transfer coefficients shown in Fig. 1. The model describes the methylation of Fdopa in the circulation (actually in peripheral organs), the loss of methyl-Fdopa from the circulation, the methylation of Fdopa in brain tissue, the exchange of Fdopa and methylFdopa between the circulation and brain tissue, and the decarboxylation of Fdopa in the tissue. The model has too many compartments to be evaluated by PET. We used known relationships between the parameters to reduc...

Summary:In 11 normal volunteers and six patients with Parkinson's disease, we compared six different analyses of dopaminergic fu nction with L-3, 4-dihydroxy-6-[18F]fluorophenylalanine (FDOPA) and positron emission tomography (PET). The caudate nucleus, putamen, and several reference regions were identified in PET images, using magnetic resonance imaging (MRI). The six analy ses included two direct determinations of DOPA decar boxylase activity (kr;, kj), the slope-intercept plot based on plasma concentration (K), two slope-intercept plots based on tissue content (k�, k�), and the striato-occipital ratio [R(n]. For all analyses, the difference between two groups of subjects (normal volunteers and patients with Parkinson's disease) was larger in the putamen than in the caudate. For the caudate nucleus, the DOPA decarbox ylase activity (kr;, kj), tissue slope-intercept plots (k;, The tracer L-3,4-dihydroxy-6-esF]fluorophenyl alanine (FDOPA) has been used widely to evaluate striatal dopaminergic functions in humans by posi tron emission tomography (PET). The enzyme aro matic amino acid decarboxylase (AAAD), or L-DOPA decarboxylase, is responsible for the re-