Prominent microglial activation in cortical white matter is selectively associated with cortical atrophy in primary progressive aphasia.

AIMS: Primary progressive aphasia (PPA) is a clinical syndrome characterized by selective language impairments associated with focal cortical atrophy favouring the language dominant hemisphere. PPA is associated with Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and significant accumulation of activated microglia. Activated microglia can initiate an inflammatory cascade that may contribute to neurodegeneration, but their quantitative distribution in cortical white matter and their relationship with cortical atrophy remain unknown. We investigated white matter activated microglia and their association with grey matter atrophy in 10 PPA cases with either AD or FTLD-TDP pathology. METHODS: Activated microglia were quantified with optical density measures of HLA-DR immunoreactivity in two regions with peak cortical atrophy, and one nonatrophied region within the language dominant hemisphere of each PPA case. Nonatrophied contralateral homologues of the language dominant regions were examined for hemispheric asymmetry. RESULTS: Qualitatively, greater densities of activated microglia were observed in cortical white matter when compared to grey matter. Quantitative analyses revealed significantly greater densities of activated microglia in the white matter of atrophied regions compared to nonatrophied regions in the language dominant hemisphere (P < 0.05). Atrophied regions of the language dominant hemisphere also showed significantly more activated microglia compared to contralateral homologues (P < 0.05). CONCLUSIONS: White matter activated microglia accumulate more in atrophied regions in the language dominant hemisphere of PPA. While microglial activation may constitute a response to neurodegenerative processes in white matter, the resultant inflammatory processes may also exacerbate disease progression and contribute to cortical atrophy.

Nuclear carrier and RNA-binding proteins in frontotemporal lobar degeneration associated with fused in sarcoma (FUS) pathological changes.

AIMS: We aimed to investigate the role of the nuclear carrier and binding proteins, transportin 1 (TRN1) and transportin 2 (TRN2), TATA-binding protein-associated factor 15 (TAF15) and Ewing's sarcoma protein (EWS) in inclusion body formation in cases of frontotemporal lobar degeneration (FTLD) associated with fused in sarcoma protein (FTLD-FUS). METHODS: Eight cases of FTLD-FUS (five cases of atypical FTLD-U, two of neuronal intermediate filament inclusion body disease and one of basophilic inclusion body disease) were immunostained for FUS, TRN1, TRN2, TAF15 and EWS. Ten cases of FTLD associated with TDP-43 inclusions served as reference cases. RESULTS: The inclusion bodies in FTLD-FUS contained TRN1 and TAF15 and, to a lesser extent, EWS, but not TRN2. The patterns of immunostaining for TRN1 and TAF15 were very similar to that of FUS. None of these proteins was associated with tau or TDP-43 aggregations in FTLD. CONCLUSIONS: Data suggest that FUS, TRN1 and TAF15 may participate in a functional pathway in an interdependent way, and imply that the function of TDP-43 may not necessarily be in parallel with, or complementary to, that of FUS, despite each protein sharing many similar structural elements.

Progressive supranuclear palsy with dementia: cortical pathology.

Patients with progressive supranuclear palsy (PSP) often develop dementia, and cortical pathology has been documented in PSP. However, there are no reports correlating dementia in PSP with cortical pathology. We hypothesized that cases of PSP presenting with cognitive impairment would have more severe cortical tau pathology than those without. We compared 7 cases of PSP presenting with cognitive deficits (group 1) with 4 cases of PSP that did not (group 2). The subcortical tau pathology was almost identical in both groups. The cortical tau pathology was strikingly different in group 1, in which it was on average moderate, compared with group 2, in which it was minimal. The accumulation of cortical neuronoglial tau in PSP cases with dementia suggests that neurofibrillary pathology is central to the cause of dementia in PSP.

Neocortical synapse density and Braak stage in the Lewy body variant of Alzheimer disease: a comparison with classic Alzheimer disease and normal aging.

Substantial numbers of cortical and subcortical Lewy bodies are seen in approximately one quarter of patients whose brains show sufficient histopathologic changes for a neuropathologic diagnosis of definite Alzheimer disease (AD). This subset of cases has been named the Lewy body variant of AD (LBV). Despite comparable dementia and the presence of neocortical senile plaques in LBV patients, the overall burden of neuropathologic changes, in particular neurofibrillary tangles (NFT), is less than in classic AD. While NFT frequency correlates with dementia severity in classic AD, the cognitive impairment in patients with LBV cannot be completely explained by such changes. Since several studies have suggested a role for synapse loss in relation to dementia severity in classic AD, we decided to investigate the role of synapse loss as a candidate for the cognitive impairment of LBV. The Braak staging method is based upon the distribution and severity of neurofibrillary changes, and one therefore would expect LBV cases to be assigned to lower Braak stages. In the present study we assigned a Braak stage to 14 LBV cases, 31 classic AD cases, and a group of 10 non-demented aged controls. We compared the severity of synapse loss as determined by ELISA immunoassay for synaptophysin and Braak stage among the three diagnostic groups. When compared to normal controls, synaptophysin concentrations were statistically significantly lower in both demented groups. There was comparable synapse loss in LBV and AD despite significantly lower Braak stages in the LBV cases. These results suggest a major role for loss of synapses as the substrate of cognitive impairment in LBV.

Frontal lobe dementia with novel tauopathy: sporadic multiple system tauopathy with dementia.

We present a novel tauopathy in a patient with a 10-yr history of progressive frontal lobe dementia and a negative family history. Autopsy revealed mild atrophy of frontal and parietal lobes and severe atrophy of the temporal lobes. There were occasional filamentous tau-positive inclusions, but more interesting were numerous distinctive globular neuronal and glial tau-positive inclusions in both gray and white matter of the neocortex. Affected subcortical regions included substantia nigra, globus pallidus, subthalamic nucleus, and cerebellar dentate nucleus, in a distribution similar to progressive supranuclear palsy (PSP), but without significant accompanying neuronal loss or gliosis. Predominantly straight filaments were detected by electron microscopy (EM), while other inclusions were similar to fingerprint bodies. No twisted ribbons were detected. Immuno-EM studies revealed that only the filamentous inclusions were composed of tau. Immunoblotting of sarkosyl-insoluble tau revealed 2 major bands of 64 and 68 kDa. Blotting analysis after dephosphorylation revealed predominantly 4-repeat tau. Sequence analysis of tau revealed that there were no mutations in either exons 9-13 or the adjacent intronic sequences. The unique cortical tau pathology in this case of sporadic multiple system tauopathy with dementia adds a new pathologic profile to the spectrum of tauopathies.

Cortical synapse loss in progressive supranuclear palsy.

Cortical synapse loss, the probable substrate of cognitive impairment in Alzheimer disease (AD), has not previously been evaluated in progressive supranuclear palsy (PSP). Hypothesizing that synapse loss would be greater in demented than non-demented PSP patients, we examined synaptophysin concentrations in 8 cases of PSP (5 demented and 3 nondemented cases). We found a decrease in mean synaptophysin concentration in these 8 cases in frontal, temporal, and parietal lobes, and in cerebellum, compared to the means in corresponding lobes of 16 controls. The decreases were similar to those in 28 cases of AD, but not as great. We determined synaptophysin concentration from motor cortex in only 4 of our PSP cases, 2 demented and 2 non-demented. The average concentrations in these 4 cases were lower than in AD motor cortex; both were lower than controls. When demented and non-demented PSP cases were compared, neocortical synaptophysin concentrations in non-demented PSP cases were lower than in demented cases. There appears to be a link between AD and PSP, in that synapse loss is found in both. However, the basis and significance of the prominent neocortical synapse loss in PSP, especially in non-demented subjects, remain to be explored.

Neuropathologic evidence that the Lewy body variant of Alzheimer disease represents coexistence of Alzheimer disease and idiopathic Parkinson disease.

We undertook this study to investigate the neuropathologic relationships among Alzheimer disease (AD), idiopathic Parkinson disease (PD), and the Lewy body variant of AD (AD/LBV). We retrieved 30 autopsy cases in which Lewy bodies (LB) had been identified in the substantia nigra (SN) in routine hematoxylin-eosin-stained sections. Twenty-two of the cases had a primary clinical diagnosis of dementia and neuropathologic changes of AD; 12 of these demented patients also had clinical parkinsonism. Eight cases had clinical and neuropathologic evidence of PD with minimal or no AD neuropathology, though 6 had clinical dementia. Controls consisted of 6 cases of AD without SN LB by hematoxylin-eosin, and 5 neurologically normal aged controls. Paraffin sections of SN, superior temporal gyrus, and cingulate gyrus from each case were immunostained with rabbit anti-ubiquitin antiserum, randomized, and analyzed individually by light microscopy, and the density of LB-like profiles in each section were graded. None of 5 nondemented aged controls showed any neocortical LB, even though 2 had significant numbers of incidental SN LB by ubiquitin immunostaining. Of 6 AD cases without SN LB by hematoxylin-eosin, 3 had rare SN LB on ubiquitin stain, 1 of which showed rare neocortical Lewy-like profiles. Seven of 8 PD cases showed neocortical LB, including the 6 with dementia. Twenty-one of 22 AD cases with SN LB showed ubiquitin-immunoreactive Lewy-like bodies in the neocortex that were statistically significantly greater in number than in either pure PD or pure AD cases. The frequent occurrence of LB in the neocortex in PD alone suggests that AD/LBV likely represents mixed AD/PD. However, AD neuropathology may favor or promote the formation of neocortical LB in patients who go on to develop mixed AD/PD pathology.

Contribution of asymmetric synapse loss to lateralizing clinical deficits in frontotemporal dementias.

BACKGROUND: Synapse loss has been found to be the major correlate of cognitive decline in Alzheimer disease (AD), and prefrontal synapse loss has been found in patients with frontotemporal dementia (FTD). OBJECTIVE: To see if our hypothesis that within each FTD case, regional synapse loss would correlate with lateralizing neuropsychologic and neurobehavioral deficits would be correct. DESIGN: We analyzed synaptophysin as a marker for synapse loss in snap-frozen brain samples, using an enzyme-linked immunosorbent assay technique. Quantitative results were obtained by comparing patient data with a standard curve made by analyzing serial dilutions of a recombinant synaptophysin protein fragment. A board-certified neuropsychologist and a board-certified neurologist, both unaware of the synaptophysin results, determined areas of primary neuropsychologic and neurobehavioral dysfunction. Relationships between areas of primary dysfunction and synapse loss were analyzed using the binomial test. PATIENTS: Six cases of FTD, 28 cases of AD, and 16 nondemented control subjects. RESULTS: Five of 6 FTD cases had regional synaptophysins correlating with lateralizing frontal or temporal deficits. Three of 6 correlated in 2 or more regions. Although our results were higher than that expected based on a pure-chance mechanism (50% vs 34%), statistical significance was not attained. CONCLUSIONS: We found a trend for an association between synapse loss and lateralizing neuropsychologic and neurobehavioral deficits in FTD. Studies in larger numbers of FTD cases are planned with the goal of attaining statistically significant conclusions.

Glutamate transporter EAAT2 splice variants occur not only in ALS, but also in AD and controls.

OBJECTIVE: To ascertain the specificity of alternatively spliced mRNA variants of the astroglial glutamate transporter EAAT2 for ALS. BACKGROUND: An important hypothesis for ALS pathogenesis is that motor neuron injury may result from chronically elevated glutamate levels in the CNS. Supporting this idea are reports of decreased glutamate transport in ALS. This in turn has recently been suggested to be due to the presence of aberrant mRNA splice variants for EAAT2 in ALS. METHODS: Postmortem human brain tissue was obtained from different brain regions of patients with ALS, normal controls (NC), and patients with AD and Lewy body dementia (LB)-neurodegenerative diseases in which motor neurons are unaffected. Brain RNA was analyzed for EAAT2 isoforms using reverse transcription PCR and cDNA cloning/sequencing methods. RESULTS: Splice variants lacking exons 7 or 9 were present in ALS brain, as previously reported, but were also present in brains from NC, AD, and LB patients. PCR product sequence analyses from non-ALS brain show variant splicing identical to that reported for ALS. Quantitative PCR analysis shows that these isoforms may be somewhat more abundant in ALS than AD, LB, and NC brains. CONCLUSIONS: EAAT2 mRNA splice variants are found in the brains of NC and AD patients, as in ALS. The authors cannot exclude the possibility that quantitative changes in variant EAAT2 isoforms might relate directly, or indirectly, to ALS pathology. However, the qualitative presence of these "abnormal" EAAT2 splice variants does not appear to be sufficient to explain motor neuron degeneration in ALS.

The wide spectrum of myofibrillar myopathy suggests a multifactorial etiology and pathogenesis.

BACKGROUND: Myofibrillar myopathy (MFM) is characterized by nonhyaline lesions (foci of myofibrillar destruction) and hyaline lesions (cytoplasmic inclusions composed of compacted myofibrillar residues) on light and electron microscopy. Immunocytochemistry demonstrates the abnormal expression of desmin and numerous other proteins. The clinical, laboratory, and histologic features of MFM are heterogeneous, making a diagnosis difficult. RESULTS: We diagnosed eight patients with MFM over the preceding 3 years. MFM was inherited in an autosomal dominant pattern in one patient, developed sporadically in five patients, and was induced by an experimental chemotherapy, Elinafide (Knoll, Parsippany, NJ), in two patients. Age at onset ranged from 14 to 64 years. The pattern of weakness was variable but involved proximal and distal muscles. Five patients had evidence of a cardiomyopathy. Electromyography demonstrated muscle membrane instability and small, polyphasic motor unit potentials. Serum creatine kinase levels were normal to moderately elevated (<10x normal). Light and electron microscopy demonstrated the characteristic pattern of nonhyaline and hyaline lesions and the associated abnormalities on immunocytochemistry. CONCLUSIONS: Patients demonstrate a wide spectrum of clinical, laboratory, and histologic abnormalities. Chemotherapy-induced MFM has abnormalities on immunocytochemistry similar to the those of hereditary and sporadic cases. The pathogenesis of MFM is likely heterogeneous. However, MFM is distinctive in that it can preferentially affect distal muscles and has a frequent association with cardiomyopathy. The cardiomyopathy may be amenable to treatment with pacemaker insertion or cardiac transplantation.

Analysis of tau haplotypes in Pick's disease.

Pick's disease (PiD) is characterized by the deposition of tau protein as three-repeat tau Pick bodies, whereas progressive supranuclear palsy (PSP) involves the deposition of four-repeat tau neurofibrillary tangles. PSP is associated with the tau H1 haplotype. The authors investigated a possible association between PiD and the tau H1 or H2 haplotype. There was no difference between the tau H2 haplotype or H2H2 genotype frequency in PiD cases and control subjects. No tau mutations were identified in pathologically typical cases of PiD, with antibody 12-E8-negative Pick bodies.

Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype.

OBJECTIVE: To analyze the association of polymorphisms in the tau gene with pathologically confirmed corticobasal degeneration (CBD). BACKGROUND: The authors previously described an extended tau haplotype (H1) that covers the human tau gene and is associated with the development of progressive supranuclear palsy (PSP). The authors now extend this analysis to CBD, a neurodegenerative condition with clinical and neuropathologic similarities to PSP. Like PSP, CBD is associated with accumulation of aggregates containing the 4-repeat isoforms of tau. Because of difficulty in diagnosis of CBD, the authors only analyzed cases with pathologically confirmed CBD. METHODS: The authors collected 57 unrelated, neuropathologically confirmed cases of CBD. Tau sequencing in these cases failed to show the presence of pathogenic mutations. Polymorphisms that spanned the tau gene were analyzed in all CBD cases and controls. RESULTS: Analyzing tau polymorphisms in CBD cases showed that the frequency of H1 and H1/H1 was significantly increased when analyzing all cases and when separating by country of origin. H1 frequency in all CBD cases was 0.921, compared with a control frequency of 0.766 (X(2) = 9.1, p = 0.00255 [1df], OR 3.56 [8.43 > CI 95% > 1.53]). The H1/H1 frequency was also significantly higher at 0.842 compared with 0.596 in age-matched controls (X(2) = 17.42, p = 0.00016, 2df), OR 3.61 [7.05 > CI 95% > 1.85]). CONCLUSIONS: The CBD tau association described here suggests that PSP and CBD share a similar cause, although the pathogenic mechanism behind the two diseases leads to a different clinical and pathologic phenotype.

Evidence for regulated expression of neuropeptide Y gene by rat and human cultured astrocytes.

A series of studies from our laboratory have established that fetal rat and human neuropeptide Y (NPY) cortical neurons in aggregate cultures are differentially regulated. In a preliminary study we found that primary astrocytes produce substantial amounts of immunoreactive (IR) NPY. We addressed the question: Is astrocyte production of NPY-IR a regulated process? The effects of brain-derived neurotrophic factor (BDNF, 50 ng/ml), basic fibroblast growth factor (bFGF), substance P (1 microM), forskolin (10 microM), or phorbol 12-myristate-13-acetate (PMA, 20 nM) on NPY-IR production was tested on rat and human primary astrocyte cultures. Of these agents, PMA and bFGF markedly induced NPY-IR production by rat as well as human astrocytes, forskolin induced NPY-IR production by human but not rat astrocytes, and neither BDNF nor substance P induced NPY-IR production by rat or human astrocytes. The molecular size of PMA-induced NPY-IR was found to be consistent with that of proNPY. Moreover, PMA induced the accumulation of mRNA corresponding in size to the neuronal NPY-mRNA. Immunocytochemical analysis of human post-mortem neocortex revealed co-existence of NPY-IR with astrocyte markers. These results indicate that cultured astrocytes express NPY gene in a regulated manner and they support our proposition that in situ reactive astrocytes may express NPY gene under some physiological/pathological conditions.

Familial dementia due to adult polyglucosan body disease.

BACKGROUND: Adult polyglucosan body disease (APBD) is a rare disorder, presenting with varying combinations and severity of upper and lower motor neuron dysfunction, sensory deficits, dementia, and urinary incontinence. Onset is in the 40s or 50s. The diagnosis is made by finding polyglucosan bodies (PB) in histologic sections of brain or spinal cord, peripheral nerve, or dermal sweat glands. Although 2 pairs of the 22 previously reported cases were siblings, the familial nature of the disease has not been emphasized. METHODS: We report 2 adult siblings, a male and a female, each of whom had the clinical diagnosis of vascular dementia. Both were confirmed at autopsy to have APBD. We characterized the lesions in autopsy tissues using a battery of histological stains, lectin histochemistry, and electron microscopy. RESULTS: Innumerable PB were distributed throughout brain, heart, skeletal muscle, liver, and dermal sweat glands. PB were highlighted by periodic acid Schiff stain and concanavalin A lectin. Ultrastructurally, PB were composed of aggregates of filaments within axons and astrocytic processes, and lying free in the neuropil, but not within neuronal perikarya. CONCLUSIONS: It is important to consider APBD in cases of familial dementia of unknown etiology. Ante-mortem biopsy of axillary skin may be diagnostic.

Primary epithelioid hemangioendothelioma of the clivus.

We describe the clinical, radiologic, and pathologic features of a primary intracranial hemangioendothelioma arising in the clivus in a 38-year-old female, emphasizing the importance of including this rare entity in the differential diagnosis of tumors arising at the base of the skull. To our knowledge, this is the first reported case of a clival hemangioendothelioma. Aside from its unusual location, this case is also notable for its apparent rapid growth and mixed epithelioid-spindle cell morphology. Appropriate neuroimaging studies may offer crucial information, ensuring that this uncommon entity is included in the differential diagnosis of a clival mass.

Disseminated cytomegalovirus infection presenting with acalculous cholecystitis and acute pancreatitis.

Disseminated cytomegalovirus (CMV) infection occurs predominantly in immunocompromised hosts. Symptomatic CMV cholecystitis and pancreatitis are quite rare, and, to our knowledge, there are no reports of these occurring simultaneously. We describe a patient with a history of chronic myelogenous leukemia (treated with chemotherapy) who presented with recurrent unexplained fevers and an acute abdomen. At surgery, cholecystitis and pancreatitis were found, and a cholecystectomy was performed. The patient developed disseminated intravascular coagulation, eventual sepsis, and multiorgan failure. At autopsy, widespread disseminated CMV infection was found, with CMV-associated foci of acute inflammation and necrosis in the pancreas and in the surgically resected gallbladder. A review of our autopsy files revealed only one renal transplant patient with CMV inclusions and chronic pancreatitis. No pancreatitis was seen in 27 patients with acquired immunodeficiency syndrome. Cytomegalovirus should be considered as a possible cause of pancreatitis and cholecystitis in immunocompromised patients.

Identification of Campylobacter pylori by endoscopic brush cytology.

To investigate the value of Papanicolaou-stained endoscopic brush samples in the diagnosis of Campylobacter pylori infection of the upper gastrointestinal tract, 138 brush and biopsy samples from the esophagus, stomach, and duodenum, taken concomitantly, were reviewed retrospectively. In 35 cases, Campylobacter-like organisms (CLOs) were found in both cytology and biopsy samples. In 15 cases, CLOs were seen in biopsy material only, and in 8 cases, CLOs were found in cytology material only. CLOs were found in 49% of the gastric specimens and 33% of the Barrett's esophagus specimens by histologic or cytologic examination or by both methods. CLOs were found by at least one method in 64% of the gastric samples with active gastritis 40% with borderline gastritis, 15% without gastritis, and in 64% with adenocarcinoma. Cytologic examination of endoscopic brush samples is a valuable technique for the diagnosis of gastric Campylobacter infections and can be performed easily in cytopathology laboratories.

TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers.

OBJECTIVES: To determine whether TMEM106B single nucleotide polymorphisms (SNPs) are associated with frontotemporal lobar degeneration (FTLD) in patients with and without mutations in progranulin (GRN) and to determine whether TMEM106B modulates GRN expression. METHODS: We performed a case-control study of 3 SNPs in TMEM106B in 482 patients with clinical and 80 patients with pathologic FTLD-TAR DNA-binding protein 43 without GRN mutations, 78 patients with FTLD with GRN mutations, and 822 controls. Association analysis of TMEM106B with GRN plasma levels was performed in 1,013 controls and TMEM106B and GRN mRNA expression levels were correlated in peripheral blood samples from 33 patients with FTLD and 150 controls. RESULTS: In our complete FTLD patient cohort, nominal significance was identified for 2 TMEM106B SNPs (top SNP rs1990622, p(allelic) = 0.036). However, the most significant association with risk of FTLD was observed in the subgroup of GRN mutation carriers compared to controls (corrected p(allelic) = 0.0009), where there was a highly significant decrease in the frequency of homozygote carriers of the minor alleles of all TMEM106B SNPs (top SNP rs1990622, CC genotype frequency 2.6% vs 19.1%, corrected p(recessive) = 0.009). We further identified a significant association of TMEM106B SNPs with plasma GRN levels in controls (top SNP rs1990622, corrected p = 0.002) and in peripheral blood samples a highly significant correlation was observed between TMEM106B and GRN mRNA expression in patients with FTLD (r = -0.63, p = 7.7 × 10(-5)) and controls (r = -0.49, p = 2.2 × 10(-10)). CONCLUSIONS: In our study, TMEM106B SNPs significantly reduced the disease penetrance in patients with GRN mutations, potentially by modulating GRN levels. These findings hold promise for the development of future protective therapies for FTLD.

Asymmetric TDP-43 distribution in primary progressive aphasia with progranulin mutation.

OBJECTIVE: Primary progressive aphasia (PPA) results from an asymmetric degeneration of the language dominant (usually left) hemisphere and can be associated with the pathology of Alzheimer disease (AD) or frontotemporal lobar degeneration (FTLD). This study aimed to investigate whether the anatomic distribution of TDP-43 inclusions displayed a corresponding leftward asymmetry in a patient with PPA with a mutation in the progranulin gene and FTLD pathology. METHODS: Brain tissue from a 65-year-old patient with PPA and progranulin mutation was analyzed using immunohistochemical methods for TDP-43. Analysis was performed in the superior temporal gyrus, inferior temporal gyrus, inferior parietal lobule, orbitofrontal cortex, entorhinal cortex, and dentate gyrus. Neuronal intranuclear inclusions, neuronal cytoplasmic inclusions, and dystrophic neurites were quantified using modified stereologic analysis. Analysis of variance was used to determine significant effects. RESULTS: All 3 types of inclusions predominated on the left side of analyzed cortical regions. They were also more frequent in language areas than in memory-related areas. CONCLUSION: These results demonstrate a phenotypically concordant distribution of abnormal TDP-43 inclusions in primary progressive aphasia (PPA). This contrasts with PPA cases with Alzheimer pathology where no consistent leftward asymmetry of neurofibrillary degeneration or amyloid deposition has been demonstrated despite the leftward asymmetry of the atrophy, and where neurofibrillary tangles show a greater density in memory than language areas despite the predominantly aphasic phenotype. This case suggests that the TDP-43 inclusions in PPA-frontotemporal lobar degeneration are more tightly linked to neuronal death and dysfunction than neurofibrillary and amyloid deposits in PPA-Alzheimer disease.