32, Number 4, November 2012
Wolfgang Froestl, Andreas Muhs, Andrea Pfeifer
Cognitive Enhancers (Nootropics). Part 1: Drugs interacting with Receptors
Abstract: Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer’s disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 18 categories according to their mechanism(s) of action, in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease-modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs, whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. The review covers the evolution of research in this field over the last 25 years.
Naoki Kasahata, Toshiki Uchihara, Satoshi Orimo, Ayako Nakamura, Yoshihisa Makita (Handling Associate Editor: Kurt Jellinger)
Limbic and Nigral Lewy Bodies and Alzheimer’s Disease Pathology Mimicking Progressive Supranuclear Palsy in a 75-year-old Man with Preserved Cardiac Uptake of MIBG
Abstract: A 75-year-old man developed l-dopa non-responsive parkinsonism, supranuclear ophthalmoplegia, neck dorsiflexion, and dementia. Atrophy of the midbrain tegmentum on MRI and normal myocardial uptake of MIBG led to the clinical diagnosis of progressive supranuclear palsy (PSP). Autopsy revealed depigmentation of the substantia nigra and locus ceruleus. Alzheimer’s disease pathology was advanced with PSP-like neurofibrillary tangles distribution, and Lewy bodies were abundant in limbic lobe, while scarce in lower brainstem nuclei. Tuft-shaped astrocytes were not apparent. Although decreased myocardial uptake of MIBG is a rule in patients harboring Lewy bodies, its normal uptake may be related to their absence in lower brainstem nuclei.
Fumihiko Yasuno, Satoshi Tanimukai, Megumi Sasaki, Chiaki Ikejima, Fumio Yamashita, Chiine Kodama, Katsuyoshi Mizukami, Takashi Asada
Combination of antioxidant supplements improved cognitive function in the elderly
Abstract: Although nutrients or agents with antioxidant properties were reported to show a preventive effect on cognitive decline in animal studies, epidemiologic data on select antioxidants have shown conflicting results. We investigated whether a combination of antioxidants from supplements is effective for the improvement of cognitive function of elderly. Forty-one subjects from a community dwelling aged 65 years and older took supplements containing n-3 polyunsaturated fatty acids (n-3 PUFA), lycopene, and Ginkgo biloba extracts (GE) daily for 3 years. The data of 622 subjects without supplement intake were used as control. We investigated the changes in cognitive function during a 3-year follow-up. We also investigated the influence of apolipoprotein E (APOE) genotype on the effect of antioxidants. We found that a combination of antioxidants improved cognitive function of aged persons after 3 years. Our present study also indicated this improvement in cognitive function with supplement intake in both APOE4 non-carrier (E4-) and APOE4 carrier (E4+) groups. Especially, in E4+, we found a large effect size of the improvement of cognition. When multiple antioxidants are used in combination, they protect against vulnerability to other agents and synergistically potentiate their antioxidant properties. These synergistically potentiated antioxidant effects of agents contribute to the improvement of cognitive function.
D. Richard Lachno, Julie K. Emerson, Hugo Vanderstichele, Celedon Gonzales, Ferenc Martényi, Robert J. Konrad, Jayne A. Talbot, Stephen L. Lowe, Paul E. Oefinger, Robert A. Dean
Validation of a Multiplex Assay for Simultaneous Quantification of Amyloid-β Peptide Species in Human Plasma with Utility for Measurements in Studies of Alzheimer’s Disease Therapeutics
Abstract: The aim of this study was to validate the INNO-BIA plasma amyloid-β (Aβ) forms assay for quantification of Aβ1-40 and Aβ1-42 according to regulatory guidance for bioanalysis and demonstrate its fitness for clinical trial applications. Validation parameters were evaluated by repeated testing of human EDTA-plasma pools. In 6 separate estimates, intra-assay coefficients of variation (CV) for repeated testing of 5 plasma pools were ≤ 9% and relative error (RE) varied between -35% and +22%. Inter-assay CV (n=36) ranged from 5% to 17% and RE varied from -17% to +8%. Dilutional linearity was not demonstrated for either analyte using diluent buffer, but dilution with immuno-depleted plasma by 1.67-fold gave results within 20% of target. Analyte stability was demonstrated in plasma at 2-8°C for up to 6 h. Stability during frozen storage up to 12 months and through 3 freeze-thaw cycles at ≤-70°C was also demonstrated in 5 of 6 individuals but deteriorated thereafter. Neither semagacestat nor LY2811376 interfered with the assay but solanezumab at 500 mg/L reduced recovery of Aβ1-42 by 53%. Specimens from a Phase I human volunteer study of the β-secretase inhibitor LY2811376 were tested at baseline and at intervals up to 12 h after single oral doses, demonstrating a clear treatment effect. During 1,041 clinical assay runs from semagacestat studies over 10 months, the CV for plasma quality control pools at three levels were ≤15% and RE were <10%. In conclusion, the INNO-BIA plasma assay was successfully validated and qualified for use in clinical research.
Supplementary Data for Lachno et al. article (PDF)
Cristina Lanni*, Giulia Garbin*, Antonella Lisa, Fabrizio Biundo, Alberto Ranzenigo, Elena Sinforiani, Giovanni Cuzzoni, Stefano Govoni, Guglielmina Nadia Ranzani, Marco Racchi (Handling Associate Editor: Benedetta Nacmias) *These authors contributed equally.
Influence of COMT Val158Met Polymorphism on Alzheimer's Disease and Mild Cognitive Impairment in Italian Patients
Abstract: COMT (Catechol-O methyltransferase) gene is one of the key players in synaptic plasticity and in learning and memory mechanisms. A single nucleotide polymorphism (rs4680; G to A) in the COMT coding region causes Val158Met aminoacid substitution in the corresponding protein, with Val allele exhibiting a 3- to 4-fold increase in enzyme activity compared to Met. With the purpose of examining the influence of COMT as a genetic risk factor for cognitive impairment, we analyzed a sample of 248 healthy subjects, 276 patients affected by Alzheimer's disease (AD), and 70 subjects with mild cognitive impairment (MCI), the latter condition possibly representing a prodrome for dementia. All subjects were analyzed for COMT rs4680 polymorphism and APOE genotype. Our study strengthens data showing that APOE ε4 allele is an independent risk factor for AD and also a risk factor for MCI. Neither COMT alleles nor genotypes proved to be independently associated with the risk of AD or MCI in our sample. However, we found an association between COMT GG genotype (Val/Val) and APOE ε4 carrier status and the risk of AD and MCI. In particular, when GG genotype is included into the multinomial analysis, the risk of AD and MCI due to APOE ε4 allele is increased of about 2-3 fold; moreover, the risk conferred by the combination of G and ε4 alleles is more pronounced in male patients. To our knowledge, this synergistic effect is here shown for first time on a population sample representative of Caucasian patients.
Min-Jeong Kim, Kyoung-Min Lee, Young-Don Son, Hyeon-Ae Jeon, Young-Bo Kim, Zang-Hee Cho (Handling Associate Editor: Henryk Barthel)
Increased Basal Forebrain Metabolism in Mild Cognitive Impairment: An Evidence for Brain Reserve in Incipient Dementia
Abstract: Cholinergic dysfunction is well known to significantly contribute to the cognitive decline in Alzheimer’s disease (AD). However, it has not been clarified whether the cholinergic dysfunction is a primary event or a retrograde event secondary to neuronal loss of the cholinergic targets. Analysis of the in vivo neuronal activity of the basal forebrain in the early stages of AD could yield more information about this issue. In the present study, uptake of [18F]-fluorodeoxyglucose (FDG) in the basal forebrain was measured in 13 patients with mild cognitive impairment (MCI), 20 with early AD, and 14 healthy subjects using high-resolution research tomograph-PET. The FDG uptake was compared among the groups and correlated with the Mini Mental Status Examination (MMSE) score. The MCI patients showed significantly higher FDG uptake in the basal forebrain than the healthy subjects and the AD patients, and those did not developed dementia after 2 years showed even higher uptake than those developed dementia. The basal forebrain metabolism showed an inverted-U relationship with MMSE score in highly educated subjects, and cross-voxel analysis over the whole brain in MCI patients revealed a significant correlation in uptake between the basal forebrain and the fronto-temporal cortices. These findings indicate that in MCI patients, neuronal activity in the basal forebrain is initially increased over that in normal aging and then decreased only with further cognitive decline. The increase is consistent with a secondary compensation against neurodegeneration at target areas, and may provide brain reserve against functional impairments at incipient stages of dementia.
Supplementary Data for Kim et al. article (PDF)
Kina Höglund, Anna Bogstedt, Susanne Fabre, Ali Aziz, Peter Annas, Hans Basun, Lennart Minthon, Lars Lannfelt, Kaj Blennow, Niels Andreasen (Handling Associate Editor: Panos Alexopoulos)
Longitudinal Stability Evaluation of Biomarkers and Their Correlation in Cerebrospinal Fluid and Plasma from Patients with Alzheimer’s Disease
Abstract: There is an increasing demand for biomarkers in clinical treatment trials to demonstrate target engagement and to support disease modification claims. To be able to detect treatment related effects, a prerequisite is that the levels of the biomarker are stable over time or that the change over time is known. In the present study, the stability of α- and β-cleaved soluble amyloid-β protein precursor (sAβPPα and sAβPPβ), Aβ1-40 together with the phosphorylated form of neurofilament heavy/medium (pNfH/M) in cerebrospinal fluid (CSF) was analyzed in a cohort of 51 patients with Alzheimer’s disease. In addition, the stability of Aβ1-40, Aβ1-42, and sAβPPβ in plasma was explored. Plasma and CSF was sampled at baseline and after 6-months follow up, and all patients were on stable treatment with acetylcholinesterase inhibitors. During this 6-month longitudinal follow-up, we saw a small, but consistent and statistically significant increase in CSF levels of sAβPPβ (103% of baseline levels) and a statistically significant decrease in the CSF levels of pNfH/M (91% of baseline levels). The mean level of the CSF biomarkers were very stable between baseline and endpoint, with within-patients coefficients of variation (CVs) of 5.84 -17.3%, while the variability was larger for the plasma biomarkers, with CVs of 14.1 -42.3%. This stability suggests that these biomarkers may have the potential to detect and monitor biochemical changes induced by disease-modifying drugs.
Prashant R. Bharadwaj*, Giuseppe Verdile*, Renae K. Barr, Veer Gupta, John W. Steele, M. Lenard Lachenmayer, Zhenyu Yue, Michelle E. Ehrlich, Gregory Petsko, Shulin Ju, Dagmar Ringe, Sonia E. Sankovich, Joanne M. Caine, Ian G. Macreadie, Sam Gandy, Ralph N. Martins *These authors contributed equally.
Latrepirdine (DimebonTM) Enhances Autophagy and Reduces Intracellular GFP-Aβ42 Levels in Yeast
Abstract: Latrepirdine (DimebonTM), an anti-histamine, has shown some benefits in trials of neurodegenerative diseases characterized by accumulation of aggregated or misfolded protein such as Alzheimer’s disease (AD) and has been shown to promote the removal of α-synuclein protein aggregates in vivo. An important pathway for removal of aggregated or misfolded proteins is the autophagy-lysosomal pathway, which has been implicated in AD pathogenesis, and enhancing this pathway has been shown to have therapeutic potential in AD and other proteinopathies. Here we use a yeast model, Saccharomyces cerevisiae, to investigate whether latrepirdine can enhance autophagy and reduce levels of amyloid-β (Aβ)42 aggregates. Latrepirdine was shown to upregulate yeast vacuolar (lysosomal) activity and promote transport of the autophagic marker (Atg8) to the vacuole. Using an in vitro green fluorescent protein (GFP) tagged Aβ yeast expression system, we investigated whether latrepirdine-enhanced autophagy was associated with a reduction in levels of intracellular GFP-Aβ42. GFP-Aβ42 was localized into punctate patterns compared to the diffuse cytosolic pattern of GFP and the GFP-Aβ42 (19:34), which does not aggregate. In the autophagy deficient mutant (Atg8Δ), GFP-Aβ42 showed a more diffuse cytosolic localization, reflecting the inability of this mutant to sequester GFP-Aβ42. Similar to rapamycin, we observed that latrepirdine significantly reduced GFP-Aβ42 in wild-type compared to the Atg8Δ mutant. Further, latrepirdine treatment attenuated Aβ42-induced toxicity in wild-type cells but not in the Atg8Δ mutant. Together, our findings provide evidence for a novel mechanism of action for latrepirdine in inducing autophagy and reducing intracellular levels of GFP-Aβ42.
Supplementary Data for Bharadwaj et al. article (PDF)
Jussi Mattila, Hilkka Soininen, Juha Koikkalainen, Daniel Rueckert, Robin Wolz, Gunhild Waldemar, Jyrki Lötjönen; for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: J. Wesson Ashford)
Optimizing the Diagnosis of Early Alzheimer's Disease in Mild Cognitive Impairment Subjects
Abstract: In the diagnostic process of Alzheimer’s disease (AD), there may be considerable delays between first contact to outpatient services and a final, definitive diagnosis. In Europe the average delay is 20 months. Nevertheless, patient data preceding clinical AD diagnoses often contains early signs of the disease. Several studies have analyzed data of mild cognitive impairment (MCI) subjects, showing that conversion from MCI to AD can be predicted with a classification accuracy of 60-80%. This accuracy may not be high enough for influencing diagnostic decisions. In this work, the prediction problem is approached differently; a target prediction accuracy is defined first and is then used for identifying MCI patients for whom the required accuracy can be reached. The process uses a novel disease state index method in which patient data are statistically compared to a high number of previously diagnosed cases. It is shown that the disease index values derived from heterogeneous patient data can be used for identifying groups of patients for whom the prediction accuracy reaches the previously set target level. The results also show that 12 months before receiving clinical AD diagnoses, approximately half (51.5%, 95% confidence interval: 48.6%-54.2%) of MCI subjects who progressed to AD can be classified with a high accuracy of 87.7%, possibly enough to support earlier diagnostic decisions.
Han-Chang Huang, Ke Xu, Zhao-Feng Jiang
Curcumin-Mediated Neuroprotection against Amyloid-β-Induced Mitochondrial Dysfunction Involves the Inhibition of GSK-3β
Abstract: The deposition of amyloid-β (Aβ) peptides in senile plaques is one of pathological hallmarks of Alzheimer’s disease (AD). Mitochondrial dysfunction is an early event of cell apoptosis. Increasing evidence indicates that Aβ induces neuronal apoptosis through mitochondrial dysfunction. Curcumin, an anti-oxidative component of turmeric (Curcuma longa), has shown anti-tumor, anti-inflammatory, and anti-oxidative properties. In this study, we investigated the protective effects of curcumin against mitochondrial dysfunction induced by Aβ. Based on the assay results of mitochondrial metabolic markers, we found that curcumin protects human neuroblastoma SH-SY5Y cells against the Aβ-induced damage of mitochondrial energy metabolism. Curcumin inhibits Aβ-induced mitochondrial depolarization of membrane potential (Δψm) and suppresses mitochondrial apoptosis-related proteins including cytochrome c, caspase-3, and Bax, which are activated by Aβ. Aβ-induced disturbances of redox state are linked to mitochondrial dysfunction. Curcumin normalizes cellular antioxidant enzymes (including SOD and catalase) in both protein expression and activity and decreases oxidative stress level in Aβ-treated cells. Both total GSK-3β expression and phospho-Ser9 GSK-3β (pSer9-GSK-3β) are down-regulated in the cells pre-treated with curcumin. This study demonstrates curcumin-mediated neuroprotection against Aβ-induced mitochondrial metabolic deficiency and abnormal alteration of oxidative stress. Inhibition of GSK-3β is involved in the protection of curcumin against Aβ-induced mitochondrial dysfunction.
Javier Escudero, Emmanuel Ifeachor, John P. Zajicek, for the Alzheimer’s Disease Neuroimaging Initiative
Bioprofile Analysis: A New Approach for the Analysis of Biomedical Data in Alzheimer’s Disease
Abstract: This article presents a new approach for the analysis of biomedical data to support the management and care of patients with Alzheimer’s disease (AD). The increase in prevalence of neurodegenerative disorders such as AD has led to a need for objective means to assist clinicians with the analysis and interpretation of complex biomedical data. To this end, we propose a “Bioprofile” analysis to reveal the pattern of disease in the subject’s biodata. From the Bioprofile, personal “Bioindices” that indicate how closely a subject’s data resemble the pattern of AD can be derived. We used an unsupervised technique (k-means) to cluster variables of the ADNI database so that subjects are divisible into those with the Bioprofile of AD and those without it. Results revealed that there is an “AD pattern” in the biodata of most AD and mild cognitive impairment (MCI) patients and some controls. This pattern agrees with a recent hypothetical model of AD evolution. We also assessed how the Bioindices changed with time and we found that the Bioprofile was associated with the risk of progressing from MCI to AD. Hence, the Bioprofile analysis is a promising methodology that may potentially provide a complementary new way of interpreting biomedical data. Furthermore, the concept of the Bioprofile could be extended to other neurodegenerative diseases.
Supplementary Data for Escudero et al. article (PDF)
Sabrina K. Segal, Carl W. Cotman, Lawrence F. Cahill
Exercise-Induced Noradrenergic Activation Enhances Memory Consolidation in Both Normal Aging and Patients with Amnestic Mild Cognitive Impairment
Abstract: Post-trial pharmacological activation of the noradrenergic system can facilitate memory consolidation. Because exercise activates the locus coeruleus and increases brain norepinephrine release, we hypothesized that post-trial exercise could function as a natural stimulus to enhance memory consolidation. We investigated this in amnestic mild cognitive impairment (aMCI) and cognitively normal elderly individuals by examining the effects of an acute bout of post-learning, aerobic exercise (6 minutes at 70% VO2 max on a stationary bicycle) on memory for some emotional images. Exercise significantly elevated endogenous norepinephrine (measured via the biomarker, salivary alpha-amylase) in both aMCI patients and controls. Additionally, exercise retrogradely enhanced memory in both aMCI patients and controls. Acute exercise that activates the noradrenergic system may serve as a beneficial, natural, and practical therapeutic intervention for cognitive decline in the aging population.
Qianhua Zhao, Yunyun Xiong, Ding Ding, Qihao Guo, Zhen Hong (Handling Associate Editor: Jiong Shi)
Synergistic Effect between Apolipoprotein E ε4 and Diabetes Mellitus for Dementia: Result from a Population-Based Study in Urban China
Abstract: Diabetes is thought to contribute to cognitive impairment in the elderly. The risk may be modified by genetic factors such as apolipoprotein E (APOE). We aim to determine the prevalence of dementia in Chinese diabetics and non-diabetic individuals, and assess the effect of the APOE genotype. A cross-sectional study was conducted among participants aged 50 and over in an urban community. Subjects were 1:1 matched for age and gender (diabetes group (n=497) versus non-diabetes group (n=497)). Each subject was interviewed for dementia and related risk factors. Fasting blood samples were drawn for glucose and APOE. Subjects were screened using the Mini Mental State Examination (MMSE) and were examined by a series of neuropsychological tests if screened positive (indicated by an MMSE score below 19, 21, and 24, respectively according to different educational attainment). A diagnosis of dementia was defined according to DSM-IV criteria. The prevalence of all-cause dementia, Alzheimer’s disease, and vascular dementia in diabetics (4.8%, 2.7%, 1.4%) was higher than that of non-diabetics (2.2%, 1.2%, 0.4%) (all-cause dementia, diabetics versus non-diabetics, p<0.05). APOE ε4 carriers had higher prevalence of dementia and AD (diabetics: 9.2%, 7.55%, non-diabetics: 3.3%, 3.3%) than APOE ε4 non-carriers (diabetics: 6.3%, 2.3%, non-diabetics: 2.35%, 0.7%) (p<0.05). Diabetics carrying the APOE ε4 allele had a 3.982-fold [95%CI, 1.418-11.184] likelihood of having dementia compared with those without these two factors. This study showed that the prevalence of dementia was significantly higher in diabetics than non-diabetics. APOE ε4 further enhanced the risk.
Elizabeth Head, Heather L. Murphey, Amy L.S. Dowling, Katie L. McCarty, Samuel R. Bethel, Jonathan A. Nitz, Melanie Pleiss, Jenna Vanrooyen, Mike Grossheim, Jeffery R. Smiley, M. Paul Murphy, Tina L. Beckett, Dieter Pagani, Frederick Bresch, Curt Hendrix (Handling Associate Editor: Gene Bowman)
A Combination Cocktail Improves Spatial Attention in a Canine Model of Human Aging and Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) involves multiple pathological processes in the brain, including increased inflammation and oxidative damage, as well as the accumulation of amyloid-β (Aβ) plaques. We hypothesized that a combinatorial therapeutic approach to target these multiple pathways may provide cognitive and neuropathological benefits for AD patients. To test this hypothesis, we used a canine model of human aging and AD. Aged dogs naturally develop learning and memory impairments, human-type Aβ deposits, and oxidative damage in the brain. Thus, 9 aged beagles (98-115 months) were treated with a medical food cocktail containing (1) an extract of turmeric containing 95% curcuminoids; (2) an extract of green tea containing 50% epigallocatechingallate; (3) N-acetyl cysteine; (4) R-alpha lipoic acid; and (5) an extract of black pepper containing 95% piperine. Nine similarly aged dogs served as placebo-treated controls. After 3 months of treatment, 13 dogs completed a variable distance landmark task used as a measure of spatial attention. As compared to placebo-treated animals, dogs receiving the medical food cocktail had significantly lower error scores (t(11)=4.3, p=0.001) and were more accurate across all distances (F(1,9)=20.7, p=0.001), suggesting an overall improvement in spatial attention. Measures of visual discrimination learning, executive function and spatial memory, and levels of brain and cerebrospinal fluid Aβ were unaffected by the cocktail. Our results indicate that this medical food cocktail may be beneficial for improving spatial attention and motivation deficits associated with impaired cognition in aging and AD.
Seong Hye Choi, Mikel Olabarrieta, Oscar L. Lopez, Victoria Maruca, Steven T. DeKosky, Ronald L. Hamilton, James T. Becker; Alzheimer’s Disease Research Center (Handling Associate Editor: Mark Bondi)
Gray Matter Atrophy associated with Extrapyramidal Signs in the Lewy Body Variant of Alzheimer’s Disease
Abstract: Up to 60% of the patients with Alzheimer’s disease (AD) can have cortical or brainstem Lewy bodies (LB), and extrapyramidal signs (EPS) have been found to be associated with LB in AD patients. However, the relationship between EPS and brain volumes has not been studied in the LB variant of AD using structural magnetic resonance imaging (MRI). The purpose of this study was to determine the relationship between patterns of brain atrophy and clinical EPS in patients with pathologically confirmed AD. We compared gray matter structure using voxel-based morphometry in 29 Definite AD cases, 16 (55%) of whom also had LBs identified with α-synuclein immunohistochemistry. Multivariate models analyzed brain volume at a voxel level accounting for subject group, Mini-Mental State Examination (MMSE), EPS, total brain volume, and the time from MRI scan to death. There was no significant difference in gray matter volume in the Definite AD patients as a function of LB. There was a significant association between gray matter volumes and the MMSE in AD patients, both with and without LBs. There was a significant correlation between gray matter volume and EPS only in the group of AD patients with LBs, and not in those with pure AD. These findings suggest that that the etiology of EPS in patients with the LB variant of AD is associated with neuronal loss in the nigrostriatal tracts. By contrast, the source of the EPS in AD alone appears to be less well localized.
Cristian E. Leyton, Olivier Piguet, Sharon Savage, James Burrell, John R. Hodges (Handling Associate Editor: Peter Nestor)
The Neural Basis of Logopenic Progressive Aphasia
Abstract: Logopenic progressive aphasia (LPA) is defined clinically by impairments of naming and sentence repetition. The relation between these impairments and their neural basis has, however, not yet been determined. We aimed to localize cortical thinning associated with naming and repetition deficits using cortical thickness measurements. Consecutive LPA cases (n=15) were matched with healthy controls (n=16). All LPA cases underwent general cognitive testing and language assessment using the Progressive Aphasia Language Scale. Word retrieval and verbal short-term memory, the core cognitive processes involved in LPA, were assessed using visual confrontation naming and forward digit-span tasks. Cortical thickness was estimated vertex-by-vertex using Freesurfer. The pattern of cortical thinning for the LPA group as well as the location of cortical thinning linked to the impairment of each core cognitive process was estimated using general linear models. LPA cases showed extensive left-sided cortical thinning in which the temporo-parietal junction had the greatest involvement. Impaired naming was associated with cortical thinning of the supramarginal gyrus (BA 40), while reduced digit-span score, regarded as a surrogate marker for sentence repetition, was correlated with thinning of the left superior temporal gyrus (BA 22 and 42). These results suggest that the core manifestations of LPA emerge from the damage to segregated and non-overlapping cortical regions typically affected in this focal presentation of Alzheimer’s disease.