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1.  Assessment of cognition in mild cognitive impairment: A comparative study 
The demand for rapidly administered, sensitive, and reliable cognitive assessments that are specifically designed for identifying individuals in the earliest stages of cognitive decline (and to measure subtle change over time) has escalated as the emphasis in Alzheimer’s disease clinical research has shifted from clinical diagnosis and treatment toward the goal of developing presymptomatic neuroprotective therapies. To meet these changing clinical requirements, cognitive measures or tailored batteries of tests must be validated and determined to be fit-for-use for the discrimination between cognitively healthy individuals and persons who are experiencing very subtle cognitive changes that likely signal the emergence of early mild cognitive impairment. We sought to collect and review data systematically from a wide variety of (mostly computer-administered) cognitive measures, all of which are currently marketed or distributed with the claims that these instruments are sensitive and reliable for the early identification of disease or, if untested for this purpose, are promising tools based on other variables. The survey responses for 16 measures/batteries are presented in brief in this review; full survey responses and summary tables are archived and publicly available on the Campaign to Prevent Alzheimer’s Disease by 2020 Web site ( A decision tree diagram highlighting critical decision points for selecting measures to meet varying clinical trials requirements has also been provided. Ultimately, the survey questionnaire, framework, and decision guidelines provided in this review should remain as useful aids for the evaluation of any new or updated sets of instruments in the years to come.
PMCID: PMC4042858  PMID: 21575877
Cognition; Neuropsychological assessment; Alzheimer’s disease; Mild cognitive impairment; Clinical trials
2.  Frontotemporal Lobar Degeneration with TDP-43 Proteinopathy and Chromosome 9p Repeat Expansion in C9ORF72: Clinicopathologic Correlation 
Mutations in C9ORF72 resulting in expanded hexanucleotide repeats were recently reported to be the underlying genetic abnormality in chromosome 9p-linked frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kD (TDP-43) proteinopathy (FTLD-TDP), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration with motor neuron disease (FTLD-MND). Several subsequent publications described the neuropathology as being similar to that seen in cases of FTLD-TDP and ALS without C9ORF72 mutations, except that cases with mutations have p62 and ubiquitin positive, TDP-43 negative inclusions in cerebellum, hippocampus, neocortex, and basal ganglia. The identity of this protein is as yet unknown, and its significance is unclear. With the goal of potentially uncovering the significance of these TDP-43 negative inclusions, we compared the clinical, pathologic, and genetic characteristics in 5 cases of FTLD-TDP and FTLD-MND with C9ORF72 mutations to 20 cases without mutations. We confirmed the apparent specificity of p62 positive, TDP-43 negative inclusions in cerebellum, hippocampus, cortex, and basal ganglia to FTLD with C9ORF72 mutations. p62 positive, TDP-43 negative inclusions in hippocampus correlated with hippocampal atrophy, but no additional correlations were uncovered. However, although ambiguity of TDP sub-typing has previously been reported in cases with C9ORF72 mutations, this is the first report to show that although most FTLD cases with C9ORF72 mutations were TDP type B, some of the pathologic characteristics in these cases were more similar to TDP types A and C than to TDP type B FTLD cases without mutations. These features include greater cortical and hippocampal atrophy, greater ventricular dilatation, more neuronal loss and gliosis in temporal lobe and striatum, and TDP-43 positive fine neuritic profiles in the hippocampus in FTLD cases with C9ORF72 mutations compared to FTLD-TDP type B cases without mutations, implying that the C9ORF72 mutation modifies the pathologic phenotype of FTLD-TDP type B.
PMCID: PMC3449045  PMID: 22702520
C9ORF72; repeat expansion; p62; ubiquitin; TDP-43; FTLD; ALS
3.  Cognition assessment using the NIH Toolbox 
Neurology  2013;80(11 Suppl 3):S54-S64.
Cognition is 1 of 4 domains measured by the NIH Toolbox for the Assessment of Neurological and Behavioral Function (NIH-TB), and complements modules testing motor function, sensation, and emotion. On the basis of expert panels, the cognition subdomains identified as most important for health, success in school and work, and independence in daily functioning were Executive Function, Episodic Memory, Language, Processing Speed, Working Memory, and Attention. Seven measures were designed to tap constructs within these subdomains. The instruments were validated in English, in a sample of 476 participants ranging in age from 3 to 85 years, with representation from both sexes, 3 racial/ethnic categories, and 3 levels of education. This report describes the development of the Cognition Battery and presents results on test-retest reliability, age effects on performance, and convergent and discriminant construct validity. The NIH-TB Cognition Battery is intended to serve as a brief, convenient set of measures to supplement other outcome measures in epidemiologic and longitudinal research and clinical trials. With a computerized format and national standardization, this battery will provide a “common currency” among researchers for comparisons across a wide range of studies and populations.
PMCID: PMC3662346  PMID: 23479546
4.  Words and objects at the tip of the left temporal lobe in primary progressive aphasia 
Brain  2013;136(2):601-618.
Eleven of 69 prospectively enrolled primary progressive aphasics were selected for this study because of peak atrophy sites located predominantly or exclusively within the anterior left temporal lobe. Cortical volumes in these areas were reduced to less than half of control values, whereas average volume elsewhere in the left hemisphere deviated from control values by only 8%. Failure to name objects emerged as the most consistent and severe deficit. Naming errors were attributed to pure retrieval failure if the object could not be named even when the denoting word was understood, the object recognized and the two accurately matched. Surprisingly many of the naming errors reflected pure retrieval failures, without discernible semantic or associative component. The remaining set of errors had associative components. These errors reflected the inability to define the word denoting the object more often than the inability to define the nature of the pictured object. In a separate task where the same object had to be linked to verbal or non-verbal associations, performance was abnormal only in the verbal format. Excessive taxonomic interference was observed for picture–word, but not picture–picture, matching tasks. This excessive interference reflected a blurring of intra- rather than inter-category distinctions as if the acuity of word–object associations had been diminished so that correspondences were easier to recognize at generic than specific levels. These dissociations between verbal and non-verbal markers of object knowledge indicate that the reduced neural mass at peak atrophy sites of the left temporal tip, accounting for half or more of the presumed premorbid volume, was unlikely to have contained domain-independent semantic representations of the type that would be expected in a strictly amodal hub. A more likely arrangement entails two highly interactive routes—a strongly left lateralized temporosylvian language network for verbal concepts, and a presumably more bilateral or right-sided inferotemporal/fusiform object recognition network, which remained relatively spared because peak atrophy sites were concentrated on the left. The current results also suggest that the left anterior temporal neocortex should be inserted into the language network where it is likely to play a major role in selecting verbal labels for objects and mediating the progression of word comprehension from generic to specific levels of precision.
PMCID: PMC3572925  PMID: 23361063
dementia; semantic; language; naming; frontotemporal
5.  Verbal and nonverbal memory in primary progressive aphasia: The Three Words-Three Shapes Test 
Behavioural neurology  2013;26(1):67-76.
To investigate cognitive components and mechanisms of learning and memory in primary progressive aphasia (PPA) using a simple clinical measure, the Three Words Three Shapes Test (3W3S).
PPA patients can complain of memory loss and may perform poorly in standard tests of memory. The extent to which these signs and symptoms reflect dysfunction of the left hemisphere language versus limbic memory network remains unknown.
3W3S data from 26 patients with a clinical diagnosis of PPA were compared with previously published data from patients with typical dementia of the Alzheimer type (DAT) and cognitively healthy elders.
PPA patients showed two bottlenecks in new learning. First, they were impaired in the effortless (but not effortful) on-line encoding of verbal (but not non-verbal) items. Second, they were impaired in the retrieval (but not retention) of verbal (but not non-verbal) items. In contrast, DAT patients had impairments also in effortful on-line encoding and retention of verbal and nonverbal items.
PPA selectively interferes with spontaneous on-line encoding and subsequent retrieval of verbal information. This combination may underlie poor memory test performance and is likely to reflect the dysfunction of the left hemisphere language rather than medial temporal memory network.
PMCID: PMC3534773  PMID: 22713398
6.  Youthful Memory Capacity in Old Brains: Anatomic and Genetic Clues from the Northwestern SuperAging Project 
The Northwestern University SuperAging Project recruits community dwellers over the age of 80 who have unusually high performance on tests of episodic memory. In a previous report, a small cohort of SuperAgers was found to have higher cortical thickness on structural MRI than a group of age-matched but cognitively average peers. SuperAgers also displayed a patch of ACC where cortical thickness was higher than in 50- to 60-year-old younger cognitively healthy adults. In additional analyses, some SuperAgers had unusually low densities of age-related Alzheimer pathology and unusually high numbers of von Economo neurons in the anterior cingulate gyrus. SuperAgers were also found to have a lower frequency of the ε4 allele of apolipoprotein E than the general population. These preliminary results show that above-average memory capacity can be encountered in advanced age. They also offer clues to potential biological factors that may promote resistance to age-related involutional changes in the structure and function of the brain.
PMCID: PMC3541673  PMID: 23198888
7.  Syntactic and morphosyntactic processing in stroke–induced and primary progressive aphasia 
Behavioural neurology  2013;26(1-2):35-54.
The paper reports findings derived from three experiments examining syntactic and morphosyntactic processing in individuals with agrammatic and logopenic variants of primary progressive aphasia (PPA-G and PPA-L, respectively) and stroke-induced agrammatic and anomic aphasia (StrAg and StrAn, respectively). We examined comprehension and production of canonical and noncanonical sentence structures and production of tensed and nontensed verb forms using constrained tasks in experiments 1 and 2 using the Northwestern Assessment of Verbs and Sentences (NAVS [57]) and the Northwestern Assessment of Verb Inflection (NAVI, Thompson and Lee, experimental version), respectively. Experiment 3 examined free narrative samples, focusing on syntactic and morphosyntactic measures, i.e. production of grammatical sentences, noun to verb ratio, open-class to closed-class word production ratio, and the production of correctly inflected verbs. Results indicate that the two agrammatic groups (i.e., PPA-G and StrAg) pattern alike on syntactic and morphosyntactic measures, showing more impaired noncanonical compared to canonical sentence comprehension and production and greater difficulties producing tensed compared to nontensed verb forms. Their spontaneous speech also contained significantly fewer grammatical sentences and correctly inflected verbs, and they produced a greater proportion of nouns compared to verbs, than healthy speakers. In contrast, PPA-L and StrAn individuals did not display these deficits, and performed significantly better than the agrammatic groups on these measures. The findings suggest that agrammatism, whether induced by degenerative disease or stroke, is associated with characteristic deficits in syntactic and morphosyntactic processing. We therefore recommend that linguistically sophisticated tests and narrative analysis procedures be used to systematically evaluate the linguistic ability of individuals with PPA, contributing to our understanding of the language impairments of different PPA variants.
PMCID: PMC3591467  PMID: 22713394
8.  Superior Memory and Higher Cortical Volumes in Unusually Successful Cognitive Aging 
It is “normal” for old age to be associated with gradual decline in memory and brain mass. However, there are anecdotal reports of individuals who seem immune to age-related memory impairment, but these individuals have not been studied systematically. This study sought to establish that such cognitive SuperAgers exist and to determine if they were also resistant to age-related loss of cortical brain volume. SuperAgers were defined as individuals over age 80 with episodic memory performance at least as good as normative values for 50- to 65-year-olds. Cortical morphometry of the SuperAgers was compared to two cognitively normal cohorts: age-matched elderly and 50- to 65-year-olds. The SuperAgers’ cerebral cortex was significantly thicker than their healthy age-matched peers and displayed no atrophy compared to the 50- to 65-year-old healthy group. Unexpectedly, a region of left anterior cingulate cortex was significantly thicker in the SuperAgers than in both elderly and middle-aged controls. Our findings identify cognitive and neuroanatomical features of a cohort that appears to resist average age-related changes of memory capacity and cortical volume. A better understanding of the underlying factors promoting this potential trajectory of unusually successful aging may provide insight for preventing age-related cognitive impairments or the more severe changes associated with Alzheimer’s disease. (JINS, 2012, 18, 1081–1085)
PMCID: PMC3547607  PMID: 23158231
Structural magnetic resonance imaging (MRI); Neuropsychology; Dementia; Freesurfer; Elderly; Neuroimaging
9.  Literacy, Cognitive Function, and Health: Results of the LitCog Study 
Journal of General Internal Medicine  2012;27(10):1300-1307.
Emerging evidence suggests the relationship between health literacy and health outcomes could be explained by cognitive abilities.
To investigate to what degree cognitive skills explain associations between health literacy, performance on common health tasks, and functional health status.
Two face-to-face, structured interviews spaced a week apart with three health literacy assessments and a comprehensive cognitive battery measuring ‘fluid’ abilities necessary to learn and apply new information, and ‘crystallized’ abilities such as background knowledge.
An academic general internal medicine practice and three federally qualified health centers in Chicago, Illinois.
Eight hundred and eighty-two English-speaking adults ages 55 to 74.
Health literacy was measured using the Rapid Estimate of Adult Literacy in Medicine (REALM), Test of Functional Health Literacy in Adults (TOFHLA), and Newest Vital Sign (NVS). Performance on common health tasks were globally assessed and categorized as 1) comprehending print information, 2) recalling spoken information, 3) recalling multimedia information, 4) dosing and organizing medication, and 5) healthcare problem-solving.
Health literacy measures were strongly correlated with fluid and crystallized cognitive abilities (range: r = 0.57 to 0.77, all p < 0.001). Lower health literacy and weaker fluid and crystallized abilities were associated with poorer performance on healthcare tasks. In multivariable analyses, the association between health literacy and task performance was substantially reduced once fluid and crystallized cognitive abilities were entered into models (without cognitive abilities: β = −28.9, 95 % Confidence Interval (CI) -31.4 to −26.4, p; with cognitive abilities: β = −8.5, 95 % CI −10.9 to −6.0).
Cross-sectional analyses, English-speaking, older adults only.
The most common measures used in health literacy studies are detecting individual differences in cognitive abilities, which may predict one’s capacity to engage in self-care and achieve desirable health outcomes. Future interventions should respond to all of the cognitive demands patients face in managing health, beyond reading and numeracy.
PMCID: PMC3445686  PMID: 22566171
health literacy; cognitive abilities; health tasks; patient-reported outcomes; physical health; mental health
10.  Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis 
Whitcomb, David C. | LaRusch, Jessica | Krasinskas, Alyssa M. | Klei, Lambertus | Smith, Jill P. | Brand, Randall E. | Neoptolemos, John P. | Lerch, Markus M. | Tector, Matt | Sandhu, Bimaljit S. | Guda, Nalini M. | Orlichenko, Lidiya | Alkaade, Samer | Amann, Stephen T. | Anderson, Michelle A. | Baillie, John | Banks, Peter A. | Conwell, Darwin | Coté, Gregory A. | Cotton, Peter B. | DiSario, James | Farrer, Lindsay A. | Forsmark, Chris E. | Johnstone, Marianne | Gardner, Timothy B. | Gelrud, Andres | Greenhalf, William | Haines, Jonathan L. | Hartman, Douglas J. | Hawes, Robert A. | Lawrence, Christopher | Lewis, Michele | Mayerle, Julia | Mayeux, Richard | Melhem, Nadine M. | Money, Mary E. | Muniraj, Thiruvengadam | Papachristou, Georgios I. | Pericak-Vance, Margaret A. | Romagnuolo, Joseph | Schellenberg, Gerard D. | Sherman, Stuart | Simon, Peter | Singh, Vijay K. | Slivka, Adam | Stolz, Donna | Sutton, Robert | Weiss, Frank Ulrich | Wilcox, C. Mel | Zarnescu, Narcis Octavian | Wisniewski, Stephen R. | O'Connell, Michael R. | Kienholz, Michelle L. | Roeder, Kathryn | Barmada, M. Michael | Yadav, Dhiraj | Devlin, Bernie | Albert, Marilyn S. | Albin, Roger L. | Apostolova, Liana G. | Arnold, Steven E. | Baldwin, Clinton T. | Barber, Robert | Barnes, Lisa L. | Beach, Thomas G. | Beecham, Gary W. | Beekly, Duane | Bennett, David A. | Bigio, Eileen H. | Bird, Thomas D. | Blacker, Deborah | Boxer, Adam | Burke, James R. | Buxbaum, Joseph D. | Cairns, Nigel J. | Cantwell, Laura B. | Cao, Chuanhai | Carney, Regina M. | Carroll, Steven L. | Chui, Helena C. | Clark, David G. | Cribbs, David H. | Crocco, Elizabeth A. | Cruchaga, Carlos | DeCarli, Charles | Demirci, F. Yesim | Dick, Malcolm | Dickson, Dennis W. | Duara, Ranjan | Ertekin-Taner, Nilufer | Faber, Kelley M. | Fallon, Kenneth B. | Farlow, Martin R. | Ferris, Steven | Foroud, Tatiana M. | Frosch, Matthew P. | Galasko, Douglas R. | Ganguli, Mary | Gearing, Marla | Geschwind, Daniel H. | Ghetti, Bernardino | Gilbert, John R. | Gilman, Sid | Glass, Jonathan D. | Goate, Alison M. | Graff-Radford, Neill R. | Green, Robert C. | Growdon, John H. | Hakonarson, Hakon | Hamilton-Nelson, Kara L. | Hamilton, Ronald L. | Harrell, Lindy E. | Head, Elizabeth | Honig, Lawrence S. | Hulette, Christine M. | Hyman, Bradley T. | Jicha, Gregory A. | Jin, Lee-Way | Jun, Gyungah | Kamboh, M. Ilyas | Karydas, Anna | Kaye, Jeffrey A. | Kim, Ronald | Koo, Edward H. | Kowall, Neil W. | Kramer, Joel H. | Kramer, Patricia | Kukull, Walter A. | LaFerla, Frank M. | Lah, James J. | Leverenz, James B. | Levey, Allan I. | Li, Ge | Lin, Chiao-Feng | Lieberman, Andrew P. | Lopez, Oscar L. | Lunetta, Kathryn L. | Lyketsos, Constantine G. | Mack, Wendy J. | Marson, Daniel C. | Martin, Eden R. | Martiniuk, Frank | Mash, Deborah C. | Masliah, Eliezer | McKee, Ann C. | Mesulam, Marsel | Miller, Bruce L. | Miller, Carol A. | Miller, Joshua W. | Montine, Thomas J. | Morris, John C. | Murrell, Jill R. | Naj, Adam C. | Olichney, John M. | Parisi, Joseph E. | Peskind, Elaine | Petersen, Ronald C. | Pierce, Aimee | Poon, Wayne W. | Potter, Huntington | Quinn, Joseph F. | Raj, Ashok | Raskind, Murray | Reiman, Eric M. | Reisberg, Barry | Reitz, Christiane | Ringman, John M. | Roberson, Erik D. | Rosen, Howard J. | Rosenberg, Roger N. | Sano, Mary | Saykin, Andrew J. | Schneider, Julie A. | Schneider, Lon S. | Seeley, William W. | Smith, Amanda G. | Sonnen, Joshua A. | Spina, Salvatore | Stern, Robert A. | Tanzi, Rudolph E. | Trojanowski, John Q. | Troncoso, Juan C. | Tsuang, Debby W. | Valladares, Otto | Van Deerlin, Vivianna M. | Van Eldik, Linda J. | Vardarajan, Badri N. | Vinters, Harry V. | Vonsattel, Jean Paul | Wang, Li-San | Weintraub, Sandra | Welsh-Bohmer, Kathleen A. | Williamson, Jennifer | Woltjer, Randall L. | Wright, Clinton B. | Younkin, Steven G. | Yu, Chang-En | Yu, Lei
Nature genetics  2012;44(12):1349-1354.
Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07.
PMCID: PMC3510344  PMID: 23143602
11.  Clinically concordant variations of Alzheimer pathology in aphasic versus amnestic dementia 
Brain  2012;135(5):1554-1565.
Primary progressive aphasia is a neurodegenerative syndrome characterized by gradual dissolution of language but relative sparing of other cognitive domains, especially memory. It is associated with asymmetric atrophy in the language-dominant hemisphere (usually left), and differs from typical Alzheimer-type dementia where amnesia is the primary deficit. Various pathologies have been reported, including the tangles and plaques of Alzheimer’s disease. Identification of Alzheimer pathology in these aphasic patients is puzzling since tangles and related neuronal loss in Alzheimer’s disease typically emerge in memory-related structures such as entorhinal cortex and spread to language-related neocortex later in the disease. Furthermore, Alzheimer pathology is typically symmetric. How can a predominantly limbic and symmetric pathology cause the primary progressive aphasia phenotype, characterized by relative preservation of memory and asymmetric predilection for the language-dominant hemisphere? Initial investigations into the possibility that Alzheimer pathology displays an atypical distribution in primary progressive aphasia yielded inconclusive results. The current study was based on larger groups of patients with either primary progressive aphasia or a typical amnestic dementia. Alzheimer pathology was the principal diagnosis in all cases. The goal was to determine whether Alzheimer pathology had clinically-concordant, and hence different distributions in these two phenotypes. Stereological counts of tangles and plaques revealed greater leftward asymmetry for tangles in primary progressive aphasia but not in the amnestic Alzheimer-type dementia (P < 0.05). Five of seven aphasics had more leftward tangle asymmetry in all four neocortical regions analysed, whereas this pattern was not seen in any of the predominantly amnestic cases. One aphasic case displayed higher right-hemisphere tangle density despite greater left-hemisphere hypoperfusion and atrophy during life. Although there were more tangles in the memory-related entorhinal cortex than in language-related neocortical areas in both phenotypes (P < 0.0001), the ratio of neocortical-to-entorhinal tangles was significantly higher in the aphasic cases (P = 0.034). Additionally, overall numbers of tangles and plaques were greater in the aphasic than amnestic cases (P < 0.05), especially in neocortical areas. No significant hemispheric asymmetry was found in plaque distribution, reinforcing the conclusion that tangles have greater clinical concordance than plaques in the spectrum of Alzheimer pathologies. The presence of left-sided tangle predominance and higher neocortical-to-entorhinal tangle ratio in primary progressive aphasia establishes clinical concordance of Alzheimer pathology with the aphasic phenotype. The one case with reversed asymmetry, however, suggests that these concordant clinicopathological relationships are not universal and that individual primary progressive aphasia cases with Alzheimer pathology exist where distributions of plaques and tangles do not account for the observed phenotype.
PMCID: PMC3338929  PMID: 22522938
neurodegenerative disorders; primary progressive aphasia; AD pathology; hemispheric differences; stereology
12.  Verb and noun deficits in stroke-induced and primary progressive aphasia: The Northwestern Naming Battery1 
Aphasiology  2012;26(5):632-655.
Word class naming deficits are commonly seen in aphasia resulting from stroke (StrAph) and primary progressive aphasia (PPA), with differential production of nouns (objects) and verbs (actions) found based on StrAph type or PPA variant for some individuals. Studies to date, however, have not compared word class naming (or comprehension) ability in the two aphasic disorders. In addition, there are no available measures for testing word class deficits, which control for important psycholinguistic variables across language domains. This study examined noun and verb production and comprehension in individuals with StrAph and PPA using a new test, the Northwestern Naming Battery (NNB; Thompson & Weintraub, experimental version), developed explicitly for this purpose. In addition, we tested verb type effects, based on verb argument structure characteristics, which also is addressed by the NNB.
Fifty-two participants with StrAph (33 agrammatic, Broca’s (StrAg); 19 anomic (StrAn)) and 28 PPA (10 agrammatic (PPA-G); 14 logopenic (PPA-L); 4 semantic (PPA-S)) were included in the study. Nouns and verbs were tested in the Confrontation Naming and Auditory Comprehension subtests of the NNB, with scores used to compute noun to verb ratios as well as performance by verb type. Performance patterns within and across StrAph and PPA groups were then examined. The external validity of the NNB also was tested by comparing (a) NNB Noun Naming scores to the Boston Naming Test (BNT; Kaplan, Goodglass, & Weintraub, 1983) and Western Aphasia Battery (WAB-R, Kertesz, 2007) Noun Naming subtest scores, (b) NNB Verb Naming scores to the Boston Diagnostic Aphasia Examination (BDAE; Goodglass, Kaplan & Barresi, 2001) Action Naming score (for StrAph participants only), and (c) NNB Comprehension subtest scores to WAB-R Auditory Comprehension subtest scores.
Outcomes and Results
Both agrammatic (StrAg and PPA-G) groups showed significantly greater difficulty producing verbs compared to nouns, but no comprehension impairment for either word class. Whereas, three of the four PPA-S participants showed poorer noun compared to verb production, as well as comprehension. However, neither the StrAn or PPA-L participants showed significant differences between the two word classes in production or comprehension. In addition, similar to the agrammatic participants, the StrAn participants showed a significant transitivity effect, producing intransitive (one-argument) verbs with greater accuracy than transitive (two- and three-argument) verbs. However, no transitivity effects were found for the PPA-L or PPA-S participants. There were significant correlations between NNB scores and all external validation measures.
These data indicate that the NNB is sensitive to word class deficits in stroke and neurodegenerative aphasia. This is important both clinically for treatment planning and theoretically to inform both psycholinguistic and neural models of language processing.
PMCID: PMC3505449  PMID: 23188949
primary progressive aphasia (PPA); word class deficits; naming deficit patterns; verb argument structure production
13.  Quantitative classification of primary progressive aphasia at early and mild impairment stages 
Brain  2012;135(5):1537-1553.
The characteristics of early and mild disease in primary progressive aphasia are poorly understood. This report is based on 25 patients with aphasia quotients >85%, 13 of whom were within 2 years of symptom onset. Word-finding and spelling deficits were the most frequent initial signs. Diagnostic imaging was frequently negative and initial consultations seldom reached a correct diagnosis. Functionality was preserved, so that the patients fit current criteria for single-domain mild cognitive impairment. One goal was to determine whether recently published classification guidelines could be implemented at these early and mild disease stages. The quantitative testing of the recommended core and ancillary criteria led to the classification of ∼80% of the sample into agrammatic, logopenic and semantic variants. Biological validity of the resultant classification at these mild impairment stages was demonstrated by clinically concordant cortical atrophy patterns. A two-dimensional template based on orthogonal mapping of word comprehension and grammaticality provided comparable accuracy and led to a flexible road map that can guide the classification process quantitatively or qualitatively. Longitudinal evaluations of initially unclassifiable patients showed that the semantic variant can be preceded by a prodromal stage of focal left anterior temporal atrophy during which prominent anomia exists without word comprehension or object recognition impairments. Patterns of quantitative tests justified the distinction of grammar from speech abnormalities and the desirability of using the ‘agrammatic’ designation exclusively for loss of grammaticality, regardless of fluency or speech status. Two patients with simultaneous impairments of grammatical sentence production and word comprehension displayed focal atrophy of the inferior frontal gyrus and the anterior temporal lobe. These patients represent a fourth variant of ‘mixed’ primary progressive aphasia. Quantitative criteria were least effective in the distinction of the agrammatic from the logopenic variant and left considerable latitude to clinical judgement. The widely followed recommendation to wait for 2 years of relatively isolated and progressive language impairment before making a definitive diagnosis of primary progressive aphasia has promoted diagnostic specificity, but has also diverted attention away from early and mild disease. This study shows that this recommendation is unnecessarily restrictive and that quantitative guidelines can be implemented for the valid root diagnosis and subtyping of mildly impaired patients within 2 years of symptom onset. An emphasis on early diagnosis will promote a better characterization of the disease stages where therapeutic interventions are the most likely to succeed.
PMCID: PMC3577099  PMID: 22525158
aphasia; logopenic; semantic; agrammatic; anomic
14.  Comparing measures of decline to dementia in amnestic MCI subjects in the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set 
International psychogeriatrics / IPA  2012;24(10):1553-1560.
Many studies have investigated factors associated with the rate of decline and evolution from mild cognitive impairment to Alzheimer’s disease (AD) dementia in elderly patients. In this analysis we compared the rates of decline to dementia estimated from three common global measures of cognition: Mini Mental Status Examination (MMSE) score, Clinical Dementia Rating sum of boxes score (CDR-SB), and a neuropsychological tests composite score (CS).
A total of 2,899 subjects in the National Alzheimer’s Coordinating Center Uniform Data Set age 65+ years diagnosed with amnestic mild cognitive impairment (aMCI) were included in this analysis. Population-averaged decline to dementia rates were estimated and compared for standardized MMSE, CDR-SB, and Composite scores using Generalized Estimating Equations (GEE). Associations between rate of decline and several potential correlates of decline were also calculated and compared across measures.
The CDR-SB had the steepest estimated slope, with a decline of .49 standard deviations (SD) per year, followed by the MMSE with .22 SD/year, and finally the CS with .07 SD/year. The rate of decline of the three measures differed significantly in a global test for differences (p<.0001). Age at visit, BMI at visit, APOE ε4 allele status, and race (black vs. white) had significantly different relationships with rate of decline in a global test for difference among the three measures.
These results suggest that both the rate of decline and the effects of AD risk factors on decline to dementia can vary depending on the evaluative measure used.
PMCID: PMC3614357  PMID: 22717299
neuropsychological testing; Alzheimer’s Disease; cognitive assessment; aging
15.  Semantic Interference during Object Naming in Agrammatic and Logopenic Primary Progressive Aphasia (PPA) 
Brain and Language  2012;120(3):237-250.
This study examined the time course of object naming in 21 individuals with primary progressive aphasia (PPA) (8 agrammatic (PPA-G); 13 logopenic (PPA-G)) and healthy age-matched speakers (n=17) using a semantic interference paradigm with related and unrelated interfering stimuli presented at stimulus onset asynchronies (SOAs) of −1000, −500, −100 and 0 ms. Results showed semantic interference (SI) (i.e. significantly slower RTs in related compared to unrelated conditions) for all groups at −500, −100 and 0 ms, indicating timely spreading activation to semantic competitors. However, both PPA groups showed a greater magnitude of SI than normal across SOAs. The PPA-L group and six PPA-G participants also evinced SI at −1000 ms, suggesting an abnormal time course of semantic interference resolution, and concomitant left hemisphere cortical atrophy in brain regions associated with semantic processing. These subtle semantic mapping impairments in non-semantic variants of PPA may contribute to the anomia of these patients.
PMCID: PMC3299898  PMID: 22244508
primary progressive aphasia; semantic interference; word interference paradigms; naming deficits in primary progressive aphasia; Free Surfer; cortical thickness
16.  Dissociations Between Fluency And Agrammatism In Primary Progressive Aphasia 
Aphasiology  2012;26(1):20-43.
Classical aphasiology, based on the study of stroke sequelae, fuses speech fluency and grammatical ability. Nonfluent (Broca's) aphasia often is accompanied by agrammatism; whereas in the fluent aphasias grammatical deficits are not typical. The assumption that a similar relationship exists in primary progressive aphasia (PPA) has led to the dichotomization of this syndrome into fluent and nonfluent subtypes.
This study compared elements of fluency and grammatical production in the narrative speech of individuals with PPA to determine if they can be dissociated from one another.
Speech samples from 37 individuals with PPA, clinically assigned to agrammatic (N=11), logopenic (N=20) and semantic (N=6) subtypes, and 13 cognitively healthy control participants telling the “Cinderella Story” were analyzed for fluency (i.e., words per minute (WPM) and mean length of utterance in words (MLU-W)) and grammaticality (i.e., the proportion of grammatically correct sentences, open-to-closed-class word ratio, noun-to-verb ratio, and correct production of verb inflection, noun morphology, and verb argument structure.) Between group differences were analyzed for each variable. Correlational analyses examined the relation between WPM and each grammatical variable, and an off-line measure of sentence production.
Outcomes And Results
Agrammatic and logopenic groups both had lower scores on the fluency measures and produced significantly fewer grammatical sentences than did semantic and control groups. However, only the agrammatic group evinced significantly impaired production of verb inflection and verb argument structure. In addition, some semantic participants showed abnormal open-to-closed and noun-to-verb ratios in narrative speech. When the sample was divided on the basis of fluency, all the agrammatic participants fell in the nonfluent category. The logopenic participants varied in fluency but those with low fluency showed variable performance on measures of grammaticality. Correlational analyses and scatter plots comparing fluency and each grammatical variable revealed dissociations within PPA participants, with some nonfluent participants showing normal grammatical skill.
Grammatical production is a complex construct comprised of correct usage of several language components, each of which can be selectively affected by disease. This study demonstrates that individuals with PPA show dissociations between fluency and grammatical production in narrative speech. Grammatical ability, and its relationship to fluency, varies from individual to individual, and from one variant of PPA to another, and can even be found in individuals with semantic PPA in whom a fluent aphasia is usually thought to accompany preserved ability to produce grammatical utterances.
PMCID: PMC3244141  PMID: 22199417
17.  Functional Decline Associated With Polypharmacy and Potentially Inappropriate Medications in Community-Dwelling Older Adults With Dementia 
This study provides empirical evidence on whether polypharmacy and potentially inappropriate prescription medications (PIRx, as defined by the 2003 Beers criteria) increase the likelihood of functional decline among community-dwelling older adults with dementia. Data were from the National Alzheimer’s Coordinating Center, Uniform Data Set (9/2005–9/2009). Study sample included 1994 community-dwelling participants aged ≥65 with dementia at baseline. Results showed that participants having ≥5 medications were more likely to have functional decline than participants having <5 medications. However, the increased likelihood was only apparent in participants who did not have PIRx. Instead of magnifying the associated risk as hypothesized, PIRx appeared to have a protective effect albeit marginally statistically significant. Therefore, increased medication burden may be associated with functional decline in community-dwelling older adults with dementia who are not prescribed with PIRx. More research is needed to understand which classes of medications have the most deleterious effect on this population.
PMCID: PMC3298080  PMID: 22207646
Beers criteria; Alzheimer’s disease; prescription drug utilization
18.  Concurrent Impairments in Sleep and Memory in Amnestic Mild Cognitive Impairment 
Whereas patients with Alzheimer's disease (AD) experience difficulties forming and retrieving memories, their memory impairments may also partially reflect an unrecognized dysfunction in sleep-dependent consolidation that normally stabilizes declarative memory storage across cortical areas. Patients with amnestic mild cognitive impairment (aMCI) exhibit circumscribed declarative memory deficits, and many eventually progress to an AD diagnosis. Whether sleep is disrupted in aMCI and whether sleep disruptions contribute to memory impairment is unknown. We measured sleep physiology and memory for two nights and found that aMCI patients had fewer stage-2 spindles than age-matched healthy adults. Furthermore, aMCI patients spent less time in slow-wave sleep and showed lower delta and theta power during sleep compared to controls. Slow-wave and theta activity during sleep appear to reflect important aspects of memory processing, as evening-to-morning change in declarative memory correlated with delta and theta power during intervening sleep in both groups. These results suggest that sleep changes in aMCI patients contribute to memory impairments by interfering with sleep-dependent memory consolidation.
PMCID: PMC3468412  PMID: 22300710
Long-term memory; Memory consolidation; Mild cognitive impairment; Slow-wave sleep; Polysomnography; Aging
19.  The Cognitive Change in Women Study (CCW): Informant Ratings of Cognitive Change but not Self Ratings are Associated with Neuropsychological Performance Over Three Years 
The value of self-reported memory complaints for identifying or predicting future cognitive decline or dementia is controversial, but observations from a third party, or “informant”, may prove more useful. The relationship between Informant and Self ratings of cognitive status and neuropsychological test scores was examined in a cohort of 384 non-demented, community-dwelling women, aged sixty and older, participating in a single-site Women’s Health Initiative ancillary study. Each participant and her respective informant separately completed the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)1. Participants also underwent neuropsychological testing and responded to questionnaires on depression and functioning in complex activities of daily living. All neuropsychological test scores were significantly correlated (p-values <.05 to <.01) with Informant IQCODE ratings while Self ratings overestimated cognitive functioning in some domains. Furthermore, the Self and Informant ratings were both positively correlated with depression and negatively correlated with participants’ activity level. Therefore, Informant judgments of functional abilities are robust predictors of cognitive status in high functioning non-demented women. These results suggest that informants may be sensitive to changes that are not clinically significant but that may represent an incipient trend for decline.
PMCID: PMC3220881  PMID: 22086219
Normal Aging; IQCODE; Informant-rating; Self-rating; Cognitive impairment; Screening
20.  Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia 
Brain  2011;134(9):2456-2477.
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.
PMCID: PMC3170532  PMID: 21810890
behavioural variant frontotemporal dementia; diagnostic criteria; frontotemporal lobar degeneration; FTD; pathology
21.  APOE E4 is a susceptibility factor in amnestic but not aphasic dementias 
The goal of this study was to determine if the apolipoprotein ε (ApoE) gene, which is a well-established susceptibility factor for Alzheimer’s disease (AD) pathology in typical amnestic dementias, may also represent a risk factor in the language-based dementia, primary progressive aphasia (PPA). Apolipoprotein E genotyping was obtained from 149 patients with a clinical diagnosis of PPA, 330 cognitively healthy individuals (NC) and 179 patients with a clinical diagnosis of probable Alzheimer’s disease (PrAD). Allele frequencies were compared among the groups. Analyses were also completed by gender and in two subsets of PPA patients, one where patients were classified by subtype (logopenic, agrammatic and semantic) and another where pathologic data were available. The allele frequencies for the PPA group (ε2:5%, ε3:79.5%, and ε4:15.4%) showed a distribution similar to the NC group but significantly different from the PrAD group. The presence of an ε4 allele did not influence the age of symptom onset or aid in the prediction of AD pathology in PPA. These data show that the ε4 polymorphism, which is a well-known risk factor for AD pathology in typical amnestic dementias, has no similar relationship to the clinical syndrome of PPA or its association with AD pathology.
PMCID: PMC3100354  PMID: 21346518
22.  The Neuropsychological Profile of Alzheimer Disease 
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.
Alzheimer disease (AD) targets neuroanatomical networks for episodic memory before those for language, executive functions, and visuospatial abilities. Therefore, amnestic dementia is strongly associated with early AD pathology.
PMCID: PMC3312395  PMID: 22474609
23.  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 
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. Bio-marker 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.
PMCID: PMC3312024  PMID: 21514250
Alzheimer’s disease; Dementia; Diagnosis; Magnetic resonance brain imaging; Position emission tomography; Cerebrospinal fluid
24.  Anatomy of Language Impairments in Primary Progressive Aphasia 
Primary progressive aphasia (PPA) is a clinical dementia syndrome characterized by progressive decline in language function but relative sparing of other cognitive domains. There are three recognized PPA variants: agrammatic, semantic, and logopenic. Although each PPA subtype is characterized by the nature of the principal deficit, individual patients frequently display subtle impairments in additional language domains. The present study investigated the distribution of atrophy related to performance in specific language domains (i.e., grammatical processing, semantic processing, fluency, and sentence repetition) across PPA variants to better understand the anatomical substrates of language. Results showed regionally specific relationships, primarily in the left hemisphere, between atrophy and impairments in language performance. Most notable was the neuroanatomical distinction between fluency and grammatical processing. Poor fluency was associated with regions dorsal to the traditional boundaries of Broca’s area in the inferior frontal sulcus and the posterior middle frontal gyrus, whereas grammatical processing was associated with more widespread atrophy, including the inferior frontal gyrus and supramarginal gyrus. Repetition performance was correlated with atrophy in the posterior superior temporal gyrus. The correlation of atrophy with semantic processing impairment was localized to the anterior temporal poles. Atrophy patterns were more closely correlated with domain-specific performance than with subtype. These results show that PPA reflects a selective disruption of the language network as a whole, with no rigid boundaries between subtypes. Further, these atrophy patterns reveal anatomical correlates of language that could not have been surmised in patients with aphasia resulting from cerebrovascular lesions.
PMCID: PMC3112000  PMID: 21368046
25.  Sleep Influences the Severity of Memory Disruption in Amnestic Mild Cognitive Impairment: Results from Sleep Self-Assessment and Continuous Activity Monitoring 
Sleep is important for declarative memory consolidation in healthy adults. Sleep disruptions are typical in Alzheimer’s disease, but whether they contribute to memory impairment is unknown. Sleep has not been formally examined in amnestic mild cognitive impairment (aMCI), which is characterized by declarative-memory deficits without dementia and can signify prodromal Alzheimer’s disease. We studied 10 aMCI patients and 10 controls over 2 weeks using daily sleep surveys, wrist-worn activity sensors, and daily recognition tests. Recognition was impaired and more variable in aMCI patients, whereas sleep was similar across groups. However, lower recognition of items learned the previous day was associated with lower subjective sleep quality in aMCI patients. This correlation was not present for information learned the same day, thus did not reflect nonspecific effects of poor sleep on memory. These results indicate that inadequate memory consolidation in aMCI patients is related to declines in subjective sleep indices. Furthermore, participants with greater across-night sleep variability exhibited lower scores on a standardized recall test taken prior to the 2-week protocol, suggesting that consistent sleep across nights also contributes to successful memory. Physiological analyses are needed to further specify which aspects of sleep in neurological disorders impact memory function and consolidation.
PMCID: PMC3025089  PMID: 20592579
declarative memory; sleep; amnestic mild cognitive impairment; memory consolidation

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