Primary progressive aphasia: diagnosis, varieties, evolution.

A referred cohort of 67 clinically defined PPA patients were compared to 99 AD patients with formal language and nonverbal cognitive tests in a case control design. Language fluency was determined at the first and last follow up visits. Quantitation of sulcal and ventricular atrophy on MRI was carried out in 46 PPA and 53 AD patients. Most PPA patients (57%) are relatively fluent when first examined. Visuospatial and memory functions are initially preserved. Aphemic, stuttering, "pure motor" presentation, or agrammatic aphasia are seen less frequently. Later most PPAs become logopenic and nonfluent, even those with semantic aphasia (dementia). In contrast, AD patients were more fluent and had relatively lower comprehension, but better overall language performance. MRI showed significant left sided atrophy in most PPA patients. Subsequent to PPA, 25 patients developed behavioral manifestations of frontotemporal dementia and 15 the corticobasal degeneration syndrome, indicating the substantial clinical overlap of these conditions. Language testing, particularly fluency scores supported by neuroimaging are helpful differentiating PPA from AD. The fluent-nonfluent dichotomy in PPA is mostly stage related. The aphemic-logopenic-agrammatic and semantic distinction is useful, but the outcomes converge.     

Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. EURODEM Incidence Research Group

OBJECTIVE: To study the difference in risk for dementing diseases between men and women. BACKGROUND: Previous studies suggest women have a higher risk for dementia than men. However, these studies include small sample sizes, particularly in the older age groups, when the incidence of dementia is highest. METHODS: Pooled analysis of four population-based prospective cohort studies was performed. The sample included persons 65 years and older, 528 incident cases of dementia, and 28,768 person-years of follow-up. Incident cases were identified in a two-stage procedure in which the total cohort was screened for cognitive impairment, and screen positives underwent detailed diagnostic assessment. Dementia and main subtypes of AD and vascular dementia were diagnosed according to internationally accepted guidelines. Sex- and age-specific incidence rates, and relative and cumulative risks for total dementia, AD, and vascular dementia were calculated using log linear analysis and Poisson regression. RESULTS: There were significant gender differences in the incidence of AD after age 85 years. At 90 years of age, the rate was 81.7 (95% CI, 63.8 to 104.7) in women and 24.0 (95% CI, 10.3 to 55.6) in men. There were no gender differences in rates or risk for vascular dementia. The cumulative risk for 65-year-old women to develop AD at the age of 95 years was 0.22 compared with 0.09 for men. The cumulative risk for developing vascular dementia at the age of 95 years was similar for men and women (0.04). CONCLUSION: Compared with men, women have an increased risk for AD. There are no gender differences in risk for vascular dementia.     

Routine clinical diagnosis of primary progressive non-fluent aphasia

It may be difficult to distinguish between a primary progressive aphasia at a very mild stage from the beginning of Alzheimer's disease (AD). However, this may be achieved by carrying out simple neuro-psychological tests. Nine non-fluent PPA (NFPPA) and 76 AD patients with comparable MMSE as well as 58 control subjects were evaluated using simple tests: MMSE, fluency, apraxia, naming, digital span, story memory, 5 words memory test. NFPPA patients had significantly impaired functions during the semantic category fluency and naming tests as compared to AD patients, whereas they showed a better delayed recall of the 5 words and story memory tests. As compared to AD, MMSE of NFPPA patients was also better in the time orientation and word recall sub-tests, although inferior in words repetition and language items. Thus, with comparable MMSE, NFPPA patients have more lexico-semantic difficulties, but a better delayed verbal memory than AD patients. These simple tests easily confirm the language impairment of NFPPA patients as opposed to the mnestic difficulties of AD, even at very early stages of these pathologies.     

Preservation of reasoning in primary progressive aphasia: further differentiation from Alzheimer's disease and the behavioral presentation of frontotemporal dementia

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

Gender differences in the relation between comorbidity and mortality of patients with Alzheimer's disease. Systematic Assessment of Geriatric drug use via Epidemiology (SAGE) Study Group.

OBJECTIVE: To investigate whether differences in the number and type of comorbid conditions may help explain the gender gap in mortality among patients with AD. BACKGROUND: The prevalence and incidence of AD are higher among women, who also have more severe cognitive impairment and accelerated decline. However, men have an exceedingly higher mortality. METHODS: The authors conducted a retrospective cohort study on 5,831 men and 17,918 women with a diagnosis of AD. Data were from the Systematic Assessment of Geriatric drug use via Epidemiology (SAGE) database, which includes information on residents of 1,492 nursing homes in five US states (1992-1995). Men and women were compared with respect to demographic characteristics, dementia severity, psychiatric and behavioral symptoms, indicators of physical disability, and general health status. Also compared were age- and race-adjusted prevalence of all comorbid conditions at each level of cognitive impairment. In survival analyses, the risk of death and of hospitalization were determined by gender and level of cognitive impairment. Finally, gender-related differences in the intensity of pharmacologic treatment were examined. RESULTS: Women were older than men (83+/-7 versus 81+/-7 years) and were more likely to exhibit severe cognitive deterioration (27% versus 19% among men). Overall, there were no significant gender-related differences on several measures of physical disability (activities of daily living performance, gait and history of falls, incontinence, pressure sores), but significantly more women were underweight (45% versus 37% among men). However, the age- and race-adjusted 1-year mortality rate was 17% for women and 31% for men. The mortality rate of women at the highest degree of dementia severity was lower than the rate for men with minimal cognitive impairment. At any level of cognitive impairment, the prevalence of arrhythmia, chronic obstructive pulmonary disease, PD, and cancer was higher among men. Women were also less likely to be hospitalized, and they received fewer medications for each given disease. CONCLUSIONS: The survival advantage of women with AD relative to men may occur as a result of fewer comorbid clinical conditions associated with the diagnosis of dementia.     

Cognitive profiles differ in autopsy-confirmed frontotemporal dementia and AD

BACKGROUND: Frontotemporal dementia (FTD) is currently distinguished from AD primarily on the basis of behavioral features because studies of cognition have shown negligible or inconsistent differences. However, the poor discriminability of cognitive measures may relate to reliance on imprecise clinically diagnosed groups. Therefore, a retrospective examination of neuropsychological test performance in autopsy-confirmed patients is warranted. OBJECTIVE: To compare the pattern of cognitive deficits exhibited by patients with autopsy-confirmed FTD and AD. METHODS: The profiles of cognitive deficits exhibited by patients with neuropathologic diagnosis of FTD (n = 14) or AD (n = 28) were compared. The Mattis Dementia Rating Scale (MDRS), letter and category fluency tests, Wechsler Intelligence Scale for Children-Revised block design test, Boston naming test, and clock drawing test were administered. RESULTS: Multivariate analysis of covariance controlling for age, education, and level of dementia revealed that patients with FTD performed significantly worse than patients with AD on letter and category fluency tests but significantly better on the MDRS memory subscale, block design test, and clock drawing test. A logistic regression model, validated in an independent clinical sample, used letter fluency, MDRS memory, and block design scores to correctly classify 91% of AD patients and 77% of FTD patients. CONCLUSIONS: A double dissociation in the pattern of cognitive deficits exhibited by FTD and AD patients was demonstrated. The FTD patients were more impaired than AD patients on word generation tasks (i.e., verbal fluency) that are sensitive to frontal lobe dysfunction but less impaired on tests of memory and visuospatial abilities sensitive to dysfunction of medial temporal and parietal association cortices.     

Neuropsychological differences between men and women with Alzheimer's disease

Background: It has been suggested that men and women with Alzheimer's disease (AD) at comparable levels of global cognitive impairment perform differently on neuropsychological measures. Such differences may have practical implications for designing cognitive interventions that address symptoms of dementia.

Methods: We compared men (n = 86) and women (n = 96) with AD on tests of immediate and delayed prose memory, verbal fluency, semantic fluency, semantic memory and confrontation naming. Mean years for age, education and duration of illness were 70.81 (SD = 7.55), 13.37 (SD = 3.38) and 2.17 (SD = 1.72) for men and 73.11(SD = 8.53), 12.27 (SD = 2.86) and 2.42 (SD = 1.92) for women. The groups were comparable in global cognitive functioning as indicated by Dementia Rating Scale total scores for men of 89.27 (SD = 29.80) and women of 90.86 (SD = 30.20).

Results: Men earned significantly better scores in immediate prose memory, semantic verbal fluency, semantic memory and response naming. Men and women performed similarly on the remaining tests. When the variables of age, education and duration of disease were controlled, the significant effect of gender was maintained only on tests of semantic fluency, semantic memory and confrontation naming.

Conclusions: The hypothesis of the study was partially confirmed in that women with AD evidenced greater impairment than men with AD on three of six neuropsychological measures even after potentially confounding variables were controlled.     

A longitudinal study of language decline in Alzheimer's disease and frontotemporal dementia.

Language decline is usually the fastest and predominant change in primary progressive aphasia (PPA). In Alzheimer's disease (AD), it is usually associated with global cognitive deficits. Decreased speech output, reduced conversational initiation, echolalia, and changes in the pragmatics of conversation are seen in the behavioral variant of frontotemporal dementia (FTD-bv), however, the evolution of language disturbance in FTD-bv patients is rarely examined systematically with a standardized language battery. We aimed to longitudinally track the nature of language change in FTD-bv, PPA, and AD using a standardized measure of language functioning. We also explored the nature of language deficits between semantic dementia (SD) patients and the fluent subgroup of PPA patients. The Western Aphasia Battery was administered to 105 AD, 20 FTD-bv, 54 PPA, and 10 SD patients on 2 occasions with approximately 1 year between assessments. Ninety-nine of these patients were examined an additional year. FTD-bv and PPA patients showed a faster language decline than AD patients. The eventual overlap in language functioning in FTD-bv and PPA suggests that these syndromes belong to the same spectrum of disorders. In conclusion, longitudinal language assessment provides us with a unique understanding of the evolution and progression of language deterioration in various dementias.     

Rate of cognitive change measured by neuropsychologic test performance in 3 distinct dementia syndromes

Progressive decline in cognition is a hallmark feature of dementia, and the rate and profile of cognitive decline has been well characterized in Alzheimer disease (AD). Less is known about decline in cognition over time in other forms of dementia such as the behavioral variant of frontotemporal dementia (FTD) and primary progressive aphasia (PPA). The present study examined rate of cognitive decline across domains of memory, language, and executive function measured by neuropsychologic tests, in AD (n=84), FTD (n=66), and PPA (n=44). Patients were in the mild stages of dementia, with comparable duration of illness at the baseline evaluation. A best linear unbiased predictor (BLUP) analysis was used in which the slope of the relationship between a cognitive measure and time was estimated for each person. AD subjects demonstrated a floor effect on measures of memory at baseline and a decline on measures of language and executive functioning over time. FTD showed the greatest decline over time on the Mini-Mental State Examination, executive functioning, and naming. PPA patients demonstrated prominent decline on language measures, verbal memory measures, and attention. Results suggest that the profile of rate of change over time has unique features on the basis of the type of dementia syndrome. However, there is overlap in the profiles of decline likely influenced by the overlap in cognitive constructs measured by neuropsychologic tests. The comparison of the rate of decline in FTD and PPA may also reflect the neuroanatomic overlap in these syndromes over time.     

The Addenbrooke's Cognitive Examination Revised (ACE-R): a brief cognitive test battery for dementia screening

There is a clear need for brief, but sensitive and specific, cognitive screening instruments as evidenced by the popularity of the Addenbrooke's Cognitive Examination (ACE). OBJECTIVES: We aimed to validate an improved revision (the ACE-R) which incorporates five sub-domain scores (orientation/attention, memory, verbal fluency, language and visuo-spatial). METHODS: Standard tests for evaluating dementia screening tests were applied. A total of 241 subjects participated in this study (Alzheimer's disease=67, frontotemporal dementia=55, dementia of Lewy Bodies=20; mild cognitive impairment-MCI=36; controls=63). RESULTS: Reliability of the ACE-R was very good (alpha coefficient=0.8). Correlation with the Clinical Dementia Scale was significant (r=-0.321, p<0.001). Two cut-offs were defined (88: sensitivity=0.94, specificity=0.89; 82: sensitivity=0.84, specificity=1.0). Likelihood ratios of dementia were generated for scores between 88 and 82: at a cut-off of 82 the likelihood of dementia is 100:1. A comparison of individual age and education matched groups of MCI, AD and controls placed the MCI group performance between controls and AD and revealed MCI patients to be impaired in areas other than memory (attention/orientation, verbal fluency and language). CONCLUSIONS: The ACE-R accomplishes standards of a valid dementia screening test, sensitive to early cognitive dysfunction.     

Alzheimer's disease and head circumference

OBJECTIVE: Larger brains may contain more neurons and synaptic connections, providing a greater reserve against cognitive decline in Alzheimer's disease (AD). Larger head circumference (HC) may therefore be associated with later detection and diagnosis of AD. We investigated HC in nondemented individuals and AD patients using cross-sectional and prospective analyses. METHODS: The cross sectional analysis compared mean HC between 592 AD patients and 459 nondemented controls. Prospective analysis was based on the same initially normal controls who were followed longitudinally for conversion to dementia. Diagnosis of AD was made by neurologists using NINDS-ADRDA criteria. RESULTS: When compared to AD patients, controls had a significantly larger mean HC by 0.58 cm in men and by 0.31 cm in women, but these differences were no longer significant after adjustment for age and years of education. HC varied inversely with age and directly with years of education but did not vary with presence/absence of dementia in first-degree relatives or with apolipoprotein-E (ApoE) genotype. In the prospective analysis, the hazard ratio for time to conversion to AD was not significant for HC when adjusted for age at entry, ApoE allele status, family history of dementia, gender, and years of education. ApoE allele status, first degree relative with dementia, and baseline age conferred an increased risk for conversion to AD, consistent with other studies. CONCLUSIONS: We observed a smaller HC in AD patients compared to nondemented individuals, but AD per se accounted for little of this difference. HC was not a statistically significant predictor for conversion to AD in our longitudinal group.     

Volumetric study of lobar atrophy in Pick complex and Alzheimer's disease

BACKGROUND: Lobar atrophy is an important neuroimaging feature of Pick complex (PiC). However, differences in patterns of focal brain atrophy between PiC and Alzheimer's disease (AD), and among PiC subgroups, have not been studied quantitatively. OBJECTIVE: To compare volumetric measures among primary progressive aphasia (PPA), frontotemporal dementia (FTD) and AD; to assess association between brain atrophy and cognition. PATIENTS: Seventeen patients with PPA, 11 with FTD and 24 with probable AD were studied. METHODS: We measured total and regional volume quantitatively using MRI and computerized volumetry. Contributing factors were controlled statistically or by adopting brain volume ratios. We investigated the classifying power of volumetry and correlated regional brain volume with cognitive and language test scores. RESULTS: The ratio for fronto-temporo-central region was smaller on the left in PPA and on the right in FTD. AD and some PPA patients had smaller parietal lobes. The frontal ratios correctly classified 93% of PPA and FTD patients, but only 50% of the entire PiC and AD patients. Language-dependent examinations correlated with the left fronto-temporal volume. CONCLUSIONS: Brain atrophy differs in PPA, FTD and AD, but there is some morphological overlap between PiC and AD in parietal volumes. Focal brain atrophy is most consistently associated with language impairments.     

The accuracy of early diagnosis and predictors of death in Alzheimer's disease and vascular dementia--a follow-up study

A total of 87 patients with mild or moderate degree of dementia of the Alzheimer type (AD) or vascular dementia (VD) was identified (DSM-III criteria), and their cognitive capacity was evaluated by means of rating scales and psychometric tests. Three years later 30 patients (34%) were dead. Significantly more VD than AD patients died. Eight of the survivors declined to participate in a follow-up study, and 1 patient was excluded by mistake. Of the survivors, 17 had indisputably suffered cognitive decline during the follow-up period (4 VD and 13 AD, 35%). In the case of 11 patients (2 VD and 9 AD) cognitive decline remained doubtful, and 20 patients (9 VD and 11 AD, 42%) underwent no intellectual deterioration during the follow-up period. The results underline the problems of early diagnosis of dementia according to DSM-III criteria. For both sexes a high ischemia score and a low body mass index predicted death. A low score on a verbal fluency test predicted death for men but not for women, and a high difference between systolic and diastolic blood pressure increased the risk of death for men but not for women.     

Gender differences in language of Alzheimer disease patients revisited.

Results of recent investigations suggest that Alzheimer disease (AD) has a more deleterious effect on language in women than in men. This intriguing finding motivated an analysis of the language performance of probable AD patients, equally divided as to gender, on a variety of language comprehension and production tests. Cross-sectional data were available for 63 probable AD subjects and longitudinal data were available for 26. In addition to analysis of covariance used with the cross-sectional data, effect sizes were calculated. The longitudinal data were analyzed with repeated-measures analyses of covariance. The sum of scores on the orientation items of the Mini-Mental State Examination was used as the covariate in both analyses. No significant differences between the performance scores of male and female subjects were obtained for either the cross-sectional or longitudinal data. All effect sizes of gender were relatively small, with female patients outperforming males on most language tests. Results are discussed in the context of previous findings and comparison of the effect sizes among studies.     

Apolipoprotein E epsilon4 genotype and gender: effects on memory.

OBJECTIVE: Episodic recognition memory for odors and visual was assessed in apolipoprotein E (ApoE) epsilon4-positive and epsilon4-negative men and women diagnosed with Alzheimer disease (AD) and a healthy age- and gender-matched comparison group. METHODS: A total of 38 AD patients and 38 age- and gender-matched healthy older adults completed a recognition memory task involving three categories of stimuli: odors, faces, and symbols. RESULTS: In the healthy comparison group, men who were epsilon4 negative outperformed epsilon4-positive men in recognition memory for odors and committed fewer false-positive errors. However, there were no significant differences between epsilon4-negative and epsilon4-positive women in the comparison group. No significant gender or ApoE status differences were detected in recognition memory for faces or symbols in the comparison group. In patients with AD, epsilon4-negative women outperformed epsilon4-positive women in recognition memory for odors and committed significantly fewer false-positive errors. However, there were no significant differences between epsilon4-positive and epsilon4-negative men. There were no significant gender or ApoE status differences in recognition memory for faces or symbols in AD patients. CONCLUSION: The results demonstrate that recognition memory for olfactory stimuli may be particularly impaired in healthy older men with the epsilon4 allele. In patients with AD, odor memory impairments may be less severe in women who are negative for the epsilon4 allele. The results offer new insight into how recognition memory is affected by gender, the epsilon4 allele, and the modality of the stimulus to be remembered in healthy older adults and patients with AD.     

Subcortical dementia revisited: similarities and differences in cognitive function between progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multiple system atrophy (MSA)

To examine the similarities and differences in cognitive function between three predominantly subcortical dementing disorders associated with parkinsonism we compared the profiles of cognitive performance in 39 patients with Progressive Supranuclear Palsy (PSP), 26 patients with Multiple System Atrophy (MSA) and 25 with Corticobasal Degeneration (CBD) with those of 30 patients with classic cortical dementia, Alzheimer's Disease (AD), using two different cognitive screening tests: Dementia Rating Scale (DRS) and Addenbrooke's Cognitive Examination (ACE). The cognitive profile on ACE and DRS subtests distinguished subcortical diseases from each other as well as from AD. All parkinsonian syndromes were characterized by a disproportionate impairment in verbal fluency, particularly letter fluency. The three diseases differed, however, in the degree of language, memory and visuospatial impairment. We conclude that similarities, as well as differences, between PSP, MSA and CBD can be detected using a brief, clinically applicable cognitive screening test. The pattern of cognitive impairment is likely to reflect a different distribution of pathology, in particular a higher degree of cortical involvement in PSP and CBD.     

Primary progressive aphasia: PPA and the language network

Primary Progressive Aphasia (PPA) is a behaviorally focal dementia syndrome with deterioration of language functions but relative preservation of other cognitive domains for at least the first two years of disease. In this study, PPA patients with impaired word finding but intact comprehension of conversational speech and their matched control subjects were examined using voxel-based morphometry (VBM) and functional magnetic resonance imaging (fMRI). fMRI compared signal changes during phonological and semantic language tasks with those during a control task (matching letters). PPA patients showed longer reaction times and reduced accuracy versus controls on the language tasks, but no performance differences on the control task. VBM demonstrated reduced gray matter in left superior temporal and inferior parietal regions in the PPA group. However, these patients showed a normal pattern of activation within the classical language regions. In addition, PPA patients showed activations, not seen in normals, in fusiform gyrus, precentral gyrus, and intra-parietal sulcus. These activations were found to correlate negatively with measures of naming and task performance. The additional activations in PPA may therefore represent a compensatory spread of language-related neural activity or a failure to suppress activity in areas normally inhibited during language tasks.     

Alzheimer's disease and frontal variant of frontotemporal dementia

The aim of this study was to investigate whether a brief neuropsychological battery consisting of a limited number of cognitive tests and an evaluation of the behavioural domains intended to discriminate between frontotemporal dementia (fv–FTD) and Alzheimer's disease (AD), constitutes a useful instrument for making a differential clinical diagnosis between these two pathologies. Nineteen fv–FTD and 39 AD patients were compared on cognitive tasks (assessing memory, executive functions, language and constructional praxis) and on the NPI behavioural assessment. A stepwise discriminant analysis was performed to identify the linear combination of cognitive and behavioural measures able to best discriminate between the two groups. One test for each of the investigated cognitive domains (Delayed Prose Recall, FAS verbal fluency, Boston naming test, Rey's Figure A Copy) and the four subscales of the Neuropsychiatry Inventory (NPI) which best differentiated between fv–FTD and AD patients (apathy, disinhibition, euphoria, aberrant motor behaviour) were used. The analysis selected Rey's Figure A Copy, FAS verbal fluency and NPI apathy subscale as the best discriminants between fv–FTD and AD patients. The final equation assigned 73.7% of the fv–FTD patients and 94.7% of the AD patients to the correct diagnostic group. A validation study conducted on a new independent sample of 11 fv–FTD and 22 AD patients confirmed the high sensitivity (82.6 %) and specificity (81.8%) of the diagnostic equation in assigning fv–FTD and AD patients to the correct dementia group. Although both cognitive and behavioural differences exist between FTD and AD, previous studies have aimed at differentiating the two pathologies by considering the two aspects separately and discriminant analyses were focused only on neuropsychological or neuropsychiatric evaluations. The present results emphasise the importance of rating both cognitive and behavioural clinical features of the two syndromes as objectively as possible to improve differential diagnostic accuracy.     

ApoE E4 is a susceptibility factor in amnestic but not aphasic dementias

The goal of this study was to determine if the apolipoprotein ε gene, which is a well-established susceptibility factor for Alzheimer 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 sex and in 2 subsets of PPA patients: 1 in which the patients were classified by subtype (logopenic, agrammatic, and semantic) and another in which 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 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.