Alzheimer Disease & Associated Disorders - An International Journal Spongiform Change in Dementia with Lewy Bodies and Alzheimer's Disease

Transcription

1 Alzheimer Disease & Associated Disorders - An International Journal Spongiform Change in Dementia with Lewy Bodies and Alzheimer's Disease --Manuscript Draft-- Manuscript Number: Full Title: Article Type: Keywords: Corresponding Author: ADAD-D--00 Spongiform Change in Dementia with Lewy Bodies and Alzheimer's Disease Original Study Dementia with Lewy Bodies, spongiform change, vacuolization, Alzheimer's disease, entorhinal cortex, perirhinal cortex, semi-quantitative grading of vacuolization, Braak stage, amyloid plaques, tangles. Abdullah Sherzai, MD, MAS, PhD (c) Loma Linda University Loma Linda, CA UNITED STATES Corresponding Author Secondary Information: Corresponding Author's Institution: Loma Linda University Corresponding Author's Secondary Institution: First Author: Abdullah Sherzai, MD, MAS, PhD (c) First Author Secondary Information: All Authors: Abdullah Sherzai, MD, MAS, PhD (c) Steven D Edland, PhD Eliezer Masliah, MD, PhD Lawrence Hansen, PhD Donald P Pizzo, PhD Ayesha Sherzai, MD Jody Corey-Bloom, MD, PhD All Authors Secondary Information: Manuscript Region of Origin: Abstract: UNITED STATES Background: Dementia with Lewy Bodies (DLB) is characterized neuropathologically by brainstem and cortical Lewy bodies and Lewy neurites, neuronal loss in brainstem nuclei, as well as Alzheimer's disease (AD) pathology. Previous studies have suggested that spongiform change in the entorhinal cortex may also be a pathologic feature; however, this change has not been well characterized. Design/Method: An autopsy series of 0 subjects with DLB and 0 subjects with AD, matched on age, gender, and last Mini Mental State Examination (MMSE) prior to death. Using semistereological methods on representative sections through the transentorhinal and perirhinal cortices, quantitative counts and semi-quantitative grading of vacuolization were performed by one rater (AS) blinded to subjects' diagnoses. In addition, electron microscopy (EM) of representative sections was performed. Results: Vacuolization was - fold more prominent in the perirhinal, as compared to transentorhinal, cortex. Moderate to severe vacuolization was found in.% of DLB, but only. % of AD subjects. There were statistically significant differences between mean numbers of vacuoles in the perirhinal (DLB M=.; AD M=.; p<0.00) and transentorhinal (DLB M=.; AD: M=0.; p<0.00) cortices in DLB as well as AD cases. EM revealed both axonal and dendritic pathology, with dilatation, vacuole Powered by Editorial Manager and Preprint Manager from Aries Systems Corporation

2 formation, and abnormal membranous profiles. Conclusions: While the exact mechanism remains to be elucidated, vacuolization appears to be more specific for DLB than AD, with disproportionate involvement of the perirhinal cortex. Suggested Reviewers: Ravi K Raghavan, MD Loma Linda University Medical Center rraghavan@llu.edu Adam S Fleisher, MD, MAS Geriatric neurologist, Associate director of brain imaging, Banner Alzheimer's Institute adam.fleisher@bannerhealth.com John Olichney, MD Associate Professor, Center for Mind and Brain, UC Davis jmolichney@ucdavis.edu Charles DeCarli, MD Director of Alzheimer's Disease Center, UC Davis charles.decarli@ucdmc.ucdavis.edu James B Leverenz, MD Associate Professor of Neurology and Psychiatry & Behavioral Sciences, University of Washington leverenz@uw.edu Powered by Editorial Manager and Preprint Manager from Aries Systems Corporation

3 *Cover Letter

4 *Manuscript (All Manuscript Text Pages, including Title Page, References and Figure Legends) Spongiform change in Dementia with Lewy bodies and Alzheimer's disease Abdullah Sherzai, Loma Linda, CA, United States; Steven D Edland, La Jolla, CA, United States; Eliezer Masliah, La Jolla, CA, United States; Lawrence Hansen, La Jolla, CA, United States; Donald P Pizzo, La Jolla, CA, United States; Ayesha Sherzai, La Jolla, CA, United States and Jody Corey-Bloom, San Diego, CA, United States. The authors declare no conflicts of interest. Laboratory or institution of origin: University of California San Diego, La Jolla, CA Corresponding author: Abdullah Sherzai, MD, MAS, PhD(c) Loma Linda University, Department of Neurology, Campus Street, CP 0, Loma Linda CA Phone: --, Fax: 0 00, adsherzai@llu.edu

5

6 Abstract Background Dementia with Lewy Bodies (DLB) is characterized neuropathologically by brainstem and cortical Lewy bodies and Lewy neurites, neuronal loss in brainstem nuclei, as well as Alzheimer's disease (AD) pathology. Previous studies have suggested that spongiform change in the entorhinal cortex may also be a pathologic feature; however, this change has not been well characterized. Design/Method An autopsy series of 0 subjects with DLB and 0 subjects with AD, matched on age, gender, and last Mini Mental State Examination (MMSE) prior to death. Using semi-stereological methods on representative sections through the transentorhinal and perirhinal cortices, quantitative counts and semi-quantitative grading of vacuolization were performed by one rater (AS) blinded to subjects diagnoses. In addition, electron microscopy (EM) of representative sections was performed. Results Vacuolization was - fold more prominent in the perirhinal, as compared to transentorhinal, cortex. Moderate to severe vacuolization was found in.% of DLB, but only. % of AD subjects. There were statistically significant differences between mean numbers of vacuoles in the perirhinal (DLB M=.; AD M=.; p<0.00) and transentorhinal (DLB M=.; AD: M=0.; p<0.00) cortices in DLB as well as AD cases. EM revealed both axonal and dendritic pathology, with dilatation, vacuole formation, and abnormal membranous profiles. Conclusions While the exact mechanism remains to be elucidated, vacuolization appears to be more specific for DLB than AD, with disproportionate involvement of the perirhinal cortex. Spongiform change in Dementia Lewy body and Alzheimer's disease

7 Keywords Dementia with Lewy Bodies, spongiform change, vacuolization, Alzheimer s disease, entorhinal cortex, perirhinal cortex, semi-quantitative grading of vacuolization, Braak stage, Amyloid plaques, Tangles. Spongiform change in Dementia Lewy body and Alzheimer's disease

8 Introduction Although still debated, Dementia with Lewy Bodies (DLB) is perhaps the second most common cause of dementia after Alzheimer s disease (AD). The clinical presentation is characterized by fluctuating cognitive impairment, attentional deficits, and visuospatial dysfunction, along with well-formed complex visual hallucinations and mild parkinsonian symptoms., Yet, in the majority of cases, the distinction between DLB and AD can be subtle, making it very difficult to diagnose in life. - Neuropathologic studies have demonstrated the presence of Lewy bodies in both subcortical and cortical regions of the brain, neuronal loss in brainstem nuclei, and spongiform change in the temporal lobes of patients with DLB. Although vacuolization has been identified in a number of neurodegenerative diseases, -, two studies have suggested that vacuolization, especially temporal lobe vacuolization, may be an important neuropathological feature of Lewy body disease., A previous study has suggested that the spongiform change or vacuolization may result from degeneration of terminal axons of large pyramidal neurons; however, this unique finding has not been well characterized. Thus, the objective of the current study was to examine the nature and degree of temporal lobe spongiform change in a large series of well-characterized, autopsy-confirmed DLB and AD patients, and to explore potential associations with vacuole distribution and density. Spongiform change in Dementia Lewy body and Alzheimer's disease

9 Methods. Subjects: Subjects included in the study were followed clinically at the University of California San Diego (UCSD) Alzheimer s disease Research Center (ADRC) and came to autopsy between 0 and 00 with a pathological diagnosis of DLB or AD. Subjects had been evaluated at the UCSD ADRC with standardized medical, neurological, neuropsychological and laboratory examinations. To be included in the study, subjects had to have no other confounding pathological diagnoses and have a MMSE score > 0 within years of their death. There were 0 autopsy-proven DLB patients who met all the requirements for inclusion. A random sample of AD cases, matched on the basis of age, gender, last MMSE prior to death, and interval from last MMSE to death, was obtained using the SAS macro gmatch.. Tissue Examination: All autopsies were performed according to a standardized protocol. The left hemibrain was fixed by immersion in 0% formalin for days. The paraffin-embedded blocks from midfrontal, rostral superior temporal and inferior parietal areas of neocortex, anterior cingulate gyrus, posterior cingulate gyrus, hippocampus, entorhinal cortex, basal ganglia/substantia innominata, mesencephalon and pons were cut at mm thickness for haematoxylin and eosin (H E) and thioflavin-s staining. All slides had a unique numeric identifier, assigned by Department of Pathology University of California, San Diego. Total plaque, neuritic plaque and neurofibrillary tangle counts were determined by the same examiner (L.H.) with the same criteria used consistently. Lewy-body pathology was graded on a semi-quantitative scale following current criteria of the DLB Consortium. All of the DLB cases included in this study met DLB criteria for a pathological diagnosis of DLB, based on the presence of brainstem and cortical LBs [identified by H E and anti-ubiquitin Spongiform change in Dementia Lewy body and Alzheimer's disease

10 immunostaining, as recommended by the Consortium on DLB. The neuropathological diagnosis of Alzheimer s disease was based on both NIA and CERAD criteria for Alzheimer s disease, as well as on the exclusion of brainstem and cortical Lewy bodies. Almost all of the Alzheimer s disease patients included in the present study displayed significant numbers of neurofibrillary tangles in each of the neocortical regions examined (Braak stages V or VI), thereby fulfilling NIA-Reagan guidelines for a high likelihood that their dementia was attributable to Alzheimer s disease pathology. As mentioned above, DLB or Alzheimer s disease cases with significant coexistent vascular (>0 ml of infarcted brain tissue, two or more cortical microinfarcts, two or more lacunes, or hippocampal sclerosis) or other pathology (that could by itself cause dementia) were excluded from analyses. Quantification of the vacuoles was performed using a video camera (Sony DCX-0, Tokyo, Japan) and software program (Bioquant Nova Prime system; Bioquant Image Analysis Corporation, Tennessee) that controlled the motorized stage (ASI-XYZ, ASI Inc., Eugene, OR) on a BH- microscope (Olympus, Melville, NY). Entorhinal/ perirhinal structures were circumscribed using a marker, which was then traced and delineated by the program (figure ). A (0 x0 um) grid was overlaid on each section and manually examined for vacuoles. Vacuoles were defined as orbicular spaces, ranging from um to um without evidence of any cellular or vascular remnants (figure ). Depending on the size of the entorhinal/ perirhinal section, there were 0 to 0 high power (0X) grids to be viewed for quantification. Vacuole density within each dissector box on the grid was scored on a 0 to scale. Boxes containing or less vacuoles were scored as 0; boxes containing to 0 vacuoles were scored as ; boxes containing to 0 vacuoles were scored as ; boxes containing to 0 vacuoles were scored as, and boxes containing or more vacuoles were scored as. The scorer (A.S.) was blinded to the patient clinical information and pathologic presentation. The dissector box scores were then summed and overall vacuole pathology score calculated using the categories None (sum = 0), Mild (sum = to ), Moderate (sum = 0 to ), and Severe (sum >=0). Once scoring of the vacuoles was complete in all the grids, the program created a two dimensional depiction of vacuole density across the circumscribed tissue (figure ). Spongiform change in Dementia Lewy body and Alzheimer's disease

11 Electron Microscopy: An entorhinal cortex section was fixed overnight in % glutaraldehyde at degrees centigrade immediately before embedding for electron microscopy (EM). The section was then washed twice for minutes each in 0. M sodium cacodylate buffer ph., fixed in % osmium tetroxide for min, rinsed in distilled water twice for minutes each, quickly rinsed in 0% ethanol, en bloc stained for 0 minutes to an hour with ethanol uranyl acid solution, and then dehydrated through graded ethanol solutions. The section was then placed in : propylene oxide/00% ethanol for minutes, propylene oxide for minutes twice, and then a : mixture of Epon and propylene oxide for 0 minutes. The brain regions of interest (hippocampus and entorhinal cortex) were subsequently cut out, positioned in a BEEM capsule, covered with fresh Epon, allowed to stand for 0 minutes to hour, and finally polymerized for to hours in a degrees centigrade oven. The resulting blocks containing the regions of interest were then trimmed, cut on a Reichert Ultracut E ultramicrotome, viewed on a Zeiss 0B transmission electron microscope, and photographed.. Statistical Analysis: The distribution of continuous matching variables was compared in cases versus controls using a t-test. Plaque counts, tangle counts, and inclusion counts were compared between groups using Wilcoxon's matched pairs rank sum test. Categorical variables were compared in cases versus controls using Fisher's exact test. Association between semi-quantitative measures of plaque, tangle, and inclusion body levels was tested using Spearman rank correlation coefficients. Spongiform change in Dementia Lewy body and Alzheimer's disease

12 Results The demographic and clinical characteristics of the patient groups are shown in table. There were no group differences with regard to age at death (DLB M=. years; AD M=. years; p<0.), gender (DLB M=; AD M=; p=), global severity of dementia on the MMSE at last evaluation (DLB M=.; AD M=.; p<0.), or interval from last examination to death (DLB M=. years; AD M=. years; p<0.) (Table ). Plaque and tangle densities were consistently higher in AD, and Lewy body pathology was higher in DLB, consistent with the neuropathological diagnoses (Table ). In both AD and DLB, vacuolization was - fold more prominent in the perirhinal, as compared to entorhinal, cortex (p<0.00) (Table ). Vacuolization was found to a variable extent in % of DLB subjects, but only % of AD subjects. Of the 0 AD subjects, had no vacuolization, whereas only of the DLB subjects had no vacuolization; of the AD and 0 of the DLB had mild vacuolization; of the AD as opposed to of the DLB subjects had moderate vacuolization; and none of the AD, but 0 of the DLB, had severe vacuolization (overall p<0.00) (Table ). The mean number of vacuoles per examined section was significantly higher in DLB cases compared to AD cases in the perirhinal (. versus.; p<0.00) and entorhinal (. versus 0.0; p<0.00) cortices. Almost all of the vacuoles in the entorhinal cortex were seen in the transentorhinal cortex, as illustrated in the representative section on Figure. Although there were statistically significant correlations (p<0.0) between perirhinal vacuolization scores and numbers of superior temporal diffuse and neuritic plaques, superior temporal tangles, and mid-frontal tangles in AD cases, there were no statistically significant correlations between entorhinal or perirhinal vacuolization scores and neuropathological features in LBV cases. There were also no statistically significant correlations between degree of vacuolization and numbers of Lewy bodies within either group (Table ). Furthermore, there Spongiform change in Dementia Lewy body and Alzheimer's disease

13 were no statistically significant correlations between degree of vacuolization and gender, age at onset, or duration of disease from onset (data not presented). EM revealed both axonal and dendritic pathology, with dilatation, vacuole formation, and abnormal membranous profiles (Figure, in addition to alterations of smooth endoplasmic reticulum. Spongiform change in Dementia Lewy body and Alzheimer's disease

14 Discussion In this study we found a consistent pattern of greater temporal lobe vacuolization in the DLB, as compared to AD, subjects; in addition, the perirhinal cortex was afflicted with spongiform change to a significantly greater extent than the entorhinal cortex. Vacuolization did not appear to be a marker of clinical severity, duration of disease, or patient age, but was strongly correlated with Lewy body pathology, consistent with previous studies. Although vacuolization in DLB, as compared to AD, subjects has previously been reported,, to our knowledge, the preponderance of perirhinal vacuolization, as compared to entorhinal involvement, is a novel finding that has not previously been described; yet may provide important clues to the pathophysiology of this dementia syndrome. Electron microscopy demonstrated vacuolization in dendrites and axons, as well as pathologic changes in smooth endoplasmic reticulum. Although there is limited information regarding the mechanism or the significance of these vacuoles, previous observations have linked degree of spongiform change with loss of the large pyramidal neurons in the entorhinal cortex, and with the disappearance of ubiquitin-positive granular structures (UPG)., 0 The occurrence of spongiform change without significant gliosis may suggest that the large pyramidal neurons in the transentorhinal and perirhinal cortex degenerate more rapidly in DLB than in AD. The pattern and extent of vacuolization in DLB may also shed light on why DLB subjects experience greater visuoperceptual abnormalities than AD subjects, since previous studies have suggested that perirhinal cortex might play a role, not only in declarative memory, but in visual perception and object identification. - Thus, lesions in perirhinal cortex could lead to difficulty representing visual aspects of object information, and these defective visual perceptions may play a role in the development of visual hallucinations, delusional, misidentifications, visual agnosias, and visuocontructive aberrancies often observed in DLB. In support of this notion is the finding that DLB patients with hallucinations, as compared to those without hallucinations, demonstrate hypometabolism in visual association areas, including the perirhinal cortex. Spongiform change in Dementia Lewy body and Alzheimer's disease

15 This study is not without limitations. This was a convenience sample of cases from one academic medical center and the vacuolization was rated using a semi-quantitative technique. In summary, we sought to investigate the nature and degree of temporal lobe spongiform change in DLB and AD. We found that spongiform change was significantly more prevalent in DLB as compared to AD, specifically in the perirhinal as opposed to entorhinal cortices. While the exact mechanism of this phenomenon remains to be elucidated, findings on EM suggest that the vacuolization may be related to alterations of smooth endoplasmic reticulum involved in packaging and transport of defective proteins and that, along with Lewy bodies and Lewy neurites, vacuolization should be included as an important histopathologic hallmark of Lewy, 0, body disease. Spongiform change in Dementia Lewy body and Alzheimer's disease 0

16 Abbreviations AD Alzheimer's disease MMSE Mini Mental State Examination DLB Dementia with Lewy Bodies PD Parkinson s disease H&E Hemotoxylin and Eosin EM Electron Microscopy MF Mid Frontal IF Inferior Frontal ST Superior Temporal HP Hippocampal VVS Ventral visual stream Spongiform change in Dementia Lewy body and Alzheimer's disease

17 References. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. ; :-.. Perry R, McKeith IPerry E. Lewy body dementia--clinical, pathological and neurochemical interconnections. J Neural Transm Suppl. ; :-0.. Crystal HA, Dickson DW, Lizardi JE, et al. Antemortem diagnosis of diffuse Lewy body disease. Neurology. 0; 0:-.. McKeith IG, Fairbairn AF, Bothwell RA, et al. An evaluation of the predictive validity and inter-rater reliability of clinical diagnostic criteria for senile dementia of Lewy body type. Neurology. ; :-.. Nelson PT, Jicha GA, Kryscio RJ, et al. Low sensitivity in clinical diagnoses of dementia with Lewy bodies. J Neurol. :-.. Luis CA, Barker WW, Gajaraj K, et al. Sensitivity and specificity of three clinical criteria for dementia with Lewy bodies in an autopsy-verified sample. Int J Geriatr Psychiatry. ; :-. Spongiform change in Lewy body dementia and Alzheimer's disease

18 Mok W, Chow TW, Zheng L, et al. Clinicopathological concordance of dementia diagnoses by community versus tertiary care clinicians. Am J Alzheimers Dis Other Demen. 00; :-.. Hansen LA, Masliah E, Terry RD, et al. A neuropathological subset of Alzheimer's disease with concomitant Lewy body disease and spongiform change. Acta Neuropathol. ; :- 0.. Brun APassant U. Frontal lobe degeneration of non-alzheimer type. Structural characteristics, diagnostic criteria and relation to other frontotemporal dementias. Acta Neurol Scand Suppl. ; : Boeve BF, Maraganore DM, Parisi JE, et al. Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology. ; :-00.. Smith TW, Anwer U, DeGirolami U, et al. Vacuolar change in Alzheimer's disease. Arch Neurol. ; :-.. Masters CL, Kakulas BA, Alpers MP, et al. Preclinical lesions and their progression in the experimental spongiform encephalopathies (kuru and Creutzfeldt-Jakob disease) in primates. J Neuropathol Exp Neurol. ; :-0.. Fujino YDickson DW. Limbic lobe microvacuolation is minimal in Alzheimer's disease in the absence of concurrent Lewy body disease. Int J Clin Exp Pathol. 00; :-.. Iseki E, Marui W, Akiyama H, et al. Degeneration process of Lewy bodies in the brains of patients with dementia with Lewy bodies using alpha-synuclein-immunohistochemistry. Neurosci Lett. 000; :-.. Holdstock JS. The role of the human medial temporal lobe in object recognition and object discrimination. Q J Exp Psychol B. 00; :-.. Terry RD, Peck A, DeTeresa R, et al. Some morphometric aspects of the brain in senile dementia of the Alzheimer type. Ann Neurol. ; 0:-. Spongiform change in Dementia Lewy body and Alzheimer's disease

19 McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 00; :-.. Hansen LASamuel W. Criteria for Alzheimer's disease and the nosology of dementia with Lewy bodies. Neurology. ; :-.. Iseki E, Odawara T, Li F, et al. Age-related ubiquitin-positive granular structures in nondemented subjects and neurodegenerative disorders. J Neurol Sci. ; :-. 0. Iseki E, Li FKosaka K. Close relationship between spongiform change and ubiquitin-positive granular structures in diffuse Lewy body disease. J Neurol Sci. ; :-.. Eacott MJ, Gaffan DMurray EA. Preserved recognition memory for small sets, and impaired stimulus identification for large sets, following rhinal cortex ablations in monkeys. Eur J Neurosci. ; :-.. Buckley MJGaffan D. Perirhinal cortex ablation impairs configural learning and pairedassociate learning equally. Neuropsychologia. ; :-.. Murray EABussey TJ. Perceptual-mnemonic functions of the perirhinal cortex. Trends Cogn Sci. ; :-.. Murray EA, Bussey TJ, Hampton RR, et al. The parahippocampal region and object identification. Ann N Y Acad Sci. 000; :-.. Tyler LK, Stamatakis EA, Bright P, et al. Processing objects at different levels of specificity. J Cogn Neurosci. 00; :-.. Eacott MJGaffan EA. The roles of perirhinal cortex, postrhinal cortex, and the fornix in memory for objects, contexts, and events in the rat. Q J Exp Psychol B. 00; :0-.. Mori E, Shimomura T, Fujimori M, et al. Visuoperceptual impairment in dementia with Lewy bodies. Arch Neurol. 000; :-. Spongiform change in Lewy body dementia and Alzheimer's disease

20 Johnson DK, Morris JCGalvin JE. Verbal and visuospatial deficits in dementia with Lewy bodies. Neurology. 00; :-.. Perneczky R, Drzezga A, Boecker H, et al. Cerebral metabolic dysfunction in patients with dementia with Lewy bodies and visual hallucinations. Dement Geriatr Cogn Disord. 00; :-. 0. McKeith IG, Perry EKPerry RH. Report of the second dementia with Lewy body international workshop: diagnosis and treatment. Consortium on Dementia with Lewy Bodies. Neurology. ; :0-0.. Hohl U, Tiraboschi P, Hansen LA, et al. Diagnostic accuracy of dementia with Lewy bodies. Arch Neurol. 000; :-. Spongiform change in Dementia Lewy body and Alzheimer's disease

21 FIGURE LEGENDS: Figure. Line tracing of entorhinal and perirhinal cortex vacuolization (severe, DLB) Figure. X Vacuolization of perirhinal cortex at 0X magnification, DLB Figure. EM of dilatation of myelinated axons in temporal cortex, DLB Spongiform change in Lewy body dementia and Alzheimer's disease

22 Table Table. Clinical and demographic variables AD (N=0) DLB (N=0) P* Age at death (years). (-). (-) 0. Gender (% female) Last MMSE.. 0. Interval to death (years).. 0. AD: Alzheimer's Disease DLB: Lewy Body Dementia * Continuous variables were compared using a t-test.

23 Table Table. Pathologic variables AD DLB (N=0) P* Diffuse Plaques MF. (0, 0-0). (, - 0) 0.0 IP. (0, - 0). (0, - 0) <0.0 ST.0 (0, 0-0). (, - 0) <0.00 HP. (., - ). (., 0 - ) <0.0 Amyloid MF. (, 0 - ). (, 0 - ) 0.0 IP. (, 0 - ). (, 0 - ) 0. ST 0. (0, 0 - ).0 (0, 0 - ) 0. HP 0. (, 0 - ).0 (0, 0 - ) 0. Neuritic Plaques MF. (., - 0). (, - 0) <0.0 IP. (, - 0). (., - 0) 0.0 ST.0 (, - 0) 0. (, - 0) 0.0 HP. (., - ). (, 0 - ) 0.0 Tangles MF. (, 0 - ). (0, 0 - ) <0.00 IP.0 (, 0 - ). (, 0 - ) <0.00 ST. (., 0 - ). (, 0 - ) <0.00 HP 0.0 (, - ). (, 0 - ) <0.00 Lewy Bodies 0.0 (0, 0 - ) <0.00 Braak Stage. (, - ). (, 0 - ) <0.00 Vacuolization Entorhinal 0. (0, 0 - ). (, 0 - ) <0.00 Perirhinal. (0, 0 - ). (, 0 - ) <0.00 AD: Alzheimer's Disease DLB: Lewy Body Dementia MF: Midfrontal, IP: Inferior parietal, ST: Superior Temporal, HP: Hippocampus

24 Table Table. Percent of Subjects with Given Severity of Spongiform Change AD (n=0) DLB (n=0) None Mild Moderate Severe 0 AD: Alzheimer's Disease DLB: Lewy Body Dementia

25 Table Table. Correlations between entorhinal and perirhinal vacuolization scores and neuropathological features in Lewy body (LBD) and Alzheimer disease (AD) cases AD ONLY LBD ONLY Ento Peri Ento Peri MF LB MF PLAQUES IP PLAQUES ST PLAQUES 0. 0.** HP PLAQUES MF NP IP NP ** ST NP ** HP NP MF TANGLES 0. 0.** IP TANGLES ST TANGLES ** HP TANGLES MF AMYLOID IP AMYLOID ST AMYLOID HP AMYLOID Braak Stage

26 LBD=Lewy Body Disease; AD=Alzheimer disease; MF=Mid-frontal; LB= Lewy bodies; IP= inferior parietal; ST=superior temporal; HP=hippocampal; NP= neuritic plaque; Ento=entorhinal cortex; Peri=perirhinal cortex; **p >0.0.

27 Figure and Common.Links.ClickHereToDownloadHighResolutionImage

28 Figure Common.Links.ClickHereToDownloadHighResolutionImage

29 Abdullah Sherzai Common.Links.ClickHereToDownload

30 Corey-Bloom Common.Links.ClickHereToDownload

31 Masliah Common.Links.ClickHereToDownload

32 Hansen Common.Links.ClickHereToDownload

33 Pizzo Common.Links.ClickHereToDownload

34 Ayesha Sherzai Common.Links.ClickHereToDownload

35 Edland Common.Links.ClickHereToDownload