A Longitudinal Case Study of an Atypical Early-Onset Posterior Cortical Dementia with Hyperostosis Frontalis Fernando Entenza, M.D., Univ. Central del Caribe, Puerto Rico Maria T. Margarida-Julia Psy.D., Univ. de Puerto Rico 29th International Conference of Alzheimer Disease International San Juan, Puerto Rico May 1-4, 2014
Disclosures Dr. Entenza No conflicts of interest Dr. Margarida-Julia No conflicts of interest No grants or other external funds used
Introduction Case study of an under-recognized focal degenerative syndrome which 1. Describes its earliest manifestations 2. Exemplifies the benefits of a multidisciplinary evaluation 3. Calls attention to special needs of this population 4. Raises questions about the nature of PCA & HFI
Background Information Right handed 54 year-old married man Doctorate degree Highly specialized professional Under my care since age 43 Presented for treatment of Bipolar Disorder Diagnosed Bipolar Disorder Type I at the age of 35 Claimed mood cycling since age 21 Medical conditions Metabolic syndrome Obesity Insulin-requiring DM-II Arterial hypertension Hypercholesterolemia Obstructive sleep apnea (using CPAP) Lumbar HNP
Family History Paternal grandfather Suspected AD Father Died due to AD in his 70's Apparent early-onset Older sister (58) Eldest daughter Atypical Bipolar Disorder since age 17 Another daughter High impulsivity Very poor judgment Possible mood cycling Undergoing dementia evaluation Initial symptom was memory loss
1. Atypical 11-Year Course BIPOLAR DISORDER Worsening over the 11-year span Abnormally persistent mood cycling Mixed-manic or mixed-depressive symptoms Abnormal auditory perceptions & ideas of reference (occasional) Anxiety (associated with new workplace challenges and with greater depressive symptoms) COGNITIVE SYMPTOMS Insidious over the past 3 years Adapting to new work procedures & routines, and driving routes Although learning proficiently in the end Navigation problems in familiar places These were initially present only during heightened depressive symptoms Brief medical leave-of-absences in the last 3 years
Treatment at Cognitive Evaluation Divalproex ER 2,750mg QHS Lamotrigine 200mg QD Bupropion XL 150mg a/w Bupropion SR 100mg QD Quetiapine XR 100 mg QAM + 300 mg QHS Clonazepam 0.25 mg QAM + 0.5 mg QHS
2. Findings Normal Physical & neurological exams Dementia laboratory workup HbgA1c = 6.4% Ceruloplasmin level Abnormal APOE є 3-4 genotype MRI neuroanatomy PET regional brain metabolism Neuropsychological testing M.R.A. E.E.G
Parietal Atrophy & Hyperostosis Frontalis Interna Axial views
Parietal Atrophy & Hypometabolism Coronal Oblique T1 views PET - Coronal view
Parietal Hypometabolism (L > R) Brain FDG-PET Axial views
Parietal Hypometabolism and Atrophy Sagittal views
Medial Temporal Lobe Unaffected Axial views
Hyperostosis Frontalis Interna Internal Growths Source: http://www.annclinlabsci.org/content/34/2/206/f1.large.jpg
Headache Evaluation 8 Years Earlier at Age 46 Earlier stages of HFI prefrontal compression and Parietal Atrophy
Healthy individuals Normal eye-tracking and fixation on mostly relevant aspects of the scene PCA patients (poor top-down guidance and control of saccadic movements) (1) May fixate on relatively uninformative aspects of the scene (2) May miss important contextual information Source: Crutch SJ, et al. The Lancet Neurology. February 2012, Vol.11(2):170 178.
Neuropsychological Testing SCALED SCORES Test EIWA-III (1) WAIS-III (2) Full Scale IQ Verbal Comprehension 84 (80-88) 14% Below average 95 Working Memory 98 Perceptual Organization Processing Speed 83 87 74 (70-79) 4% Borderline 82 Below average 82 Below average 70 Borderline 76 Borderline (1) EIWA-III standardization for Puerto Rico, a translated version of WAIS III, consists of 330 adults divided in 3 age groups (16 to 19, 20 to 44 and 60 to 64). The sample used the 2000 Puerto Rico census and it is stratified by educational level). (Manual de Administración y Puntuación. (2) WAIS-III was normalized using a representative U.S. sample of 2,450 adults. Hispanic subjects represented 12-13% of the test's normative sample. Standardization and Norms Development, p. 19-35). SCALED SCORES Test EIWA-III (1) WAIS-III (2) Verbal IQ 86 Below aver. 81 Below aver. Verbal Comprehension Vocabulary Similarities Information Working Memory Arithmetic Digit span Letter-Number Sequencing Performance IQ 82 Below aver. 70 Borderline Perceptual Organization Picture Completion Block Design Reasoning Matrix Processing Speed Digit Symbol-Coding Symbol Search 11 8 8 9 10 10 9 8 4 7 8 Average scores = 9 11 8 5 7 6 7 8 5 6 4 5 6
Neuropsychological Testing Relatively preserved episodic memory Significant problems with attention and other executive functions GENERAL COGNITIVE FUNCTIONING Test Score Range MMSE 20/ 30 Dementia MOCA 14 / 30 Dementia INECO Frontal Screening 15.5 / 30 Frontal deficits Dementia Rating Scale (DRS-2) Initiation / Perseveration California Verbal Learning Test II (CVLT-II) Short-Term Free Recall Short-Term Cued Recall Long-Term Free Recall Long-Term Cued Recall Total Learning Curve (1-5) COWAT Verbal Fluidity (Total) Animals Fruits Vegetables Trail A Trail B Wisconsin Card Sort Total errors Non-perseverative errors Conceptual answers Completed categories SS (standard score): 3 MEMORY FUNCTIONS -1 1-1 1-1 VERBAL FUNCTIONS 13 10 8 7 EXECUTIVE FUNCTIONS 67 sec - < 55 93 < 55 0 / 6 PE 3; 1% Severe Below average High average Below average High average Below average Severe Borderline Below average Below average Severe Severe 1% Severe 47% 1% Severe Severe
Most Significant Deficits NEUROPSYCHOLOGICAL TESTING Function Cognitive Test Level of Impairment Visuo-spatial processing EIWA-III Matrix subset MOCA cube & clock drawing MMSE pentagons Trails A (67 sec) & B (-) (visual tracking) Moderate Spatial memory INECO Spatial Working Memory subset Moderate Non-Visual Executive functions: Cognitive flexibility Planning Sustained & divided attention Memory & Learning Verbal fluency, naming, comprehension INECO Motor Series (motor programming) INECO Go-No-Go (inhibitory control) Wisconsin Card Sorting Test DRS-2 Initiation/Perseveration subset EIWA-III & INECO Frontal Screen CVLT-II COWAT Verbal abstraction tasks Moderate Mild Mild
Management & Outcome Developments 1-year following DX Improvements seen and reported Retirement Voluntarily stopped driving Acetylcholinesterase inhibitor Memantine Relocation to Central Florida Overall functioning and cognition MOCA = 23 / 30 (from 14 / 30) Except for episodic memory & visuospatial abilities -1 clock number placement -1 cube copy -4 recall Quality-of-life Anxiety & depressive symptoms Successful regime reductions Quetiapine discontinued Clonazepam reduced
Before Rx 01 / 2013 Age 54 After Rx Improved 10 / 2013 Age 55
Case Summary Premorbid chronic atypical neuropsychiatric disorder (bipolar disorder features) Metabolic syndrome Possible familial early-onset dementia pattern APO E4 risk factor Early-onset insidious degenerative disorder L > R (dorsal) parietal atrophy and hypometabolism Spared medial temporal lobe Pre-existent HFI compressing prefrontal areas Visuospatial + non-visual executive deficits Subjective and objective response to usual AD Rx But episodic retrieval-verbal recall deficits are worsening over time Without obvious hippocampus pathology
3. PCA Patients Special Needs Neuro-ophthalmologic evaluation Elements of Balint syndrome like simultagnosia (visual field perception), optic apraxia (reaching using vision), oculomotor apraxia (fixating eyes) Registration for financial and social benefits and services (SSDI, pension, DOT, etc.) Early safety measures (driving, machinery) Occupational therapy / sensory team evaluation Assistive equipment for the visually impaired (simplified displays, talking books and watches) Peer-support groups and psychotherapy Take advantage of the preserved memory and insight Neuropsychological testing Tests relying on intact vision are not valid Memory tests/tasks will underestimate clinical progression This & other PCA phenotypes may resemble frontal lobe syndromes
4. Discussion CASE PCA HFI Demographics 54 y/o MALE with metabolic syndrome Early-onset Post-menopausal, diabetic FEMALE Posterior atrophy & hypometabolism YES YES NO Visual processing problems Spatial memory Visual tracking (21) Visual perception Spatial memory Visual attention Visuospatial reasoning Possibly via FEF compression Frontal atrophy No functional evidence yet YES, in later stages Possibly via frontal compression Working memory YES Superior Parietal lesions (19) Both spatial & non-spatial (10), via DLPFC compression Episodic memory / retrieval Relatively preserved But worsening Relatively preserved, but often progressive Inferior PL (22) NO Other non-visual executive functions Cognitive flexibility Planning Sustained & divided attention Motor programming No evidence (21) Dorsal & Ventral PPC (22) Goal directed and reflective attention No evidence Neuropsychiatric syndrome Atypical Bipolar Anxiety syndrome (20) "Hyperactivity syndrome" in AD (16) (agitation, irritability, aberrant motor behavior, euphoria, and disinhibition) Depression, if any
Anterior and Inferior Parts of the Intra-Parietal Sulcus visual search in the absence of distractors (R) Temporo-Parietal Junction multisensory attention to a change in relevant information Functional Anatomy of the Parietal Cortex Superior Parietal Lobule top-down (goal-directed) spatial shifts in attention & working memory Precuneus (Medial PL) top-down (goal-directed) non-spatial shifts in attention Inferior Parietal Lobule & Inferior Parietal Sulcus episodic retrieval (22) Behrmann M, et al. Parietal Cortex and Attention. Curr Opin Neurobiol 2004. 14:212 217. (23) Hutchinson JB, et al. Posterior parietal cortex and episodic retrieval: Convergent and divergent effects of attention and memory. Learn Mem. 2009;16: 343-356
References 1. Du, A-T, et al. Brain 2007; 130(4):1159-1166. 2. Kemp PM, et al. J Neurol Neurosurg Psychiatry 2003; 74:715-719. 3. Berthier ML, et al. J Neurol Neurosurg Psychiatry 1991; 54:1110-1111 4. Hof PR, et a. Acta Neuropathol 1993; 86(3):215-223. 5. Ross SJ, et al. J Neurol Neurosurg Psychiatry 1996; 61:388-395. 6. Galton CJ, et al. Brain 2000; 123(3):484-498. 7. Crutch SJ, et al. Alzheimer s & Dementia 2013; 1-3. 8. Lehmann M, et al. Alzheimer s Dement 2012; 8:502-512. 9. Attanasio F, et al. J Clin Endocrinol Metab 2013; 98(2):453-457. 10. de Zubicaray GI, et al. J Neurol Neurosurg Psychiatry 1997; 63(3):309-314. 11. Paulus KS, et al. Neurol Sci. 2002;22:459 462. 12. Thomas G, et al. BJM Case Reports 2012; doi:10.1136/bcr.07.2011.4439 13. de Souza LC, et al. Brain. 2011 Jul; 134(Pt 7):2036-43. 14. Sitek EJ, et al. PLoS One. 2013; 8(4): e61074. 15. Quiroz YT, et al. J Neurol Neurosurg Psychiatry. 2013 ; 84(5):556-61. 16. Balthazar ML, et al. Hum Brain Mapp. 2014; 35(4):1237-46. 17. Snowden JD, et al. Cortex 2007; 43(7):835 845. 18. Crutch SJ, et al. The Lancet Neurology. 2012; 11(2):170 178. 19. Koenigs M, et al. The Journal of Neuroscien. 2009; 29(47):14980 14986. 20. Everhart DE, et al. Applied Neuropsychology: Adult. 2012; 19(3):229-236. 21. Aresi A, Giovagnoli AR. J Alzheimer's Disease. 2009; 18(1):65-70. 22. Berhmann M, et al. Curr Opin Neurobiol. 2004; 14:212-217. 23. Hutchinson JB, et al. Learn. Mem. 2009; 16: 343-356