Casebook of Clinical Neuropsychology Edited by Joel E. Morgan Ida Sue Baron Joseph H. Ricker OXFORD 201149 Early-Onset Alzheimer Disease Ruth E. Yoash-Gantz Early-onset Alzheimer disease (EAD) is defined as onset prior to age 65. As reported in 2007, incidence of early-onset dementias in the United States, including EAD was 200,000 to 500,000 people (Alzheimer's Association, 2007), Harvey, Skelton-Robinson and Rossor (2003) report a prevalence figure for EAD (45-64 age group) as 35 per 100,000 people based on an epidemio- logical catchment area prevalence survey in several London boroughs. These rates are comparable to those obtained in the Northern Health Region study (34,6; Newens et al, 1993), the Framingham study (31.8; Kokmen, Beard, Offord, & Kurland, 1989), and Finland (32.7; Sulkava et al, 1985). Neuropsychological profiledifferences between EAD and late-onset Alzheimer disease (LAD) remain unclear. Studies in the 1980s and 1990s, prior to genetic and neuropathology discoveries, generally concluded there were clinically distinct profiles. Filley, Kelly, and Heaton (1984) noted greater impairment in Verbal 1Q than Perfor- mance 1Q Loring and Largen (1985) found that an EAD group had greater deficits on age- adjusted tests of sustained concentration and mental tracking than did an LAD group. Others (Jacobs et al., 1994; Kono, Kuzuya, Yamamoto, & Endo, 1994; Seltzer & Sherwin, 1983) found that EAD had more frequent language impairment, consistent with Filley et al. (1986). Noted focal degenerative changes included naming, praxis, calculation (left hemisphere; Haxby et al, 1990), executive dysfunction and behavior dysregula- tion (frontal lobes; Johnson, Head, Kim, Starr, & Cotman, 1999), and visuospatial loss (right pari- etal lobe; Benson, Davis, & Snyder, 1988). More recent comparative findings of cognitive profiles in EAD and LAD have been mixed, Caine and Hodges (2001) found that cortical visuospatial functions are more impaired in EAD than in LAD. Suribhatla etal. (2004) found that after adjusting for overall dementia severity and premorbid 1Q, there was greater frontopari- etal/right hemisphere involvement in EAD and greater temporal/left hemisphere involvement in LAD and they hypothesized these differences may be related to age of onset of AD and corre- sponding genetic risk profiles. Licht, McMurtray, Saul, and Mendez (2007) compared EAD with very LAD and found preferentially impaired verbal fluency and motor-executive deficits in the LAD group, but differences disappeared when age was considered. ‘They did not find dis proportionate language or visuospatial deficits in EAD compared with LAD, Mendez (2006) discussed three potential diag- nostic errors in early-onset dementias. Although. EAD is the predominant cause of early onset dementia, there are numerous other causes, Sec- ondly, the traditional model of LAD is charac terized by prominent memory difficulty and word-finding problems, but EAD may have pre- dominant cognitive deficits other than memory Joss. Finally, EAD may present with greater neu- ropsychiatric than cognitive deficits, Several studies have noted different progres- sion rates for EAD than for LAD. ‘These studies have found a greater rate of decline in EAD than 533534 in LAD (Jacobs et al, 1994; Kono et al., 1994; Seltzer & Sherwin, 1983). More recently, Greicius, Geschwind, and Miller (2002) reported that disease progression in EAD is sometimes more rapid than in LAD. Consensus on the clinical diagnosis of Alzheimer disease was reached in 1984 with the development of the NINCDS-ADRDA criteria (McKhann et al., 1984), and these criteria con- tinue to be applied in the diagnosis of both EAD and LAD. Advances in neuroimaging and neu- ropathology have been useful in increasing diag- nostic accuracy. Positron emission tomography (PET) scans and neuropathology suggest more severe deficits in parietal areas in EAD than in LAD (Frisoni et al., 2005; Kemp et al., 2003). Due to these and other scientific advances in neuropathology and neuroimaging, proposed new guidelines have recently been published (Dubois et al., 2007). The goal of the proposed guidelines is to define the clinical, biochemical, structural, and metabolic presence of AD, rather than relying on traditional functional measure- ment and effort to determine etiology. Genomics has uncovered differences between EAD and LAD. Cases of EAD are more likely to have a genetic etiology than are cases developing after age 65 (Lleo et al., 2002), which are mostly comprised of sporadic occurrence (no genetic risk factor). Three genes have been associated with EAD, each seeming to correspond with a somewhat different age of onset (Lovestone, 1999). The presenelin-I (PS-1) gene on chromo- some 14 has been associated with onset between ages 30 and 40 years, and mutations in this gene were found in 95 of 101 cases with onset before age 35 (Filley et al, 2007). The amyloid precur- sor protein (APP) gene on chromosome 21 is associated with onset between ages 40 and 50 years. Finally, the presenelin-2 (PS-2) gene on chromosome 1 is associated with onset between ages 50 and 65 years. The Case of Mr. Smith Mr. Smith was referred for evaluation by his pri mary care provider following concerns raised by his wife regarding declining memory. At the time of evaluation, Mr. Smith was a 65-year-old, married, right-handed, Caucasian male with 16 years of formal education, He was a minister Neurodegenerative Disorders for many years, retiring early due to cognitive deficit the year prior to this evaluation; he wag unable to write or deliver sermons. He was living at home with his full-time employed wife, ang they had four adult children assisting in care, ‘Mrs. Smith provided most of his personal his. tory; he was unable to recall most of his adult life, including his 30+ years as a minister, Mr. Smith had normal developmental milestones as reported by his wife. He was honorably dis- charged from 2 years of noncombat service in the Army. ‘Mr. Smithis medical diagnoses at time of eval- uation included diabetes mellitus (treated with oral hypoglycemic) and essential tremor. He had no history of head injury or other insult to the brain, Cognitive decline began 5 years prior to the current evaluation. He had undergone dementia evaluation 2 years prior to this exam and magnetic resonance image (MRI) of the brain at that time was negative. He was placed on Aricept, became weak, and the medication was discontinued. Those outside records were not available. Mrs, Smith reported his strong family history of “memory loss” including his mother, two maternal aunts, and a recently deceased brother. Mr. Smith was receiving ongoing pri- mary care. Medications at the time of evaluation included paroxetine, glyburide, propranolol, and buspirone. 1 ‘Mr. Smith had no history of psychiatric diag: nosis, treatment, or hospitalization. He denied auditory or visual hallucinations. He denied depression or mania. He reported occasional anxiety and confusion “once in a great while” He had no history of alcohol or other substance use, including tobacco. Mrs. Smith reported he had a gun at home but neither of them knew its location, Mr. Smith was independent in four out of six activities of daily living (ADIs) at the time of evaluation. He needed reminders to bathe as his personal hygiene had declined, and he needed assistance in dressing. In the prior year, he had developed balance instability and began stum- bling and falling, but there was no report of injury to the head. He was dependent on others for almost all instrumental activities of daily living (IADLs). He was no longer driving. He spent his days at home alone and called his wife at work approximately 10 times per day, askingEarly-Onset Alzheimer Disease where she was (despite having called her work phone number). Mrs. Smith reported that often she returned home from work to find things broken or missing. He was able to do light house- keeping only, but no cooking. He used a gas heater but tended to leave it on and unattended. ‘Mrs. Smith reported that he was beginning to become increasingly confused toward the latter part of the day, often changing into pajamas in the late afternoon. On interview and observation, Mr. Smith appeared to be physically fit, was dressed in casual clean clothing, and his hygiene was good. He carried two broken pairs of glasses in his pockets. He did not wear hearing aids, He ambu- lated independently and gait appeared normal, He had poor ability to do alternating movements and was unable to maintain balance during tandem walking. Mr. Smith was polite during testing despite becoming increasingly uncoop- erative. He often stopped answering questions, stood up, and left the testing room: Testing was eventually discontinued, He fatigued casily. Mood was euthymic and affect was quite labile. He appeared quite anxious at times and seemed to cover his confusion with attempts at humor. Spontaneous language was fluent without para- phasic/dysarthric speech error, There was sig- nificant word-finding difficulty. He had poor ability to attend to tasks, was very easily con- fused, and had poor ability to maintain a mental set or understand test instructions. He was ori- ented to name only. He stated his age was 230.” then “62.” He was unable to recall date of birth. He did not recall attending 4 years of college or working lifelong as a minister, Instead, he stated he worked in a steel mill, an occupation he held prior to entry in the military. He stated he had . 535 six children instead of four, and he could not remember their names or ages, He was unable to name any US. Presidents since 1960. He was unable to recall any current events. Mr. Smith was administered the following tests: Repeatable Battery for the Assessment of Neurop- sychological Status (RBANS), Boston Naming Test, Controlled Oral Word Association Test (COWA), Greek Crosses, Clock Test, Wechsler Memory Scale-Revised (WMS-R, Mental Control only), Stroop ‘Test, Trail Making Test (TMT), Finger Tapping Test (FT; unwilling), Hand Dynamometer (HD; unwilling), Geriatric Depression Scale (GDS), Clinical and Caregiver Interviews, and Review of Records, Test Findings Mr. Smiths behavior and functional level limited the extent of testing. (see Table 49-1). Given Mr. Smith's presentation during the clinical interview, it was clear that dementia was the likely diagnostic category (obvious learning/ memory impairment, obvious impairment in another cognitive domain, obvious functional decline). ‘The goal of testing was to document level of severity and to determine type of demen- tia, The RBANS was selected as an initial screen- ing measure due to its normative base and because the patient was college educated. ‘The Dementia Rating Scale was considered; however, there were concerns that the patient may hit the ceiling on several of the subtests, thus obfuscat ing results Mr. Smith had overall moderately severe cere- bral dysfunction of a diffuse nature on the focused test battery. He refused motor testing (Finger Tapping and Hand Dynamometer); thus, Table 49-1. Test Scores Tet - Score RBANS (Index Scores) “1192 Total Scale SS =45 22-299 Immediate Memory ss=40 WMS-R Mental Control T=00 Visuoconstruetion Greek Crosses Language SS=57 Clock Test (Sunderland system) Raw=4 Attention $S= 60 Stroop-Word T<20 Delayed Memory ss=40 Color r<20 TMT-Part A T<20 Color Word T=20 Part B _T<18 Gps Raw=2Sanaa F i 536 information ‘regarding possible hemispheric lateralization was not available. Although it is unlikely to see such lateralization with EAD, it is preferable that testing include brief evaluation of, motor/sensory testing to rule out diagnoses associated with lateralized deficits (e.g., cerebro- vascular disease in this case), Mr. Smith's RBANS performance was mark- edly impaired; Attention and Language domains were least impaired. Learning (RBANS, List Learning, Story Memory) was severely impaired; he lost set on Story Memory and began telling a story about a girl he knew in school. On retrieval tasks (RBANS, List Recall, Story Recall, Figure Recall), he demonstrated the rapid rate of initial forgetting characteristic of Alzheimer disease. Recognition memory was fraught with false- Positive responses, another memory characteris tic typical for Alzheimer disease, Because these patients have minimal memory storage, and little ability to retrieve from storage, they tend to respond in the affirmative when given a yes/no format. Mr. Smith’s expressive language functioning was also markedly impaired, Word-finding difficulty was noted during the interview, Con- frontation naming (Boston Naming ‘Test) was severely impaired, with a raw sore of 25/60 (z = -11,92), including 24 spontaneous correct responses and one additional from stimulus cue. Errors included “octopus” for helicopter, “crutches” for stilts, “gallatin” for noose, and “an active tar” for volcano, Category fluency (RBANS, Animal Nami ing, (z = -3,40) was mod- erately severely impaired and letter fluency (COWA, z = -2.99) was moderately impaired. Mr. Smith had severely impaired visuo- spatial performances. He performed within the severely impaired range on a test of construc- tional praxis (Greek Crosses, see Figure 49-1). When asked to draw a clock face, he drew a circle (a) Neurodegenerative Disorderg: and inserted seven two-digit numbers in the area of the clock face from 3:00-7:00. "Then, he drew the numbers 15 to 20 outside the clock = (Clock Test, see Figure 49-2). This was a sever impaired performance. Mr. Smith’s executive functioning was alsy severely impaired. He performed within thi range on tests of perceptual set shifing (Stroop ‘Test) and efficiency in following new sequential procedures (‘Trail Making Test). He was unable to establish or maintain a mental set. Although overlearned social judgment was adeqiiate early in testing, his confusion and paranoia quickly led to disinhibition, agitation, and impulsivity, He demonstrated poor novel judgment and insight. . Mr. Smith did not endorse symptoms of depression on the GDS, consistent with his his: tory. He was somewhat suspicious of the testing environment due to his confusion, Discussion ‘The pattern of Mr. Smith's test performances together with his medical history and family his- tory indicate likely EAD. His frequent falls and mild bilateral upper extremity tremor are not inclusive or exclusive signs of AD. His severely ~ impaired visuospatial and memory functions and moderately to severely impaired language functions were consistent with AD. Further- more, the progression of his ADL/IADL decline was quite steep and consistent with the presenile ~ (prior to age 65) form of AD. Efforts to schedule the feedback session via telephone to the Smith home resulted “in - ‘Mr. Smith disconnecting the call, either due to suspicion or to impaired procedural memory regarding use of the phone, Mrs, Smith was contacted at work to arrange the appointment. Mr. Smith was very defensive, denied memory Figure 49-1, (a) Mr. Smith’ first attempt at copying Greek Cross, (b) second attempt, (c) and copy of Greek Cross stimuliEarly-Onset Alzheimer Disease is te $y TE 1G se Figure 49-2. Mr. Smith’s drawing of a clock face from memory. Note the loss of set with numbers advancing beyond those found on a clock, and extending outside the border of the clock, problems, and became easily agitated when diag- nosis was presented. He was taken to another room to chat with the technician so that the examiner could focus attention on educating Mrs. Smith and discussing recommendations. Recommendations included refraining from driving, removing all guns from: the home, removing the gas heater from the basement, rou- tinely assessing home environment for needed modifications to ensure safety, removing all medications (including those for pets) to a safe location, monitoring morning glucose by Mrs. Smith before leaving for work, obtaining Safe Return Kit and caregiver support from the Alzheimer’s Association, referral to VAMC Eldercare Team for ongoing monitoring and tance, consideration of trial of another cho- linesterase inhibitor, and geiting legal affairs in order (powers of attorney, Living Wills, etc.) Note that there was no recommendation for brief written notes and reminders; Mr. Smiths level of confusion would negate benefit from these ‘measures and could add to disruptive behavior. Mr. Smiths rate of decline continued over the next year, An MRI of the brain 1 month after evaluation noted moderately pronounced atro- phy and mild microvascular white matter dis ease. Mr. Smith entered the home of an elderly female neighbor and was hostile toward her, accusing her of conspiring against him. Trials of other cholinesterase inhibitors were ineffective. Mr. Smith began wandering from the home and flagging down passing cars, looking for his wife. He became incontinent. He had two brief adult daycare placements that failed due to agitation. ‘Mr. Smith was intolerant of nonfamily care pro- 537 viders and they did not qualify for VA Aid and Attendance for Mrs. Smith to be the primary paid caregiver. The daughters provided care when they were not working. Mrs. Smith pur- sued guardianship. ‘Mr. Smith was admitted to the VA dementia care unit within 14 months of the evaluation. He ‘was 67 years old. On admission, motor agitation and aggression were noted to increase across the course of the day. Within 6 months, he was non- ambulatory and dysphagic, was oriented to name only, was unable to respond to Scripture pas- sages, and was dependent for all ADLs. Family continued to be very involved in his care. Aggressive behavior continued and multiple medication trials were attempted. Nutritional status became compromised with significant loss of weight. Expressive language ceased. He suc- cumbed to several respiratory infections. He expired 4 years and 8 months after diagnosis at the age of 70. Conclusion Mr. Smith’ case is considered prototypical of EAD. Symptoms began at approximately age 60 with a reverse chronological loss of autobi graphical information. He had a strong family history of “memory loss” in two first-degree and two second-degree relatives, ‘The rate of decline rapidly increased over time and was significantly complicated by psychiatric and behavioral dis ruptions. Mr, Smith was physically robust at the time he was admitted for long term-care at age 67, but his paranoia had become increasingly problematic at home. While such behavioral dis turbances are common causes of institutional- ization of most dementia patients, EAD patients are generally physically stronger, thus creating tougher management issues for the caregiver. Mr. Smith’s pattern of cognitive decline is consistent with EAD. At the time of this evalua- tion, reportedly 5 years affer onset, he no longer recalled much of his adulthood. Verbal fluency measures noted the typical ‘cortical dementia” pattern with greater category/seman. tic impairment than letter/phonemic impair- ment. This is believed to be due to the loss of acetylcholine affecting “memory for words? which are generally stored semantically rather than phonemically,538 ‘Mr. Smith’ visuospatial performance was also severely impaired with inability to produce fairly simple geometric figures (Greek Crosses). His loss of mental set and lack of recall of a clock face on the Clock Testis also consistent with AD. ‘Mr. Smith’s learning and memory pattern is consistent with AD. He demonstrated very poor acquisition of new verbal information and a rapid rate of initial forgetting. He was unable to recall any information following the delay, and recognition memory was replete with false- positive responding. Visual memory was also characterized by loss of all information; often these patients will deny that they were exposed to the stimuli, Executive performance among EAD patients is typically fraught with inability to maintain a mental set. Mr. Smith completed Trails A slowly but without error. He was unable to complete ‘Trails B; after numerous clarifications by the ‘examiner, he was able to complete only six con- nections in 8 minutes. He was unable to respond correctly to any items on the Stroop Color/Word task. 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