1. HPI A 73-year-old woman is brought to your practice by her husband who is concerned for his wife’s well-being. He explains that for the past few months he has noticed a severe decline in his wife’s short term memory. At first he attributed this to “normal aging”, but has recently noticed that has become less involved in her bridge club and rarely leaves the house. Of most concern, however, is a recent episode in which his wife had been preparing a meal for their son’s visit and had left the gas stove on for several hours unattended. What other questions would you like to ask?

2. HPI Medical Hx: Tonsilectomy (1948), Hysterectomy (1989) Family Hx: Mother suffered from dementia and HTN, Father had HTN and CAD Social Hx: Married 55 years, 2 children, works as a substitute teacher What is your differential diagnosis?

3. Differential Diagnosis MCI Dementia – Alzheimer’s disease – Vascular dementia – Mixed dementia – Dementia with Lewy bodies (DLB) – Frontotemporal dementia (FTD) Depression (“Pseudodementia”) Hypothyroidism Normal pressure hydrocephalus (NPH) Infection – Neurosyphilis Head trauma – Chronic subdural hematoma Side effect of medication Vitamin deficiency – B12 What is your next step in assessing the patient?

4. Physical Exam Vitals: – BP 115/48 – T 37.3 – RR 22 Gen: The patient is calm and cooperative CV, Resp, abdominal exams: all wnl Psych: negative depression screen Neuro: – alert and oriented to person and place, unable to name the day of the week. – Registration 3/3, recall 0/3 at 5 minutes – Unable to recall what the patient ate for breakfast this AM – MMSE: 21/30 – Speech is fluent and appropriate in content – CN II-XII grossly intact – Motor: Strength 5/5 proximal and distal bilateral upper and lower extremeties – Sensory: intact to light touch, pinprick, and vibration throughout – MSRs 2+ and equal in upper and lower extremeties – Downgoing plantar response bilaterally – No resting or intention tremor – Tone normal (no rigidity) – Gait is smooth; not wide-based

5. Laboratory tests CBC: normal WBC: 6,000 TSH: 2.7 uU/mL (normal) Free T4: normal B12: 816 pg/mL (normal) VDRL/RPR: negative What would you like to do next?

6. MRI MRI can detect patterns of cerebral atrophy suggestive of various neurodegenerative diseases. In AD, cortical atrophy is seen as accentuation of the sulci and is localized most commonly to the frontal, temporal, and parietal lobes. Commonly, hippocampal atrophy is seen. What does this pattern of atrophy suggest? What further testing can we perform?

7. Neuropsychological Tests Tests were preformed in order to identify lapses in cognitive function and abilities. Patient was found to be profoundly affected by short-term memory loss, testing in the 3 rd percentile. The patient was asked to draw a clock face displaying a time of 2:45. The patient scored a four based on the following scale:

8. Alzheimer’s Disease AD is the most common cause of dementia (~50%) Alzheimer disease (AD) is a neurodegenerative disorder of uncertain cause and pathogenesis that primarily affects older adults. The main clinical manifestations of AD are selective memory impairment and dementia. AD symptoms are likely a result of the accumulation of neuritic (senile) plaques as well as neurofibrillary tangles. How would you like to proceed with this patient?

9. Histological interpretations Light micrograph of human brain tissue in Alzheimer's disease, showing a senile plaque (pale area in center), a characteristic histological feature of the disease. Alzheimer's disease is a form of progressive dementia; the brain is smaller than normal, with degenerative changes affecting the frontal and temporal lobes. Senile plaques are extracellular tangled masses of filaments & granules, often centered around an area of amyloid beta. Amyloid beta is derived from the larger protein amyloid precursor protein (APP) located on chromosome 21. Other genes associated with AD are presenilin 1 and 2. The main other feature of Alzheimer's disease is the formation of neurofibrillary tangles, masses of thickened filaments in the cytoplasm of neurons (nerve cells).

10. Histological features cont’d Neurofibrillary tangles are bundles of filaments in the cytoplasm of the neurons that displace the nucleus. They are composed of abnormal tau protein (tauopathy), which normally acts as a microtubule stabilizing protein. In pyramidal neurons, they often have an elongated flame shape, as demonstrated in this slide.

11. Treatment While treatments are available that can modulate the course of the disease and/or ameliorate some symptoms, there is no cure, and the disease inevitably progresses in all patients. Most treatments are designed to augment the neurotransmitter acetylcholine. Acetylcholinesterase inhibitors (Aricept) are the only drugs that are known to slow the progress of AD-related memory loss. NMDA glutamate receptor antagonists (memantine/Namenda) are also commonly used to slow the progression of AD. Antidepressants and antipsychotics are frequently employed to treat behavioral disturbances.

12. Summary The patient and her husband were given information on the disease and some symptoms that might manifest as its progression continues. Language deficits, loss of mathematical skills and eventual loss of learned motor skills are commonly found in late-stage AD. In final stages, patients may become incontinent, mute, or unable to walk.

13. Neuropsychological Testing Role in Diagnosis Helpful in the evaluation of individuals with cognitive impairment and dementia. Cognitive testing under standardized conditions using demographically appropriate norms is more sensitive to the presence of impairments, especially impairments of executive function. Can establish a baseline in order to follow the patient over time. Neuropsychological assessment can also help differentiate between dementia and depression. Can assess competencies and guide recommendations pertaining to driving, financial decisions, and need for increasing supervision