KI course /19/2012. Dementia. Clinical aspects. FRANCESCA MANGIALASCHE MD, Geriatrician, PhD candidate

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1 Dementia Clinical aspects FRANCESCA MANGIALASCHE MD, Geriatrician, PhD candidate Aging Research Center, Karolinska Institutet, Stockholm, Sweden Perugia University Department of Gerontology and Geriatrics, University of Perugia, Italy 1 What is dementia? De mens = without mind Dementia: an acquired clinical syndrome characterized by the development of multiple cognitive deficits that are severe enough to interfere with daily life/functioning, including social and professional functioning. (DSM-IIIR, APA 1987) 2 1

2 What is dementia? Cognitive impairment (memory, abstract thinking, judgement, language, executive function, visuospatial abilities) Behavioural problems (anxiety, depression, agitation, delusions, hallucinations, psychosis) Functional disability Brain disease(s) Distribution of brain damage Different combination of signs and symptoms Different progression Different prognosis 3 Cognitive continuum NORMAL DEMENTIA DEMENTIA 4 2

3 Brain Aging Cognitive continuum Age Associated Memory Impairment (AAMI) Age Related Memory Decline (ARMD) Age Related Cognitive Decline (ARCD) Benign Senescent Forgetfulness (BSF) Cognitive Impairment No Dementia (CIND) Memory Impairment Mild Cognitive Disorder (MCD) Mild Cognitive Impairment (MCI) Mild Neurocognitive Disorder (MND) Questionable dementia (QD) Dementia 5 What causes dementia? Neurodegenerative diseases Alzheimer s disease (AD) Lewy Body dementia (LDB) Frontotemporal dementia (FTD) Vascular dementia Dementia due to treatable illnesses Toxic disorders (alcohol, drugs) Nutritional deficits (B12, folate)) Infections disorders (HIV, Lyme disease, Syphilis) Brain tumors Depression Hydrocephalus 6 3

4 Cognitive continuum DEMENTIA Alzheimer s AD disease Vascular dementia VaD Both vascular and degenerative diseases often contribute to the development of dementia among the elderly Viswanathan et al., Neurology Dem entia Incidence per 1000 personyears Gao et al, 1998; All continents Fratiglioni et al, 2000; Europe Birth Childhood- Adult life- 10 Old 0 2 nd decade Middle age 0 Transition age Dementia Prevalence per 100 Fratiglioni et al, 1999; All continents Lobo et al, 2000; Europe In the general population 70% of the patients with dementia are over 75 years old 8 4

5 Clinical aspects of Vascular dementia and Alzheimer s disease 9 Vascular dementia (VaD) Large vessel VaD Small vessel VaD (Subcortical VaD) Multi-infarct VaD Strategic-single infarct VaD Hypoperfusion Hemorrhagic VaD Roman et al., Neurology

6 Vascular dementia (Vad) Large vessel VaD Multi-infarct VaD Strategic-single infarct VaD Infarcts in the right dorsolateral frontal region and the bilateral posterior parietal regions (T1-weighted axial MRI). Small infarcts involving the anterior dorsomedial nucleus of the thalamus bilaterally (T1-weighted axial MRI). 11 Black., J R Coll Physicians, 2011 Vascular dementia (Vad) Small vessel VaD (Subcortical VaD) Obliteration and occlusion, resistance, autoregulation, endothelial changes in small vessels Image from Westman E Sub-cortical brain changes: ischaemic white matter lesions (WMLs) and lacunar infarcts (T2-weighted MRI). 12 6

7 Clinical features: Vascular dementia Abrupt onset Stepwise progression Focal neurological signs or symptoms History of cerebrovascular disease and risk factors Cognitive: Impaired executive functions; Spotty deficits Criteria for diagnosis: 1. Dementia 2. Cerebrovascular disease 3. A relationship between the above two disorders 13 Alzheimer s disease (AD) Most common cause of dementia (?) Pathogenesis not yet clear 3 neuropathological hallmarks: Amyloid-rich senile plaques Neurofibrillary tangles Loss of neurons and synapses These changes begin years before the onset of symptoms 14 7

8 Alzheimer s disease (AD) Amyloid-hypothesis: neuritic plaques 1. Aβ production 2. Aβ aggregation 3. Aβ accumulation APP: Amyloid Precursor Protein Aβ Neuritic plaques (Senile plaques) sappα sappβ β-secretase (BACE1) Aβ α-secretase Aβ γ-secretase 15 Alzheimer s disease (AD) Tau hypothesis: Neurofibrillary tangles Cell skeleton Neurofibrillary tangles (NFTs) 16 8

9 Alzheimer s disease (AD) Early Mild-Moderate Early Learning and memory Thinking and planning Mild-Moderate Speaking and understanding speech Your sense of where your body is in relation to objects Severe Severe Severe impairment of different cognitive functions 17 The Progress of Alzheimer s Disease 30 Early diagnosis Mild-moderate Severe Cognitive symptoms 25 MMSE score Loss of functional indipendence (ADL) Behavioral problems 5 Nursing home placement Death Years Feldman H, Gracon S. In: Clinical Diagnosis and Management of Alzheimer s Disease. 1996:

10 How do we diagnose Alzheimer s disease? Personal history (subject and proxy) Physical examination (neurological examination) Neuropsychological testing Functional status Blood test (vitamin B12, folic acid, thyroid function) Neuroimaging (morphological, functional) CSF 19 AD DSM-IV criteria A. Multiple cognitive deficits manifested by both: 1. Memory Impairment 2. One (or more) of the following cognitive disturbances: Aphasia, apraxia, agnosia, and disturbances in executive functioning (e.g., planning, abstracting, organizing, sequencing) B. Cognitive deficits cause significant decline in social or occupational functioning and represent a decline from previous levels of functioning. C. The course is characterized by gradual onset and continuing cognitive decline. D. The cognitive deficits are not due to other CNS conditions or systemic conditions known to cause dementia. 2 STEPS, EXCLUSION DIAGNOSIS! 20 American Psychiatric Association,

11 In-vivo diagnosis of Alzheimer disease Presence of Dementia (a syndrome) + Exclusion of other causes of the dementia syndrome Brain Imaging 21 AD clinical diagnostic criteria Clinical AD AD Neurophatology Clinical atypical presentation Extensive AD neuropathology in asymptomatic subjects 22 11

12 Diagnosis of Alzheimer disease: morphological neuroimaging AD brain Cortical atrophy and athrophy in the medial temporal lobes (T1-weighted MRI). Normal brain (T1-weighted MRI). Images from Westman E 24 12

13 Diagnosis of Alzheimer disease: functional neuroimaging Positron emission tomography (PET): 18 fluorodeoxyglucose 18 FDG uptake: biomarkers of neuronal degeneration In AD patients the affected brain regions include: Hippocampus, Posterior cingulate cortex Temporoparietal regions CMRglc mmol/min/100cc High Frontal cortex Low Healthy Subject Alzheimer Patient Image from Westman E 25 Diagnosis of Alzheimer disease: functional neuroimaging Positron emission tomography (PET): [ 11 C] Pittsburgh Compound B (PIB) [ 11 C] PIB uptake: biomarkers of brain β-amyloid deposition HC: healthy control; AD: Alzheimer s disease Rowe te al., Neurology

14 Brain imaging in prognosis: PIB retention in MCI converter and non-converter AD: Alzheimer s disease; HC: healthy control; MCI: mild cognitive impairment Forsberg et al Neurobiology of Aging AD Treatment Disease modifying drugs: work in progress βamyloid Tau Mangialasche et al., Lancet Neurol 2010 Cholinergics Others 28 14

15 AD Treatment Disease modifying drugs: role of functional neuroimaging Anti-amyloid drug 11 C-PiB PET images from patients treated with bapineuzumab (A, B) and placebo (C, D) in a RCT. Changes from screening (baseline) to week 78. (Mean 11 C-PiB PET changes are shown at the top centre of each panel for each patient). Rinne et al., Lancet Neurol Conclusions Dementia is among the most common chronic disorders in older adults AD and VaD are the most common causes of dementia, with mixed dementia (AD+VaD) being common in very advanced age Brain morphological and functional imaging can support diagnosis, prognosis and treatment monitoring in AD Further development and standardization of neuroimaging techniques is needed to validate their application for diagnostic and prognostic purposes in AD 30 15

16 Thank you for your attention! 31 16