Dementia_MDM202_2022_ppt (1).pptx

Dementia neurobiology and clinical aspects Dr Gosia Raczek Academic Consultant in Old Age Psychiatry, SPFT Honorary Senior Clinical Lecturer, Centre for Dementia Studies BSMS Dementia is NOT the illness - it is a syndrome, caused by a number of various disorders. These disorders usually start many...

Dementia neurobiology and clinical aspects Dr Gosia Raczek Academic Consultant in Old Age Psychiatry, SPFT Honorary Senior Clinical Lecturer, Centre for Dementia Studies BSMS Dementia is NOT the illness - it is a syndrome, caused by a number of various disorders. These disorders usually start many years before their clinical manifestation, thus people have the illness before it progresses to the stage when it causes dementia. Dementia • An objective decline in memory and other cognitive abilities • These should be present for at least 6 months for a confident clinical diagnosis and have a progressive character. • Evidence of change in functional abilities • Dementia is a syndrome NOT a specific diagnosis Cognitive domains Language Memory Executive function Perception Praxis Arithmetic Dementia Research Centre Prevalence Expected community prevalence 50-60% Alzheimer’s disease (AD) 15% Vascular dementia (VaD) 10-15 % Lewy body dementias (to include dementia with Lewy bodies and Parkinson’s disease dementia) 1-2% frontotemporal lobar degeneration (FTLD) - but nearly as common as AD in people under 60 mixed cases alcohol related (ARBI) less common disorders: e.g. HD, CJD FTLD LBD VaD AD Presenting symptoms Forgetfulness (‘just old age’) Difficulties with learning new things and grasping ideas Giving up hobbies and interests Getting muddled in new situations Difficulties finding words Difficulties with handling bills etc. Social withdrawal Personality change - apathy but also disinhibition, ‘out-of-character’ behaviour Circadian rhythm disturbance Weight loss Poorly controlled medical conditions (poor meds adherence) Neuropathology of dementia disorders Microscopically • Intra neuronal inclusion bodies (various, depending on condition) • Extra neuronal changes (amyloidbeta plaques) Macroscopically • Region specific atrophy depending on dementia disorder • Generalised brain atrophy • Enlarged ventricles Neurofibrillary tangle (tau) amyloid plaque Pick’s bodies (tau) Neuropathological mechanisms Misfolding of proteins Abnormal accumulation Neuroinflammatory environment Damaged neurons Cell death β - amyloid Tau TDP43 FUS α-synuclein Prion protein Alzheimer’s disease Auguste D Alois Alzheimer 37th meeting of Southern German Psychiatrists – 3/11/1907 Pathology: “striking peculiar degeneration of cortical nerve cells Bundles of fibrils rolled up like coils or twisted like strings as the only remnant of cells Extraordinary number of peculiar patches disseminated throughout the cortex” Findings known to occur in patients dying from senile dementia Alzheimer’s Disease Pathology APP b-Amyloid Cell loss Plaques Tangles Tau Neurotransmitters Tau-P Cognitive Deficit Aβ1-42 peptide generation Amyloid precursor protein (APP) α-secretase Non-amyloidogenic metabolism β-secretase g-secretase Ab peptide Amyloidogenic metabolism Amyloid plaque AD pathology - tau • Neurofibrillary tangles consist of bundles of filaments twisted around each other in pairs (paired helical filaments PHF). • PHF are composed of a protein called tau, which is a normal protein present in all nerve cells and functions to stabilise intracellular transport tracks known as microtubules Tau Braak and Braak staging Time scale for progression of AD patholology Smith, 2002 AD pathology - neuroinflammation Neuronal cell loss- loss of neurotransmitters • atrophy of selective regions (hippocampus, temporal and parietal cortex) • cholinergic neurones in nucleus basalis are atrophied in AD • terminals and receptors in hippocampus • cholinergic neurones from nucleus basalis project to cerebral cortex Brain atrophy and imaging in AD HC - hippocampus HC entorhinal cortex AD - hippocampus AD entorhinal cortex Brain atrophy and imaging in AD Alzheimer’s disease cascade A/T(N) framework (Jack et al, 2018) Risk factors for Alzheimer’s disease Age Vascular risk factors Lack of exercise Low level of education Diet Family history Genetic: APP, PS1, PS2 (Autosomal dominant AD) Apolipoprotein E4 TREM2 MS4A, CR1, PICALM, BIN1, CLU, EPHA1, ABCA7, CD33, CD2AP Typical presentation Impaired episodic memory Visuospatial dysfunction Word - finding difficulties Visual perceptual/ spatial difficulties Apraxia Difficulties with arithmetic Difficulties reading/ spelling Other aspects of aphasia (speech production/ grammar/semantics) • Executive dysfunction (multitasking/problem solving) • Apathy • Behavioural problems (aggression, paranoid delusions) • • • • • • • • Atypical presentation • Posterior cortical atrophy (PCA) • Logopenic aphasia • Behavioural (frontal) AD Lewy Body Dementias (α-synucleinopathies) ‘The terrorist inside my husbands brain’ (Susan Schneider Williams, Neurology 201687:1308-11) ‘He died from suicide in 2014 at the end of an intense, confusing, and relatively swift persecution at the hand of the disease’ ‘Not until the coroner’s report, 3 months after his death, would I learn that it was diffuse DLB that took him’ ‘He had been struggling by symptoms that seemed unrelated: constipation, urinary difficulty, heartburn, insomnia, poor sense of smell- and a lot of stress’ ‘His fear and anxiety skyrocketed…..panic attacks, antipsychotics’ ‘Doctor appointments, psychiatrist, testing, and examinations kept us in constant motion’ ‘It felt like he was drowning in symptoms - and I was drowning along with him’ LBD - epidemiology • Lewy body dementia incorporates two forms: Dementia a with Lewy bodies (DLB) and Parkinson’s disease dementia • 2nd most common degenerative form of dementia (up to 23% in people with dementia) • Lewy bodies are present in up 30% of all autopsy dementia samples • Overlap with AD and CV Lewy bodies • Hallmark of PD, DLB and PDD • Found in dopaminergic neurons of the substantia nigra in about 90% of patients with PD • Composed of a protein, alphasynuclein • Rare familial forms of PD are caused by mutation on αsynuclein gene α-synuclein • a protein of largely unknown function • localised in cytosol and mitochondria • predominantly neuronal (some in glial cells) • encoded by SNCA gene, in 3 splicing isoforms α-synuclein pathology and staging of PD DLB - Clinical presentation • Essential feature - dementia defined as progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function or with usual daily activities. • Disproportionate attentional, executive and visual processing deficits relative to memory and naming. • Fluctuating cognition with pronounced variations in attention, alertness and arousal • Recurrent visual hallucinations, typically well formed and detailed • REM sleep behaviour disorder • Spontaneous features of parkinsonism Frontotemporal Lobar Degeneration (FTLD) FTLD - Clinical presentation • classical syndromes: - behavioural variant FTD (bv-FTD) - progressive non-fluent aphasia (PNFA) - semantic dementia (SD) • motor disorders: - parkinsonian syndromes (PSP, CBD) - motor neurone disease • second most common neurodegenerative dementia after AD in people under 65 FTLD - neuropathology • Affect mainly frontal and temporal lobes • Striking regional atrophy • Three main pathologies: tau, TDP43, FUS Semantic dementia Behavioural variant FTD FTLD - neuropathology bv-FTD tau TDP-43 FUS PNFA SD PSP/CBD MND Vascular dementia • Not a neurodegenerative dementia • But vascular pathology is very common and appears to interact with neurodegenerative changes in pathogenesis of dementia disorders • Can result from ischemic or hemorrhagic brain damage. Vascular dementia • The three most common mechanisms causing disease • Single, strategically placed infarcts • multiple cortical infarcts • subcortical small-vessel disease. • Clinical deficits are determined by the size, location, and type of cerebral damage. • Because of the variety of pathogenic mechanisms involved in vascular dementia, clinical manifestations can be heterogeneous. strategic infarct affecting both thalami strategic infarct in territory of posterior cerebral artery affecting the hippocampus Other cognitive disorders • < 65 years of age • Rapid Progression • Non-classic presentation • Other medical problems • Family History • Substance abuse, lifestyle • Presence of abnormal signs on CNS examination Other cognitive disorders - Huntington’s disease • Huntington’s disease (HD) - autosomal dominant mutation in huntingtin gene on chromosome 4 - chorea, cognitive and behavioural symptoms, middle age onset. • neuropsychiatric syndrome includes anxiety and depression, apathy, irritability, disinhibition, psychosis, compulsive behaviour Other cognitive disorders - HIV Stages Cognitive impairment in HIV • asymptomatic neurocognitive • rare with antiretroviral treatment (around impairment • mild neurocognitive disorder • HIV-associated dementia 2%) • relationship between HIV infection and dementia in general e.g. AD still unclear Other cognitive disorders - prion disorders • A prion is a protein that can adopt at least 2 conformational states, one of which is self-perpetuating • Cause a family of progressive neurodegenerative disorder • Affect both humans and animals • Unique: inherited, de novo or acquired • Multifocal spongiform change without inflammation that is invariably fatal sporadic CJD variant CJD Prion disorders - sporadic CJD • Accounts for 85% of all CJD • Peak age of onset: 55-75 years of age • Average survival: 5 months. 85% die within a year • Incidence: 1 per million per year • Most common presenting symptoms: cognitive (39%), cerebellar (21%) and behavioural (20%) Prion disorders - variant CJD • Caused by eating BSE or blood transfusion • Younger patients • Psychiatric prodrome • Longer duration of illness • Pulvinar sign • Painful parasthesias • genetic susceptibility Diagnostic steps • History • Examination • Blood screen • Cognitive screen • Neurological examination • Neuropsychological Ax • Neuroimaging (CT, MRI, SPECT, PET, multimodal imaging) • Fluid biomarkers (CSF, soon plasma) Treatment • No cure or disease modifying treament (despite recent licensing of aducanumab by the FDA and promising press release re: lecanemab) • Symptomatic treatments for cognitive (AD) and some neuropsychiatric (LBD) symptoms are available • Drugs that improve some psychiatric symptoms in nonneurogenerative context are not always effective in dementia disorders (e.g antidepressants don’t improve depression in AD, but may be more effective in PD) Livingston et al., 2020. Lancet Commission on Dementia Risk factors and prevention The Lancet 2020 396413-446DOI: (10.1016/S0140-6736(20)30367-6) Thank you [email protected]