Neuropathology - Common Neurocognitive Disorders PDF

Neuropathology Common Neurocognitive Disorders BMS 100 Week 14 Topics for today Definition of major and mild neurocognitive disorders (dementia General Epidemiology, Pathogenesis and Clinical Features of: Alzheimer’s Disease Lewy Body Dementia Parkinson’s Disease Dementia Frontotemporal Dementias Va...

Neuropathology Common Neurocognitive Disorders BMS 100 Week 14 Topics for today Definition of major and mild neurocognitive disorders (dementia General Epidemiology, Pathogenesis and Clinical Features of: Alzheimer’s Disease Lewy Body Dementia Parkinson’s Disease Dementia Frontotemporal Dementias Vascular Dementia Brief overview of Neurocognitive Disorder Assessment Neurodegenerative disorders progressive loss of neurons with associated secondary changes in white matter tracts ▪ selective, affecting one or more groups of neurons while leaving others intact sometimes neurons next to degenerating ones are completely normal finding common to many are protein aggregates that are resistant to degradation through the ubiquitinproteasome system ▪ form inclusions within neurons Some of these disorders are extremely common ▪ Parkinson disease, Alzheimer disease What is dementia? early – mild neurocognitive disorder late – major neurocognitive disorder ▪ generalized, progressive impairment of cognitive function, accompanied by impairment in ADLs ▪ not impaired level of consciousness ▪ executive function, memory, attention can all be affected ADLs/iADLs? Activities of daily living versus instrumental activities of daily living ▪ Instrumental activities of daily living (IADLs) are things you do every day to take care of yourself and your home. They are one way to measure how well you can live on your own. ▪ While activities of daily living (ADLs) are basic self-care tasks like bathing, IADLs require more complex planning and thinking. Dementia – classifying severity Mild neurocognitive disorder ▪ ADLs not significantly impaired ▪ Reduction in function of one (or more) major cognitive domain noted complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition ▪ Often patient is aware of (and frustrated by) deficit Major neurocognitive disorder ▪ ADLs and iADLs are affected iADLs often impaired first - shopping, food preparation, finances, medication management ▪ Larger impairment of one or more major cognitive domains ▪ Often patient is relatively unaware of deterioration Alzheimer disease Most common cause of dementia in elderly ▪ prevalence of 1 in 8 in older populations, 40% in those in the 80-90 year old group ▪ 6th leading cause of death General pathological findings: ▪ neurofibrillary tangles ▪ beta-amyloid plaques ▪ cerebral atrophy ▪ often loss of widely-distributed cholinergic neurons in the nucleus basalis of Meynert Alzheimer disease - pathology Neuritic plaques (beta-amyloid): ▪ focal, spherical collections of dilated, tortuous, neuritic processes (dystrophic neurites) often around a central amyloid core, which may be surrounded by clear halo amyloid core contains several abnormal proteins: ▪ Aβ, a peptide derived through specific processing events from a larger molecule, amyloid precursor protein (APP) ▪ Other proteins are present in plaques in lesser abundance, including components of the complement cascade and pro-inflammatory cytokines (more next semester) Alzheimer disease - pathology Neuritic plaques – cont… ▪ range in size from 20 to 200 μm in diameter ▪ microglial cells and reactive astrocytes are present at their periphery ▪ Plaques are found in the hippocampus, amygdala, and neocortex primary motor and sensory cortices tend to be spared Neurofibrillary tangles: ▪ bundles of filaments in the cytoplasm of the neurons that displace or encircle the nucleus ▪ basophilic fibrillary structures with H&E staining ▪ commonly found in cortical neurons especially in the entorhinal cortex, pyramidal cells of hippocampus, amygdala, basal forebrain Alzheimer disease - pathology Neurofibrillary tangles cont… ▪ insoluble and resistant to clearance in vivo major component of many “tangled filaments” is abnormally hyperphosphorylated forms of the protein tau ▪ Tau = axonal microtubule-associated protein that enhances microtubule assembly Other components include MAP2 (another microtubule-associated protein) and ubiquitin Alzheimer disease A, Plaques with dystrophic neurites surrounding amyloid cores are visible (arrows). B, Plaque core and surrounding neuropil are immunoreactive for Aβ. C, Neurofibrillary tangle is present within one neuron, and several extracellular tangles are also present (arrows). D, Silver stain showing a neurofibrillary tangle within the neuronal cytoplasm. E, Tangle (upper left) and neurites around a plaque (lower right) contain tau, demonstrated by immunohistochemistry. Cerebral atrophy Alzheimer disease - pathophysiology What is APP for? ▪ membrane-associated protein that is thought to be a receptor for an as yet unidentified ligand ▪ is cloven as part of normal breakdown of cellular proteins depending on where it is cut, it can either be soluble or insoluble insoluble forms accumulate in the extracellular space and are thought to be important in the pathogenesis of Alzheimer disease Aggregates of beta-amyloid are directly neurotoxic and also activate microglia and astrocytes, resulting in chronic inflammatory injury to neurons It is thought that accumulation of beta-amyloid is responsible for neurofibrillary tangles within neurons Genetic risk factors for AD Presenilin 1 and presenilin 2 ▪ Associated with severe early-onset AD ▪ Variants in a normal gene whose protein is very important in regulating neuronal intracellular calcium levels in association with LTP (long-term potentiation) ▪ Interestingly, same protein is also involved in cleaving APP (performs similar function as secretase) Apolipoprotein E4 ▪ One of 4 subtypes of apolipoproteins that help transport cholesterol throughout the CNS ▪ Those that are heterozygous for E4 have approximately double the risk of late-onset AD (LOAD) (about 25% of Caucasian population) Those that are homozygous have a 16X increased risk of LOAD Apo E4 positivity is not as strongly “causative” of AD as presenilin mutations that increase risk of AD The infectious theory of Alzheimer’s disease – less accepted, likely will be abandoned APP may be a primitive component of the innate immune system ▪ Seems to cause death of bacteria and viruses ▪ What virus is getting into the brain? Likely herpes family – HSV-1, HHV-6 and HHV-7 ▪ HHV 6 and 7 are viruses that cause benign skin infections in kids, however the virus seems to be able to migrate into the CNS and remain dormant ▪ In some Alzheimer patients, the amyloid accumulation may lead to chronic inflammation instead of performing a virus-fighting role Insulin Resistance and AD Type II diabetes – the most common disorder of glucose metabolism ▪ Due to genetic and lifestyle factors, the diabetic patient develops resistance to insulin Fewer receptors Downregulation of intracellular signaling linked to the insulin receptor ▪ You already know that insulin Increases “storage” of glucose – glycogenesis in the liver Decreases “new production” of glucose – gluconeogenesis in the liver Inhibits lipogenolysis Insulin Resistance and AD Insulin also increases the transport of glucose from the bloodstream into liver and muscle Therefore, type II diabetics have longterm increased blood levels of: ▪ Glucose ▪ Free fatty acids DM type 2 as a causative factor in AD Insulin resistance seems to be an important component of AD pathophysiology in a large component of the population ▪ AD is much more common in those with type 2 diabetes mellitus than in those without Why? ▪ Insulin resistance likely reduces synaptogenesis Insulin seems to have a role in normal neuronal physiology and synaptic plasticity As resistance to insulin builds due to long-term hyperglycemia, then the intracellular signaling cascades are down-regulated → decreased plasticity ▪ Remember dendritic spine remodelling? ▪ Insulin resistance increases the levels of circulating proinflammatory cytokines May lead to glial activation → neuronal damage DM type 2 as a causative factor in AD Why? cont… ▪ Recall that insulin resistance is linked (partially caused) by long-term hyperglycemia As blood glucose increases, it becomes nonenzymatically linked to the basement membrane of brain capillaries → a “leaky” blood-brain barrier ▪ An extracellular protein whose function is altered by high levels of glucose binding to it = AGE (advanced glycation end-product) Systemic pro-inflammatory cytokines can then leak through into the brain → maladaptive glial activation and neuronal damage DM type 2 as a causative factor in AD Why? cont… ▪ Insulin resistance is linked to elevated levels of free fatty acids (FFAs) in the blood Decreased insulin activity → increased triglyceride breakdown → increased circulating FFAs High levels of FFAs can cause microglial activation → neuronal damage Excellent free article on AD and DM II Ferreira LSS, Fernandes CS, Vieira MNN and De Felice FG (2018) Insulin Resistance in Alzheimer’s Disease. Front. Neurosci. 12:830. doi: 10.3389/fnins.2018.00830 See explanatory notes below Alzheimer disease – clinical features Slow development of impaired cognition ▪ short-term memory and executive functions (planning, logic) impaired relatively early personality changes and loss of normal inhibitions can follow some time after ▪ language deficits and loss of learned motor skills tend to result from more advanced disease ▪ incontinence and impaired ambulation result from severe disease impaired mobility related to development of pneumonia and sepsis Alzheimer disease – clinical features 4 “A”’s and one “D” of Alzheimer disease ▪ anterograde amnesia ▪ aphasia ▪ Apraxia – difficulty with motor planning to perform tasks or movements ▪ Agnosia – difficulty recognizing/identifying objects, persons, or sounds although sensation is intact ▪ disturbance in executive function Anterograde amnesia + at least one of the other criteria are used to help make the diagnosis Dementia with Lewy bodies Genetically-determined disorder ▪ tau protein is mutated results in aggregation of tau protein, or alteration of how tau interacts with microtubules frontal and temporal lobes show more marked atrophy Parkinson-like movement disorder ▪ We’ll be doing Parkinson’s disease next week: tremor, rigidity, bradykinesia typically the dementia antecedes (comes before) the movement symptoms, or presents early with the movement disorder Dementia with Lewy Bodies Dementia that usually predates the diagnosis of Parkinson’s ▪ presence of Lewy bodies in neurons – likely aggregates of misfolded alpha-synuclein 0.1 – 5% of general elderly population Dementia with Lewy bodies Clinical Features: ▪ Fluctuations in cognitive function with varying levels of alertness and attention AD tends to be more constant ▪ Visual hallucinations that are vivid other hallucinations may be present AD rarely involves hallucinations ▪ Parkinsonian motor features (usually later or close to the same time as the onset of dementia) ▪ Anterograde memory loss: usually less prominent than that found in AD ▪ More prominent executive function deficits Psychosis? Executive Functions? Psychosis = “impairment in reality testing” – characterized by delusions and hallucinations ▪ Delusions – beliefs that are not compatible with reality and are not normal beliefs for a culture The idea of an “angel” or “Santa Claus” is not a delusion The idea that an alien is stealing thoughts from your head is a delusion We’ll discuss more next semester as we cover psychiatric illness ▪ Hallucinations – perception of a stimulus that isn’t there Audible – hearing voices that do not exist (common) Visual – seeing things that aren’t there (a less common type of hallucination) Psychosis? Executive Functions? Executive Functions ▪ Very complex set of cognitive functions that seem to be orchestrated by the prefrontal cortex ▪ Include activities like: Shifting effectively between tasks Inhibiting unwanted or inappropriate behaviours or responses Selecting and paying attention to information that applies to a particular task Using working memory to accomplish tasks Planning tasks ▪ Executive functions often rely on memory and verbal fluency, but can be lost with even when memory and verbal fluency are not that impaired ▪ Executive functions are your brain’s “taskmaster” to keep you doing things effectively and appropriately, either in a social or job or school context Parkinson’s disease dementia Patients with long-standing PD without cognitive impairment who slowly develop a dementia ▪ associated with visual hallucinations and fluctuating alertness ▪ called Parkinson’s disease dementia, very similar entity to Lewy body dementia Lewy bodies are also present in Parkinson’s disease dementia Frontotemporal dementias Large group, with a diverse nomenclature Characterized by deficits in executive function ▪ poor mental flexibility, abstract reasoning ▪ response inhibition, planning/organization, and increased distractibility Behavioural variants (most common) ▪ behavioural disinhibition (socially inappropriate behaviour, impulsive, careless) ▪ apathy or inertia ▪ loss of sympathy or empathy ▪ Perseverative, stereotyped, or compulsive/ritualistic behaviour ▪ hyperorality and dietary changes FTD – a summary Less prominent memory deficits than AD Prominent behavioural symptoms ▪ often language and atypical motor symptoms can be present as well i.e. language subtypes can involve progressive inability to form words or use language Constant, non-fluctuating course with often rapid decline (faster decline than Lewy body dementia or AD) More common in younger patients ▪ As the patient population ages, FTDs become less common and AD becomes more common Vascular dementia Multiple small infarcts (often affecting gray matter of the cortices) or hypertension (often affecting white matter) can present with dementia Common cause of dementia, second after Alzheimer disease ▪ We will discuss vascular pathology of the CNS next week ▪ small vessel changes characteristic of hypertension (arteriolosclerosis) and multiple emboli are typical of small vessel disease ▪ many vascular disorders can be involved actually multiple “diseases” Vascular dementia Clinical presentation varies based on pattern of injury ▪ Can present very similar to Alzheimer disease ▪ unlike Alzheimer disease, depression and psychosis can be prominent features although can occur with Alzheimer disease, is more common with vascular-type dementias psychosis will frequently include delusions and hallucinations; agitation can be dangerous to both the patient and the caregiver lack of motivation is common ▪ gait abnormalities are common (gait apraxia), and lateralizing signs (increased tone/reflexes) often present ▪ often progresses in a step-wise fashion, corresponding to discrete vascular insults MMSE – asssessment of dementia/cognition MMSE assesses: ▪ ▪ ▪ ▪ Orientation Short, recent, remote, remote memory Sustained concentration Executive functions Recognition Registration Sequencing and organization Comprehension Perceptual - motor skills FYI FYI