Dementia with cases
文摘
科学
2024-07-06 07:00
澳大利亚
If you would like to view past exciting content, please click on the following link.In the neurology department, Oliver, a 60-year-old male, has been brought by his son due to recent changes in behavior, including increased aggression, rudeness, and a noticeable disinterest in family interactions. Oliver has also begun to repeat conversations. Additionally, a 72-year-old female named Iris was brought in by her son. She remains homebound, embarrassed by her inability to control urination. Iris struggles to locate items in her house, forgetting where she places them, and her son has observed an unusual gait where it appears as if her feet are sticking to the ground. Moreover, Alasdair, a 35-year-old male, has been brought by his partner because he has started repeating conversations and misplacing items recently. He experiences jerking movements in his left arm and has fallen twice recently. His medical records indicate a corneal transplantation six months prior.All these individuals are diagnosed with dementia, which is characterized by a decline in cognitive functions sufficient to impair everyday activities while consciousness remains intact. Dementia can stem from both reversible and irreversible causes. Reversible causes include alcohol dependency, hypothyroidism, vitamin B12 deficiency, neurosyphilis, normal pressure hydrocephalus (NPH), and depression. Irreversible causes encompass Alzheimer's disease, the most prevalent form of dementia, followed by vascular dementia, frontotemporal dementia, Lewy body dementia, Parkinson's disease, Huntington's disease, and Creutzfeldt-Jakob disease (CJD).Focusing on irreversible causes, particularly Alzheimer’s disease, this is a crucial topic for exams. Within the neuron's cell membrane lies a molecule called amyloid precursor protein (APP). Typically, old APP is cleaved by alpha secretase and gamma secretase into a soluble peptide. However, if beta secretase joins gamma secretase, the resulting fragments are insoluble, forming a monomer known as amyloid beta. These monomers clump outside neurons, forming beta-amyloid plaques that disrupt brain function. Additionally, amyloid plaques can accumulate around cerebral blood vessels, leading to amyloid angiopathy, which increases the risk of cerebral hemorrhage. Neurons are structurally supported by microtubules, stabilized by a protein called tau. Beta-amyloid plaques trigger pathways that activate a kinase enzyme, which phosphorylates tau. Phosphorylated tau fails to support microtubules, clumps into neurofibrillary tangles inside neurons, and disrupts their function, leading to cell death as Alzheimer's progresses. This disease, therefore, is classified as a tauopathy. Importantly, tau tangles form inside neurons, unlike beta-amyloid plaques which are external. The progression of Alzheimer's is also linked to decreased acetylcholine levels in the nucleus basalis and hippocampus due to reduced activity of choline acetyltransferase, an enzyme crucial for acetylcholine synthesis.Alzheimer's disease can manifest in two forms: sporadic or familial. Sporadic Alzheimer’s, the late-onset type, likely results from a mix of genetic and environmental factors and represents the majority of cases. A key genetic factor implicated in this form is the e4 allele of the apolipoprotein E gene, or APOE-e4, which is less effective at breaking down beta-amyloid compared to other alleles, increasing the likelihood of beta-amyloid plaque formation. In contrast, familial Alzheimer's disease refers to early-onset cases and involves several gene mutations, accounting for about 5 to 10% of total cases. Notably, mutations in the PSEN-1 or PSEN-2 genes on chromosomes 14 and 1, respectively, which encode the presenilin-1 and presenilin-2 subunits of gamma-secretase, alter the enzyme’s cleavage site on APP. This results in beta-amyloid fragments that more readily aggregate and form plaques. Additionally, trisomy 21, or Down syndrome, leads to an extra gene for APP on chromosome 21, promoting more amyloid plaque formation.Vascular dementia, another major form, arises from chronic poor cerebral blood flow due to atherosclerosis in arteries like the internal carotid arteries. This condition can progress to chronic ischemia or lead to acute blockages from embolized plaque, resulting in ischemic strokes. The brain tissue damage from these strokes, characterized by liquefactive necrosis, cumulatively impairs cognitive functions, a process that can worsen with subsequent strokes. This subtype is known as multi-infarct dementia.Frontotemporal dementia involves the degeneration of the frontal and temporal lobes, sparing the parietal and occipital lobes. A notable subtype, Pick disease, features tau protein aggregates known as Pick bodies, consisting solely of the 3R isoforms of tau. These aggregates disrupt the neuron's microtubule system, leading to neuronal death and significant brain atrophy.Lastly, Lewy body dementia is characterized by the accumulation of misfolded alpha-synuclein proteins within cortical and substantia nigra neurons, forming Lewy bodies. These eosinophilic inclusions are also seen in Parkinson’s disease, though their exact role in neuronal degeneration is not fully understood.Parkinson's disease can also lead to dementia. This genetic disorder progresses slowly, primarily affecting individuals over the age of 50. It is characterized by the degeneration of dopamine-producing neurons in the substantia nigra, part of the basal ganglia. Normally, there is a balance in the basal ganglia between dopamine, which facilitates movement, and acetylcholine, which inhibits it. In Parkinson’s disease, the reduction of dopaminergic neurons leads to decreased movement, speech and swallowing difficulties, and cognitive impairments such as dementia in advanced stages.Moving on to Huntington's disease, an autosomal dominant neurodegenerative disorder that typically emerges around 40 years of age. It is caused by a mutation in the Huntington disease (HD) gene on chromosome 4, which includes a CAG trinucleotide repeat expansion that codes for glutamine. The resultant mutated huntingtin protein accumulates in the neuronal cells of the caudate and putamen within the basal ganglia, leading to neuronal death. These brain regions, which form the dorsal striatum, are crucial for inhibiting movement. Their impairment results in movement disorders like chorea and athetosis and cognitive issues such as dementia. An essential concept in Huntington's disease is anticipation, where the trinucleotide repeats increase with each generation, leading to an earlier onset and more severe disease manifestations. This phenomenon, known as repeat expansion, occurs more frequently during sperm production, hence anticipation is typically more pronounced when the biological father is the carrier.Lastly, Creutzfeldt-Jakob disease (CJD), the most common type of spongiform encephalopathy, is another rare dementia cause. These neurodegenerative diseases are characterized by the accumulation of misfolded prion proteins, which transform from α-helices into β-pleated sheets, making them resistant to proteolytic degradation. When these misfolded prions enter neurons, they induce the misfolding of normal prion proteins, leading to neuron death and brain cyst formation, giving it a sponge-like appearance.CJD is categorized into four types: familial (fCJD), which arises from mutations in the PRNP gene that encodes the prion protein; variant (vCJD), linked to consuming meat from cattle affected by bovine spongiform encephalopathy, commonly known as "Mad cow disease"; iatrogenic (iCJD), caused by medical procedures using contaminated organs or instruments; and sporadic (sCJD), which occurs randomly without a known cause.Let's briefly review the reversible causes of dementia. Common reversible factors include chronic alcohol use, hypothyroidism, vitamin B12 deficiency, and tertiary syphilis. Another significant reversible cause is depression, where cognitive impairment linked to this condition is termed pseudodementia. A notable characteristic of pseudodementia is the affected individuals often express anxiety about their memory loss, unlike other forms of dementia such as Alzheimer's disease. A particularly important reversible cause to consider is normal pressure hydrocephalus (NPH), which is often mistaken for Alzheimer's disease in the elderly. NPH results from abnormal venous drainage of cerebrospinal fluid, leading to hydrocephalus. Initial symptoms typically include urinary incontinence and gait disturbances, followed by dementia, as the frontal lobe is predominantly affected.Shifting focus to clinical presentations, while all these disorders can lead to dementia, they also present with other symptoms that are crucial for accurate diagnosis. Generally, dementia is first noticed by close family members or friends observing changes in cognition. This includes memory impairments, leading to repetitive conversations or misplacement of items. Language difficulties might make it hard for individuals to recall common words. Impairments in concentration and executive functions can make complex tasks challenging, such as managing finances. Visuospatial difficulties may hinder recognition of faces or navigation in familiar places. Changes in personality are also commonly observed.Specific symptoms can guide the identification of various dementia causes. For exams, it's important to remember that Alzheimer's disease starts insidiously and progresses gradually. It unfolds in three phases: first, the asymptomatic phase; second, a predementia phase known as mild cognitive impairment, characterized by a gradual onset of memory impairment without significant impairment in other cognitive domains or daily functioning—this is distinct from normal aging because the memory loss is more severe than expected for the person’s age. The third phase is the dementia phase, where significant memory loss occurs, followed by a slow, gradual decline in other cognitive functions such as language, visuospatial skills, and executive functions. Memory types include episodic memory, which is the recollection of events, and semantic memory, related to knowledge of words and vocabulary. Initially, episodic memory deteriorates while semantic memory remains unaffected. As the condition progresses, both types of memory are impaired. Episodic memory can be further classified into immediate, recent, and long-term memory. Immediate memory, sometimes referred to as procedural memory, is used for tasks like repeating a phone number immediately after hearing it. Recent memory is what allows recalling a list of three words five minutes later, which is often impaired early in Alzheimer's because the disease initially affects the hippocampus, responsible for recent memory. Long-term memory, which recalls events from years past, typically remains intact until the later stages of the disease. For instance, a person with Alzheimer's might recall their wedding details from 50 years ago but forget events from the previous day.The symptoms of vascular dementia vary based on which brain regions are affected. For instance, damage in the temporal lobe may impair an individual's ability to form new memories or recall past events. A stroke in the left parietal lobe can lead to aphasia, affecting speech. Should a subsequent stroke affect the frontal lobe, changes in personality may arise. A hallmark of vascular dementia is the sudden onset of symptoms, with cognitive functions declining progressively with each stroke. This form of dementia also presents neurological deficits that align with the stroke-affected brain regions and might coexist with other manifestations of atherosclerosis such as coronary artery disease, often compounded by conditions like hypertension and diabetes. In multi-infarct dementia, there's a characteristic stepwise decline in cognition. Each stroke causes a sudden downturn in cognitive abilities, such as memory or language, with periods of stability in between, contrasting the gradual cognitive decline seen in Alzheimer's disease.Individuals with frontotemporal dementia typically show symptoms before the age of 65, often presenting early with behavioral changes and relatively preserved memory functions. These changes include altered personality, impaired judgment, apathy, and disinhibition. Perceptual-motor functions are also compromised, affecting coordination skills. There are two variants of frontotemporal dementia: the behavioral variant, which involves disinhibition, apathy, lack of empathy, compulsive behaviors, hyperorality, and dietary changes, followed by declines in social cognition or executive abilities; and the language variant, marked by a significant reduction in language abilities, including speech production, word finding, object naming, grammar, and word comprehension.Lewy body dementia and Parkinson's disease dementia are similar, both characterized by dementia and parkinsonism, which includes symptoms such as tremor (T), rigidity (R), akinesia or bradykinesia (A), and postural instability (P). Lewy body dementia is distinguished by the onset of dementia occurring within a year before or after motor symptoms, often featuring vivid visual hallucinations, fluctuating attention, and a sleep behavior disorder where individuals act out dreams. In contrast, Parkinson’s disease typically begins with motor symptoms, with dementia developing years later.Huntington's disease, an autosomal dominant disorder, is characterized by chorea—sudden, involuntary movements that appear dance-like—and athetosis, which are slower, writhing movements. It also involves psychiatric symptoms such as depression, psychosis, and aggression. The progression of the disease leads to severe physical and cognitive decline, with individuals often succumbing to complications like aspiration pneumonia or suicide within 10 to 20 years after diagnosis.For the test, remember that Creutzfeldt-Jakob Disease (CJD) exhibits a long incubation period, but once symptoms manifest, there is a rapid progression to dementia, often developing within weeks to months. CJD is also associated with ataxia, which is a lack of coordination in voluntary movements, and myoclonus, a sudden, involuntary muscle jerk—similar to what is seen with hiccups. In CJD, myoclonus is typically generalized and often triggered by sudden stimuli, hence the term "startle myoclonus." Unfortunately, CJD invariably leads to death as there is currently no cure for the disease.For Normal Pressure Hydrocephalus (NPH), it’s crucial to note that it affects the elderly and symptoms gradually appear, presenting with dementia, urinary incontinence, and a distinctive "magnetic" gait, where it appears as though the feet are glued to the floor.Regarding the diagnosis process, cognitive assessments like the Montreal Cognitive Assessment (MoCA) or the Mini-Mental State Examination (MMSE) are used. These tests evaluate various cognitive domains such as orientation (knowing the time, place, or current president), registration (repeating words immediately after hearing them), recall (remembering those words after a delay), and language skills (naming objects or repeating phrases). Attention can be tested by tasks like spelling a word backward, and executive functions are assessed by following written commands or performing sequential tasks. The MMSE scores up to 30 points, with scores below 24 suggesting cognitive impairment.Distinguishing between delirium and dementia is also essential: delirium is acute, often fluctuating, and linked directly to physiological disturbances from acute insults like infections or medication changes. It's characterized by impaired consciousness and awareness. In contrast, dementia is gradual, with progressive cognitive decline and typically intact consciousness until the later stages.Once dementia is diagnosed, identifying whether it's reversible is key. Tests might include checking TSH levels for hypothyroidism, vitamin B12 for deficiencies, and performing a rapid plasma reagin (RPR) test for syphilis. For NPH, a brain MRI may show ventriculomegaly with no cortical atrophy, and a lumbar puncture will indicate normal opening pressure.On irreversible dementia, Alzheimer’s disease is generally diagnosed based on clinical presentation, and brain imaging can reveal hippocampal atrophy early on, progressing to broader cortical atrophy. This results in "ex vacuo ventriculomegaly" due to the brain shrinkage. A definitive diagnosis, however, typically comes from a brain biopsy showing amyloid plaques and neurofibrillary tangles, usually confirmed post-mortem.Vascular dementia diagnosis benefits from imaging like CT or MRI, which would reveal multiple cortical and subcortical infarcts and signs of cerebral ischemia, such as brain cortex atrophy.Diagnosing frontotemporal dementia typically involves brain imaging, such as a CT or MRI, which shows atrophy primarily in the frontal and temporal lobes. This atrophy is indicated by narrower gyri, wider sulci, and ex vacuo ventriculomegaly, while the parietal and occipital lobes generally remain unaffected.For Lewy body dementia, diagnosis primarily hinges on the symptom pattern. The hallmark for suspecting this condition is the onset of dementia within a year of developing parkinsonism symptoms, combined with vivid visual hallucinations. A definitive diagnosis, however, can only be confirmed through a brain autopsy that identifies Lewy bodies within the neurons.Parkinson disease dementia diagnosis begins with confirming Parkinson disease itself, requiring the presence of bradykinesia along with another "TRAP" symptom (tremor, rigidity, or postural instability), and excluding other causes. A definitive diagnosis includes findings from a brain autopsy, such as Lewy bodies and loss of pigmented neurons in the substantia nigra.Huntington disease is suspected in individuals around 40 years old presenting with dementia, specific movement disorders (chorea and athetosis), and psychiatric symptoms, which may be mistaken for substance abuse. Family history plays a crucial role in raising suspicion. The diagnosis is confirmed by polymerase chain reaction testing of the HD gene to detect CAG repeat expansions. Brain MRI typically reveals atrophy of the caudate and putamen alongside ex vacuo ventriculomegaly.In the case of Creutzfeldt-Jakob Disease (CJD), typical MRI findings include basal ganglia and thalamus enhancement. EEG often shows periodic sharp wave bursts. A diagnosis is supported by these findings along with the clinical presentation, and may include a lumbar puncture revealing elevated 14-3-3 protein levels. A definitive diagnosis occurs post-mortem via brain biopsy showing spongiform changes.Here's a comprehensive treatment overview for various forms of dementia, highlighting both reversible and irreversible causes and their respective management strategies.- **Alcohol dependence** is managed with medications such as acamprosate, disulfiram, and naltrexone, which help curb alcohol cravings and consumption.- **Hypothyroidism** treatment involves thyroid hormone replacement to restore normal hormone levels.- **Vitamin B12 deficiency** is corrected with B12 supplementation, which can reverse the neurologic symptoms if caught early.- **Syphilis** is treated effectively with penicillin, which can prevent or reverse the progression of neurosyphilis.- **Normal Pressure Hydrocephalus (NPH)** is treated with a ventriculoperitoneal shunt to drain excess cerebrospinal fluid, improving symptoms like gait disturbances, although cognitive improvements are less predictable.- **Alzheimer’s disease** treatments include cholinesterase inhibitors (donepezil, rivastigmine, galantamine) that enhance cholinergic transmission, improving some symptoms. Memantine, an NMDA-receptor antagonist, is another option, particularly for those who can’t tolerate cholinesterase inhibitors.- **Vascular dementia** management focuses on stroke prevention through controlling risk factors like hypertension, diabetes, and cholesterol, along with lifestyle modifications and antiplatelet therapy like aspirin. Cholinesterase inhibitors are sometimes used despite mixed evidence of their efficacy.- **Frontotemporal dementia** has no treatments to delay progression, but SSRIs and atypical antipsychotics can manage behavioral symptoms and psychosis, respectively.- **Lewy body dementia** treatment includes managing motor symptoms with Parkinson’s disease medications like levodopa. Care must be taken with dopamine agonists due to the risk of exacerbating hallucinations and confusion. Antipsychotics are generally avoided as they can worsen motor symptoms.- **Parkinson’s disease dementia** is managed with rivastigmine to address cognitive symptoms and Parkinson’s medications to help with motor symptoms.- **Huntington’s disease** therapy involves using neuroleptics and tetrabenazine to manage chorea and other movement disorders, though these treatments do not extend survival.- **Creutzfeldt-Jakob Disease (CJD)** currently has no treatment to alter its course; thus, the focus is on preventing transmission and providing supportive care.These approaches aim to manage symptoms, improve quality of life, and slow disease progression where possible. For many of these conditions, especially irreversible dementias, the therapeutic strategies are about symptom management rather than curative treatments.To summarize, dementia is characterized by a decline in cognitive functions such as memory, language, or executive function, which significantly impairs daily activities. It may arise from reversible causes such as alcohol dependence, hypothyroidism, vitamin B12 deficiency, neurosyphilis, and normal pressure hydrocephalus (NPH). However, more commonly, dementia stems from irreversible causes including Alzheimer's disease—the most prevalent type—vascular dementia, frontotemporal dementia, Parkinson disease dementia, Lewy body dementia, Huntington disease, and Creutzfeldt-Jakob disease.Diagnosis typically relies on symptom presentation and is supported by clinical assessments like the Montreal Cognitive Assessment (MoCA) or the Mini-Mental State Examination (MMSE). Further differentiation among the various causes of dementia can often be achieved through specific symptomatology linked to each condition, alongside imaging techniques such as CT or MRI scans. In some cases, definitive diagnosis may require histological examination, such as a brain biopsy, though this is usually performed post-mortem.Understanding these distinctions and diagnostic strategies is crucial for managing dementia effectively, focusing on both alleviating symptoms and, where possible, addressing reversible causes to improve outcomes.Now let's go back to our cases. For **Oliver**, the behavioral changes with relatively preserved memory indeed suggest frontotemporal dementia, particularly given his age and symptoms. A brain CT or MRI would be the next appropriate step to confirm the diagnosis by identifying the characteristic atrophy in the frontal and temporal lobes.**Iris** presents with the classic triad of symptoms for normal pressure hydrocephalus (NPH) — urinary incontinence, dementia, and a "magnetic" gait. An MRI would be crucial here to observe the enlarged ventricles typical of NPH, and a lumbar puncture can confirm normal opening pressure. If diagnosed, the placement of a ventriculoperitoneal shunt could potentially reverse her symptoms and significantly improve her quality of life.For **Alasdair**, his young age combined with rapid cognitive decline, myoclonus, ataxia, and a notable history of corneal transplantation raise a strong suspicion for iatrogenic Creutzfeldt-Jakob disease (CJD). This form of CJD could have been transmitted through the surgical procedure, making it a priority to confirm via further diagnostic testing such as MRI, EEG, and possibly a lumbar puncture for elevated 14-3-3 protein levels."Robbins Basic Pathology" Elsevier (2017)"Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)"Adams and Victor's Principles of Neurology, Ninth Edition" McGraw Hill Professional (2009)"Antidepressants for treating depression in dementia" Cochrane Database of Systematic Reviews (2018)"Clinical predictors of progression to Alzheimer disease in amnestic mild cognitive impairment" Neurology (2007)"Genetics of dementia" The Lancet (2014)"Creutzfeldt-Jakob disease: updated diagnostic criteria, treatment algorithm, and the utility of brain biopsy" Neurosurgical Focus (2015)"Structural and Functional Neuroimaging of Visual Hallucinations in Lewy Body Disease: A Systematic Literature Review" Brain Sciences (2017)"Current concepts and controversies in the pathogenesis of Parkinson’s disease dementia and Dementia with Lewy Bodies" F1000Research (2017) - - - - - - - END - - - - - - -
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