BMS200 Dementia Slides (2) PDF

Dementia BMS200 Dr. Nishanth Lakshman, PhD Date: November 25th, 2024  Learning Outcomes Review briefly the pathophysiology and risk factors of dementia, including Alzheimer’s Disease, Vascular Dementia, Lewy Body dementia, Frontotemporal Dementia, and Parkinson’s Dementia. Critique the e...

Dementia BMS200 Dr. Nishanth Lakshman, PhD Date: November 25th, 2024  Learning Outcomes Review briefly the pathophysiology and risk factors of dementia, including Alzheimer’s Disease, Vascular Dementia, Lewy Body dementia, Frontotemporal Dementia, and Parkinson’s Dementia. Critique the evidence that hearing impairment is a modifiable risk for dementia. Develop a hypothesis for the pathophysiology of traumatic brain injury and its relation to the etiology of dementia. Critique the connection between gut microbiome and the pathophysiology of dementia  Dementia Dementia refers to a decline in cognitive ability acquired over time, leading to difficulties in successfully carrying out daily activities. The most frequently affected cognitive function in dementia is memory. This condition involves a significant cognitive impairment that hinders the ability to perform routine daily tasks. Disorders associated with dementia often exhibit distinctive cellular inclusions and the accumulation of extracellular proteins, accompanied by varying levels of glial and microglial activation.  Dementia Risk factors - Risks during early life (under 45 years), such as lower levels of education, impact cognitive reserve. Risk factors in midlife (45–65 years) and later life (over 65 years) contribute to the reserve and can initiate neuropathological processes. - Less education - Cognitive ability generally improves with education until it reaches a plateau in late adolescence, coinciding with the peak plasticity of the brain. Beyond the age of 20, there are relatively limited additional gains in cognitive ability with further education. - Cognitive decline - Individuals engaged in cognitively challenging occupations typically exhibit less cognitive decline both before and, in some cases, after retirement compared to those in less demanding jobs.  Dementia Risk factors - Hearing Loss - Hearing impairment in midlife, as assessed through audiometry, is linked to a more pronounced decline in volume in the temporal lobe, encompassing the hippocampus and entorhinal cortex. - Traumatic Brain Injury - In both humans and mouse models, a solitary and severe traumatic brain injury (TBI) is correlated with extensive hyperphosphorylated tau pathology. - Hypertension - Hypertension in midlife, defined as starting from the age of 40, was linked to diminished brain volumes and heightened white matter hyperintensity volume, while there was no observed association with amyloid deposition. - Alcohol - Consuming over 21 units per week and prolonged abstinence were both linked to a 17% rise in dementia risk compared to consuming less than 14 units. Additionally, consuming more than 14 units was associated with right-sided hippocampal atrophy as observed in MRI scans.  Dementia Risk factors - Obesity - Recent findings provide additional support for the connection between higher BMI and the development of dementia. - Smoking - Ceasing smoking, even in later years, lowers this risk. Exposure to second- hand smoke was linked to greater memory decline, and the risk escalated with the duration of exposure, even after accounting for other influencing factors. - Depression - It is also a component of the prodrome and initial phases of dementia. There is a potential for reverse causation, where depressive symptoms may arise from neuropathological changes associated with dementia that occur years before the clinical onset of dementia. - Social isolation - Social interaction, now acknowledged as a protective factor, boosts cognitive reserve or promotes positive behaviors. However, isolation may also manifest as part of the early stages of dementia. Numerous studies indicate that reduced social contact raises the risk of dementia.  Dementia Risk factors - Physical Inactivity - Individuals may discontinue exercise due to the early signs of dementia, making inactivity both a potential consequence and a contributing factor in dementia. This relationship might be more pronounced as a risk factor in individuals with cardiovascular morbidity. - Air pollution - Studies on animal models indicate that airborne particulate pollutants expedite neurodegenerative processes by influencing cerebrovascular and cardiovascular diseases, Aβ deposition, and the processing of amyloid precursor protein. - Diabetes - In general, type 2 diabetes poses a distinct risk for the onset of subsequent dementia. - Lowering these risk factors could provide protection for individuals, regardless of whether they have a genetic predisposition or not. - Comprehensive interventions, such as addressing the intricate physical and social needs of individuals impacted by dementia, can have a substantial impact when implemented collectively.  Dementia - Pathophysiology Pathogenesis of Dementia The pathological anatomy of dementing diseases is frequently intricate and widespread, making it challenging to pinpoint and quantify specific areas. Memory impairment - central feature of many dementias - occurs with extensive disease in several different parts of the cerebrum, but the integrity of discrete parts of the diencephalon and of the medial temporal lobes is fundamental memory. Impairment of language function - associated specifically with disease of the dominant cerebral hemisphere, particularly the perisylvian parts of the frontal, temporal, and parietal lobes. Loss of capacity for reading and calculation - related to lesions in the posterior part of the left (dominant) cerebral hemisphere;  Dementia - Pathophysiology Loss of use of tools and imitation of gestures (apraxias) - related to loss of tissue in the dominant parietal region. Impairment in drawing or constructing simple and complex figures with blocks, sticks, picture arrangements, etc. - observed with parietal lobe lesions, more often with right-sided (nondominant) than with left-sided ones. Problems with modulation of behavior and stability of personality - generally related to frontal lobe degeneration  Dementia - Pathophysiology Dementia of the degenerative types: - The clinical manifestation arising from cerebral disease is significantly influenced by both the location and the extent of the lesion. - Degenerative types of dementia are often associated with evident structural abnormalities in the cerebral cortex, but the diencephalon and basal ganglia are also implicated. - In some cases, dementia may stem from purely thalamic degenerations due to the integral relationship between the thalamus and the cerebral cortex, particularly concerning memory. - Alzheimer's disease serves as a notable example, where the primary site of damage is the hippocampus. However, the degeneration of the cholinergic nuclei in the basal frontal region, which project to the hippocampus, significantly exacerbates the decline in memory function. Dementia - Pathophysiology Dementia of the degenerative types - Biochemistry of the proteins: - Intracellular, especially intracytoplasmic, inclusions have a historical connection deeply intertwined with neurodegenerative disorders, being among the initial histologic abnormalities recognized in diseased cells. - The disruption of normal protein homeostasis likely plays a central role in the progression of these disorders. - In neurodegenerative disorders, the inclusions signify compromised native cellular proteins and their stress response conjugates. - Cells activate stress responses in the presence of damage; hence, the presence of stress response inclusions doesn't pinpoint the specific cause of damage but rather indicates the cellular attempt to protect itself. Dementia - Pathophysiology These accumulations of proteins can induce disease through various pathways. Dementia - Pathophysiology Arteriosclerotic cerebrovascular disease - It follows a distinct trajectory compared to neurodegenerative diseases. - It results in multiple infarctions scattered throughout the thalami, basal ganglia, brainstem, and cerebrum, affecting motor, sensory, visual projection areas, as well as association areas. - Arteriosclerosis itself, in the absence of vascular occlusion and infarction, does not lead to progressive dementia. Instead, the cumulative impact of recurring strokes impairs intellectual function. - The progression of the disease, often evident in a step-by-step manner due to successive strokes, is typically observed in affected individuals, known as multi-infarct or vascular dementia.  Dementia - Pathophysiology Severe cerebral trauma lesions - They are typically located in the cerebral convolutions, particularly in the frontal and temporal poles, the corpus callosum, and the thalamus. - In certain instances, extensive degeneration of the deep cerebral hemispheres occurs due to mechanical disruption of the deep white matter, a phenomenon known as axonal shearing or diffuse axonal injury. - Some cases of dementia may involve mechanisms other than the outright destruction of brain tissue. - Chronic hydrocephalus, regardless of its origin, is frequently linked to a general decline in cognitive function. Although the compression of cerebral white matter is likely a contributing factor, this aspect has not been definitively established. - Similarly, extrinsic compression of one or both cerebral hemispheres by chronic subdural hematomas may yield a similar effect. Dementia - Pathophysiology *A diffuse inflammatory process is, at least in part, responsible for dementia in conditions such as syphilis, cryptococcosis, chronic meningitides, and viral infections like HIV encephalitis, herpes simplex encephalitis, and subacute sclerosing panencephalitis. Presumably, this involves both a loss of neurons and an inflammatory disruption of function in the remaining neurons. *Prion diseases, exemplified by Creutzfeldt-Jakob disease, lead to a widespread loss of cortical neurons, gliosis, and spongiform changes, resulting in distinct patterns of cognitive dysfunction. *Dementing states in adult forms of leukodystrophy typically manifest as a subcortical dementia syndrome with prominent frontal lobe features. Extensive white matter lesions may arise from advanced multiple sclerosis, progressive multifocal leukoencephalitis, or certain vascular dementias. Dementia - Pathophysiology The sequestration of proteins or other macromolecules renders them ineffective in their typical functions. As these aggregates grow, they can physically obstruct axons, dendrites, or the movement of materials within the cytoplasm. This process hampers cellular protein recycling and disrupts homeostasis. Initially, these aggregated proteins form ultrastructural fibrils that can be highly cytotoxic. Consequently, it seems that cellular stresses arising from various factors can disrupt proteostasis, leading to the formation of toxic fibrils that perpetuate and intensify cellular stress. Fundamentally, neurodegenerative diseases largely revolve around disorders of proteostasis, encompassing compromised cellular pathways controlling protein synthesis, folding, trafficking, aggregation, disaggregation, and degradation. Cerebral Cortical Neurodegenerative Diseases Alzheimer Disease (AD) - Alzheimer's disease (AD) constitutes the majority of neurodegenerative dementia cases, marked by the abnormal accumulation of two proteins: β-amyloid and tau. - AD is a gradual and progressive neurological disorder clinically characterized by memory loss, cognitive impairment, and eventual dementia. - It stands as the most prevalent form of dementia in the elderly, encompassing over half of all cases. - While Alzheimer's affects a maximum of 1%-2% of individuals under 65, the incidence rises to 40% or more in those aged 85 and above. - Women are affected twice as frequently as men. - Although most cases are sporadic, familial variants are also documented. Cerebral Cortical Neurodegenerative Diseases Alzheimer Disease (AD) – Pathology - In Alzheimer's disease (AD) brains, cortical atrophy is evident, accompanied by hydrocephalus ex vacuo. - The gyri narrow, sulci widen, and cortical atrophy is particularly noticeable in the parahippocampal regions. - Over the course of the disease, the atrophy of the temporal, frontal, and parietal cortex intensifies.  Cerebral Cortical Neurodegenerative Diseases Alzheimer Disease (AD) – Pathology: - Neuritic plaques (senile plaques) o Spherical deposits of β-amyloid accumulate extracellularly. o In the advanced stages of the disease, senile plaques occupy substantial volumes of the affected cerebral gray matter. o These plaques are encircled by reactive astrocytes and microglia, and they exhibit swollen, distorted neuronal processes known as dystrophic neurites. o While the detection of these plaques is essential for diagnosing Alzheimer's disease (AD), their quantity and distribution do not align closely with the severity of clinical disease. Cerebral Cortical Neurodegenerative Diseases Alzheimer Disease (AD) – Pathology: - Neurofibrillary Tangles o Collections of polymerized tau filaments are found intracytoplasmically. o The distribution of these filaments correlates with the clinical severity of Alzheimer's disease (AD). o Tangles in the entorhinal cortex and parahippocampal gyrus are observable in asymptomatic individuals many years before the typical onset age of AD, potentially signifying the earliest phases of the disease. Cerebral Cortical Neurodegenerative Diseases Alzheimer Disease (AD) - Pathology - Cytopathologic features include intracellular neurofibrillary tangles, composed partially of hyperphosphorylated forms of the tau protein that typically binds to microtubules, and extracellular amyloid plaques with a core of β-amyloid peptides, surrounded by altered nerve fibers and reactive glial cells. - The β-amyloid peptides are derived from amyloid precursor protein (APP), a transmembrane protein extending into the extracellular fluid from all nerve cells. - APP undergoes hydrolysis at three distinct sites by α-secretase, β-secretase, and γ-secretase: - α-secretase produces non-toxic peptides. - β-secretase and γ-secretase generate toxic peptides (40-42 AA).  Cerebral Cortical Neurodegenerative Diseases Alzheimer Disease (AD) - Pathology - Toxic polypeptides aggregate extracellularly, adhering to AMPA receptors and Ca2+ ion channels, thereby augmenting Ca2+ influx. - These polypeptides also trigger an inflammatory response, resulting in the production of intracellular tangles. - Ultimately, the compromised cells undergo cell death, contributing to a third aspect of the brain pathology in individuals with this neurodegenerative disease: atrophy characterized by gyral narrowing, sulcal widening, ventricular enlargement, and a reduction in brain weight.  Cerebral Cortical Neurodegenerative Diseases Alzheimer Disease (AD) – Clinical Features: - Progressive decline in memory and cognitive abilities, along with challenges in language and alterations in behavior. - Individuals with mild cognitive impairment are now more readily identified, as they transition to full-blown dementia at a rate of approximately 15% per year. - Alzheimer's disease follows an unrelenting progression, transforming once intelligent and productive individuals into individuals who are demented, non-verbal, incontinent, and bedridden. - Common medical complications such as bronchopneumonia, urinary tract infections, and pressure ulcers often contribute to mortality. Cerebral Cortical Neurodegenerative Diseases Alzheimer Disease (AD) – Clinical Features: AD occurs in three stages: - Presymptomatic - The patient does not exhibit cognitive impairment. There is a mounting body of evidence suggesting the accumulation of extracellular β-amyloid and the initiation of tangle formation, particularly in the hippocampus and adjacent temporal cortex. - Mild cognitive impairment (MCI) - Patients undergo a mild decline in memory and cognitive function that concerns them but doesn't disrupt their daily activities. A notable proportion of individuals with Mild Cognitive Impairment (MCI) will eventually develop Alzheimer's Disease (AD), although many will not. Those with low levels of CSF β-amyloid 1-42 or elevated amyloid load identified through positron emission tomography (PET) scanning seem more prone to advancing to AD. - Alzheimer Disease - Patients exhibit evident dementia upon clinical examination and neuropsychological evaluation. Impairments in activities of daily living are observed.  Cerebral Cortical Neurodegenerative Diseases Pick Disease (Frontotemporal Lobe Dementia - FTLD): - Distinguished by the accumulation of abnormal tau without β-amyloid. - Typically commences in the fifth to seventh decades, making it nearly as prevalent as Alzheimer's Disease in this age group. - In contrast to Alzheimer's Disease, which usually starts with memory difficulties, FTLD initiates with disruptive and inappropriate behavior. - Although the majority of frontotemporal dementia cases are sporadic, the disease has a strong hereditary component, with up to 40% of cases having a family history of dementia.  Cerebral Cortical Neurodegenerative Diseases Pick Disease (Frontotemporal Lobe Dementia - FTLD): - It stands as the second most common cause of early-onset dementia in individuals under 65, constituting ten percent of pathologically confirmed cases. - Moreover, it is the third most common cause of dementia in individuals over 65. - Commonly known as Pick's disease, this dementia syndrome frequently occurs in pre- senile patients and is categorized into behavioral variant (bvFTD) and primary progressive aphasia (PPA) subtypes. Cerebral Cortical Neurodegenerative Diseases Pick Disease (Frontotemporal lobe dementia - FTLD) - Pathology - In Pick disease, cortical atrophy primarily occurs in the frontotemporal regions. - The atrophy can reach severe levels, causing affected gyri to be reduced to thin slivers, a condition known as knife-edge atrophy. Cerebral Cortical Neurodegenerative Diseases Pick Disease (Frontotemporal lobe dementia - FTLD) - Pathology - The affected cortex experiences a significant loss of neurons and displays pronounced astrogliosis. - Residual neurons exhibit highly argentophilic and tau-immunoreactive round cytoplasmic inclusions known as Pick bodies. These formations result from densely aggregated straight tau filaments. A. In hematoxylin and eosin–stained sections, Pick bodies are basophilic, spherical, intracytoplasmic, intraneuronal aggregates of tau protein (arrows). They tend to be round rather than angular like the neurofibrillary tangles (NFTs) in Alzheimer disease, but like NFTs, they are argentophilic (silver impregnation) (B).  Cerebral Cortical Neurodegenerative Diseases Pick Disease (Frontotemporal lobe dementia - FTLD) – Clinical Features - Three main clinical syndromes: 1. Behavioral variant Individuals afflicted with this disorder demonstrate a gradual and progressive onset of personality and associated abnormalities. These may encompass apathy, disinhibition, perseveration, impaired judgment, limited abstraction ability, loss of empathy, bizarre affect, eating disorders, and a general sense of disengagement. Insight is typically compromised, and some individuals may exhibit euphoria or repetitive compulsive behaviors. Notably, an initial diagnosis of depression is often encountered.  Cerebral Cortical Neurodegenerative Diseases Pick Disease (Frontotemporal lobe dementia - FTLD) – Clinical Features - Three main clinical syndromes: 2. Primary Progressive Aphasia Semantic variant In the semantic variant, individuals gradually experience a decline in their capacity to comprehend the meaning of words, objects, individuals, and specific emotions. 3. Primary Progressive Aphasia Nonfluent/agrammatic variant Experience a profound difficulty in generating words, frequently accompanied by noticeable motor speech impairment. - Motor neuron disease may accompany any of these three clinical syndromes. - Frontotemporal dementia (FTD) can occur sporadically or be inherited. Symptomatic sporadic Pick disease typically manifests in mid- adult life and advances relentlessly, leading to death in 3–10 years. Cerebral Cortical Neurodegenerative Diseases Lewy Body Disease (LBD): - Presenting as either Parkinson’s disease and dementia (PDD) or dementia with Lewy bodies (DLB), Lewy body disease (LBD) ranks as the second most prevalent cause of neurodegenerative dementia, following Alzheimer’s disease (AD). - The disease is characterized by the widespread engagement of cortical neurons with Lewy body inclusions and is distinguished by the absence or a limited number of neurofibrillary tangles and amyloid plaques.  Cerebral Cortical Neurodegenerative Diseases Lewy Body Dementia (LBD) – Pathophysiology: - The development of Lewy body dementia (LBD) is believed to involve both genetic and environmental factors. - The identification of alpha-synuclein aggregates in Lewy bodies has led to the recognition of α-synuclein duplications and triplications, which clinically manifest as Parkinson's disease (PD) or dementia with Lewy bodies (DLB).  Cerebral Cortical Neurodegenerative Diseases Lewy Body Dementia (LBD) – Pathophysiology: - Lewy bodies, characterized as intraneuronal cytoplasmic inclusions, consist of straight neurofilaments measuring 7–20 nm in length, surrounded by amorphous material. - These bodies contain epitopes recognized by antibodies against phosphorylated and nonphosphorylated neurofilament proteins, ubiquitin, and α-synuclein.  Cerebral Cortical Neurodegenerative Diseases Lewis Body Disease (LBD) – Pathophysiology - The principal neuropathological hallmark in LBD is the distribution of Lewy bodies and Lewy neurites across specific brainstem nuclei, the substantia nigra, amygdala, cingulate gyrus, and ultimately, the neocortex. - The presence of α-synuclein aggregates in neurons and glia molecularly categorizes Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) as synucleinopathies. Cerebral Cortical Neurodegenerative Diseases Lewis Body Disease (LBD) – Pathophysiology - Formal criteria delineate three progressive stages: (1) Brainstem predominant; (2) transitional limbic; and (3) diffuse neocortical. - PD typically begins with nonmotor features such as constipation and/or hyposmia, followed by anxiety, depression, rapid eye movement sleep behavior disorder (RBD), parkinsonism, and ultimately dementia. The clinical manifestation of PDD occurs when limbic and cortical areas are affected. - A significant cholinergic deficit, stemming from involvement of the basal forebrain and pedunculopontine nucleus, is prevalent in most DLB patients and may be linked to characteristic fluctuations, inattention, and visual hallucinations. Cerebral Cortical Neurodegenerative Diseases Lewis Body Dementia (LBD) – Clinical Features - Most researchers view PDD and DLB as different points along a spectrum of LBD pathology. In terms of cognition, both PDD and DLB typically present with marked executive, attentional, and visuospatial deficits, while episodic memory tends to remain relatively preserved. - Cognitive decline in LBD extends to impact daily living activities beyond other symptoms associated with Parkinson's disease.  Cerebral Cortical Neurodegenerative Diseases Lewis Body Dementia (LBD) – Clinical Features - In DLB, early psychosis, featuring well-formed visual hallucinations, fluctuating cognition, rapid eye movement sleep behavior disorder (RBD), and parkinsonism, serves as the primary diagnostic criteria. - RBD, often prodromal, is a distinctive feature where patients act out their dreams, sometimes violently, potentially causing harm to themselves or their bed partners.  Cerebral Cortical Neurodegenerative Diseases Lewis Body Dementia (LBD) – Clinical Features - Anosmia is also more indicative of LBD. - Both PDD and DLB have a prodromal phase characterized by mild cognitive impairment (MCI), where cognitive deficits do not significantly affect daily life. - Prodromal DLB shares similar cognitive disturbances with PDD but is also associated with hallucinations unrelated to medications, RBD, fluctuations in attention, or parkinsonism.  Vascular Dementia Traditionally, the phrase "vascular dementia" has been employed to characterize a subset of dementia cases primarily attributed to one or more symptomatic strokes. This condition is notably prevalent in populations with limited access to medical care, where vascular risk factors tend to be inadequately treated. The term "vascular contributions to cognitive impairment and dementia" (VCID) has emerged to acknowledge the observation that pathological changes involving the cerebral vasculature are highly prevalent in the elderly and contribute to cognitive impairment, either in isolation or, more commonly, in conjunction with other neurodegenerative processes. Both symptomatic strokes and asymptomatic vascular lesions, often identified through brain magnetic resonance imaging (MRI) scans, play significant roles in contributing to cognitive impairment. Approximately half of stroke survivors exhibit some degree of cognitive impairment, and this impairment tends to increase progressively with extended follow-up periods. Vascular Dementia Subtypes of Cerebrovascular Disease Associated with VICD: Large Cerebral Strokes - Symptomatic strokes, whether ischemic or hemorrhagic, signify irreversible damage to specific regions of the cerebral cortex, subcortical white matter, or other subcortical and infratentorial structures. The resulting cognitive impairment is influenced by the size and location of these strokes. - The occurrence of multiple strokes and larger volumes of infarcted territory is correlated with an increased probability of poststroke cognitive dysfunction.  Vascular Dementia Cerebral Small-Vessel Disease - Frequently lacks clinical symptoms and is typically identified only during assessments for cognitive decline or other related symptoms. - The two prevalent age-related pathologies associated with cerebral small vessels are arteriolosclerosis and cerebral amyloid angiopathy. - Arteriolosclerosis involves the thickening of arterioles due to the infiltration of plasma proteins into the vessel wall. - Cerebral amyloid angiopathy is characterized by the deposition of the β-amyloid peptide in the walls of small cerebral arteries, arterioles, and capillaries, leading to the loss of normal wall structure. - Despite differences in their underlying pathogenic mechanisms, both cerebral small-vessel diseases result in a similar spectrum of ischemic and hemorrhagic brain lesions.  Vascular Dementia Influence of Concurrent Brain Pathologies - Several studies examining clinicopathologic correlations have confirmed that when cerebrovascular and neurodegenerative lesions coincide, the resulting cognitive and functional decline exceeds what would be anticipated based on the impact of each disease mechanism when considered separately. - The synergy between cerebrovascular and neurodegenerative processes could also play a role in the development of dementia. - These interactions may encompass the compromise of the blood-brain barrier, potentially allowing the infiltration of neurotoxic or inflammatory agents into the brain. - Additionally, there may be disruptions in the clearance of β-amyloid and other pathogenic molecules from the brain, postulated to occur through perivascular drainage pathways influenced by physiological vascular motion. Hearing Impairment and Dementia Sensorineural hearing loss (SNHL) in the elderly is typically characterized as age- related SNHL. Various mechanisms contribute to the decline in auditory function, and the manifestations can vary depending on the affected segment of the auditory pathways. Brain atrophy serves as a common factor connecting cognitive decline, Mild Cognitive Impairment (MCI), Alzheimer’s Disease (AD), and hearing loss. Indeed, all these conditions contribute to brain atrophy. In a cross-sectional study encompassing 6,451 individuals intended to be representative of the US population, with an average age of 59.4 years, a decline in cognition was observed with each 10 dB reduction in hearing. This decline persisted even below the clinical threshold, indicating that subclinical levels of hearing impairment (below 25 dB) were significantly associated with lower cognition. Hearing Impairment and Dementia Several theories have been proposed: - Increased Cognitive Load: Hearing loss likely elevates the cognitive effort needed to process and comprehend speech, as diminished or distorted sensory input demands increased cognitive engagement. This could lead to relevant structural changes in the brain and neurodegeneration, impacting other cognitive processes such as working memory. - Changes in Brain Structure and Function: Hearing loss is associated with a decrease in the overall volume of the brain and the primary auditory cerebral cortex in the temporal lobe. Chronic hearing impairment also results in reduced activation of central auditory pathways, dysfunction of the auditory– limbic pathway, and atrophy of the frontal lobe and hippocampus. Hearing Impairment and Dementia - Common Pathological Conditions: Both hearing loss and cognitive impairment stem from a shared neurodegenerative process in the aging brain, involving the degeneration of the stria vascularis, loss of hair cells and primary afferent neurons, and alterations in neurotransmitter release. - Social Disengagement: Challenges in communication arising from hearing loss can lead to social isolation, considered a risk factor for cognitive disorders. This isolation may result in reduced cognitive stimulation, apathy, and potentially depression. Social withdrawal also triggers negative biological mechanisms, including increased transcription of pro-inflammatory genes, thereby elevating the overall inflammatory status—a significant risk factor for potential damage to cerebral functions. Hearing Impairment and Dementia Traumatic Brain Injury (TBI) and Dementia Beyond the immediate debilitating effects, severe traumatic brain injury (TBI), particularly recurrent mild TBIs, can trigger prolonged neurodegenerative processes that result in pathological features resembling those seen in Alzheimer's disease (AD). While post-traumatic neurodegeneration is a frequent occurrence, determining specific types of post-traumatic dementia in clinical practice remains uncertain. There is evidence suggesting that cerebrovascular dysfunction (CVD) plays a crucial role in the onset of dementia following TBI. Traumatic Brain Injury (TBI) and Dementia 1. Considering the research article (Ramos-Cejudo, et al.) provided in this lecture, what are your reflections on the cerebrovascular connection between traumatic brain injury (TBI) and dementia? 2. Can you formulate a hypothesis regarding the pathophysiology of traumatic brain injury and its connection to the etiology of dementia? Gut Microbiome and Dementia Accumulating evidence indicates a significant role of the intestinal microbiota in the initiation and progression of neurodegenerative diseases. Recent reports have highlighted a connection between dysfunctions in the intestinal microbiota and dementia. The mounting data suggest that the gut microbiota actively contributes to the development of various conditions, including obesity, diabetes, cancers, aging, autoimmune diseases, and neuropsychiatric disorders like depression and Alzheimer's disease (AD). The involvement of gut microbiota in AD pathogenesis is realized through diverse pathways, including abnormalities in Aβ, tau phosphorylation, neuroinflammation, neurotransmitter dysregulation, and oxidative stress. Nevertheless, the precise roles and mechanisms of gut microbiota in individuals with AD remain unclear. Gut Microbiome and Dementia Drawing on the earlier discussion and the attached course article, review the case below and attempt to answer the following questions for yourself: - Can you evaluate the suggested mechanism for how dysbiosis influences the onset of dementia by identifying limitations in their hypothesis? - In addition to the mechanisms proposed in current research, what other hypotheses related to microbiota do you believe play a role in the onset of dementia? Case: Mrs. Anderson, a 65-year-old retired teacher, has been experiencing memory loss, difficulty with language, and changes in behavior over the past two years. Her family has noticed these progressive cognitive decline symptoms and has sought medical advice. Mrs. Anderson does not have a significant medical history, but her family reports that she has struggled with gastrointestinal issues, including irregular bowel movements and occasional abdominal discomfort. Post-Assessment - MCQ Which of the following neurodegenerative diseases is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain? A) Vascular dementia B) Lewy body dementia C) Frontotemporal dementia D) Alzheimer's disease Post-Assessment - MCQ Which of the following neurodegenerative diseases is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain? A) Vascular dementia B) Lewy body dementia C) Frontotemporal dementia D) Alzheimer's disease Post-Assessment - MCQ Which type of dementia is associated with motor symptoms such as tremors, rigidity, and bradykinesia? A) Alzheimer's disease B) Vascular dementia C) Lewy body dementia D) Parkinson's dementia Post-Assessment - MCQ Which type of dementia is associated with motor symptoms such as tremors, rigidity, and bradykinesia? A) Alzheimer's disease B) Vascular dementia C) Lewy body dementia D) Parkinson's dementia Post-Assessment - MCQ Which type of dementia is associated with a gradual decline in cognitive function due to multiple small strokes or impaired blood flow to the brain? A) Alzheimer's disease B) Vascular dementia C) Lewy body dementia D) Frontotemporal dementia E) Parkinson's dementia Post-Assessment - MCQ Which type of dementia is associated with a gradual decline in cognitive function due to multiple small strokes or impaired blood flow to the brain? A) Alzheimer's disease B) Vascular dementia C) Lewy body dementia D) Frontotemporal dementia E) Parkinson's dementia  References Loscalzo, J. et al. (2022) Harrison’s principles of internal medicine Chapters: 431 Alzheimer’s Disease, 432 Frontotemporal Dementia, 433 Vascular Dementia, 434 Dementia with Lewy Bodies. Kasper, D. L. et al. (2019) Harrisons Manual of Medicine, 20th Edition. Chapter 185 (Page 999-1007) Ropper A, Samuels M, Klein JP, Prasad S. Adams and Victor’s Principles of Neurology, Twelfth Edition. 12th ed. McGraw-Hill Education; 2023. Strayer DS, Rubin E, eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine. 7th ed. Lippincott Williams and Wilkins; 2014.  References Livingston, G., Huntley, J., Sommerlad, A., Ames, D., Ballard, C., Banerjee, S., Brayne, C., Burns, A., Cohen-Mansfield, J., Cooper, C., Costafreda, S. G., Dias, A., Fox, N., Gitlin, L. N., Howard, R., Kales, H. C., Kivimäki, M., Larson, E. B., Ogunniyi, A., Orgeta, V., … Mukadam, N. (2020). Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet (London, England), 396(10248), 413–446. https://doi.org/ 10.1016/S0140-6736(20)30367-6 Ramos-Cejudo J, Wisniewski T, Marmar C, et al. Traumatic Brain Injury and Alzheimer's Disease: The Cerebrovascular Link. EBioMedicine. 2018;28:21-30. doi:10.1016/ j.ebiom.2018.01.021 Bisogno A, Scarpa A, Di Girolamo S, De Luca P, Cassandro C, Viola P, Ricciardiello F, Greco A, Vincentiis M, Ralli M, Di Stadio A. Hearing Loss and Cognitive Impairment: Epidemiology, Common Pathophysiological Findings, and Treatment Considerations. Life (Basel). 2021 Oct 17;11(10):1102. doi: 10.3390/life11101102. PMID: 34685474; PMCID: PMC8538578.