2024 Aging and Neurocognitive Disoders PDF

NORMAL AGING AND NOT SO NORMAL AGING Dr. Nicole Kostiuk, R.Psych Aging Aging occurs when the rate of cell loss exceeds the rate of cell regeneration Mechanisms That Underlie Aging Oxygen radical accumulation Accumulation of age products Failure of DNA repair Genes for senescence Programmed cell deat...

NORMAL AGING AND NOT SO NORMAL AGING Dr. Nicole Kostiuk, R.Psych Aging Aging occurs when the rate of cell loss exceeds the rate of cell regeneration Mechanisms That Underlie Aging Oxygen radical accumulation Accumulation of age products Failure of DNA repair Genes for senescence Programmed cell death Telomere loss Normal Aging 1. 2. 3. 4. 5. 6. Time Clocks: Biological and Sociological Neuronal Electrophysiological Metabolic Biochemical Functional Time Clocks: Biochemical Processes – Keep a record of how much life has been lived and how much time is left to live. – The amount of time cells can divide is finite. – Approximately 50 – Influenced by lengths of telomeres – Get shorter until stop making new cells – Repair extend life? Time Clocks: Sociological Expectations Social clocks set limits to what can be done at different stages of life. Senescence vs Developmental Models Senescence is associated with a disease model Retirement occurs because aging results in “work impairments” Lifespan developmental model views changes as normal stages Retirement is a developmental phase Neuronal Loss of cells after mid-twenties 45% by the 9th decade in some areas Increase in abnormal protein accumulations in the brain E.g., Neurofibrillary tangles, senile plaques, and lipofuscin Lipofuscin: also found in liver, kidney, heart muscle, adrenal, and ganglion cells. Unknown functional significance Brain Volume Morphologic changes occur in the brain throughout the lifespan Gray matter peaks age 4-6, then declines White matter peaks age 20, then stabilizes Whole brain volume begins to decline age 60 Neural Changes With Aging Some age-related changes in brain structure and activity are region-specific e.g., volume declines measured by structural imaging: – more prominent in the frontal lobes – less pronounced in primary sensory areas Changes in brain volume with age forthree different brain regions. Frontal Lobes Last to Develop, First to Decline Different brain regions show different trajectories of growth and decline over the lifespan Some show general decline in volume over lifespan Some show curvilinear pattern Focal Changes in the Normally Aging Brain Changes on MRI common over the age of 60 ”T2 Hyperintensities” Typically in the subcortical or periventricular white matter No associated clinical pathology Etiology most likely small penetrating vessel change: “small vessel ischemic disease” Hypertension Arteriosclerosis Possible minor infarctions Demyelination METABOLIC Decreases in glucose metabolism and rCBF in many areas of the brain - from anterior to posterior with age Biochemical Decreases in enzymes involved in synthesis and increase in monoamine oxidase results in overall decrease in: Dopamine Norepinephrine GABA Acetylcholine Degeneration of the nucleus basalis of Meynert “Cholinergic Deficiency Syndrome” Role of acetylcholine Could play a role in STM changes Finding in Alzheimer’s Disease Age-Related Changes in Functional Activity Do our brains become more active or less active with age? Less efficient Dedifferentiated Autonomic Nervous System Normal aging decreases the body’s ability to withstand stress Ability to maintain homeostasis decreases Increased response to stress Slower return to homeostasis after stress This starts as early as the third decade Hearing 71% of people over 70 have hearing loss Loss at all frequencies Especially noticeable in 50s 80% of the hearing impaired don’t use hearing aids Secondary impacts Speech comprehension Isolation/paranoia Dementia Vision Age 40-45 far-sightedness almost universal By age 70, good uncorrected vision is rare Glare Progressive constriction of pupillary dilation Colour vision less vivid Macular degeneration is common Associated with high incidences of depression Decreased tearing Tactile and Proprioception Little change in basic tactile sensation until 50-55 Perception declines with age e.g., astereognosis Proprioception: vestibular apparatus becomes less effective Balanced is compromised Increases fall risk Increases risk of trauma Bone and brain! Taste and Smell Taste buds decline from 345 to 88 Threshold for detection increases Recognition decreases Elderly perceive tastes as less intense Sweet is the taste that stays the longest Decreased appetite Increased risk of poisoning Flavor enhancement increases eating Zinc deficiency causes taste disorder Olfaction appears to decline with age Gradual and unnoticed Personality Personality changes accompany changes in the brain: Declines in: Neuroticism Extroversion Openness Impulsiveness Increases in : Agreeableness, Conscientiousness Suspiciousness (appropriate awareness?) “Aging Out” Phenomenon Emotional Regulation Improves with Age Cope better with emotionally distressing situations Negative moods don’t persist as long Positive moods persist longer May be due to: Positive attentional biases Depression in the Elderly Depression may present differently in the elderly May not reach full criteria for MDD Depressive Disorder, NOS common (15-17%) Subjective and cognitive depression infrequent Somatic symptoms usually predominate Marked psychomotor retardation and decreased initiative May be misdiagnosed as medical illness or dementia Depression in the Elderly Misleading term “pseudodementia” Prevalence reflected in level of functioning – 10-15% prevalence in community dwellers – 20-30% prevalence in medically ill – 60% cognitively intact nursing home patients Depression and Medical Illness Depression more prevalent with real medical illness But depression is often attributed to medical illness Illness is considered a “good reason” to be depressed Depression may be related to medical illness But may still be treatable Only 5-10% of significant depression in the elderly are recognized and properly treated Disproportionate rate of suicide in the elderly Over 80% of suicides in elderly are associated with depression Typically white male widowers Depression is associated with increased mortality within six months Cognitive Changes With Aging “General decline” viewpoint: – Decline in all abilities with age – Due to a general reduction in mental resources or a general slowing in processing speed Some aspects of cognition are more compromised with age than others – Novel problem solving declines even as accumulated knowledge increases with age – Cognitive functions supported by frontal and temporal regions show greater decline with age Verbal and Nonverbal Skills Verbal skills – resistant to aging – can be relatively intact even in very old persons Nonverbal skills – Begin to decline earlier than verbal skills Crystallized Versus Fluid Intelligence Speed declines more than power Crystallized – Not obviously deteriorated until 70s or 80s – Some improve with age Fluid – Declines with age – Some start in 30s, perhaps earlier – Decreased cognitive flexibility Learning Learning is affected by slowed processing and speed of retrieval – Compensate by: Slower presentation Ample time to respond Semantic context Gist intact May lose details Attention and Memory Declines with age – Encoding – Working Memory – e.g., Digit Span Backwards – Retrieval Relatively intact with age – Attention span e.g., Digit Span Forward – Recognition – Storage Sex Differences in Cognitive Abilities Men and women’s brains are different Effect size is modest Influences of reproductive hormones on brain organization during fetal brain development After menopause modest loss of verbal memory skills Restored with estrogen replacement therapy Issues in Measuring the Neuropsychological Effects of Normal Aging Cross sectional studies may exaggerate age trends Longitudinal studies often result in attrition of less capable individuals Test scores vs real life measures, Medical illnesses confound Reversible Dementias An analysis of 39 articles describing 5,620 people with dementia-like symptoms reported that 9 percent had symptoms that were mimicking dementia and were potentially reversible Common causes of these symptoms were: – – – – – – Depression Delirium Side effects from medications Thyroid problems Certain vitamin deficiencies Excessive use of alcohol Alzheimer's Association. 2014 Alzheimer's Disease Facts and Figures Pain 25 to 50 percent of elderly people in the community experience pain on a regular basis 85 percent of the elderly in residential facilities report chronic pain Chronic pain is an intrapersonal experience, not a diagnosis Pain associated with inf lammation > decreased immune system functioning > brain problems Impairs cognition Chronic back pain can cause premature aging by shrinking the brain’s gray matter as much as 11 percent in one year Equivalent to 10 to 20 years of normal brain aging GI Problems and Cognition GI problems are the MOST common cause of cognitive problems in the elderly. Constipation and diarrhea/incontinence Insufficient diet (remember changes in taste and smell) Stomach less elastic and higher level of satiating hormone, cholecystokinin Feel fuller sooner Inability to absorb nutrients properly Dental problems Dry Mouth One in five older adults has xerostomia Makes it harder to eat Results in significant deficiencies of fiber, potassium, vitamin B- 6, calcium and zinc There is a significant correlation between dry mouth and the number of medications taken Digestive System Stomach lining thins Gastric ref lux is common Ulcers and GI bleeding increase – Complicated by loss of 30-40% of the pain receptors in the stomach lining which make less sensitive to acid and bleeding Vitamin and nutrient absorption decreases Nutritional deficiencies occur Metabolism slows Dehydration Electrolyte and body water decreases Less thirst perception Prone to dehydration Thyroid Thyroid problems one of the most common causes of mental illness in the elderly But typical thyroid tests may not show abnormalities Hair loss Eczema, spots Brittle nails Indicative of body deregulation including thyroid Sleep Sleep patterns change Shorter More fragmented Sleep onset earlier Earlier awakening Substance Abuse Baby boomers are high drug users Drug of choice is alcohol Increases risk for dementia 94% of primary care physicians miss the diagnosis Medications Two thirds of older adults are taking at least one prescription drug Thirty-seven percent are taking at least five drugs Another twenty percent are taking seven or more medications at once The average number of drugs prescribed to people over sixty is fifteen per year The majority are also taking herbs, vitamins and supplements, which interact with drugs Side Effects 90% of those over age 65 will suffer from side effects 67% are not told anything about potential side effects Side effects are often misdiagnosed as another illness and medicated Issues of Pharmacotherapy in the Elderly Multiple medical conditions leads to multiple medications Increased potential for adverse interactions Tolerance decreases with age because liver doesn’t metabolize as quickly e.g., Half life of valium is 40 hours; in elderly could be 100 hours! Decreased body water content means higher concentrations of medication Decreased brain volume means CNS has less reserve to combat side effects Therefore, the effects of drugs at usual doses may create a host of problems including significant cognitive impairment Medications That Can Cause Cognitive Problems Certain classes of medications have known adverse effects on the CNS which can be potentiated in the elderly Sedatives Narcotics Stimulants Antacids Antibiotics Salicylates Statins Anticholinergics Common Medications with Anticholinergic Effects Narcotics: Morphine, Hydrocodone, Fentanyl Benzodiazepines: Lorazepam, Clonazepam, Diazepam Antidepressants: Tricyclics (e.g., amitriptyline, imipramine, etc.); SSRIs (e.g., paroxetine, sertraline, etc.) Less effect than Tricyclics Antihistamines: Diphenhydramine (Benadryl), Promethazine (Phenergan) Cough and cold suppressants: Dextrorphan/pseudoephedrine Skeletal Muscle Relaxants: Cyclobenzaprine (Flexeril) Antispasmodics: Atropine, Oxybutynin (Ditropan), Ranitidine (Zantac) Antidiarrheals: Diphenoxylate Anti-Parkinsonian (some): Trihexyphenidyl, Benztropine, Artane Travel sickness medications: Meclizine, Scopolamine Anticonvulsants (some): Oxycarbazine, Carbamazepine, Valproic acid Sleep aids (some): Diphenhydramine Neurocognitive Disorders Refers specifically to delirium and mild/major neurocognitive disorders Disorders in which central feature is impairment (decline/deterioration/or change) in memory, attention, perception or thinking Many other disorders also have impairments in these areas But not as the primary characteristic and/or does not occur in the neurodevelopmental period Often comorbid with anxiety, depression, personality changes, paranoia, aggression D E L I R IUM Delirium A. A disturbance in attention and awareness B. The disturbance develops over a short period of time (usually hours to days), represents a change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day C. An additional disturbance in cognition (e.g., memory deficit, disorientation, language, visuospatial, or perception) D. The disturbances in A and C are not better explained by another preexisting, established, or evolving neurocognitive disorder and do not occur in the context of a severely reduced level of arousal, such as coma E. There is evidence from the history, physical examination, or laboratory findings that the disturbance is a direct physiological consequence of another medical condition, substance intoxication or withdrawal, or exposure to a toxin, or is due to multiple etiologies Fluctuation in Symptoms Hallmark of delirium Helps to distinguish ”Sundowning” “Lucid intervals” with relatively greater coherence more common in the morning Examples: Acceleration or slowing of thought Total disorganization of thought Speech sparse or pressured and incoherent Disjointed or perseverative speech and behavior Depression in consciousness or hypervigilant and difficulty falling asleep Restless/hyperactive or sluggish/stuporous Fear Perceptual Disturbance Misinterpretations Illusions Hallucinations Most commonly visual Disturbance of Sleep-Wakefulness Cycle Periods of somnolence may be counterbalanced by excessive alertness, intense agitation, and frenzied excitement 3 subtypes 1. Hyperactive 2. Hypoactive 3. Mixture of both Psychomotor Activity Increased Decreased Often shifts abruptly between extremes Course of Delirium Usually develops over short period of time Can be abrupt e.g., after seizures, TBI Often times over hours or days with prodromal symptoms e.g. Restlessness, thinking difficulties, hypersensitivity to stimuli Slower onset implicates systemic illness or metabolic imbalance Duration is usually brief Less than one week Rare to persist more than one month Course of Delirium Is a life-threatening condition Often reversible Up to 50% experience permanent cognitive impairment May unmask a prior dementing process 20-25% of hospitalized delirious patients will die as a result of the underlying medical condition and/or subsequent complications Mortality rates similar to acute myocardial infarction or sepsis 35-40% of those who survive delirium will die within the next year, relative to other patients who have been treated and discharged Medications Can Cause/Promote Delirium SSRI’s For patients prone to delirium: Tricyclic antidepressants Low toxicity Anticholinergics Minimal anticholinergic side-effects Benzodiazepines Short half-life Corticosteroids Minimal effect on cardiovascular and Sedative hypnotics Anticonvulsants Antiparkinsonian drugs Anti-inflammatories Antineoplastic respiratory systems No effect on seizure threshold Risk Factors Predisposing: Precipitating: Older age Surgery Dementia Drug side effects Severity of physical/chronic illness Drug withdrawal Polypharmacy Infections Metabolic disturbances Iatrogenic complications Depression Metabolic derangements Sleep deprivation Pain Sensory loss/dysfunction Acute injury Respiratory failure Myocardial infarction Infections Treatment of Delirium Directed towards underlying etiology If cannot identify, treat all concerning conditions simultaneously Masks the true etiology Neuroleptics to address hallucinations/sleep disturbance Benzodiazepines for alcohol withdrawal syndrome Naloxone for narcotic overdoses Mood stabilizers for agitation If successful, then the delirium may completely remit If not completely successful, permanent brain damage may result Geriatric patients show slower recovery even when the underlying insult is corrected Delirium Versus Dementia Many features of an acute, toxic state which distinguishes it from the slow, insidious decline of a dementia Not necessarily mutually exclusive Impossible to diagnose dementia when there is delirium other than recognizing a pre-existing dementia M I L D AN D MA JOR N EUR O C O G N I T IVE D I S OR D E R S Mild Neurocognitive Disorder A. Evidence of modest cognitive decline from a previous level of performance in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition) based on: 1. Concern of the individual, a knowledgeable informant, or the clinician that there has been a mild decline in cognitive function; and 2. A modest impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment B. The cognitive deficits do not interfere with capacity for independence in everyday activities (i.e., complex instrumental activities of daily living such as paying bills or managing medications are preserved, but greater effort, compensatory strategies, or accommodation may be required) C. The cognitive deficits do not occur exclusively in the context of delirium D. The cognitive deficits are not better explained by another mental disorder (e.g. MDD, Schizophrenia) DSM-5 Major Neurocognitive Disorder A. Evidence of signif icant cognitive decline from a previous level of performance in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition) based on: 1. Concern of the individual, a knowledgeable informant, or the clinician that there has been a significant decline in cognitive function; and 2. A substantial impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment B. The cognitive deficits interfere with independence in everyday activities (i.e., at minimum, requiring assistance with complex instrumental activities of daily living such as paying bills or managing medications) C. The cognitive deficits do not occur exclusively in the context of delirium D. The cognitive deficits are not better explained by another mental disorder (e.g. MDD, Schizophrenia) DSM-5 Specify whether due to: Alzheimer’s disease Frontotemporal lobar degeneration Lewy body disease Vascular disease Traumatic brain injury Substance/medication use HIV infection Prion disease Parkinson’s disease Huntington’s disease Another medical condition Multiple etiologies Unspecified DSM-5 Specify Behavioral Disturbance Without behavioral disturbance: If the cognitive disturbance is not accompanied by any clinically significant behavioral disturbance With behavioral disturbance: e.g. psychotic symptoms, mood disturbance, agitation, apathy, or other behavioral symptoms DSM-5 Specify Current Severity Mild: Difficulties with instrumental activities of daily living, e.g., housework, managing money Moderate: Difficulties with basic activities of daily living, e.g., feeding, dressing Severe: Fully dependent DSM-5 General Course of Dementia Diagnosis is based upon a pattern of cognitive deficits as opposed to etiology Depending upon etiology and treatment, the dementia may be progressive, static or remitting, e.g.: – Progressive: Alzheimer’s Disease – Static: Chronic Severe TBI – Remitting: Acute Stroke NEUROCOGNITIVE DISORDER DUE TO ALZHEIMER’S DISEASE NCD Due to Alzheimer’s Disease A. The criteria are met for Major or Mild NCD B. There is insidious onset and gradual progression of impairment in one or more cognitive domains (for Major NCD, at least two domains must be impaired) Complex Attention Executive Function Learning and Memory Language Perceptual-Motor Social Cognition DSM-5 NCD Due to Alzheimer’s Disease C. Criteria are met for either probable or possible Alzheimer’s disease as follows: Probable AD is diagnosed if either of the following is present; otherwise, Possible AD should be diagnosed.) 1. Evidence of a causative AD genetic mutation from family hx or genetic testing 2. All three of the following are present: a. Clear evidence of a decline in memory and learning (and at least one other cognitive domain) (based on detailed hx or serial np testing) b. Steady progressive, gradual decline in cognition, without extended plateaus c. No evidence of mixed etiology (i.e., absence of other neurodegenerative or cerebrovascular disease, or another neurological, mental, or systemic disease or condition likely contributing to cognitive decline) D. The disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease, the effects of a substance, or another mental, neurological, or systemic disorder DSM-5 Diagnostic Markers of AD Hallmarks – Cortical atrophy – Amyloid plaques and tau-neurofibrillary tangles – Interferes with communication at synapses and transportation – Both processes may result in cell death For early-onset cases with autosomal dominant inheritance, a mutation in one of the known causative AD genes – Amyloid precursor protein (APP) – Presenilin 1 (PSEN1) – Presenilin 2 (PSEN2) Apolipoprotein E4 cannot serve as a diagnostic marker because it is only a risk factor and neither necessary or sufficient for disease occurrence DSM-5 Neurofibrillary Tangles and Amyloid Plaques Defining neurobiological characteristics: brain riddled with large numbers of neurofibrillary tangles and amyloid plaques. But also found in normal aging, particularly beyond age 70 –Neurof ibrillary tangles: twisted pairs of helical filaments found within the neuron. –Amyloid plaques: deposits consisting of aluminium silicate and amyloid peptides, meaning that they are basically a buildup or a conglomeration of proteins. Amyloid Plaques are Necessary but Not Sufficient Most controls show no evidence of amyloid-beta deposition (NC–), but a substantial portion (25%) do (NC+). Most patients with MCI show moderate (MCI +) or severe amyloid-beta deposition (MCI + +), but as many as 40– 50% show no evidence of amyloid-beta pathology (MCI–). The vast majority of clinically diagnosed patients with AD show heavy amyloid-beta deposition (AD). Their number correlate strongly with cognitive function Cortical Atrophy Net result of accumulating tangles and amyloid plaques: loss of synapses and cells Cell loss becomes visible on brain imaging Cortical atrophy Widened cortical sulci Widely distributed across brain Increased degeneration of limbic system Hippocampus, amygdala, olfactory system Enlarged ventricles False negatives in earlier stages because of age expectations Low correlation with neuropsychological indices due to slow momentum Vascular system intact Greater Volume Loss in Degenerative Conditions From a neuroimaging perspective, the underlying theme of degenerative disorders is some degree of cerebral atrophy or parenchymal volume loss greater than the norm Degeneration of Cholinergic Pathways Severe loss in Nucleus Basalis of Meynert In the basal forebrain Responsible for production of acetylcholine Progressive course results in widespread degeneration and cognitive deterioration Metabolic Changes in DAT Stage 1 typically demonstrates bilateral metabolic temporoparietal hypoperfusion (glucose metabolism on PET, blood f low on SPECT) Stage 2 typically demonstrates diffuse metabolic hypoperfusion Course of DAT Length of illness: 2-20 years Mean duration 7-10 years Generally slowly progressive Later-onset progresses slower Most common pattern is an insidious onset Earliest sign: episodic memory, involving acquisition and storage Downplayed Personality changes Social withdrawal Apathy Decreased interest Irritability In the later stages, gait and motor disturbances Clinical Course of DAT Stage One (1-3 years) Able to function relatively independently in familiar environments Some difficulty in novel settings Prefers familiar routines/settings Mild cognitive problems. Impairment in recent memory Learning problems Declining initiative Inefficiency in everyday tasks May have mood disturbances Structural neuroimaging likely remain normal Clinical Course of DAT Stage Two (2-10 years) More rapid decline of cognition and personality Adequate functioning in familiar settings and overlearned tasks Worsening memory Word-finding deficits Disorientation Mood changes Changes on Imaging EPS symptoms Florid psychosis may occur when dementia becomes severe Clinical Course of DAT Stage 3 (8-12 years) Profound cognitive impairment All aspects Require 24 hour supervision Sleep disturbance and behavioural abnormalities Hallucinations Clinical Course of DAT Stage 4 Severe dementia and complete dependence Disoriented Unable to follow basic routines Emergence of psychosis Increasingly sedentary Incontinence Clinical Course of DAT Stage 5 Severe disability Noncommunicative Difficulty chewing/swallowing Nonambulatory Muscle wasting and weight loss Increased vulnerability to pneumonia/illness Functional Losses in DAT Impaired hygiene and incontinence – Usually late manifestations – Suggests more advanced stage of dementia Functional losses may occur in stages that appear to reverse normal early human development with sequential loss of: – Speech, ambulation and continence – Sitting, smiling, posture and feeding Psychosis and DAT Thought disorder is common 40% will experience psychotic symptoms Most prevalent in the moderate stage Hallucinations are less common Mostly auditory or visual Uncertain etiology Delusions more common Simple, paranoid claims about family and environment Theft, imposter Capgras syndrome Not continuous; episodic outbursts Predictor of more rapid decline Early Identification of DAT Significant brain changes have already occurred years prior to diagnosis As early as age 30! Ideally, one would like to identify persons who are presymptomatic but at risk, in order to preserve neurons Smith and Bondi (2008) Risk Factors Getting OLD!! Female Lower levels of education/lower premorbid intellectual status Down’s syndrome History of head injury History of psychiatric illness Chronic depression Alcohol abuse Marital Status Or at least a dog! Risk Factors Smoking Cardiovascular risk factors Elevated blood cholesterol in midlife High blood pressure Small vessel/cerebrovascular disease Diabetes mellitus Toxins Olfactory loss Genetics Particularly early onset Or homozygous for ApoE4 Causative Genes Early-onset, familial inheritance (approximately 100 families world-wide) have one of three genetic mutations: 1. APP mutation a mutation of the gene on chromosome 21 coding for amyloid precursor protein aberrant breakdown of this protein is linked to the formation of amyloid deposits 2. presenilin 1 mutation or 3. presenilin 2 mutation involves the protein presenilin affects the accumulation of amyloid plaques Increased Genetic Risk Apolipoprotein E Plays a role in clearing amyloid plaques 3 common isoforms: epsilon-2, epsilon-3, and epsilon-4 ApoE-4 allele increases risk of DAT Inheriting one E4 gene increases risk 4x; inheriting two E4 genes increases risk 16x ApoE-2 may be at decreased risk 15% of general population have E4 40% of Alz patients have E4 45% of those with DAT do not carry E4 genotype Prevalence of DAT Late onset (after age 65 years) is much more common than early onset Few cases develop before 50 years Up to 10% of people over 65 have symptoms consistent with DAT Average age of diagnosis is 75 50% of individuals over age 85 meet criteria Less than 5% have familial variant Early Detection? Screening of the general geriatric population is not useful Low yield High false-positives Also high false negatives Younger Advanced education/high cognitive reserve Expectations for Neuropsychological Assessment Results Brief mental status examinations and neurocognitive screening often miss early stages Neuropsychological assessment is the most sensitive and specific for detection Tests of declarative/episodic memory (i.e., verbal learning and delayed recall) Language (e.g., confrontation naming, word list generation) Executive functions (e.g., cognitive flexibility) Better than standard neurological exams, neuroimaging, and laboratory tests Blood-based biomarkers show promise Intelligence: Early stages normal crystallized Decline with advanced stages Attention/Concentration: Early problems with divided attention Alertness and basic attention relatively intact until later Language: Word finding problems; phonemic and semantic paraphasias Aphasia as disease progresses Echolalia and mutism in late stages Visuospatial: Some have early impairments in geographical orientation Impairments in design copy tasks Memory: Episodic memory impairment typically first observable symptom Limited learning Rapid forgetting Intrusion errors Heightened recency effect Impaired recognition Retrograde memory loss occurs Temporal gradient Executive Functions Problems with mental flexibility, reasoning, judgment Lack insight/awareness into their own deficits Sensorimotor: May decline in later stages Treatment and Prevention No cure Treatment focuses on slowing cognitive decline. Acetylcholinesterase Inhibitors are treatment of choice Donepezil Rivastigmine Galantamine Does not stop the underlying decline/death of cells Medications become ineffective Some candidate drugs attempt to influence amyloid plaque deposition and tau protein formation Others target different steps in pathological cascade E.g., inflammation Major or Mild NCD with Lewy Bodies A. The criteria are met for major or mild NCD B. The disorder has an insidious onset and gradual progression C. The disorder meets a combination of core diagnostic features and suggestive diagnostic features for either probable or possible NCD with Lewy Bodies D. The disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease, cerebrovascular disease, the effects of a substance, or another mental, neurological, or systemic disorder DSM-5 Probable NCD with Lewy Bodies Onset of motor and cognitive symptoms in close proximity The individual has two core features, or one suggestive feature with one or more core features – Core diagnostic features: Fluctuating cognition with marked variations in attention and alertness ( Almost like a delirium Recurrent visual hallucinations that are well formed and detailed REM sleep behavioural disorder One or two features of parkinsonism DSM-5 Supportive Clinical Features Neuroleptic sensitivity Postural instability Repeated falls Syncope Transient episodes of unexplained loss of consciousness Severe autonomic dysfunction Orthostatic hypertension Urinary incontinence Hallucinations in other modalities Systematized delusions Apathy Anxiety Depression Course Overall slow progression Frequent fluctuations Marked confusion Periods of complete lucidity LBD Early Stage 1-3 years Mild parkinsonism Delirium Cognitive deficits present, but still fairly functional Confusion, if present, is mild Insight largely preserved Hallucinations, if present, are benign and patient has insight REM behavioural symptoms may or may not be present LBD Middle Stage 3-6 years Motor symptoms cause greater difficulty with mobility Dementia more pronounced and causing functional problems Likely need assistance with medications, finances, driving Insight slipping Confusion more frequent LBD Late Stage (>7 Years) Severe dementia Increasingly dependent with even basic activities of daily living Eventually immobile without assistance Average duration of survival is 8 years (shorter than DAT) So What are Lewy Bodies? Toxic neuronal inclusions comprised of a protein, alpha-synuclein, located in the cytoplasm of neurons These abnormal proteins displace other cell components Typically circular and have a dense protein core surrounded by a peripheral halo Also characteristic of Parkinson’s Disease LBD may be three subtypes: 1. Parkinson’s disease with dementia 2. Diffuse Lewy Body Disease 3. Lewy Body Variant of Alzheimer’s Disease Lewy Body Versus Other Dementias DLB and PD may reflect a continuum Dementia in PD usually develops after parkinsonism DLB often has cognitive symptoms prior to or at same time as parkinsonism See LBs, plaques and tangles in both DLB and DAT Relative contribution of different pathologies is unclear Survival time in pure DLB is shorter DAT patients can develop parkinsonism But usually after about 6 years versus 1 year in DLB On autopsy most DAT patients have LB pathology Schoenberg and Duff (2011) Dementia and Mild Cognitive Impairment in Adults. In Schoenberg and Scott (Eds.) The Little Black Book of Neuropsychology. New York. Springer. Prevalence After DAT, DLB is the second most common cause of dementia Responsible for 20% of all dementias 20-30% of patients with a neurodegenerative condition have comorbid DAT and LBD Onset of diffuse LBD is late 50’s Onset of Lewy Body Variant varies from 50s-80s 1.5:1 male to female ratio Schoenberg and Duff (2011) Dementia and Mild Cognitive Impairment in Adults. In Schoenberg and Scott (Eds.) The Little Black Book of Neuropsychology. New York. Springer. Functional Consequences of NCDLB More functionally impaired than would be expected for their cognitive deficits Motor impairments Autonomic impairments Sleep disorders Psychiatric symptoms Risk Factors Older age Other causes of dementia History of: Anxiety Depression Stroke Family history of Parkinson’s Disease ApoE4 allele carrier Schoenberg and Duff (2011) Dementia and Mild Cognitive Impairment in Adults. In Schoenberg and Scott (Eds.) The Little Black Book of Neuropsychology. New York. Springer. Neuropsychological Assessment Results Intelligence: Nonverbal may show mild impairment Attention/Concentration: Impaired early, particularly working memory and vigilance Disoriented to time/place due to fluctuations over hours to days Processing Speed: Impaired early Language: Variable deficits in word list generation and confrontation naming early on, progresses Hypophonia Visuospatial: Early, marked impairment common Learning and Memory: Reduced but not as impaired as other domains early Visual memory may be more impaired Becomes more impaired with disease progression Executive Functions: Impaired early Sensorimotor Functions: Micrographia Parkinsonism (tremor less common than gait problems) Rigidity Bradykinesia Psychiatric: Well-formed visual hallucinations early More disruptive as disease progresses Delusions can occur Treatment of LBD Treatment of hallucinations with neuroleptics can worsen motor symptoms (and lead to death) Treatment of motor symptoms with levodopa can aggravate hallucinations Treatment with dopamine agonists can result in compulsive behaviours May actually respond better to cholinesterase inhibitors than DAT patients F R ON T O -T E M P OR AL D E M E N T IA Initially diagnosed in 2022 with “Aphasia” but in 2023 that diagnosis was changed to “Frontotemporal Dementia”; how could such a mistake have been made? How does one mistake aphasia for FTD? There are actually three major variants of FTD Bruce Willis has the language variant Frontal or Behavioural Variant Primary Progressive Aphasia or Language Variant Motor Variant And each of these has its own variants too!! 111 Quick facts on FTD in general Like Alzheimer’s it is considered a “cortical” dementia (versus a subcortical dementia) But very different with respect to age of onset, symptom profile, and most affected brain regions Average age of onset: 55 (versus Alz which is 75) Shorter survival time and more rapid progression compared to Alz 40% have family history of dementia FTD can mimic many psychiatric conditions initially (e.g., MDD, OCD) 112 Has characteristic thinning primarily in frontal and anterior temporal regions, with less thinning in parietal lobe than Alz patients 113 FTD Diagnostic Criteria: No Motor Variant in DSM The disturbance has insidious onset and gradual progression Either 1 or 2: 1. Behavioural Variant A) Three or more of the following behavioural symptoms: Behavioural disinhibition Apathy or inertia Loss of sympathy or empathy Perseverative, stereotyped, or compulsive/ritualistic behaviour Hyperorality and dietary changes B) Prominent decline in social cognition and/or executive abilities 2. Language Variant A) Prominent decline in language ability in the form of speech production, wordfinding, object naming, grammar, or word comprehension Relative Sparing of learning and memory and perceptual-motor function 114 Behavioural Variant: Most Common Variant Occurs more frequently in men Average age of onset 54, onset after age 75 very rare Age of survival from diagnosis to death ranges from 3 to 8 years Show frontal hypometabolism early in disease process on FDGPET, even before structural changes are evident on MRI Often perform well on neuropsychological tests early in the disease process 115 Two Subtypes 1. Apathetic Reduced social cognition, reduced motivation, inertia, lack of interest in prior activities, progressive social isolation, decreased empathy, poor decision-making 2. Disinhibited Disinhibition, impulsivity (e.g., inappropriate comments in public), hyperorality (especially for sweet foods), stereotyped motor movements, perseverative behaviours, can have hyperreligiosity 116 Disinhibited Subtype is the Most Commonly Recognized Most striking symptom is lack of inhibitory control, especially in the realm of social-emotional functioning Lack insight into their own deficits For the most part, they aren’t distressed by their symptoms because of this. Frustration and anger may emerge though in response to reactions from others, or limits set by others. 117 Other Fun Facts About bvFTD Are generally more functionally impaired than patients with Alz or language variant of FTD Can be dangerous to others because of disinhibition, impulsivity, poor problem-solving that emerges early E.g., more hit and run accidents, speeding, traffic violations Cholinergic systems is unaffected so acetylcholinesterase inhibitors have little value SSRI’s are typically the treatment of choice for the emotional and behavioural symptoms of FTD 118 Primary Progressive Aphasia (Language) Variant This subtype of FTD mainly exhibits difficulties in the domain of language but there is no identifiable cause for language impairments such as stroke/vascular disease or neoplasm Difficulty with verbal expression, naming of persons and things Over time, speech has less and less content, and eventually become practically mute Difficulties in reading and writing can also develop Social withdrawal and depression not uncommon, but not typically associated with changes in personality or behaviour (unlike the frontal version) 119 Fun Facts about the Language Variant Onset age 40-80, with average onset in late 50’s Average length of time from onset to death is 12 years Exclusive impairment in language during the first two years and can remain confined to the domain of language for 10-14 years! Impairments in other cognitive domains become apparent as disease progresses, but language deficits are the most prominent Specific problems vary depending on the subtype, but all experience gradual decline in speech fluency, word finding, or object knowledge as the first and worst symptom Commonly affected aspects of language include word finding, object naming, word comprehension, semantic knowledge, and speech fluency Memory is relatively intact, although patient may have difficulty communicating their thoughts May have encoding deficits due to language problems 120 Diagnosis Can Be Difficult Forgetting vs confrontation naming problem Confused vs comprehension problems Emotionally labile vs frustrated due to communication difficulties 121 Differential Diagnosis Stroke Impairments would be abrupt May have motor or sensory symptoms affecting domains other than language Course is improvement, not worsening Alzheimer's Patients often have impairments in naming, but memory decline as well PPA patients may appear to have memory decline because they can’t express themselves though! Multiple Sclerosis and Parkinson’s Can cause motor speech deficits (e.g., dysarthria, dysphonia/hypophonia) 122 Seizure Neoplasm TBI Longstanding, no decline Acute/Rapid Stroke Early neurological insult affecting the dominant hemisphere Developmental Language Disorder Reading Disorder or Disorder of Written Expression 123 Slow, insidious, primary complaint of language decline 3 Variants of the Language Variant Nonfluent PPA Semantic PPA Logopenic PPA 124 Nonfluent or Agrammatic Variant Speech is nonfluent and effortful, with dysarthria (like Broca’s aphasia!) Stuttering, slurring, and/or pausing within words due to motor speech difficulties Speech becomes increasing agrammatical Short phrase lengths, omission of grammatical morphemes, such that speech becomes telegraphic and simpler Changes in rhythm, decreased phrase lengths between pauses, decreased rate of speech Speech is halting, laboured, slow, monopitch and imprecise articulation Progressive decline in writing too Pitch distortions may occur Repetition is intact 125 Comprehension of words and objects remain intact (at least initially) So they can understand but they can’t get the words out! Classic language measures will be unaffected (object naming, repetition, language comprehension) but verbal fluency will be down As progresses, comprehension of grammatically complex sentences becomes impaired, even while single word comprehension remains intact e.g., The boy calling his mother has a red shirt Progresses to mutism Other cognitive domains initially are unaffected 126 Semantic Variant Semantic memory includes acquired information about words, objects, people, abstract concepts, names, and language. Begins with loss of ability to finely distinguish between types of objects Progresses to broader difficulty making such distinctions Finally to complete loss of knowledge of the word and even the category Loss of semantic knowledge results in severe deficits in: confrontation naming poor verbal comprehension due to disrupted word meanings visual agnosias 127 Because of their difficulty with object naming and gradual loss of semantic knowledge, they may present with empty or circumstantial speech, but that speech is fluent, phonetically accurate, with intact syntax and prosody Patients can speak fluently but their speech may not be very meaningful because the words they use may be inappropriate As loss of semantic knowledge progresses, speech becomes increasingly vague and generic with substitutions of superordinate terms such as “animal” for “camel” or “food” for “grapes” “Get me the thingy that’s next to the green doohickey” Comprehension problems 128 Examples of responses by a patient with semantic PPA Hold your hand out with your palm up What’s a palm? Does a hyena like to laugh? What’s a hyena? Does a deer have antlers? I know what a deer is, but what are antlers? What’s a farm animal that gives milk? It’s not a frog, it’s not a horse Patients cannot recognize objects (because they have lost the meaning of what that object is) Present an object in the wrong colour, would not be able to say if it was the correct colour E.g., would not be able to say “true” to statements like “bananas are yellow” Present a tool and would not be able to say if the tool matches the object for which it is used E.g., would not be able to say that the hammer goes with a nail 129 Logopenic/Phonological Progressive Aphasia May actually be an Alzheimer’s Disease variant Single word repetition and comprehension is intact, but both are impaired for phrases/sentence Speech may be slow, with frequent word-finding pauses, but this is different from the halting, agrammatic and aprosidic speech of nonfluent PPA Have dysnomia (word finding difficulties) May make phonological paraphasic errors (i.e., substitute words with similar sounds) Spared motor speech distinguishes this from the nonfluent variant It’s not a motor problem 130 Semantic knowledge of words and objects is intact Like semantic dementia they have word-finding problems, but unlike semantic dementia but they still have knowledge of what the word means Spared grammar, object knowledge, and single word comprehension helps distinguish from the semantic variant Memory is intact in early stages 131 Examples of Patient Responses Patient was unable to find the word “microwave” when trying to describe how he made dinner the night before, referring to it as “a box shape that you open and press keys and it uses electricity” Phonemic cues were not helpful Made phonemic pharaphasic errors (e.g., damp instead of lamp) when reading Could spell high frequency words (e.g., dog) but unable to spell more complex regular words (“flage” for “flag”) and irregular words (“quire” for “choir). Motor Variant of FTD Important to identify early because it progresses rapidly with death normally occurring in the late 50’s Characterized by progressive deterioration of motor functions, with cognitive and psychological symptoms Overlap with Parkinson’s Disease and other movement disorders Decreased gait and balance Safety concerns are paramount because of increased risk of falls and subsequent TBI Cognitively demonstrate: Impaired executive functions (e.g., mental flexibility, planning, problem-solving, judgement, and impulse control) Problems with language and memory Apathy, indifference to others, and lack of insight often noted 133 Three subtypes: Progressive Supranuclear Palsy There are at least seven different subtypes of progressive supranuclear palsy alone! Corticobasal Syndrome FTD with Motor Neuron Disease 134 That was just a sampling of the few types of dementias…there are many more! In fact, this whole course was really only a sampling of all of the disorders; there are many that I didn’t even touch on: Neurodevelopmental Disorders Communication Disorders Motor Disorders Dissociative Disorders Elimination Disorders Sexual Dysfunctions Gender Dysphoria Substance-Related and Addictive Disorders Paraphilic Disorders Etc It’s impossible to present on all of them or to be an expert in all of them, so I hope you enjoyed the ones I chose!