An approach to dementia patient presentation

dementia types pathophysiology and management ; FTD; Alzheimer's disease #prion disease #CJD

1. An approach to dementia patient Prepared by: Dr Prabidhi Adhikari Moderator: Prof. Dr Mohan Belbase

2. Contents

3. Introduction Dementia is a term for several diseases that affect memory, thinking, and the ability to perform daily activities - WHO Dementia refers to a disease process marked by progressive cognitive impairment in clear consciousness.- CTP These deficits represent a decline from a previous level of functioning , so dementia does not refer to low intellectual functioning or mental retardation that are developmental and static conditions Derived the Latin root “ Demens ” , which means being “ out of one’s mind ”. used since the 13th century, its mention in the medical community was reported in the 18th century.

4. History 1906 – The first description of Alzheimer’s disease by Dr Alois Alzheimer  1910-AD named In 1976 – found ach level were lower in people with AD. 1991 – A genetic revolution begins 1995- amyloid and tau protein in the spinal fluid of people with Alzheimer’s 1980-the Alzheimer’s Society  was founded E nd of the 19th century-Czech psychiatrist Arnold Pick discovered the ‘Pick body’ 20th century- a series of neurological and neuropathological breakthroughs were seen in the field of dementia

5. Epidemiology > 55 million people have dementia worldwide, over 60% of whom live in low-and middle-income countries. 10 million new cases - Every year between 2% and 10% of all cases of dementia start before the age of 65. The prevalence doubles with every five-year increment in age after 65 Alzheimer disease is most common (contribute to 60–70% of cases) seventh leading cause of death and one of the major causes of disability and dependency among older people globally. In 2019, dementia cost economies globally 1.3 trillion US dollars ( WHO )

6. Risk factors

7. Classification

8. Classification Reversible (non degenerative) Dementia: 5% of dementia cases in older group have reversible causes. D- Depression, Drugs E- Endocrine (TSH,PTH) M-Metabolic(hypoglycemia, CLD, CKD) E-Encephalitis(limbic), Epilepsy N- Nutritional (B1,B6,B12, folate), NPH T- Tumor, toxin, trauma(SDH) A- Alcohol abuse

9. Dementia Subtypes: Features Cortical Subcortical Mixed Site of brain Motor symptoms Memory symptoms Language Calculation Co ordination Posture Examples Outer cortex Rare Common Aphasia +;dysarthria – Acalculia + Preserved Upright AD, FTD Sub cortical grey matter Usual Less marked Aphasia -; dysarthria + Acalculia – Impaired Bowed, extended PD, HD, PSP Multi infarct dementia DLB CJD

10. Etiology Huntington’s disease: develop between the ages of 30 and 50, with an estimated 30,000 cases in the United States. CJD is rare, occurring in approximately one in 1 million people annually worldwide.

11. Clinical features The hallmark feature of dementia is cognitive impairment. Patients must demonstrate impairment in one or more cognitive domains . The onset, duration, course, presentation, and associated symptoms vary depending on the type of dementia.

12. Pseudodementia Onset well demarcated History short Rapidly progressive H/o previous psychiatric difficulty or recent crisis C/o cognitive function Affective change present Behavior unaffected No nocturnal exacerbation Examination: I don’t know, little effort spent Inconsistent memory loss Specific memory gaps Dementia Indistinct Long history Initially unnoticed Uncommon Little c/o cognitive loss Apathetic, shallow emotions Compatible with memory loss Nocturnal accentuation Tries items, struggles with tasks Recent>remote, consistent No specific memory gaps Dementia vs pseudodementia

13. Diagnosis -Major Neurocognitive Disorder (DSM V) Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains*: Learning and memory Language Executive function Complex attention Perceptual-motor Social cognition Noted by individual affected ,family member , other caretaker or clinician and should be demonstrated on standard psychological testing and if that is not possible, another measurable clinical assessment. Differentiates from mild neurocognitive disorder by amount of cognitive decline.

14. Cognitive sub-domains

15. Diagnosis Initially there may be difficulty performing instrumental activities of daily living, and eventually basic activities of daily living . Basic Activities of Daily Living Instrumental Activities of Daily Living Ambulation Dressing Grooming Bathing Feeding Toileting Transportation Using the telephone Meal preparation Medication management Financial management Housekeeping Laundry

16. Screening High prevalence of dementia, especially with advancing age. Associated with higher rates of delirium, adverse drug reactions, and falls. Can help plan for future. Mini-Mental State Exam (MMSE) Mini-Cog: Draw a clock test Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)  General Practitioner Assessment of Cognition (GPCOG)  Montreal Cognitive Assessment  (MoCA) and the Addenbrooke’s Cognitive Examination-Revised (ACE-R)

17. Evaluation of cognitive domains Obtaining information: corroborate with a family member/ other informant The onset and course and duration of changes in cognitive functioning Pre-existing disabilities Educational and cultural background that could affect testing variability General medical and psychiatric history Past neurological history including prior head injuries or other CNS insults Current psychiatric symptoms and significant life stressors Current prescription and over-the-counter medication use Current and past use and abuse of alcohol and drugs Family history of dementia

18. Memory impairment: Refers to the inability to learn new information or to recall previously learned information. Short-term memory is impaired before long-term memory. Short-term memory impairment : Patients are unable to learn new information or new skills and may become overwhelmed, disoriented, or confused in new environments (i.e., traveling or moving).

19. Memory impairment : Having difficulty recalling recent events and activities? Repeating himself or herself more often/ repetitive questions, repetitive retelling of stories? Needing to rely more on lists or reminders? Misplacing or losing items? Need more reminders to attend to a particular task/ forgetting that food is cooking on the stove? Long-term memory impairment: patients will no longer recall their personal past history and will forget previously highly learned material. Procedural memory for previously learned skills may be retained longer.

20. Language Can manifest as difficulties in receptive or expressive language. Aphasia may be evident as word finding difficulties resulting in reduced fluency of productive speech, word substitutions, or mispronouncing words. Patients may have difficulty remembering names of distant family members or friends or acquaintances they see infrequently. As language impairment progresses, patients may forget names of close family and friends. Aphasia may be detected by asking the patient to name body parts or objects in the room .

21. Language They often have difficulty maintaining conversations, or may use generalized, vague terms such as “thing” and “it ” to try to maintain the conversation; eventually they stop initiating conversation. Using more generalized pronouns as substitutes for names of items Making more grammatical errors in conversation Individuals may appear more withdrawn and disengaged as their ability to engage with others through conversation becomes more impaired. They may develop paraphasic errors and have poverty of content with empty speech. Eventually, speech may become incomprehensible and unintelligible.

22. Perceptual–motor impairments Include difficulties in visual perception and visuo-construction , as well as apraxia and agnosia. There may be difficulties in navigating in familiar environments, and individuals may have more trouble during times of dusk, when lighting changes may affect perception. Apraxia, or impaired ability to carry out motor activities despite intact motor function , may manifest in the earlier stages as difficulty using familiar tools or machines (i.e., Microwave oven, washing machine) or trouble performing previously acquired skills (i.e., Knitting, woodworking). In later stages, there may be dressing, bathing, or feeding apraxias that contribute to impairment in ability to perform activities of daily living.

23. Perceptual–motor impairments Test for apraxia is to ask the patient to pantomime the use of a common object such as a hammer or a toothbrush. Agnosia, or failure to recognize or identify objects despite intact sensory function , may be reflected in the inability to recognize familiar objects, familiar faces or in later stages, one’s own reflection in the mirror. It also manifests as lack of insight into one’s own impairment and unrealistic assessment of one’s abilities. Agnosia can be evaluated by first asking the patient to close his or her eyes and then placing an object, such as a key or a coin, in the patient’s hand and asking the patient to identify it without looking at it.

24. Complex attention Individuals with impairments in typically have difficulty when there is competing stimuli, such as multiple conversations or ambient sound from the television or radio . They are easily distracted and have trouble registering new information ; thinking may also appear to take longer. Difficulty paying attention? Easily distracted in environments where there are competing stimuli? Routine tasks taking longer than usual?

25. Impairment in executive functioning Refers to disturbances in planning, organizing, sequencing, and abstracting . Impairment in this area is reflected in difficulty performing complex tasks or problem solving. This may be manifest as trouble preparing a meal, managing medications, or managing finances. Judgment is often impaired and bad decisions are made because of deficits in executive functioning combined with lack of recognition of difficulties.

26. Impairment in executive functioning Asking the patient to perform a series of simple tasks is a way to evaluate executive functioning. The patient can be asked to put a piece of paper in his or her right hand, fold it in half and put it on the floor. Difficult for a patient with impairment in the ability to plan, initiate, sequence and monitor complex behavior. Serial subtraction of 7s ; spell the word “world” backward and produce verbal word lists, such as names of animals or items in a grocery store, are other ways to test.

27. Impairment in executive functioning More difficulty with multitasking? More assistance required to plan out activities or instrumental activities of daily living? More assistance required to make decisions? More trouble in large social situations, or finding them less enjoyable?

28. Social cognition Includes the ability to recognize emotions. Impairments in social cognition may initially be manifested as difficulty recognizing social cues or emotions in others, apathy, disinhibition, and changes in levels of extraversion or introversion. Family members of the individual may describe a change in personality . As these impairments progress, behavioral changes become more overt, with individuals making sexually or politically inappropriate comments and showing disinhibited and intrusive behaviors that lack awareness for another’s personal space.

29. Behavioral and Psychiatric Symptoms of Dementia/NPS BPSD includes emotional, perceptual, and behavioral disturbances similar to those seen in psychiatric disorders. Point prevalence : 60-80% , and a cumulative risk of greater than 90% over the course Classified into 5 domains: Cognitive or perceptual : (delusions, hallucinations) Motor: (pacing, wandering, repetitive movements, physical aggression) Verbal: (yelling, calling out, repetitive speech, verbal aggression) Emotional: (euphoria, depression, apathy, anxiety, irritability) Vegetative: (disturbances in sleep and appetite)

30. Prevalence of NPS Prevalence in Past 30 Days Lyketsos , JAMA, 2002

31. Features of NPS Mood: Major depression: early in the course, half of patients with Alzheimer disease, decrease in prevalence with advanced dementia Suicidal ideation/behavior may occur especially in mildly impaired Elation and even a frank manic episode-rare Anxiety: manifest as fear of being alone , patients will search for their caregivers exhibit “ catastrophic reactions ” when confronted with their cognitive limitations or when facing changes in routine or environment.

32. Features of NPS Personality changes: FTD often presents with disinhibition and impulsivity Apathy syndrome with amotivation and withdrawal Pre-existing personality traits may become stronger or exaggerated Psychosis: Generally, occur in the middle stages of illness and often co-occur with behavioral disturbance. Common early psychotic symptom is paranoia and the belief that belongings have been stolen. In later stages, hallucinations occur , most commonly visual hallucinations . They may see deceased relatives The hallucinations are often congruent with delusions of the same theme

33. Features of NPS Sleep disturbance: Altered sleep–wake cycles can result in disrupted and fragmented sleep in about half of patients. Patients may have phase-shifted sleep , going to bed late, and sleeping late in the morning Agitation and aggression. Become more prominent with increasing levels of dementia severity. Can come in both physical and verbal forms Disinhibited social behavior Risk of wandering

34. Biological correlates Dementia-related agitation, disinhibition, and psychosis are associated with volume reductions and decreased metabolism in the orbital and dorsolateral prefrontal cortex, anterior cingulate, insula, and temporal lobes . Depressive symptoms correlate with greater temporal lobe and cingulate gyrus hypometabolism. BPSD also correlates with cholinergic, noradrenergic, dopaminergic, serotonergic, and glutamatergic neurotransmission imbalances .

35. Management Non-pharmacological approaches - First line involves participation in pleasant events, exercise, music, sensory stimulation First line pharmacotherapy only if they are severely distressed or there is an immediate risk of harm to the person or others. People with alzheimer’s disease, vascular dementia or mixed dementias with mild to moderate non-cognitive symptoms should not be prescribed antipsychotic drugs. Those with dementia with lewy bodies are particularly at risk of severe adverse reactions. Antipsychotic prescribing is accepted where there are genuine psychotic symptoms, although the risks may be similar. ( Nice guidance, 2018 )

36. Pharmacological treatment

37. Assessments Complete physical and neurological examination : focal neurologic findings Mental status examination: MINI-MSE Bedside cognitive testing : Montreal Cognitive Assessment (MoCA) Most widely employed tool for basic screening 30-point test - can be administered in the office setting in about 10 minutes. Easily accessible, and available in many languages. It is broken down by different cognitive domains and assesses visuospatial and executive functioning, confrontation naming, memory by immediate and short-term recall, attention, language, abstraction, and orientation. has a 90 percent sensitivity of detecting MCI and an 87 percent specificity in excluding those cognitively intact.

38. MoCA Score: 26 or above = normal The MoCA website states ranges may be used to grade severity: 18-25 = mild cognitive impairment 10-17= moderate cognitive impairment less than 10= severe cognitive impairment.

39. Severity assessment Clinical Dementia Rating Scale (CDR) measures several domains of function including memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Functional Assessment Staging (FAST) has been developed to track the course of Alzheimer disease and is also useful for other dementias

40. Diagnostic workup (Laboratory test) Laboratory tests can help rule out reversible causes of dementia Vitamin b12 and thyroid function test Complete blood count (CBC) Electrolyte panel and creatinine Blood urea nitrogen (BUN) Calcium and glucose levels Other metabolic abnormalities HIV, syphilis, and other infections

41. Diagnostic workup (CSF studies ) CSF Studies: These studies may be used to measure amyloid-β (Aβ) protein, tau protein, and phospho-tau , all of which may be altered in Alzheimer disease. In sporadic CJD, there may be elevations in 14-3-3, total tau, or neuron specific enolase

42. Neuroimaging Either non-contrast CT or MRI is recommended as part of the initial evaluation for dementia. Brain MRI is preferred over CT to evaluate for strokes, tumors, and other structural lesions In early stages of AD, hippocampal atrophy is often seen Occipital and frontal atrophy is more likely in dementia with Lewy bodies Frontal and antero-temporal atrophy is more likely in FTD. Persons with vascular dementia have significant microvascular changes . Volumetric MRI can quantify the volume loss.

43. Neuroimaging FDG and PET help differentiate AD from other causes of dementia and predict the progression of disease. FTD - decreased metabolism in the frontal lobes and anterior temporal lobes . Lewy body dementia - decreased metabolism in the occipital lobes . A dopamine transporter (DAT) scan can be useful to evaluate patients with parkinsonian syndromes. In CJD, EEG can show periodic sharp wave complexes . Brain amyloid PET imaging and brain tau PET imaging - research tools to identify amyloid and tau burden in AD and are very hard to incorporate in clinical practice

44. Management Psychological, behavioral, and psychosocial interventions are an important component of the management of the patient with dementia of any type. Requires a multimodal approach : targeting cognitive deficits, neuropsychiatric aspects ;level of functioning ; caregiver issues, legal issues, safety, community support, and levels of care Social and family support is crucial. Educating patients and their family about illness and providing individualized treatment plans.

45. Management Psychotherapy: Psychotherapy may be useful in earlier stages of dementia before short-term memory is too impaired Therapeutic counseling, to CBT to interpersonal psychodynamic therapy Reminiscence therapy: This therapy allows patients to recall and relive past life events, stimulating memory and mood within the context of their life history Cognitive Retraining Stimulation-Oriented Therapies End-of-Life Issues Pharmacotherapy : Treatment modalities and strategies vary with stage and type of dementia

46. Alzheimer's disease Onset and steady progression of disease , evidence of causative genetic mutation or impairment in memory and learning in addition to one cognitive domain; no evidence of anther etiology DSM -5 diagnosis – Major neuro cognitive disorder due to Alzheimer’s disease Subtypes: with or without behavioral disturbances . Three stages Preclinical stage MCI due to Alzheimer’s Dementia due to Alzheimer’s ( NIA-AA,2011 )

47. Etiology Age: 0.5 % in 65-69 yr to 8 % per yr after 85 yr Education :( increase synaptic density and greater cognitive reserve ) Head trauma:( overexpression of app – increased inflammatory mediators ) Estrogen level: On a neuronal level, estrogen increases density of a synaptic population Inflammation : Increased concentrations of acute phase reactants, cytokines, and complement protein. Population studies have demonstrated that NSAID or corticosteroid use is associated with a decreased risk of developing Alzheimer disease Nicotine : controversial effect ; indirect stimulation of nicotinic receptors via use of acetylcholinesterase inhibitors has benefit in the treatment of Alzheimer disease. Oxidative stress Genetics

48. Etiology Early onset disease autosomal dominant inheritance amyloid precursor protein: gene chromosome 21 Presenilin-1 locus chromosome 14 ; complete penetrance; account for most early-onset familial Alzheimer disease cases Presenilin-2 chromosome 1 ; rare, not fully penetrant Late onset disease mutations in APO – E (apolipoprotein epsilon 4 allele ) generally estimated that APOE4 accounts for up to 50 percent of the genetic contribution to late onset Alzheimer disease. as the number of epsilon 4 alleles an individual carries increases risk increases A single copy : two- to four-fold increased risk two APOE4 alleles: four- to eightfold risk

49. Etiology Genome wide association studies have recently identified 20 additional genes/loci associated with late onset Alzheimer disease; These include CR1, BIN1, CLU, PICALM, MS4AA/MS4A6E, CD2AP, CD33, EPHA1, ABCA7, HLA-DRB5–DRB1, SORL1, PTK2B, SLC24A4/RIN3, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, and CASS4.

50. Pathophysiology Associated with specific neuropathological changes seen in the brain on histological examination and a definitive diagnosis can be made only at autopsy . Neurotic plaque Neurofibrillary tangles

51. Neurofibrillary tangles

52. Macroscopically - widened sulci , increased ventricular size , atrophy in posterior temoral ,parietal and frontal lobes Microscopically- Amyloid plaques in neocortex,hippocampal ,subcortical regions ( insoluble deposit of fibrillar amyloid – surrounded by dystrophic neurites,astrocytes , microglia ) –more defining lesions Neurofibrillary tangles – intracellular inclusions aggregates of hyperphosphorylated MAPT)

53. Neurochemical abnormalities The excitatory synapses onto dendritic spines are particularly affected by Aβ-induced synaptic loss Aβ appears to destabilize dendritic spines, resulting in retraction and synapse loss, via modulation of the function of both α-amino-3- hydroxy-5-methyl-4-isoazole-proprionic acid (AMPA) and N-methyl-D- aspartate (NMDA) classes of postsynaptic glutamate receptors. Memantine (Namenda), a low-affinity NMDA antagonist that functions to modulate activation of NMDA receptors, has been shown to be of benefit in Alzheimer disease.

54. Neurochemical abnormalities Include deficits in ACh , norepinephrine, serotonin, dopamine, GABA, glutamate, corticotrophin-releasing hormone, and somatostatin. The most neurochemical deficits are in the cholinergic system. The activity of choline acetyltransferase is substantially reduced in patients with Alzheimer disease. Particularly in the nucleus basalis of Meynert and several neocortical regions .

55. Disease course

56. Treatment Cholinesterase inhibitors.: The first class of medications approved by the U.S. FDA for the treatment of Alzheimer Tacrine, donepezil, rivastigmine, and galantamine Donepezil is the only anti- ch drug FDA approved for the treatment of severe Alzheimer disease. Memantine : FDA approved for use only in moderate to severe Alzheimer disease and has demonstrated efficacy for both cognitive and functional improvement over placebo. monotherapy and in addition to stable doses of donepezil and is effective and well tolerated There are no data for use longer than 6 months duration. Other medications: vitamin E, gingko biloba, NSAIDs, hormone replacement therapy, selegiline, ergoloids , and anti-amyloid therapies

57. Treatment

58. Newer treatments Anti- amyloid Agents In January 2023, the US FDA approved lecanemab and Donanemab — an antibody medication that decreases β-amyloid protein build-up in the brain. Decline by approximately 25 to 35 percent compared to placebo(lecanemab) lecanemab a dministered as Iv infusion every 2 weeks . Donanemab is given as an IV infusion every four weeks Dimebon non-selective antihistamine with a weak capacity to inhibit butyryl- and acetylcholinesterase. It also weakly blocks the  N -methyl-D-aspartate receptor-signaling pathway. It also inhibits neuronal death in models for Alzheimer’s disease may have a positive effect in treating behavioral symptoms ( COCHRANE )

59. Newer treatments Anti-Tau Agents:   Saracatinib   Chelating agents : Some studies have reported the use of metal chelators for modulating metal induced neurodegeneration and it has been demonstrated that Cu, Zn, and Fe chelators efficiently inhibit the aggregation of Aβ fibrils. Gene Therapy: Employing recombinant adeno-associated viruses ( rAAVs ) allow treatment of diseases like AD. Nerve growth factor (NGF)-based gene therapy has shown positive neuronal responses in AD Peptidomimetics: peptide, mimics misfolded proteins Immunotherapy

60. Vascular dementia 10-20 % of cases –pure vascular coexistence of vascular pathology and AD pathology is common 2 nd most common /more common in men incidence increases exponentially with age, and prevalence rates are estimated to double every 5 years. four broad categories : multi-infarct dementia, small-vessel disease, post-stroke dementia and specific vascular dementia syndromes (e.g. CADASIL) cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

61. Neuropathology The commonest lesions are complete infarctions , 75% of cases, followed by lacunar infarcts and small infarcts in 50% of cases, cystic infarcts in 25% of cases, cerebral amyloid angiopathy in 10% and haemorrhages in only 2% of cases. Large infarcts- gliosis accompanies infarction resulting in scar formation. Lacunae - result from cavitating infarcts. Small-vessel disease : Damaged end-arterial wall with hyalinization, degeneration of vascular smooth muscle and other changes indicative of arteriosclerosis. Cerebral amyloid angiopathy is consequence of deposition of aggregated amyloid protein in or near vessel wall, resulting in thickening, loss of function.

62. Features Stepwise progression, prolonged plateaus or fluctuating course Focal cognitive deficits but not necessarily memory impairment Impaired executive function (difficulty problem solving, difficulty with judgement) Focal neurological signs (weakness on one side, difficulty with speech) Neuroimaging (CT or MRI) consistent with ischemia CV risk factors, concurrent peripheral vascular disease, coronary artery disease etc Strategic stroke Dementia developing after occlusion of a single large vessel in a functionally critical area Easiest to recognize, temporal relationship of event and cognitive loss usually evident

63. 1. MULTI-INFARCT DEMENTIA: M>F; Age: 60’S&70’S onset is gradual Emotional or personality changes prior to memory & intellectual impairment. somatic symptoms: headache, dizziness, tinnitus and syncope. Lacunar infarcts lead to ataxia, dysarthria and motor and sensory disturbances, culminating the picture of pseudobulbar palsy (dysarthria, dysphagia and emotional incontinence) together with bradykinesia and marche à petit pas.

64. 2.Small-vessel disease : Damage to microvasculature in brain, demyelination, axonal loss , gliosis. 2 cardinal features: white matter lesions [as periventricular lucency /deep white matter intensities] central grey matter lacunae C/f : slowly evolving dementia associated with focal neurological deficits, usually in hypertensive patients in age 50’s ,60’s.

65. Binswanger’s disease [‘encephalitis subcorticalis chronica progressiva ’] Pathological changes affecting long perforating vessels to deep white matter & subcortical nuclear masses, resulting in multiple small areas of infarction (lacunes) together with cardinal feature of diffuse demyelination of white matter . 3.Poststroke dementia The risk of dementia increases after stroke, especially in the elderly.

66. 4.Specific vascular disease CADASIL, a rare familial disorder presents with migraine Usually accompanied by aura, recurrent small subcortical infarcts leading to dementia , transient ischemic attacks and severe affective disturbance . Onset is in 40’s age , AD inheritance Caused by mutations in the NOTCH3 gene . Hereditary cerebral haemorrhage with amyloidosis ( dutch type), which presents with haemorrhagic strokes and dementia . AD disorder , mutations in the APP gene . Neuroimaging reveals white matter abnormalities in subcortical white matter and basal ganglia

67. Diagnostic Criteria Probable vascular neurocognitive disorder is diagnosed if one of the following is present : 1. Clinical criteria are supported by neuroimaging evidence of significant parenchymal injury attributed to cerebrovascular disease. 2. The neurocognitive syndrome is temporally related to one or more documented cerebrovascular events. 3. Both clinical and genetic evidence of cerebrovascular disease is present.

68. Ischemic index A score of 4 or less suggests dementia is due to Alzheimer’s disease, a score of 7 or greater suggests vascular dementia.

69. Treatment Reducing risk factors such as hypertension and hyperlipidemia Antiplatelet medications and anticoagulation with warfarin (coumadin) also provide protection from recurrent stroke

70. Dementia with Lewy Bodies Approx 15- 35 % of all dementia patients onset typically in the sixties or seventies First described 1984 – by Kosaka Memory impairment need not be prominent in early course Attention deficits, executive skills ,visuospatial deficits may be more prominent early Rapidly progressing course – usual survival time 10 yrs – slight male predominance – usual onset – 50-80 yrs

71. Core features – (at least two ) Fluctuating cognition with variation in attention and alertness ; fluctuation may be day to day or even hour to hour Recurrent formed visual hallucinations are complex, often of people or animals, usually undersized and silent, and may not be distressing to the patient Spontaneous motor parkinsonian features : Parkinsonism occurring after or anteceding dementia by no more than a year Features suggestive : REM sleep behavior disorder Severe neuroleptic sensitivity Low dopamine transporter uptake in basal ganglia Supportive features : Repeated falls & syncope Transient unexplained LOC Severe autonomic dysfunction Systematized delusion Hallucinations in other modalities Depression Relative preservation of medial temporal lobe on imaging Low uptake with reduced occipital activity on functional imaging Abnormal myocardial scintigraphy Slow wave activity on EEG with temporal lobe transient sharp waves hallucinations and delusions occurring early in a dementia syndrome strongly suggests diagnosis of DLB ( Ballard et al. 1999a ).

72. Etiopathology Lewy bodies- intracytoplasmic , spherical , neuronal inclusion bodies ,composed of abnormal fibrillar deposits of alpha synuclein Mutations and copy number variations in the gene encoding α-synuclein, β-synuclein, SNCB, and in GBA. Mutations in other genes (lrrk2, eif4g1, vps35,park2, pink1, and park7) associated with autosomal dominant or recessive Parkinson disease. ApoE ε4 allele also associated with increased risk of DLB .

73. Treatment Nonpharmacological: strategies to increase levels of arousal and attention by social interaction and environmental novel may reduce the visual hallucinations and fluctuations in cognition and function. Pharmacological: The cholinesterase inhibitors are the mainstay of treatment for the cognitive impairment of DLB. Data in regard to the usage of memantine is mixed For REM sleep disorder: BZD/melatonin/low dose quetiapine Avoid antipsychotics

74. Frontotemporal dementia Group of dementia characterized by progressive circumscribed atrophy of frontal and temporal lobe cortices. Hallmark feature- progressive change in personality and behavior with variable degree language and other cognitive impairment 3 subgroups : frontal/behavioral variant primary progressive aphasia semantic dementia The spectrum of presentations of frontotemporal lobar degeneration also includes the motor syndromes of CBD, PSP, and motor neuron disease, as there are both clinical and pathological overlaps among these.

75. 1 st described by Arnold Pick in early 20 th century Alzheimer described presence of intraneuronal inclusions(later named Pick bodies)and ballooned neurons. Pick disease= dementia + frontotemporal atrophy + pick bodies usual age of onset : 35-75 year Incidence: 3.5 and 3.3 per 100,000 person in a 45 to 64 and 50 to 59 years Approx 5% of dementias family history: 50 % cases autosomal dominant pattern C9ORF72 gene mutation Approximately 26 percent of familial, and 5 percent of sporadic mutations in GRN,MAPT gene in chromosome 17

76. Lab findings No biomarkers In the behavioral variant, there is early degeneration of the paralimbic structures of the ventromedial prefrontal cortex, anterior cingulate cortex and anterior insula. In progressive nonfluent aphasia, there is degeneration of the dominant frontal operculum through the premotor area, and the insular cortex . In the semantic variant, there is atrophy of the anterior temporal pole, which eventually spreads to the frontal areas, insula and anterior hippocampus Fronto -temporal atrophy functional imaging using PET or SPECT to demonstrate selective frontal and/or anterior temporal reduction in blood flow or metabolism

77. Treatment Currently there are no treatments for the cognitive deficits associated with FTD, and no treatments to prevent progression of the underlying pathologies. Insufficient data exists to recommend cholinesterase inhibitors study shows no benefit of memantine Symptomatic use of trazodone, second generation antipsychotics, SSRIs, and anticonvulsants may help agitation, disinhibited, and aggressive behavior. SSRIs are first-line pharmacotherapy treatments for FTD. Second-generation antipsychotic medications should be used with caution and close observation, as individuals with FTD may be more sensitive to extrapyramidal side effects

78. Prion diseases Encompass both sporadically and genetically induced neurodegenerative diseases . Infectious agents were proteins, and the term prion was created in 1982 Examples : Kuru Sporadic CJD Familial CJD Iatrogenic CJD Variant CJD GSS disease and Fatal insomnia CJD was first termed in 1922 , and was used to describe a clinical entity of rapidly progressive myoclonus, ataxia, and dementia, described in earlier case report

79. Etiology Incidence of sporadic CJD worldwide is 1 per 106 and of familial CJD is 1 per 107 per year. In sporadic CJD , the peak age of onset is 67 years , Familial and variant form typically occurs in younger individuals . Fatal insomnia usually presents between the ages of 35 and 55 . gene for the prion protein is found on chromosome 20 . Iatrogenic CJD has been associated with medical or surgical equipment contaminated with the pathological prion protein. Transmission through ingestion has also been demonstrated, as seen with Kuru and the practice of ritual endocannibalism in the Foré linguistic group in Papa New Guinea

80. Creutzfeldt Jacob disease Age of onset – 50 , Rapidly Progressive, average survival 1 year. E arly stages – failing memory, behavioral changes, poor coordination, visual impairment. Associated features – I nsomnia, depression, or unusual sensations. Late stage – Worsened mental deterioration, involuntary or jerky movements, muscle weakness, blindness, and coma. PULVINAR SIGN IN CJD

81. KURU CJD GSS FATAL INSOMNIA Very rare disease . Caused by infectious protein in contaminated brain. Sporadic and familial CJD - memory impairment and confusion, progress to cortical dementia like picture, ataxia and myoclonus. Hallmark feature: spongiform degeneration of the cortical gray matter ; reactive gliosis. EEG : bilateral periodic discharges. SPORADIC :Elevations in 14-3-3, total tau, or neuron-specific enolase in CSF. Iatrogenic CJD - cerebellar ataxia at symptom onset. EEG: diffuse slow wave pattern Variant CJD - apathy or depression, painful sensory symptoms in distal extremities. Neuropathology: prion protein plaques surrounded by a halo of vacuolar change with diffuse spongiosis . MRI [DWI/ FLAIR]-high signal abnormalities in caudate nucleus and/or putamen Initially with ataxia or dysarthria, then progresses to dementia; others include memory impairment, spastic paresis, motor impairment, behavioral disturbances. Extensive prion protein plaques, with less spongiform degeneration. EEG: Slow waves. Insomnia, present for months until other symptoms present , dysautonomia and ataxia; cognitive impairment and dementia does not appear until much later focal thalamic gliosis and minimal spongiform degeneration . Neuronal loss ,gliosis is seen in thalamus and inferior olives. PET SCAN: Hypometabolism in Thalamus.

82. Course and prognosis : Course is rapidly progressive , with the prognosis somewhere between 4 and 6 months. The familial form of the disease has a more extended course , typically of 1 to 5 years. The duration of GSS is typically 2 to 6 years , and of fatal insomnia is 1 to 2 years. Treatment: Limited to symptomatic therapies Antiepileptic medications for seizure control Clonazepam for myoclonus Small doses of antipsychotic medications for distressing psychiatric symptoms

83. Progressive Supranuclear Palsy Gradually progressive disorder with progressive supranuclear gaze palsy, postural instability and falls, and parkinsonism. DNA damage -binding protein 2 and lysosomal acid phosphatase 2 on chromosome 11 are associated with PSP. MORNING GLORY sign and HUMMINGBIRD sign on imaging.

84. Morning glory and hummingbird sign

85. References Comprehensive textbook of psychiatry; 10th edition Lishman’s organic psychiatry : textbook of psychiatry ,4 th edition Guidelines for the management of Behavioral and Psychological Symptoms of Dementia (BPSD),NHS ;2018 World health organization The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 2013