Dementia updates

1. UPDATES ON PRIMARY
DEGENERATIVE DEMENTIA
DR. SUNIL KUMAR SHARMA
SENIOR RESIDENT
DEPT. OF NEUROLOGY
G.M.C. & M.B.S. HOSPITAL, KOTA

2. Dementia
• Cognitive function declines with aging
• Age-related decline - cognitive speed, and working
memory
• General knowledge and vocabulary - stable or
improve while problem solving and reasoning decline
(Hedden and Gabrieli, 2004 ,Salthouse, 2012).

3. Dementia…
• Dementia-characterised by multiple cognitive deficits
of sufficient severity to interfere with function during
daily activities
• DSM V criteria describe cognitive impairment and
dementia in neurocognitive disorders.
• An essential part of assessment is exclusion of
depression or delirium .
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th edn. Arlington, VA: American Psychiatric Publishing; 2013.

4. DSM-V
• DSM-V -updated the prior criteria for dementia
• “mild neurocognitive disorder”= MCI
• “major neurocognitive disorder”=dementia.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th edn. Arlington, VA: American Psychiatric Publishing; 2013.

5. Mild Cognitive Impairment (MCI)
• MCI - an in-between state of normal aging and
dementia.
• In MCI, cognitive change is greater than expected for
age
• Independence & ADL are preserved
Petersen et al., 2009

7. Comparison of recent criteria for MCI.

8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th edn. Arlington, VA: American Psychiatric Publishing; 2013.

9. MCI...
• Subtyping MCI into amnestic and nonamnestic
categories has predictive value.
• The vast majority of aMCI - AD dementia
• naMCI –DLB, FTD, vascular dementia, and even
Alzheimer dementia
(Petersen et al., 2005 , Ferman et al., 2013b; Molano et al., 2010).

10. MCI…
Annual risk in the elderly-
• Gen. -1%–2%
• MCI(clinic setting) - 10%–15%
• In population-based studies - 5%–10%
• A diagnosis of MCI even with reversion to normal
has prognostic value
(Farias et al., 2009; Petersen et al., 2010; Roberts et al., 2014 ,Lopez, 2013; Roberts et al., 2014. )

11. Preclinical Stage of Dementia
• Pathophysiological processes can begin decades prior
to cognitive symptoms.
• An evolving understanding of the preclinical stages -
possible therapeutic time window.
• e.g. CSF Aβ 42 decreases ≈ 25 years before expected
symptom onset in AD
• Preclinical stages of FTD have not been studied as
much as AD.
(Bateman et al., 2012).

12. Suspected non Alzheimer
pathophysiology (sNAP)
• Neurodegeneration on FDG-PET or MRI, but without
cerebral amyloid deposition on PET/CSF.
• Significantly lower risk of becoming symptomatic
after 5 years c/t AB2 +/- other biomarker.
(Jack et al., 2012; Knopman et al., 2012, Vos et al., 2013)

13. Subjective Cognitive
Impairment(SCI)
• Recent studies –pt. with cognitive complaints, good
insight, and normal cognitive testing called SCI.
• Three times more likely than controls to develop MCI
with AD related biomarkers
(Jessen et al., 2010, 2014).

14. Biomarkers predicting the risk of
conversion Of MCI to dementia
• MRI-MCI with hippocampal volumes -25th percentile – 2
to 3 times risk compared 75th percentile
• CSF-↓ Aβ 42 and ↑ t-tau and p-tau
• APOE4 allele
• Temporal-parietal hypometabolism on FDG-PET
• Amyloid deposition on Aβ PET imaging
(Jack et al., 2010, Mattsson et al.2009, Petersen et al., 1995, 2005, Chetelat et al., 2003,Wolk et al., 2009).

15. Dementia
• 35.6 million worldwide in 2010- number would
double approximately every 20 years (Prince et al., 2013).
• Rotterdam study,UK, Rochester- indicate the
incidence of dementia may be declining.
• One possible explanation -improved treatment of
vascular risk factors.
(Schrijvers et al., 2012, Matthews et al., 2013, Rocca et al., 2011)

16. I.Syndrome of progressive
dementia(other neurologic signs
absent or inconspicuous)
• Alzheimer disease
• Some cases of Lewy-body disease
• Frontotemporal dementias-Pick disease, includin
behavioral variant, primary progressive aphasias
(several types)

17. II. Syndrome of progressive dementia
(in combinationwith other neurologic
abnormalities)
• Huntington disease (chorea)
• Lewy-body disease (parkinsonian features)
• PDD
• Corticobasal ganglionic degeneration (rigidity, dystonia)
• Dementia-Parkinson-amyotrophic lateral sclerosis
complex
• Cerebrocerebellar degeneration
• Familial dementia with spastic paraparesis, amyotrophy,
or myoclonus
• Polyglucosan body disease (neuropathy)
• Frontotemporal dementia with parkinsonism or ALS

18. Alzheimer disease

19. • Alzheimer Association in 2013-5.2 million
Americans have AD -70% of all dementia cases in
the United States (not autopsy-confirmed).
• 11% at age 65 year ↑ to 32% by age 85
• MCI is more common in men
• AD dementia is more common in women.
(Thies and Bleiler, 2013, Thies and Bleiler, 2013,Plassman et al., 2007)

24. Biomarkers in AD- CSF Biomarkers
• ↓ CSF Aβ 42 and ↑ CSF tau protein - sensitivity of
85% and specificity of 86% for AD
• These biomarkers can improve diagnosis in and
predict conversion from MCI to AD
• Data on the progression from normal or preclinical
AD are accumulating but are not ready for clinical
use at this time.
(Hulstaert et al., 1999, Hansson et al., 2006; Mattsson et al., 2009; Shaw et al., 2009,, Brunnstrom et al., 2010).

25. Neuroimaging Biomarkers
• MRI –very useful in the differential diagnosis of
dementia and as a biomarker in AD dementia.
• Medial temporal lobe atrophy of the hippocampus
and entorhinal cortex with dilatation of the temporal
horns
• Reduction in hippocampal volumes correlates with
NFT pathology at autopsy and cognitive decline
(Jack et al., 2000).

26. Neuroimaging Biomarkers…
• Medial temporal lobe atrophic in early AD and later
in the disease atrophy rates are greater in the
temporal, parietal and frontal cortices (Frisoni et al.,
2010)
• White matter hyperintensities (FLAIR or T2 MRI)
also appears to contribute to cognitive impairment in
AD.
(Frisoni et al., 2010, Provenzano et al., 2013)

27. Cerebral Amyloid Angiopathy
• Hypointense signal on MRI GRE - hemosiderin
deposition -microhemorrhages.
• In the Alzheimer’s Disease Neuroimaging Initiative
(ADNI) cohort, microhemorrhages ≈ 33% and increased
with Aβ load as measured by PiB-PET
• CAA preferentially involves the occipital lobe.
(Kantarci et al., 2013, Arvanitakis et al., 2011 )

28. SPECT and FDG-PET
• Functional imaging - not included in criteria for MCI
or AD
• Their value is recognized in selected cases, when the
structural imaging scan is not informative
• Decreased blood flow in a temporoparietal
distribution seen on SPECT correlates with
hypometabolism seen on FDG-PET and is suggestive
of AD
(Albert et al., 2011; McKhann et al., 2011, Reiman et al., 1996; Sanchez-Juan et al., 2014)

29. • FDG-PET can be used as an aid in the diagnosis of
AD dementia-differentiating AD from FTD
• Use of FDG-PET has been included as a biomarker in
the most recent AD criteria
(Foster et al., 2007; Rabinovici et al., 2011, McKhann et al., 2011)

30. Amyloid Imaging
• Pittsburgh Compound B (PiB) measure the amyloid
burden in living subjects
• Not used routinely but in clinical trials for identifying
preclinical AD, MCI due to AD, and monitoring
effectiveness of amyloid-targeted therapies.
• The deposition occurs primarily in the frontal and
temporal-parietal
• PiB-PET outperformed FDG-PET in discriminating FTD
from AD (Rabinovici et al., 2011).

31. • In a population-based study of cognitively normal
individuals > 70 yr, ≈ 1/3rd signi. beta amyloid load
(Kantarci et al., 2012b)
• F-18 analog amyloid tracers - florbetapir,
flutemetemol, and florbetaben.
• F-18 agents provide comparable results to PiB
imaging, but a longer half-life
• Florbetapir performs well compared to autopsy
confirmation (Clark et al., 2011).

32. fMRI
• Functional MRI (fMRI) measures the blood-oxygen-level
dependent (BOLD) signal
• The default mode network (DMN) refers to connected
regions of brain - at rest or not focused on the external
environment (Raichle et al., 2001).
• These changes on fMRI occur early in the disease
process.
• In cognitively normal APOE4 subjects, there is a decrease
in connectivity relative to controls (Machulda et al., 2011).

33. fMRI…
• These changes occur in the absence of brain
amyloidosis (amyloid PET ) and Aβ 42 levels in the
CSF (Sheline et al., 2010).
• May be a very early marker of the pathophysiology of
AD.
• While current use of fMRI -limited to research

34. Tau Imaging
• Tau comprises the other hallmark of the AD
pathological process, neurofibrillary tangles
• The ability to image it in vivo would be extremely
useful.
• Also implicated in a variety of other disorders
• Specificity for tau and various tau isoforms??

36. Timing of biomarkers in autosomal
dominant AD (Alzheimer network
study)
• CSF Aβ 42↓ - 20 years before clinical symp.
• Aβ PET abnormalities -15 years
• Brain volume loss and increased CSF tau-15 years
• FDG-PET abnormalities-10 years
(Bateman et al., 2012).

37. • sNAP subjects have a lower rate of progression
compared to those with amyloid positive biomarkers
(Vos et al., 2013).
• In preclinical AD, 42% of incident Aβ PET positive
cases demonstrated neurodegeneration biomarkers,
first.

38. Alzheimer Genetics
Early Onset Genes
- APP-Chromosome 21
- PSEN1- Chromosome 14
- PSEN2 -Chromosome 1.

39. Late Onset Genes
• APOE) - most important genetic risk factor for late onset
AD
3 isoforms
• E4 -high risk
• E3 -neutral risk
• E2 -protective).
•
• E4 homozygotes -mean age of onset of 68 with a lifetime
AD risk of 91
• E4 heterozygotes- mean age of onset is 76 with a 47%
lifetime risk (Liu et al., 2013).

40. • Trem 2 variants -recently identified as rare risk
variants
• Many other risk loci –their overall impact small. eg-
CD33 molecule
ATP-binding cassette subfamily A, member 7
(ABCA7)
Sortilin-related receptor L (SORL1)
Clusterin (CLU)
Phosphatidylinositol binding clathrin
assembly
Protein (PICALM),
Many others (Guerreiro et al., 2013a).
(Guerreiro et al., 2013)

41. Genetic Testing
• APP, PSEN1, PSEN2, and APOE - commercially
available
• Routine genetic testing is not recommended by the
practice parameter of the AAN
• Genetic testing currently does not change treatment
of the patient.

42. Alzheimer Pathophysiology
• Aβ is derived from APP through proteolytic
processing
• Removed efficiently by a number of mechanisms
• Drained through the cerebral vasculature and into the
CSF via the glymphatic system
(Xie et al., 2013).

44. Glymphatic system

47. Alzheimer Pathology
• Two pathological findings: extracellular plaques of
amyloid and intraneuronal NFTs of hyper-
phosphorylated tau
• Neuropathologic criteria- Most recently-2012 criteria
incorporated evaluation of coexisting pathologies and
the recognition that AD pathologic changes can occur
without cognitive decline (Montine et al., 2012).

48. TDP-43
• Originally thought to be specific for FTD
• Recent studies-shown that TDP-43 pathology occurs
in AD and may play an important role in
neurodegeneration and clinical features
• Hippocampal Sparing AD -10%
(Josephs et al., 2014; Wilson et al., 2013).

49. Treatment-non pharmacological
• Avoiding prior triggers
• Limiting changes to the environment
• Regular exercise, and shifting attention.
• Aromatherapy
• Music therapy-reduces agitation
The effects of music therapy on reducing agitation inpatients with Alzheimer’s disease, a pre-post studyInt J Geriatr Psychiatry 2010; 25: 1306–1310.

50. Treatment
• Acetylcholinesterase Inhibitors
• N-Methyl-D-aspartate Receptor Antagonist
• Vitamin E- large double-blind RCT -mild to moderate
AD-less decline and delay in progression of about
19% per year without an increase in mortality with
high-dose vitamin E
(Dysken et al., 2014)

51. Treatment of Noncognitive
Symptoms in AD
• Depression - SSRIs are preferred
• In a meta-analysis of RPCT-atypical antipsychotics a/w
an OR of 1.54 for increased mortality
• Antipsychotics - lowest effective dose for the shortest
period of time necessary.
• The Citalopram for Agitation in Alzheimer Disease Study
- SSRI citalopram ,30 mg daily improved agitation in AD
• a/w prolonged QTc-could not be routinely recommended
(Schneider et al., 2005, Porsteinsson et al., 2014).

52. Treatments under investigation…
• Therapies directed against b-amyloid- a,b-and g
secretase involved in APP processing-AB
Active immunization-
• The first active vaccine against Ab tested in humans
(2000), -AN-1792
• Severe side effects -aseptic meningoencephalitis in
≈6% -phase II trial was terminated in Jan. 2002
• Postmortem examination revealed↓ levels of
insoluble amyloid plaques

53. • CAD106 vaccine contains an Ab1–6 fragment
attached to a carrier bacteriophage Qb as an adjuvant
• Phase II trials with CAD106 did not lead to adverse
effects - study did not confirm clinical efficacy
• Phase II trials concluded in December 2012, but the
results are yet to be published

54. • ACC-001-contains a six amino acid sequence Ab1–6
• Phase II trials aborted in 2014 due to adverse effects -
strong autoimmune responses
• Other vaccines - reached phase II clinical trials
include Affitope AD-02 (Ab1–6) and V-950

55. Passive immunization
• Bapineuzumab- first humanized monoclonal
antibody
• Phase III trials did not confirm therapeutic efficacy
• Significant adverse - vasogenic edema and
intracerebral microhemorrhages

56. Passive immunization…
• Solanezumab- specific to (Ab16–24)
• Results of two multicenter randomized double-blind
placebo-controlled phase III trials - 2000 patients
from 16 countries with mild to moderate AD revealed
a reduction in cognitive decline by 34%; in mild form
of the disease

57. Gantenerumab- specifically bind to aggregated Ab
• Results of phase I clinical trials -dose-dependent
reduction of Ab plaques in the brain.
• Currently, gantenerumab is being tested (since July 2013)
in phase II/III trials
Crenezumab - a novel human IgG4 monoclonal antibody
• Reduced pro-inflammatory activity –low risk of
vaso.edema.
• Currently, a phase II trial of crenezumab (NCT01343966)
is ongoing in patients with mild to moderate AD

58. Cognitive rehabilitation

59. The Future Treatment of Alzheimer
Disease-Ongoing studies
• The A4(anti-amyloid treatment in asymptomatic AD)
study (2014-2020) -double-blind study evaluating
Solanezumab in cognitively normal florbetapir
positive persons.
• The DIAN(Dominantly Inherited Alzheimer Network)
study is evaluating solanezumab and gantenerumab
versus placebo in unaffected carriers of dominantly
inherited genes.

60. The Future Treatment of Alzheimer
Disease-Ongoing studies …
• The ApoE 4/4 study is investigating cognitively
normal APOE 4 carriers, in a double-blind fashion,
using an active amyloid vaccine and a β secretase
inhibitor.
• The Columbian kindred study will study Crenezumab
in asymptomatic carriers with PSEN1 mutation.
• “Tomorrow” trial of pioglitazone.

61. NEURODEGENERATIVE DEMENTIAS
ASSOCIATED WITH PARKINSONISM
• Synucleinopathies-DLB, PDD & MSA
• Tauopathies- CBD, Guam dementia parkinson
complex, chronic traumatic encephalopathy (CTE),
PSP and familial FTD with parkinsonism.

62. Dementia with Lewy Bodies
• More recently it has been reported that RBD can
precede other symptoms of synucleinopathies by 50
years (Claassen et al., 2010)
• naMCI were much more likely to develop DLB, with
over 80% having either attention or visual-spatial
dysfunction (Ferman et al., 2013b)
• In autopsy confirmed DLB pt. ≈ 76% will have RBD
(Ferman et al., 2011)

63. Genetics
• Chromo. 2q35-q36 was mapped as the region of
interest (Meeus et al., 2010).
• Dupli. in the α-synuclein (SNCA) gene (Kasuga et al., 2010)
• Mutations LRRK2 gene-chromo. 12 (Qing et al., 2009).
• In a multicenter study, glucocerebrosidase (GBA1)
mutations –OR of 8.28 (Nalls et al., 2013).

64. Neuroimaging in DLB
• Structural MRI-Compared to AD, DLB patients have
relatively preserved hippocampal volumes and less global
atrophy
• Amyloid Imaging - 50%–80% amyloid-positive on PiB-PET -
pattern of deposition is similar to AD (Edison et al., 2008; Kantarci et al.,
2012c).
• FDG-PET - -characteristically involving the parietal-occipital
hypometabolism.

65. • “Cingulate Island,” has been shown to have the
highest specificity in distinguishing DLB from AD
(Graff-Radford et al., 2014; Lim et al., 2009).
FDG-PET in DLB patient demonstrating
relative preservation of posterior cingulate
(arrow) (e.g., cingulate island sign).

66. •(Left)DaT-SPECT imaging with ((123)I)ioflupane in
patient with DLB. There is markedly decreased striatal
accumulation bilaterally, left greater than right.
•(Right)Normal DaT-SPECT imaging.

67. Fluorodeoxyglucose (FDG)-PET statistical stereotactic surface projection map (Cortex ID)
showing occipital hypometabolism in a DLB patient.

68. Both cohorts showed AD-associated pattern of thinning in mid-
anterior temporal, occipital and subgenual cingulate cortex, whereas
the pattern supportive for DLB included thinning in dorsal
cingulate, posterior temporal and lateral orbitofrontal regions.
Cortical thickness is a good method for differentiating between AD
and DLB

69. Conclusions: Preserved hippocampal volumes are associated with
increased risk of probable DLB competing with AD dementia in
patients with MCI. Preservation of HV may support prodromal
DLB over AD, particularly in patients with MCI with nonamnestic
features

71. Parkinson Disease Dementia (PDD)
• PDD Vs DLB - parkinsonism preceding cognitive
decline for at least 1 year.
• An MCI stage of PDD has recently been proposed
and criteria similar to MCI due to AD have been
suggested
(Litvan et al., 2012).

72. Multiple System Atrophy (MSA)
• Recently mutations in CoQ2 were shown to be
associated with MSA (Multiple-System Atrophy Research Collaboration, 2013).

73. Progressive Supranuclear Palsy
• A small midbrain to pons ratio may also predict
PSP(<0.5, sens.-66.7 % ,speci.-100 %.) (Massey et al., 2013).
• Enlargement of the third ventricle is also described in
PSP.
• FDG-PET -frontal-subcortical hypometabolism.
• Midbrain hypometabolism is also described and has been
called the “pimple sign” (Botha et al., 2014).

74. FRONTOTEMPORAL DEMENTIAS

75. Pathophysiology
• TDP-43
• Microtubule-Associated Protein Tau.
• Progranulin.
• Chromosome 9 Open Reading Frame 72.
• TMEM106B-FTLD-TDP patients demonstrated an
association with TMEM106B (Van Deerlin et al., 2010)
• TMEM106B single nucleotide polymorphisms may
protect against developing FTD in progranulin mutation
carriers (Finch et al., 2011).

76. Young onset dementia
• Age of onset before 45 is used to distinguish it from
early onset dementia.
• Wide differential diagnosis.
• At the Mayo Clinic-neurodegenerative (31.1%),
autoimmune or inflammatory (21.3%), and metabolic
(10.6%),

78. AAIC 2017:Preventive factors—
stress, diet,lifestyle
• Nine modifiable risk factors account for
approximately 35% of all cases of dementia.
• (1) early education up to age 15 years,
• (2) hypertension,
• (3) obesity,
• (4) hearing loss in mid-life,
• (5) depression,
• (6) diabetes,
• (7) physical inactivity,
• (8) smoking, and
• (9) low social contact in later life.

79. • Stress-during older age-stressful experiences such as
educational difficulties, interpersonal conflicts,
financial insecurity, and legal/justice system issues.
• They suggest that each stressful event may add
between 1 and 4 years of aging to the brain.
• Physical activity- improves executive function and
cerebral blood flow and reduce amyloid and tau
levels in the brain.

80. AAIC 2017…
• Diet- “Mediterranean- DASH Intervention for
Neurodegenerative Delay” or MIND diet includes 10
“brain-healthy” food groups –
• Green leafy vegetables, other vegetables,nuts, berries,
beans, whole grains, fish, poultry, olive oil, and wine.
• Red meat, butter, margarine, cheese, pastries, sweets,
and fried or fast food are avoided.

81. • Sleep –Pt. with sleep-disordered breathing and OSA
↑ CSF brain beta-amyloid and rapid accumulation
• Social activity and quality of life-incorporating
social activities into residential caregiving can
significantly improve residents’ mood and quality of
life.

82. Effects of brain scanning on diagnostic accuracy-
• Imaging Dementia-Evidence for Amyloid Scanning
(IDEAS) Study – PET scans provided a more precise
diagnosis for > 2/3rd of study participants than
standard tests routinely used in diagnosis

83. Conclusion

84. Thank you

85. References
• Neurological update: dementia;A. J. Larner ;10 January 2014; Springer-
Verlag Berlin Heidelberg 2014; J Neurol DOI 10.1007/s00415-014-7249-3
• Bradley’s Neurology in Clinical Practice;7th edition.
• Dementia in older people: an update; D. Lo Giudice and R. Watson;
department of Aged Care, The Royal Melbourne Hospital, Melbourne,
Victoria, Australia; 10 August 2014. doi:10.1111/imj.12572
• Research Update on Dementia and Alzheimer’s Disease;Carl I. Cohen,
M.D.; Brooklyn Alzheimer’s Assistance Center’s Spring/Summer
Newsletter, Issue 19, 2009.
• Principles Of Neurology;Adams and Victor;10th edition.
• National Institute on Aging-Alzheimer’s Association guidelines for the
neuropathologic assessment of Alzheimer’s disease: a practical approach
Thomas J. Montinea et.al. : Acta Neuropathol. 2012 January ; 123(1): 1–
11. doi:10.1007/s00401-011-0910-3.
• Alzheimer’s Association / Alzheimer’s & Dementia 13 (2017) 1181–1184;
Center stage at AAIC 2017:Preventive factors—stress, diet,lifestyle